case report and literature review vascular

• Case Report
• Open access
• Published: 24 July 2019

Vascular leiomyosarcoma originating from the right ovarian vein: a case report and literature review

• Takuro Hirano   ORCID: orcid.org/0000-0001-7712-9230 1 ,
• Hiroshi Okumura 1 ,
• Satoru Maeda 1 ,
• Mario Shimada 1 ,
• Akira Imakiire 1 ,
• Kanro Makisumi 1 ,
• Michiyo Higashi 2 &
• Shoji Natsugoe 3  

Surgical Case Reports volume  5 , Article number:  120 ( 2019 ) Cite this article

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Primary leiomyosarcoma (LMS) of vascular origin is a rare lesion, and patients with LMS of vascular origin have poorer prognoses than patients with LMS of other origins. The inferior vena cava is the most commonly affected vessel and accounts for 60% of all vascular cases. However, LMS originating from the ovarian vein is extremely rare, and we are only aware of 15 reported cases. Therefore, we report our experience with a case of LMS originating from the right ovarian vein and review the related literature.

Case presentation

A 71-year-old Japanese woman with no symptoms was admitted to our hospital because of abnormal findings in a routine abdominal ultrasonography check-up. Contrast-enhanced computed tomography of the abdomen revealed a well-defined, lobulated solid mass with a diameter of 5.5 cm in the right retroperitoneal space. The mass exhibited relatively low uptake during 18 F-fluorodeoxyglucose positron emission tomography. Based on these findings, the differential diagnosis included a retroperitoneal tumor, such as a desmoid tumor, leiomyoma, LMS, and malignant mesothelioma. Operative findings confirmed that the mass had originated from the right ovarian vessels, and en bloc excision was performed for the mass and the right ovarian vessels. The final pathological diagnosis was LMS originating from the right ovarian vein, and the surgical resection margins were free from tumor cells. After histological findings confirmed the LMS diagnosis, the patient underwent adjuvant radiation therapy and has not exhibited signs of local recurrence or metastasis in the 6 months after surgery.

Conclusions

We encountered a 71-year-old woman with LMS originating from her right ovarian vein. The prognosis of vascular LMS is generally poor. Therefore, careful follow-up will be required for our patient.

Leiomyosarcoma (LMS) is a mesenchymal tumor of smooth muscle origin. However, primary LMS of vascular origin is a rare lesion that represents < 1/100,000 of malignant tumors. Patients with LMS of vascular origin have poorer prognoses than patients with LMS of other origins [ 1 ]. The inferior vena cava is the most commonly affected vessel, accounting for 60% of all vascular cases [ 2 ], followed by the large central veins and the long saphenous veins [ 2 , 3 ]. The ovarian veins are an extremely rare site of origin of LMS, with only 15 reported cases [ 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Therefore, we report our experience with a case of primary LMS originating from the right ovarian vein and review the related literature.

A 71-year-old previously healthy Japanese woman with no symptoms was admitted to our hospital because of abnormal findings in a routine abdominal ultrasonography check-up, which supported a suspicion of main pancreatic duct dilatation and gallbladder polyps. Physical examination revealed a palpable mass with good mobility in the right lower abdomen. The laboratory findings were all within the normal ranges. Contrast-enhanced computed tomography (CT) of the abdomen revealed no abnormal findings in the pancreas and gallbladder but revealed a well-defined, lobulated solid mass with a diameter of 5.5 cm in the right retroperitoneal space (Fig.  1 a, b). Magnetic resonance imaging (MRI) of the abdomen was performed: on T1-weighted imaging, the mass showed diffuse low intensity (Fig.  2 a), and on T2-weighted imaging, the mass showed uniform low intensity (Fig. 2 b). On gadolinium enhancement, the mass showed heterogeneous and incremental enhancement (Fig. 2 c, d). On 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET), the mass had relatively low uptake, with a maximum standardized uptake value (SUVmax) of 2.4 (Fig.  3 ). Based on these findings, the differential diagnosis included a retroperitoneal tumor, such as a desmoid tumor, leiomyoma, LMS, and malignant mesothelioma.

Contrast-enhanced computed tomography of the leiomyosarcoma. Axial ( a ) and coronal ( b ) contrast-enhanced computed tomography of the patient’s abdomen revealing a well-defined, lobulated solid mass (white arrows) with a diameter of 5.5 cm in the right retroperitoneal space

Magnetic resonance imaging of the leiomyosarcoma. a Axial T1-weighted magnetic resonance imaging (MRI) of the abdomen revealing a tumor (white arrows) with diffuse low intensity. b Axial T2-weighted MRI revealing a tumor with uniform low intensity. Early-phase ( c) and late-phase ( d ) axial gadolinium-enhanced MRI revealing heterogeneous and incremental enhancement of the tumor

18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) of the leiomyosarcoma. Axial fusion images of FDG-PET revealing that the tumor (white arrows) had relatively low uptake

Exploratory laparotomy was performed through a median incision, and the operative findings confirmed that the mass was attached and connected to the right ovarian vessels. The mass was slightly adhered to the ureter, but there were no signs of invasion to the other adjacent organs. Because the mass appeared to originate from the right ovarian vessels, en bloc excision of the mass and right ovarian vessels was performed. The surgical specimen consisted of a white solid tumor (5.5 cm × 4.5 cm) (Fig.  4 a, b); the ovarian vessels passed through the dorsal side of the tumor (Fig. 4 b). Microscopically, atypical spindle cells revealed interlacing fascicles without necrosis (Fig.  5 a) and that the tumor cells connected with the right ovarian vein (Fig. 5 b) with 50 mitoses per 50 high-power fields (HPF) (Fig. 5 c). On immunohistochemical staining, the tumor cells were found to be diffusely positive for α-smooth muscle actin (α-SMA) (Fig. 5 d), desmin (Fig. 5 e), and caldesmon (Fig. 5 f) and negative for CD34, S100, c-kit, MDM2, and cyclin-dependent kinase 4 (CDK4). These findings supported a diagnosis of LMS. The surgical resection margins were free from tumor cells. The patient’s postoperative course and recovery were uneventful. Based on the histological diagnosis of LMS, the patient underwent adjuvant radiation therapy (total dose, 50.4 Gy in 25 fractions) and has not exhibited signs of local recurrence or metastasis in the 6 months after surgery.

Gross findings of the leiomyosarcoma. a , b The specimen consisting of a white solid tumor that measured 5.5 cm × 4.5 cm. b The ovarian vein (white arrow) can be seen passing through the dorsal side of the tumor

Histological findings of the leiomyosarcoma. a Hematoxylin and eosin staining (HE, × 200) showing atypical spindle cells with interlacing fascicles and b tumor cells connected to the right ovarian vein (white arrow; HE, × 100). c Mitosis in the tumor cell (black arrow; HE, × 400). Immunohistochemical staining (× 100) showed positive results for d α-SMA, e desmin, and f caldesmon

LMS is the second most common retroperitoneal sarcoma among adults [ 18 ]. Retroperitoneal LMS originates from smooth muscles within the retroperitoneum, such as the wall of the retroperitoneal veins or embryonic remnants [ 19 ]. The vena cava is the most commonly affected vessel in vascular LMS cases, and these cases have been well described. The ovarian vein is the eighth most commonly affected vessel in cases of vascular LMS that do not originate from the vena cava [ 20 ]. Therefore, LMS originating from the ovarian vein is extremely rare, and we are only aware of 15 reported cases [ 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Table  1 summarizes the 15 reported cases and our case. Median patient age at diagnosis was 55 years (range, 37–78 years) and median maximum tumor size was 7.5 cm (range, 3–28 cm). Twelve of the 15 reported cases (80%) involved nonspecific symptoms, including abdominal pain (6 cases), abdominal mass (4 cases), abdominal distension (1 case), and abdominal discomfort (1 case). Two patients complained of symptoms related to the tumor’s invasion of the ureter (repeated pyelonephritis and back pain). Our patient is the only one to have no symptoms at diagnosis.

Tumors originating from the left ovarian vein and from the right ovarian vein have been reported in 6 (40%) and 9 (60%) cases, respectively.

Three major growth patterns have been reported for retroperitoneal LMS: completely extravascular (extraluminal, 62% of cases), completely intravascular (intraluminal, 5% of cases), and a combination of extraluminal and intraluminal patterns (mixed, 33% of cases) [ 21 ]. Cases of LMS with an extraluminal pattern are usually diagnosed late in their course, while LMS cases with intraluminal and mixed patterns are more likely to show early symptoms that depend on the affected vein [ 21 ]. Among 9 reports on LMS originating from the ovarian veins, extraluminal patterns were observed in 4 cases (44.4%) and mixed patterns in 5 cases (55.6%), with no cases involving intraluminal patterns. In the present case, the growth pattern was considered to be extraluminal because the ovarian vein passed through the dorsal side of the tumor and because no tumor cells had invaded the ovarian vein lumen.

Based on these presentations, contrast-enhanced CT is especially useful for establishing the preoperative diagnosis and for determining the tumor extent and boundaries before starting surgery [ 15 ]. Previous reports have indicated that CT typically reveals a large mass with heterogeneous contrast in the longitudinal orientation, which replaces the normal ovarian vein as well as cystic and necrotic components and vascular hypertrophy [ 8 , 15 , 22 ]. Additional information regarding the lesion can be obtained using MRI [ 9 , 10 ]. Previous reports have also indicated that increased uptake during FDG-PET provided high accuracy for diagnosing LMS [ 23 ]. FDG-PET can be used to diagnose a retroperitoneal mass as an LMS originating from an ovarian vein [ 10 ]. Among the 13 cases of LMS originating from the ovarian vein, CT was performed in 13 (100%), MRI was performed in 5 (38.5%), and PET was performed in 3 (23.1%); preoperative diagnosis was made in 4 cases (30.8%). In our case, contrast-enhanced CT revealed a solid mass with no necrosis, which is less common for extraluminal LMS but typical for smaller retroperitoneal tumors [ 21 ]. Furthermore, the mass exhibited relatively low uptake during FDG-PET, which made it difficult to establish a preoperative diagnosis of LMS. In our case, the tumor was detected early, was small in size, and had a low mitotic rate. Therefore, the findings (no necrosis and low FDG accumulation) were not typical.

In retroperitoneal sarcoma cases, 60% of resected adjacent organs were found to be microscopically invaded by the tumor [ 10 ]. En bloc resection with histopathologically free margins is essentially the only procedure that can result in a good prognosis [ 15 , 24 ]. However, even after complete tumor resection, patients with retroperitoneal sarcoma have poor prognoses, based on a > 50% recurrence rate and a 5-year survival rate of 52–65% [ 18 , 25 , 26 ]. Thus, in cases of large soft tissue sarcomas with high-grade histological findings, radiation therapy and chemotherapy are considered before or after surgery to lower the risk of local recurrence and distant metastases [ 27 , 28 ]. Therefore, we performed adjuvant radiation therapy to lower the risk of local recurrence. If LMS originating from the ovarian vein had been diagnosed preoperatively in our case, comprehensive treatment with a combination of en block excision of the tumor and ovarian vessels and adjuvant therapy would have been recommended.

Metastasis is identified at diagnosis in 12% of cases of vascular LMS that did not originate from the vena cava [ 20 ], although none of the reported cases of LMS originating from the ovarian vein involved metastasis at the initial diagnosis. All of these patients underwent radical resection that did or did not involve the adjacent organs; 50% of patients (7/14) received adjuvant radiation therapy (28.6%, 4/14) or chemotherapy (21.4%, 3/14). Tumor recurrence after radical resection was observed in 50% of cases (6/12). Distant metastasis (41.7%, 5/12) was more frequent than local recurrence (8.3%, 1/12), and the popular metastatic sites were the lung (36.4%, 4/11) and liver (27.2%, 3/11). These findings are consistent with the previously reported characteristics of retroperitoneal LMS [ 18 , 29 ]. Median interval to tumor recurrence was 12 months (range, 2–17 months), and the shortest and longest recurrence-free periods were 2 months and 17 months, respectively; therefore, surveillance every 3 months for at least 2 years is recommended. Table  2 shows the correlation between tumor recurrence and clinicopathological factors based on the literature. Interestingly, all patients with > 20 mitoses/10 HPF eventually developed recurrence after radical resection, whereas no metastasis was detected in cases with < 20 mitoses/10 HPF. Thus, a low mitotic rate may predict a favorable prognosis; however, for cases without recurrence, the median observation period was only 13.5 months, which is too short for an accurate evaluation of the patients’ prognoses. In addition, younger age and tumor resection involving the adjacent organs may be potential risk factors for recurrence; however, analysis of recurrence showed no significant risk factors, which may be due to the small cohort size.

In the present case, careful follow-up will be required, despite the low mitotic rate of 10 mitoses/10 HPF, which would predict a good outcome based on the previous sentence.

We encountered a 71-year-old woman with rare vascular LMS originating from the right ovarian vein. Although the prognosis of LMS originating from the ovarian vein is obscured by its rarity and short-term observation data, the prognosis of vascular LMS is generally poor. Therefore, careful follow-up will be required for our patient.

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Abbreviations

Cyclin-dependent kinase 4

Computed tomography

18 F-fluorodeoxyglucose positron emission tomography

High-power field

• Leiomyosarcoma

Magnetic resonance imaging

α-smooth muscle actin

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Department of Surgery, Southern Region Hospital, Midorimachi 220, Makurazaki, Kagoshima, 898-0011, Japan

Takuro Hirano, Hiroshi Okumura, Satoru Maeda, Mario Shimada, Akira Imakiire & Kanro Makisumi

Department of Pathology, Kagoshima University Hospital, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan

Michiyo Higashi

Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan

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TH, SM, MS, AI, and KM participated in the surgery. TH and HO collected the data and consent and drafted the manuscript. MH performed the pathological examinations and participated in drafting the manuscript. SN participated in the design, coordination, and drafting of the manuscript. All authors read and approved the final manuscript.

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Hirano, T., Okumura, H., Maeda, S. et al. Vascular leiomyosarcoma originating from the right ovarian vein: a case report and literature review. surg case rep 5 , 120 (2019). https://doi.org/10.1186/s40792-019-0679-5

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• Ovarian vein
• Vascular leiomyosarcoma
• Retroperitoneal sarcoma

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• Published: 10 May 2024

Severe fever with thrombocytopenia syndrome with central nervous system symptom onset: a case report and literature review

• Dawei Shan 1 ,
• Weibi Chen 1 ,
• Gang Liu 1 ,
• Huimin Zhang 1 ,
• Shuting Chai 1 &
• Yan Zhang 1  

BMC Neurology volume  24 , Article number:  158 ( 2024 ) Cite this article

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Severe fever with thrombocytopenia syndrome (SFTS) is a natural focal disease transmitted mainly by tick bites, and the causative agent is SFTS virus (SFTSV). SFTS can rapidly progress to severe disease, with multiple-organ failure (MOF) manifestations such as shock, respiratory failure, disseminated intravascular coagulation (DIC) and death, but cases of SFTS patients with central nervous system (CNS) symptoms onset and marked persistent involuntary shaking of the perioral area and limbs have rarely been reported.

Case presentation

A 69-year-old woman with fever and persistent involuntary shaking of the perioral area and limbs was diagnosed with SFTS with CNS symptom onset after metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) and peripheral blood identified SFTSV. The patient developed a cytokine storm and MOF during the course of the disease, and after aggressive antiviral, glucocorticoid, and gamma globulin treatments, her clinical symptoms improved, her laboratory indices returned to normal, and she had a good prognosis.

This case gives us great insight that when patients with CNS symptoms similar to those of viral encephalitis combined with thrombocytopenia and leukopenia are encountered in the clinic, it is necessary to consider the possibility of SFTS involving the CNS. Testing for SFTSV nucleic acid in CSF and blood (mNGS or polymerase chain reaction (PCR)) should be carried out, especially in critically ill patients, and treatment should be given accordingly.

Peer Review reports

Severe fever with thrombocytopenia syndrome (SFTS) is a natural focal disease transmitted mainly by tick bites, and the causative agent is a novel Bunyavirus, also known as SFTS virus (SFTSV), belonging to the Phenuiviridae family and the Bandavirus genus, which was first isolated from patient serum by the Chinese Centre for Disease Control and Prevention in 2010 [ 1 ]. The main features of SFTS include fever, thrombocytopenia, leukopenia and gastrointestinal symptoms, and in severe cases, patients may present with multiple‑organ failure (MOF) symptoms such as shock, respiratory failure, disseminated intravascular coagulation (DIC) and death, with a mortality rate of 5–30% in East Asia [ 2 , 3 ]. SFTS may also present with central nervous system (CNS) involvement, which can severely affect the patient’s disease progression and prognosis and is manifested by seizures, psychiatric symptoms, cognitive impairment, and disorders of consciousness [ 4 , 5 ]. However, reports of patients who present with CNS symptoms as the first symptom and with marked persistent involuntary shaking of the perioral area and limbs are rare.

A 69-year-old female patient was admitted to the hospital with fever for 4 days, involuntary shaking around the mouth and limbs for 3 days, and mental abnormalities for 1 day. The patient was admitted to the emergency department of another hospital 4 days before admission because of fever, where her body temperature reached 38.7 °C and she showed poor mental status, less talking, a loss of appetite, but no headache, vomiting, and limb twitching. A routine blood examination showed a white blood cell (WBC) count of 2.28 × 10 9 /L and a platelet count of 165 × 10 9 /L. When given a cooling infusion for symptomatic treatment, her body temperature would temporarily return to normal. Three days before admission, she experienced persistent involuntary trembling around the mouth and lips, as well as trembling of the tongue and extremities. The trembling of the lips, mouth, and both distal upper limbs was especially bothersome and was aggravated by emotional excitement and accompanied by slurred speech. Two days before admission, she had persistent fever, with a body temperature up to 39.6 °C, and the effect of antipyretic drugs was not good. A routine blood examination performed in another hospital showed a WBC count of 1.78 × 10 9 /L and a platelet count of 81 × 10 9 /L, which was significantly decreased compared with the count from the previous examination. One day prior to admission, the patient experienced babbling, restlessness, irritability, and a decline in time and place orientation and calculation power.

The patient had a many-year history of hypertension, diabetes mellitus and hyperlipidaemia; denied a history of working and living in hilly, forested and mountainous areas and travelling; denied a recent history of mosquito bites; and reported a history of close contact with a pet dog in the last month.

Neurological examination after admission showed that the patient had normal arousal but had unclear speech, hyperactivity, irritability. Her time and place orientation and calculation power decreased. The patient was uncooperative in the pharyngeal reflex examination, and involuntary tongue twitching could be seen when the tongue was stretched out. The remaining cranial nerve examination did not show any abnormalities. Perioral and limb involuntary shaking was obvious and persistent, especially in the perioral area and distal part of both upper limbs. Bilateral tendon reflexes were symmetrical, bilateral pathological signs were negative, and meningeal irritation signs were negative.

On admission, viral encephalitis was considered, and intravenous acyclovir antiviral therapy (0.5 g, q8h) was empirically administered. A comprehensive examination revealed that the patient had MOF: (1) Her platelet count further decreased to 63 × 10 9 /L (normal: 100–300 × 10 9 /L), toxic granules were seen in some granulocytes of the peripheral blood smear, and heterogeneous lymphocytes accounted for 21% of the total. (2) She had impaired liver function with elevated liver enzymes (alanine aminotransferase (ALT), 76 IU/L (normal: 5–40 IU/L); aspartate aminotransferase (AST), 188 IU/L (normal: 8–40 IU/L); and gamma-glutamyl transpeptidase (γ-GT), 177 IU/L (normal: 7–50 IU/L)), which was treated with magnesium isoglycyrrhizinate injection and vitamin C for liver protection. (3) She had acute myocardial injury, with an increased heart rate of > 120 beats/minute and markedly elevated myocardial enzyme and B-type natriuretic peptide levels (myoglobin, 299 ng/mL (normal: 25–58 ng/mL); troponin T, 209 ng/L (normal: 0–14 ng/L); and B-type natriuretic peptide, 9,355 pg/mL (normal: 0-125 pg/mL)). Electrocardiograms (ECGs) showed various atypical manifestations, such as short PR intervals; atrial premature, mild ST-segment depression in leads V2V3; and T-wave changes in multiple leads. Cardiac ultrasound showed a normal left ventricular ejection fraction but abnormal segmental motion of the left ventricular wall, biventricular diastolic insufficiency and a small amount of pericardial effusion. Coenzyme Q10 and trimetazidine were given to improve myocardial energy metabolism, and fluid intake and output were closely monitored. (4) The patient had a bacterial infection of the lungs, combined with type I respiratory failure, which were treated with tracheal intubation and mechanical ventilation immediately to assist respiration and antibiotic antimicrobial therapy. The patient did not have prolonged hypoxic injury. (5) She had impaired renal function, with elevated blood urea nitrogen (BUN) (17.33 mmol/L) (normal: 1.7–8.3 mmol/L) and urinary protein. We administered measures to ensure fluid intake and without the use of nephrotoxic drugs. (6) She had impaired pancreatic function, with elevated lipase (56.5 U/L) (normal: 5.6–51.3 U/L); we administered acid-suppressing drugs to inhibit pancreatic secretion and reduce the load and damage to pancreatic tissue. (7) She had abnormal coagulation, with a prolonged prothrombin time (PT) and thrombin time (TT) (15.7 s (normal: 11–15 s) for PT and 22.6 s (normal: 14–21 s) for TT), decreased fibrinogen (1.8 g/L) (normal: 2–4 g/L), and markedly elevated plasma D-dimer (9.01 µg/mL) (normal: 0.01–0.5 µg/mL) and fibrinogen degradation products (FDPs) (28.36 µg/mL) (normal: 0–5 µg/mL). (8) A thrombus had formed in her right peroneal vein and the intermuscular veins of the right and left calves, for which low molecular heparin anticoagulation was given. (9) Her muscle enzyme profiles were variably elevated (creatine kinase (CK), 335 IU/L (normal: 24–195 IU/L); lactate dehydrogenase (LDH), 1347 IU/L (normal: 109–245 IU/L); and alpha-hydroxybutyrate dehydrogenase (α-HBDH), 645 IU/L (normal: 72–182 IU/L)), correlating with inflammatory response-mediated organ damage. (10) The patient experienced a cytokine storm, with significantly increased inflammatory factors (ferritin > 1500 ng/mL (normal: 11-306.8 ng/mL), interleukin (IL)-6 = 49.88 pg/mL (normal: 0–20 pg/mL), IL-8 = 45.99 pg/mL (normal: 0-21.4 pg/mL), and IL-10 = 25.67 pg/mL (normal: 0-5.9 pg/mL), interferon (IFN)-α = 9.76 pg/mL (normal: 0-7.9 pg/mL), and IFN-γ = 18.7 pg/mL (normal: 0-17.3 pg/mL)) in serum (Table  1 ). (11) Finally, the patient showed an electrolyte balance disorder, as evidenced by hypernatremia (154 mmol/L) (normal: 135–145 mmol/L), hyperchloremia (119 mmol/L) (normal: 96–108 mmol/L), hypocalcaemia (1.92 mmol/L) (normal: 2.03–2.67 mmol/L), and hypophosphatemia (0.54 mmol/L) (normal: 0.84–1.65 mmol/L), and treatments included calcium supplementation, phosphorus supplementation, nasal administration of plain water, and a reduction of sodium and chlorine intake.

Lumbar puncture was performed on the second day after admission (Table  2 ). Cerebrospinal fluid (CSF) was colourless and clear, with a pressure of 190 mmH 2 O (normal: 80–180 mmH 2 O) and a WBC count of 3 × 10 6 /L. CSF cytology showed scattered lymphocytes and a few mononuclear cells. The glucose level and protein counts were normal, chloride was slightly elevated (134 mmol/L) (normal: 118–128 mmol/L), immunoglobulins (Ig) were slightly elevated (IgA, 1.03 mg/dL (normal: 0-0.2 mg/dL); IgM, 0.22 mg/dL (normal: 0-0.2 mg/dL); and IgG, 6.68 mg/dL (normal: 0.48–5.86 mg/dL)), and CSF cytokine levels of IL-6 (27.46 pg/mL) (normal: 0–20 pg/mL) and IL-8 (546.93 pg/mL) (normal: 0-21.4 pg/mL) were elevated. CSF was negative for an autoimmune encephalitis antibody profile (NMDAR, CASPR2, AMPAR1, AMPAR2, LGI1, GABABR, DPPX, and IgLON5), neuroparaneoplastic syndrome antibody profile (Hu, Ri, Yo, CV2, Amphiphysin, GAD65, PNMA2, Recoverin, SOX1, Titin, Tr, and Zic4), and CNS demyelination antibody profile (AQP4, GFAP, MBP, and MOG). Metagenomic next-generation sequencing (mNGS) showed that the number of sequences of a novel Bunyavirus of the Bandavirus genus was 59 in the blood and 12 in the CSF. We also excluded acute febrile illnesses by serum and CSF mNGS, such as dengue fever, chikungunya fever, EB virus infection, renal syndrome hemorrhagic fever, and rickettsial disease.

A diagnosis of SFTS that started with symptoms of CNS and encephalitis due to a novel Bunyavirus was considered based on the patient’s clinical presentation and laboratory test results. With immediate effect, acyclovir was adjusted to the broad-spectrum antiviral drug Foscarnet sodium (3 g, q8h); intravenous infusion of dexamethasone (10 mg qd for five days) and intravenous immunoglobulin (IVIG) (0.4 g/kg for five days) were administered to regulate immune function and inhibit the cytokine storm; nifedipine and benidipine hydrochloride were given to reduce the viral-induced calcium inflow to inhibit viral replication, reduce the viral load and increase the platelet count; clonazepam (1 mg, q8h) was given to relieve the patient’s obvious symptoms of involuntary shaking; and adequate symptomatic supportive therapy was given to ensure adequate calorie and protein intake and to maintain water, electrolyte, blood glucose and acid‒base balance.

After 3 days of hospitalization, the patient’s platelet and WBC counts began to rise gradually and returned to normal levels. After 5 days of hospitalization, the patient’s involuntary shaking and psychiatric symptoms were less severe than before, but compliance with activities was still poor, and her cognitive level still had not returned to normal. After 11 days of hospitalization, the lung infection was better than before, and ventilator withdrawal training was started. After 12 days of hospitalization, cranial magnetic resonance imaging (MRI) was performed, which showed slightly high signals in the bilateral anterior temporal lobe, temporal lobe hook gyrus, insular cortex, and bilateral thalamus on fluid attenuated inversion recovery (FLAIR) and diffusion weighted imaging (DWI) (Fig.  1 a-f). After 13 days of hospitalization, a blood sample was negative for novel Bunyavirus nucleic acid. After 16 days of hospitalization, her condition was significantly better than before, she could perform activities as instructed and answer questions correctly, her time and place orientation returned to normal, and her cognitive level was better than before. A electroencephalogram (EEG) was performed, and a full-lead low-wave amplitude state was observed (Fig.  2 ). After 17 days of hospitalization, the ventilator was completely withdrawn, and the tracheal tube was removed. A repeat lumbar puncture 3 weeks after hospitalization showed a pressure of 110 mmH 2 O, a WBC count of 4 × 10 6 /L, a normal protein count, a slightly elevated glucose level (5.19 mmol/L, compared with a glucose of 7.9 mmol/L over the same period), a slightly elevated chlorine level (130 mmol/L), and a return of Ig to normal. The levels of cytokines IL-6 (4.35 pg/mL) and IL-8 (96.17 pg/mL) decreased significantly compared with the previous levels, and the levels of whole-blood cytokines returned to the normal range (IL-6, 12.22 pg/mL; IL-8, 4.62 pg/mL; IL-10, 1.27 pg/mL; IFN-α, 0 pg/mL; and IFN-γ, 1.14 pg/mL) in serum (Table  1 ). No further novel Bunyaviruses were detected by mNGS of the CSF. Meanwhile, MOF gradually recovered, and liver, heart, lung, kidney, pancreas and coagulation function; the muscle enzyme profile; inflammatory factors; and electrolyte levels gradually returned to normal levels.

After antiviral therapy, immunotherapy, life support and symptomatic treatment, the patient’s vital signs were stable 3 weeks after admission, with clear speech and normal higher cortical function to perform tasks correctly on command. The muscle strength of all four limbs was grade 5, muscle tone was normal, bilateral tendon reflexes existed symmetrically, an ataxia test was normal, bilateral pathological signs were negative, and meningeal irritation signs were negative. She was discharged from the hospital in 23 days after admission. The patient was followed up 1 month after she was discharged from the hospital and is now back to her normal living conditions, with normal functioning of the higher cortex, the ability to take care of herself, and the ability to perform all of the activities she regularly engages in.

Cranial MRI of the patient 12 days after admission. Bilateral anterior temporal lobe (a and d) , temporal lobe leptomeningeal gyrus (a and d) , insular cortex (b and e) , and bilateral thalamus (c and f) FLAIR and DWI sequences with slightly high signals

Sixteen-lead resting-state EEG of the patient 16 days after admission. Simultaneous display an EEG record in monopolar and bipolar montages. A low-amplitude state can be seen in all leads. (a) monopolar montage EEG, (b) bipolar montage EEG

Discussion and conclusions

SFTS is an infectious disease caused by SFTSV infection. The epidemic period is mainly in May-August, and SFTSV is mainly transmitted by tick bites to humans. In recent years, interpersonal and human-animal transmission has also been found. An epidemiological survey of SFTS found that 48% of the patients had had close contact with their pets within two weeks of the onset of the disease [ 6 ]. The general population is susceptible, with a higher risk of infection in residents living in areas such as hills, mountains and forests and in people who spend time outdoors. In this case, SFTSV was isolated from blood and CSF. There was no history of tick bites or travel in the wild, but there was a history of close contact with a pet dog within the past month, and we hypothesized that the infected dog might have been the source of SFTSV in this patient.

The pathogenesis of CNS involvement in SFTS patients is unclear. Previous studies have demonstrated that Bunyaviruses have neurological properties of attack, and Park et al. found viral transcripts of novel Bunyaviruses in the brain and spinal cord of an aged model ferret. It is hypothesized that novel Bunyaviruses also involve the CNS, with consequent symptoms [ 7 ]. Possible mechanisms by which SFTSV attacks the CNS include direct invasion, cytokine storms, and impaired immune function. Kaneko et al. [ 8 ] performed an autopsy on a patient with SFTS with rapid CNS involvement, and the pathological findings revealed a massive infiltration of macrophages with high haematoxylin content and inflammatory cells around the microvessels of the cerebral pontine, fibrin deposition in the vessels, and focal degenerative lesions in some neuronal cells. In a variety of brain tissues, positive SFTSV nucleocapsid protein antigens were observed in the immunoblasts infiltrating the vascular lumen, suggesting that SFTSV can invade the CNS directly for disease development. The availability of agents that recognize these antigens also suggest immunoassays are possible and available for serodiagnosis. For example, serum enzyme linked immunosorbent assay or immunofluorescence to determine SFTSV antigens and antibodies have been used for clinical diagnosis [ 9 ]. Several studies [ 10 , 11 , 12 , 13 , 14 , 15 ] have found that the blood levels of several cytokines, including IFN-α, IFN-γ, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and monocyte chemotactic protein (MCP)-1, are elevated in patients with SFTS, and IL-8 and MCP-1 levels in the CSF are significantly higher than the blood of those who present with CNS symptoms [ 10 ], suggesting that a cytokine storm may increase vascular permeability and prompt SFTSV to cross the blood‒brain barrier (BBB) and invade the CNS. SFTSV was found in the CSF of this patient, suggesting that the virus had invaded the patient’s CNS. The patient’s blood levels of IL-6, IL-8, IL-10, IFN-α, and IFN-γ were markedly elevated compared with normal ranges; IL-6 and IL-8 were elevated in the CSF; and CSF IL-8 levels were significantly higher than the blood levels, which was consistent with the results of a previous study [ 10 , 11 , 12 , 13 , 14 , 15 ], further suggesting that the cytokine storms induced by multiple elevated cytokines may increase BBB vascular permeability and contribute to the SFTSV invasion of the CNS. In patients with SFTS complicated by neurological involvement, protein and glucose levels in the CSF are normal and that an increase in leukocytes in the CSF may be uncommon. However, in the case of a high suspicion both on a clinical and epidemiological level in countries where the infection exists, in these patients the search for MCP-1 and IL-8 in the CSF and serum is indicated and CSF viral RNA detection are recommended.

According to the course of infection, SFTS can be divided into four periods: the incubation period, the febrile period, the MOF period, and the recovery period [ 1 , 2 , 3 , 16 ]. Patients with SFTS can present with neurological symptoms, which usually appear approximately 5 days after the onset of the disease (Table  3 ) and are often regarded as a complication of SFTS, which has been referred to as SFTS-associated encephalopathy/encephalitis (SFTSAE) [ 10 ]. SFTSAE mainly manifests as headache, seizures, mental abnormality, irritability, limb convulsions, cognitive impairment, and impaired consciousness, with an incidence of approximately 19.1-57.02% [ 4 , 5 , 11 , 17 ]. Most patients with SFTSAE develop impaired consciousness, such as coma, before their condition is taken seriously, which leads to a poor prognosis for the patients [ 4 , 18 ]. Most clinicians rely on the clinical manifestations to make the clinical diagnosis. SFTSV has rarely been isolated from CSF. We screened studies and case reports of SFTS with CNS involvement and found no reports of disease onset with CNS symptoms such as marked persistent involuntary shaking of the perioral area and extremities. In this case, the patient first presented with fever, followed by persistent involuntary tremors of the perioral area and limbs and mental behavioural abnormalities such as rambling, irritability and agitation; furthermore, the whole-genome sequence of SFTSV was found by mNGS of blood and CSF. The case reported here is a case of SFTS with CNS symptoms onset, accompanied by perioral and extremity persistent involuntary shaking, which has not been previously reported in the literature. It has been reported in the literature that SFTS patients can have tremors of limbs and muscles [ 8 , 17 , 19 ], but most of them occurred in the middle and late stages of the disease, and the tremor amplitude was small. In this case, the patient had large-amplitude involuntary shaking of the limbs that was persistent and intensified during agitation, which immediately attracted the clinician’s attention. An additional movie file shows this in more detail [see Additional file 1 ]. However, the specific underlying mechanism is not clear, and a description of similar symptoms of viral encephalitis and an analysis of the underlying mechanism have not been found before; therefore, further studies are needed. The course of the disease in this patient was consistent with the general pattern, with the clinical experience of the febrile period, the MOF period, and the recovery period. The febrile period lasted approximately 4 days, followed by MOF involving the liver, heart, lungs, kidneys, and pancreas, and then the recovery period began approximately 2 weeks after the disease onset, with clinical symptoms gradually returning to normal.

There are fewer reports on neurological-related ancillary investigations (CSF, cranial imaging, and EEG) in SFTS patients with CNS involvement, and we analyse this because SFTS patients rarely start with CNS symptoms and go directly to the neurology department and because such patients are generally more severely ill, making it difficult for them to cooperate in completing the relevant investigations. In a few previous studies, lumbar puncture CSF tests in SFTS patients with CNS symptoms were mostly normal, with few abnormal changes in leukocyte counts, sugars and proteins [ 10 , 20 ]. Park et al. [ 10 ] analysed head imaging and EEG in a series of SFTS patients presenting with CNS symptoms, and no new focal lesions were seen on imaging in any of the brain parenchyma, suggesting that the imaging was not specific and that the EEG in the majority of the patients showed a slow-wave background rhythm (δ-θ), a common feature of encephalitis/encephalopathy. In this patient, two lumbar punctures were performed successively, and no CSF leukocyte abnormalities were observed in any of them either; it was presumed that SFTSV infection was less likely to involve the meninges. We performed cranial MRI and EEG on the patient 12 and 16 days after admission, respectively, and slightly high signals were observed in the bilateral anterior temporal lobes, temporal lobe hook gyrus, insular cortex, and bilateral thalamus in the FLAIR and DWI sequences of cranial MRI, all of which were consistent with the general imaging manifestations of viral encephalitis and were presumed to be related to viral invasion. In addition, we should consider the similarities and differences between the above MRI changes and cortical laminar necrosis associated with hypoxia or hypotension. We found that both had MRI high signals distributed along the cortex. However, this patient’s cranial MRI showed cortical high signals only in FLAIR and DWI sequences, and no abnormal signal was found in T1WI, which was the most obvious difference from cortical laminar necrosis. Furthermore, the patient did not show hypotension or significant hypoxic injury, so the changes on cranial MRI were more likely to be inflammatory changes of viral encephalitis and less relevant to cortical laminar necrosis. The background rhythm of the EEG was an α rhythm, and the whole leads were in low amplitude, which was different from previous studies [ 10 ]. It was presumed that the patient’s brain inflammation had tended to recover at that time, but the suppression of cortical function was remained.

There are no specific drugs for the treatment of CNS symptoms in SFTS, and symptomatic supportive treatment is the mainstay. In vitro and ex vivo studies have found that nifedipine or benidipine hydrochloride can inhibit SFTSV replication, reduce viral load, increase platelet counts, and reduce morbidity and mortality, as confirmed in a retrospective clinical study [ 21 , 22 ]. Glucocorticoids can inhibit the cytokine storms caused by the overproduction of cytokines and reduce patient mortality [ 12 , 13 , 23 ], and a Japanese report documented that three SFTS patients with impaired consciousness recovered without any neurological sequelae after short-term glucocorticoid treatment. However, the authors also suggested that the dosage should be minimized and the duration of administration should be shortened to inhibit cytokine storms and provide systemic benefit, rather than high doses or prolonged use, to avoid side effects [ 24 ]. Gamma globulin, which triggers complement activation and viral neutralization and influences the differentiation process of Schwann cells to increase their regenerative potential [ 25 ], has been used to treat other virus-induced encephalitides and can be used for the treatment of CNS symptoms in SFTS. Two successful cases of combined glucocorticoid and IVIG therapy were reported in Korea [ 26 ]. Two case reports documented that plasma exchange therapy reduced cytokine levels but not viral load, presumably making plasma exchange more effective at an early stage [ 27 , 28 ]. However, these are case reports, and the findings should be confirmed by large-scale randomized controlled studies. In this case, the patient was given the broad-spectrum antiviral drug foscarnet sodium, intravenous infusion of dexamethasone and IVIG to regulate the immune function of the body and inhibit the inflammatory storm, nifedipine and benidipine hydrochloride to inhibit viral replication and reduce the viral load, and other symptomatic treatments. The patient’s clinical manifestations and laboratory indicators gradually improved.

The prognosis of patients with SFTS is related to numerous factors, and studies have shown that advanced age; significant elevations in ALT, AST, CK, CK-MB, LDH, γ-GT, and BUN; low platelet count; persistent lowering of blood calcium; and the presence of CNS symptoms are all important influences that can lead to a poor prognosis [ 29 , 30 , 31 , 32 , 33 , 34 ]. Most of these are commonly used to monitor cardiac, hepatic and renal function, and significant abnormalities in their results indicate more severe organ damage and dysfunction. In addition, there is a statistically significant difference in serum viral copy number between deceased and non-dead patients. The mean viral copy number was higher in deceased patients than in surviving patients, and patients with higher copy numbers had higher mortality rates [ 35 , 36 ]. It was shown that the serum viral load detected by polymerase chain reaction (PCR) on admission was higher in SFTSAE patients than in non-encephalitis patients [ 11 ]. The above suggests a relationship between patient serum number of SFTSV RNA copies and encephalitis CNS symptoms and mortality in SFTS patients. CNS symptoms are often considered to be associated with fatal outcomes in patients with SFTS [ 33 ], and early diagnosis and treatment of neurological symptoms can help reduce mortality. Advanced age; long intervals between onset and admission; comorbid diabetes mellitus or subcutaneous haemorrhage; pulmonary rales; low platelet count; elevated neutrophil percentages and LDH, CK, and C-reactive protein (CRP) levels; and decreased chloride concentrations are significantly associated with the development of CNS symptoms and should be taken into consideration in clinical practice [ 11 , 17 ]. We believe that changes in platelet count and CK-MB should be monitored in patients with SFTSAE. As shown in previous, decreased platelet counts and high CK-MB levels are risk factors for poor prognosis in patients with SFTS. The presence of encephalitis is evidence of a more critical condition. Monitoring changes in platelet counts may provide an initial indication of the direction of the patient’s regression. It has been found that in cardiac enzyme profiles, patients presenting with CNS symptoms have elevated CK levels earlier than LDH and AST levels, and elevated liver enzyme levels later than cardiac enzymes [ 17 ]. Therefore, early monitoring of CK-MB levels may have a predictive effect on the development of CNS symptoms in patients. Although the mortality rate of SFTS patients presenting with CNS symptoms is significantly higher [ 11 ], several studies have found [ 11 , 37 , 38 ] that the long-term prognosis of surviving patients is good, with no obvious sequelae after active treatment. In this case, the patient’s laboratory indicators were consistent with the factors leading to a poor prognosis, and the CNS symptoms were prominent, suggesting that the condition was critical, but with timely administration of treatment, the patient’s condition eventually returned to normal.

In summary, we report a case of SFTS in a patient who started with CNS symptoms accompanied by marked persistent involuntary perioral and extremity shaking, and the whole-genome sequence of SFTSV was found by mNGS of both serum and CSF (It is important to note that hospitals where mNGS analysis is unavailable should use real-time fluorescent quantitative PCR to detect SFTS-specific nucleic acids in serum and CSF.). This has given us great insight into the fact that SFTS should be considered a possible cause when patients present with common CNS symptoms of viral encephalitis, such as mental behavioural abnormalities, convulsions, and cognitive deficits, or rare symptoms, such as persistent involuntary shaking of the perioral area and limbs in the rare case of this patient, combined with thrombocytopenia and leukopenia. Prompt lumbar puncture examination for SFTSV should be performed, and appropriate treatment should be given aggressively to reduce mortality.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

severe fever with thrombocytopenia syndrome

severe fever with thrombocytopenia syndrome virus

multiple-organ failure

disseminated intravascular coagulation

central nervous system

metagenomic next-generation sequencing

cerebrospinal fluid

alanine aminotransferase

aspartate aminotransferase

gamma-glutamyl transpeptidase

electrocardiogram

blood urea nitrogen

prothrombin time

thrombin time

fibrinogen degradation products

creatine kinase

lactate dehydrogenase

alpha-hydroxybutyrate dehydrogenase

interleukin

immunoglobulin

intravenous immunoglobulin

magnetic resonance imaging

fluid attenuated inversion recovery

diffusion weighted imaging

electroencephalogram

tumour necrosis factor

monocyte chemotactic protein

blood-brain barrier

severe fever with thrombocytopenia syndrome -associated encephalopathy/ encephalitis

polymerase chain reaction

C-reactive protein

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This project was supported by National Key Research and Development Program of China (2020YFC2005403), and by China Association for Promotion of Health Science and Technology (JKHY2023001).

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Supplementary Material 1. File name: Additional file 1. File format: mp4. Title of data: Video of patient with persistent involuntary shaking of the perioral area and limbs. Description of data: We took this video on day 2 after the patient was admitted to the hospital. The patient develops persistent involuntary shaking of the perioral area and limbs, especially in the perioral area and distal limbs, which is aggravated by agitation and is accompanied by slurred speech.

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Shan, D., Chen, W., Liu, G. et al. Severe fever with thrombocytopenia syndrome with central nervous system symptom onset: a case report and literature review. BMC Neurol 24 , 158 (2024). https://doi.org/10.1186/s12883-024-03664-6

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Portal vein thrombosis as extraintestinal complications of Crohn’s disease: a case report and review of literature

• Marouf Alhalabi   ORCID: orcid.org/0000-0001-5027-2096 1 ,
• Duaa Nasri 1 &
• Widad Aji 1  

Journal of Medical Case Reports volume  18 , Article number:  246 ( 2024 ) Cite this article

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Introduction

Thrombotic events are more than twice as common in inflammatory bowel disease patients as in the general population. We report an interesting and rare case of portal vein thrombosis as a venous thromboembolic event in the context of extraintestinal manifestations of Crohn’s disease. We also conducted a literature review on portal vein thrombosis associated with inflammatory bowel disease, with the following concepts: inflammatory bowel diseases, ulcerative colitis, Crohn’s disease, portal vein, and thrombosis.

Case presentation

A 24-year-old Syrian female with active chronic Crohn’s disease was diagnosed 11 years ago and classified as A1L3B1P according to the Montreal classification. She had no prior surgical history. Her previous medications included azathioprine and prednisolone. Her Crohn’s disease activity index was 390 points. Gastroduodenoscopy revealed grade I esophageal varices, a complication of portal hypertension. Meanwhile, a colonoscopy revealed several deep ulcers in the sigmoid, rectum, and descending colon. An investigation of portal vein hypertension revealed portal vein thrombosis. We used corticosteroids to induce remission, followed by tapering; additionally she received ustekinumab to induce and maintain remission. She began on low-molecular-weight heparin for 1 week, warfarin for 3 months, and then apixaban, a novel oral anticoagulant, after excluding antiphospholipid syndrome. Primary prophylaxis for esophageal varices was not required. After 1 year, she achieved clinical, biochemical, and endoscopic remission. Despite 1 year of treatment, a computed tomography scan revealed no improvement in portal vein recanalization.

Portal vein thrombosis is a rare and poorly defined complication of inflammatory bowel disease. It is usually exacerbated by inflammatory bowel disease. The symptoms are nonspecific and may mimic a flare-up of inflammatory bowel disease, making the diagnosis difficult. Portal vein Doppler ultrasound for hospital-admitted inflammatory bowel disease patients may contribute to the diagnosis and management of this complication.

Peer Review reports

Extraintestinal manifestations can affect almost any organ system and have a negative impact on the patient’s functional status and quality of life. Extraintestinal manifestations are most commonly observed in the joints, skin, hepatobiliary tract, eyes, heart, pancreas, and vascular system. Portal vein thrombosis (PVT) is an obscure and poorly defined complication of many diseases, including cirrhosis, intraabdominal infection, intraabdominal surgery, pancreatitis, primary hematologic disorders, and inflammatory bowel disease (IBD) [ 1 ]. The prevalence of PVT in patients with IBD ranges from 0.17% to 1.7% [ 1 ], and may be associated with inherited or acquired hypercoagulability risk factors and has a benign outcome [ 1 ]. It can be difficult to diagnose PVT in patients with IBD because its extremely generic symptoms, such as abdominal discomfort, can frequently originate from any of its triggering events. Therefore, it should come as no surprise that the diagnosis is frequently made by accident when imaging is performed to check for one of these triggering processes, also the laboratory results are nonspecific [ 1 ]. We report an interesting and uncommon case of PVT associated with Crohn’s disease that was discovered when investigating the cause of esophageal varices related to portal vein hypertension. We also conducted a literature review on portal vein thrombosis associated with inflammatory bowel disease using the following concepts: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, portal vein, and thrombosis.

We evaluated a 24-year-old Syrian female with active chronic Crohn’s disease, diagnosed 11 years ago. She was classified as A1L3B1P according to the Montreal classification [ 2 ]. She had no prior surgical history; her past medications included azathioprine 2.5 mg/kg/day since diagnosis until now and prednisolone 1 mg/kg up to 40 mg during flares, then tapering [ 3 ]. Furthermore, she did not use oral contraceptive pills. Her weight was 50 kg, her height was 161 cm, and she had a body mass index of 19.29 kg/m 2 . She complained of watery, bloody diarrhea up to eight times a day, accompanied by abdominal pain in the prior month. Her Crohn’s disease activity index (CDAI) was 390 points. Initial blood tests confirmed leukocytosis, anemia, elevated fecal calprotectin (FC), and C-reactive protein (CRP) levels. Stool cultures, Clostridium difficile toxin, Escherichia coli , and Cryptosporidium , as well as microscopy for ova and parasites, all returned negative. The hypercoagulability work-up revealed negative results for anti-Beta-2 Glycoprotein-1 IgM antibodies, antinuclear antibodies (ANA), fibrinogen, protein S (activity), antithrombin III, and homocysteine, whereas lupus anticoagulant (LA1, LA2) was positive. Factor II mutation and factor V Leiden mutation were normal, whereas the methylenetetrahydrofolate reductase mutation was a homozygous mutant gene. The portal system and suprahepatic vein ultrasound revealed a thrombus that covered nearly half of the lumen of the portal vein and splenomegaly. Gogastroduodenoscopy showed grade I esophageal varices (less than 5 mm, without bleeding risk signs), which indicate portal vein hypertension owing to splenomegaly and esophageal varices. In light of the patient’s recent onset of abdominal pain and the absence of portosystemic collaterals on Doppler ultrasound, a recent PVT is a strong possibility [ 4 ]. The colonoscopy revealed several deep ulcers in the sigmoid, rectum, and descending colon Fig.  1 . The biopsies were negative for Clostridium difficile , and immunohistochemical staining was negative for cytomegalovirus (CMV) [ 3 , 5 ]. The median liver stiffness measured by FibroScan was 2.4 kPa, which suggests the absence of fibrosis. Protein electrophoresis was normal. The abdomen and pelvis contrast-enhanced computed tomography (CT) scan confirmed the PVT and displayed thickening in the descending colon (Fig.  2 ). Antiphospholipid syndrome was initially diagnosed on the basis of an antiphospholipid profile, a history of PVT (thrombotic event), and an association with Crohn’s disease [ 6 ]. She initially received corticosteroids to achieve disease remission, followed by ustekinumab to induce and maintain therapy (390 mg intravenous induction followed by 90 mg subcutaneous every 8 weeks) owing to moderate-to-severe Crohn’s disease unresponsive to azathioprine [ 7 , 8 ]. She began on low-molecular-weight heparin (LMWH) for 1 week, and warfarin for 3 months with an international normalized ratio (INR) target of 2–3. The lupus anticoagulant (LA1, LA2) was retested after 12 weeks and returned to negative [ 6 ], so we switched to apixaban, a novel oral anticoagulant (NOAC) [ 4 ]. The 1-year reevaluation indicated clinical, biochemical, and endoscopic remission with CDAI of 150 points, normal lab test, and normal endoscopy. The patient’s tests are presented in Table  1 . Despite 1 year of treatment, a CT scan revealed no improvement in portal vein recanalization. We continued 90 mg of subcutaneous (SC) ustekinumab every 8 weeks, while we stopped apixaban [ 3 , 4 ].

Colonoscopy revealed several ulcerations in the sigmoid, rectum, and descending colon

The contrast-enhanced computed tomography scan of the abdomen, which shows portal vein thrombosis

Review of literature

To facilitate this literature review, we used a combination of keywords and database subject headings to search the MEDLINE (through PubMed) database on 1 July 2023 for the following concepts: Crohn’s disease, ulcerative colitis, IBD, portal vein, PVT, and thrombosis. We also manually searched the reference lists of the included papers. We returned the research on 7 April 2024, and no new findings were obtained.

Eligibility criteria

We searched for any case reports, case series, observational, or interventional studies that addressed portal vein thrombosis associated with inflammatory bowel disease. Table 2 summarizes the basic features and treatment outcomes of the reported cases.

Crohn’s disease is linked to a variety of extraintestinal complications. Oral aphthous ulcers, peripheral arthritis, erythema nodosum, and episcleritis are frequently associated with active intestinal disease. Whereas uveitis and ankylosing spondylitis are usually unrelated to disease activity, pyoderma gangrenosum and primary sclerosing cholangitis have a questionable relationship to disease activity [ 9 ]. Venous thromboembolic events are fearsome manifestations that are related to disease activity and associated with significant morbidity and mortality [ 9 ]. Deep vein thrombosis (DVT) is the most prevalent thrombotic event, followed by pulmonary embolism (PE). The relative risk of thrombotic events in patients with inflammatory bowel disease was 2.03 [ 10 ]. Although inflammatory bowel disease treatment options have improved over the last three decades [ 11 ], thrombotic events among hospitalized individuals with inflammatory bowel disease continued to rise [ 12 ]. The overall thrombotic risk did not differ between sexes or between individuals who have ulcerative colitis or Crohn’s disease [ 13 ]. There have been very few reports of portal vein thrombosis in the context of inflammatory bowel disease. The presenting indications, symptoms, and laboratory data are all extremely nonspecific, and a PVT diagnosis is nearly always made by chance. It is important to note that PVT is related to disease activity, particularly IBD flare. We found that portal vein thrombosis affects both men and women, with a small male predominance. It is also more frequent in individuals with ulcerative colitis than in those with Crohn’s disease. It is a rare complication in Crohn’s disease, identified in only 14 cases. Hypercoagulability testing in a subset of patients (around half) revealed inherited or acquired hypercoagulability factors in some, with antiphospholipid antibodies and factor V Leiden mutation being the most common. Treatment for thrombosis in Crohn’s disease involves tailored anticoagulation (heparin, warfarin, DOACs) or even surgery, with outcomes ranging from successful resolution to bleeding or death. However, limitations include the use of case reports and retrospective studies, and the small number of CD cases, which hinder definitive conclusions. There are no recommendations for thrombophilia screening in cases of portal vein thrombosis; many reports, including ours, have included thrombophilia testing. Naymagon et al . suggested that thrombophilia testing is not required in cases of clearly triggered PVT, such as after recent surgery or in the setting of a recent or active intraabdominal infection or IBD-flare [ 1 ]; moreover, he suggested that thrombophilia testing should be undertaken if PVT is not induced, such as spontaneous PVT in an otherwise stable and inactive IBD patient, or patients with a history of previous venous thromboembolism or unexplained blood count abnormalities [ 1 ]. Furthermore, testing for antiphospholipid syndrome and paroxysmal nocturnal hemoglobinuria may affect management and should be considered in certain conditions, such as a history of autoimmune disease or arterial thrombosis for antiphospholipid syndrome and unexplained cytopenia or evidence of intravascular hemolysis for paroxysmal nocturnal hemoglobinuria. Other thrombophilia testing are often unnecessary because the results have little impact on therapy [ 1 ]. A mutation of JAK2 could be detected in splanchnic vein thrombosis and thus provide a marker of latent myeloproliferative neoplasms (MPNs), which are a major primary cause of abdominal vein thrombosis [ 14 ]. MPNs are made up of three key rare diseases: (1) polycythemia vera, which leads to an elevation in all blood cells, especially red blood cells; (2) essential thrombocythemia, which leads to an increase in platelets; and (3) primary myelofibrosis, a bone marrow disorder that leads to defects in blood cell production [ 14 , 15 ]. MPNs were diagnosed through a variety of criteria, including the typical alterations in peripheral blood cells [ 4 ], as she had chronic active CD with possible previous CD-flare and a normal blood profile which excludes MPNs [ 1 , 14 , 15 ]. We screened for antiphospholipid syndrome antibodies because the patient was a young female with a significant thrombotic event without a clear relationship with a Crohn’s disease flare. Although the lupus anticoagulant (LA1, LA2) was initially positive, it was found to be negative 12 weeks later. The explanations for the false positive in our instance were anticoagulant treatment, including therapy with LWMH, which is indicated to every patient admitted to the hospital with inflammatory bowel disease, and later warfarin for the management of portal vein thrombosis [ 3 , 6 , 13 ]. For PVT management, literature was unclear concerning the selection of anticoagulants. Most patients who require anticoagulation are started on LMWH, or unfractionated heparin, and then switched to vitamin K antagonists (VKAs) to maintain a goal international normalization rate of 2–3. While VKAs can be substituted orally with direct oral anticoagulants (DOACs) or novel oral anticoagulants (NOACs). These medications do not require monitoring of the INR because of their speedier onset of action and lesser risk of bleeding. DOACs are just as effective as VKAs for treating deep vein thrombosis, pulmonary embolism, and stroke prevention in patients with atrial fibrillation, and may be considered owing to potentially less frequent monitoring needs and a fixed dosing regimen, which could enhance medication adherence. However, owing to unbalanced hemostasis, patients with cirrhosis have been excluded from most trials. Our case was portal hypertension without cirrhosis; therefore, DOACs or NOACs are not contraindicated after excluding antiphospholipid syndrome. For Crohn’s disease treatment, ustekinumab was more suitable than tumor necrosis factor inhibitors (anti-TNFα), as ustekinumab had low immunogenicity (generating antidrug antibodies), so it is feasible to avoid a combination of azathioprine and ustekinumab, in contrast to anti-TNF treatment, which necessitates such a combination [ 3 , 6 , 7 , 9 ]. Ustekinumab helped to eliminate the drug interactions of azathioprine and warfarin, note that warfarin was the only therapeutic option owing to the initial diagnosis of antiphospholipid syndrome. In addition, ustekinumab had the lowest rate of serious infections among the biological treatments [ 7 ]. Esophageal varices primary prophylaxis is not required, as primary prophylaxis must be initiated upon the detection of high-risk varices, such as small varices with red signs, medium or large varices regardless of Child–Pugh classification, or small varices in patients classified as Child–Pugh C [ 16 ]. It is possible to discontinue anticoagulant treatment after a year, whether or not portal vein recanalization occurs, because a longer period of anticoagulant treatment is unlikely to enhance the probability of recanalization if it does not occur after a year [ 4 ].

PVT symptoms are similar to the symptoms of an inflammatory bowel disease flare. Initial tests for antiphospholipid syndrome were falsely positive [ 17 ]. The wise choice of ustekinumab as the first-line biological treatment, which aided in weaning off azathioprine, led to avoiding azathioprine–warfarin interactions. Using DOACs or NOACs for the management of portal vein thrombosis in case of portal vein hypertension. Finally, the management of esophageal varices in the context of anticoagulant treatment. The use of portal vein Doppler ultrasound, particularly during flare-ups of inflammatory bowel disease, may contribute to the diagnosis and management of this uncommon complication.

Availability of data and materials

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Abbreviations

• Portal vein thrombosis
• Inflammatory bowel disease
• Crohn’s disease

C-reactive protein

International normalized ratio

K antagonists

Computed tomography

Subcutaneous

Antiphospholipid syndrome

Direct oral anticoagulants

Novel oral anticoagulants

Low molecular weight heparin

Hepatitis B surface antigen

Hepatitis B surface antibody

Hepatitis B core antibody

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Motor polyradiculoneuropathy as an unusual presentation of neurobrucellosis: a case report and literature review

• Ahmad Alikhani 1 ,
• Noushin Ahmadi 1 ,
• Mehran Frouzanian 2 &
• Amirsaleh Abdollahi 2  

BMC Infectious Diseases volume  24 , Article number:  491 ( 2024 ) Cite this article

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Brucellosis, a zoonotic disease caused by Brucella species, poses a significant global health concern. Among its diverse clinical manifestations, neurobrucellosis remains an infrequent yet debilitating complication. Here, we present a rare case of neurobrucellosis with unusual presentations in a 45-year-old woman. The patient’s clinical course included progressive lower extremity weakness, muscle wasting, and double vision, prompting a comprehensive diagnostic evaluation. Notable findings included polyneuropathy, elevated brucella agglutination titers in both cerebrospinal fluid and blood, abnormal EMG-NCV tests, and resolving symptoms with antibiotic therapy. The clinical presentation, diagnostic challenges, and differentiation from other neurological conditions are discussed. This case underscores the importance of considering neurobrucellosis in regions where brucellosis is prevalent and highlights this rare neurological complication’s distinctive clinical and radiological features. Early recognition and appropriate treatment are crucial to mitigate the significant morbidity associated with neurobrucellosis.

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Introduction

Brucellosis, caused by Brucella species, is an infectious ailment recognized by various names such as remitting, undulant, Mediterranean, Maltese, Crimean, and goat fever. Humans contract it through the consumption of unpasteurized milk and dairy products, undercooked meat, or skin contact with infected livestock [ 1 , 2 , 3 ]. Various Brucella species, including Brucella melitensis (primarily sourced from sheep and goats), Brucella abortus (found in cattle), Brucella suis (associated with pigs/hogs), and Brucella canis (linked to dogs), can lead to illness in humans [ 3 , 4 , 5 ]. While brucellosis in humans is rarely fatal, it can lead to disability [ 6 ]. Brucellosis ranks among the most prevalent zoonotic diseases, impacting approximately 500,000 individuals yearly [ 7 ]. The combined estimate for the prevalence of brucellosis was 15.53% [ 8 ].

Neurobrucellosis, a rare complication of systemic brucellosis, can occur in adult and pediatric cases [ 9 ], and can manifest at any stage of the disease. They can present in various clinical presentations such as meningitis, encephalitis, meningoencephalitis, myelitis, radiculopathy, polyneuropathy, stroke, cerebral venous thrombosis, and occasionally psychiatric symptoms [ 10 , 11 ]. Although the mortality rate is low, patients often experience persistent neurological issues following neurobrucellosis [ 12 ]. Studies suggest that around 20% of neurobrucellosis cases result in lasting neurological problems [ 13 ]. It is uncommonly considered in cases of meningoencephalitis or polyneuropathy, making it crucial for clinicians to have a high suspicion of it in patients displaying such symptoms, especially in endemic regions, to prevent severe clinical outcomes. In this study, we present a rare case of neurobrucellosis with unusual clinical presentations in a patient admitted to our center.

Case presentation

A 45-year-old female patient, with no prior medical history, presented to our center after enduring distal pain and weakness in her lower extremities for approximately 10 months. Over this period, the muscle weakness progressed, affecting proximal muscles of upper and lower limbs, and leading to a substantial weight loss of 25–30 kg despite maintaining appetite. Initially dismissive of the limb weakness and pain, the patient sought medical attention six months after symptom onset due to the worsening symptoms and gait impairment. Over the subsequent four months, she underwent multiple medical evaluations and tests, including a lumbar X-ray. Following these initial investigations and due to low serum vitamin D levels, vitamin D and calcium supplements were prescribed, and lumbar MRI were requested for further evaluation. (Table  1 )

Upon referral to an infectious disease specialist, the patient’s history of local dairy consumption and positive serologic test for brucellosis prompted treatment with rifampin and doxycycline. However, the patient’s condition deteriorated significantly five days after starting this treatment. She experienced severe gait disorder, lower extremity weakness, diplopia, and blurred vision that had gradually worsened over two weeks. Subsequently, she presented to our center for further assessment.

Upon admission, the patient was unable to stand even with assistance and exhibited diplopia. Cranial nerve examination revealed no abnormalities, except for the II, III, and IV cranial nerves, which could not be thoroughly examined due to the presence of diplopia. The patient tested negative for Kernig and Brudzinski signs. There were no palpable supraclavicular or inguinal lymph nodes. Physical examinations of the breast, axilla, lungs, heart, and abdomen were unremarkable. Muscle strength was reduced in the lower extremities, and deep tendon reflexes of the knee and Achilles were absent. The plantar reflex was non-responsive, and certain reflexes, including biceps, triceps, and brachioradialis, were absent despite normal movement of the upper extremities. Anorectal muscle tone and anal reflex were normal.

Further investigations included normal urinalysis and abdominal and pelvic ultrasound. Chest X-ray and brain CT were also ordered. Due to the patient’s refusal of lumbar puncture, a suspicion of neurobrucellosis led to the initiation of a three-drug regimen (Table  2 ); ceftriaxone 2 g IV twice daily, rifampin 600 mg PO daily, and doxycycline 100 mg PO twice daily. The ophthalmology consultation did not reveal any ocular pathology, and the neurologist ordered brain MRI and EMG-NCV tests. The patient’s brain MRI was unremarkable, but EMG-NCV showed sensory and motor polyneuropathy. Consequently, intravenous immunoglobulin (IVIG) therapy was initiated at a daily dose of 25 g. After five days, the patient consented to lumbar puncture, confirming the diagnosis of brucellosis. Co-trimoxazole 960 mg PO three times daily was added to her treatment regimen, and IVIG therapy continued for seven days. Following a 3-day course of IVIG treatment, the neuropathy symptoms showed significant improvement. By the seventh day, there was a notable enhancement in limb strength, particularly in the upper limbs, reaching a 2-point improvement. After undergoing three weeks of intravenous therapy, the patient transitioned to oral medication. Despite disagreement regarding the necessity of a second CSF examination, the patient was discharged with a prescription for doxycycline, rifampin, and cotrimoxazole. Upon discharge, the patient could walk with the aid of a walker. However, within a month, a slight limp persisted, and by the third-month post-discharge, all symptoms had resolved completely.

Brucellosis is widely spread globally, with more than half a million reported human cases annually [ 14 , 15 ]. Countries like Kenya, Yemen, Syria, Greece, and Eritrea have experienced high rates of brucellosis. The situation of brucellosis has shown signs of improvement in many epidemic regions. However, new areas with high occurrences of this disease continue to emerge, particularly in Africa and the Middle East, where the incidence of the disease varies [ 16 ]. Brucellosis is linked to various neurological complications collectively known as neurobrucellosis, which is an uncommon condition, and only a few cases have been reported globally [ 17 , 18 , 19 , 20 , 21 ]. Our patient exhibited muscle weakness, polyneuropathy, and inability to walk, which are often not regarded as indicative of a brucella infection by many physicians. While the diagnosis of neurobrucellosis can typically be confirmed through classical clinical signs, radiological examinations, and serological tests, patients might not always display typical symptoms, as observed in our case. Hence, in regions where the disease is prevalent, clinicians should maintain a high level of suspicion if patients do not show improvement with standard treatment. Additionally, the lack of awareness among healthcare professionals and limited access to advanced laboratory facilities can lead to misdiagnosis.

The frequent manifestations of neurobrucellosis include meningitis or meningoencephalitis. Typically, it starts with a sudden headache, vomiting, and altered mental state, which can progress to unconsciousness, with or without seizures [ 22 ]. Additionally, brucellosis can lead to several central nervous system issues such as inflammation of cerebral blood vessels, abscesses in the brain or epidural space, strokes, and cerebellar ataxia. Peripheral nerve problems may include nerve damage or radiculopathy, Guillain-Barré syndrome, and a syndrome resembling poliomyelitis [ 13 ]. Nevertheless, the patient exhibited no indications of seizures, brain hemorrhage, stroke, or focal neurological impairments. Instead, the observed symptoms were consistent with radiculopathy and muscular weakness.

In only 7% of neurobrucellosis cases, the peripheral nervous system is affected. Remarkably, our case falls within this rare category, adding to its unique and intriguing nature. Previous case studies have detailed polyradiculoneuropathies, manifesting as acute, subacute, or chronic forms [ 23 ]. Our patient’s condition aligns with chronic motor polyradiculopathy. Interestingly, some of these cases exhibit sensory deficits or resemble Guillain-Barré syndrome [ 23 , 24 ]. In a prior case study conducted by Abuzinadah and colleagues, a comparable case was described as a subacute motor polyradiculopathy. The patient exhibited gradual bilateral lower limb weakness over three weeks, eventually leading to loss of mobility within seven weeks. Brucella was isolated from the cerebrospinal fluid after a two-week incubation period, and high antibody titers were detected in the patient’s serum [ 23 ]. In another study led by Alanazi and colleagues, a 56-year-old man initially diagnosed with Guillain-Barré syndrome experienced worsening symptoms despite appropriate treatment. Following plasma exchange and antibiotics, his condition improved temporarily, only to relapse, raising suspicion of chronic inflammatory demyelinating polyneuropathy, and treatment with IVIG resulted in substantial improvement. Upon further investigation, he was diagnosed with brucellosis [ 24 ]. This highlights the importance of recognizing GBS-like symptoms in regions where brucellosis is prevalent, prompting clinicians to consider the possibility of brucellosis in their diagnosis.

While there are no established criteria for diagnosing neurobrucellosis [ 25 ], certain articles have suggested several methods for its diagnosis. These methods include the presence of symptoms aligning with neurobrucellosis, isolating brucella from cerebrospinal fluid (CSF) or detecting a positive brucella agglutination titer in CSF, observing lymphocytosis, elevated protein, and decreased glucose levels in CSF, or identifying specific diagnostic indicators in cranial imaging such as magnetic resonance imaging or computed tomography (MRI or CT) [ 13 , 26 , 27 , 28 ]. Neurobrucellosis does not present a distinct clinical profile or specific CSF characteristics. Imaging observations of neurobrucellosis fall into four categories: normal, inflammatory (indicated by granulomas and enhanced meninges, perivascular spaces, or lumbar nerve roots), alterations in white matter, and vascular changes [ 29 ]. We suspected neurobrucellosis based on the patient’s clinical symptoms, geographic correlation, high brucella agglutination test titers in both cerebrospinal fluid and blood, symptom resolution following treatment, and the exclusion of other common causes.

In Iran, one differential diagnosis often confused with brucellosis is tuberculosis, as both chronic granulomatous infectious diseases are prevalent here [ 30 , 31 ]. Neurobrucellosis and tuberculosis exhibit significant similarities in clinical symptoms, lab results, and neuroimaging findings. However, deep grey matter involvement and widespread white matter lesions seen in neuroimaging, resembling demyelinating disorders, appear to be distinctive to brucellosis [ 32 ]. There is a noticeable similarity in the clinical symptoms and laboratory findings of brucellosis and tuberculosis [ 33 ]. It is crucial to thoroughly eliminate the possibility of tuberculosis in any suspected or confirmed brucellosis cases before starting antibiotic treatment.

Due to the challenging nature of treating brucellosis and the likelihood of experiencing relapses, it is crucial to provide an extended course of treatment [ 27 ]. This treatment approach should involve a combination of antibiotics that can easily penetrate the cell wall and effectively reach the central nervous system [ 27 , 34 ]. Neurobrucellosis is treated with 3 to 6 months of combination therapy comprising doxycycline, rifampicin, and ceftriaxone or trimethoprim-sulfamethoxazole [ 35 ], similar to the treatment administered to our patient. For patients allergic to cephalosporins, quinolones are recommended, which are considered to be effective in treating brucellosis [ 36 , 37 ]. In complicated situations such as meningitis or endocarditis, streptomycin or gentamicin is administered in the initial 14 days of treatment, in addition to the previously mentioned regimen. Timely and proper treatment results in a positive prognosis, with a less than 1% fatality rate for such complex cases [ 17 , 38 ]. Our patient experienced a highly positive outcome following the prescribed therapy. Initially relying on a walker, a slight limp endured for a month, and by the third month after discharge, all symptoms completely disappeared.

The present study underscores the significance of considering neurobrucellosis as a potential diagnosis when evaluating muscle weakness and radiculopathy, especially in regions where the disease is prevalent. A comprehensive patient history, precise clinical examination, positive serology in blood or cerebrospinal fluid, imaging results, or cerebrospinal fluid analysis can contribute to establishing a conclusive diagnosis.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to our team’s privacy concerns but are available from the corresponding author on reasonable request.

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A.A oversaw and treated the case, including the entire revision process. N.A. contributed to the article’s composition. M.F. authored the discussion section, along with the complete revision. AS.A. played a role in crafting the case report discussion and participated in the entire revision process.

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Alikhani, A., Ahmadi, N., Frouzanian, M. et al. Motor polyradiculoneuropathy as an unusual presentation of neurobrucellosis: a case report and literature review. BMC Infect Dis 24 , 491 (2024). https://doi.org/10.1186/s12879-024-09365-2

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F. Staderini

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The datasets generated and/or analyzed during the current study are not publicly available due to the patient's privacy reason but are available from the corresponding Author on reasonable request.

Introduction and importance

Gastric Antral Vascular Ectasia is a rare disorder that causes up to 4 % of severe acute gastrointestinal bleeding. It affects elderly females with iron deficiency anemia due to chronic blood loss as a common presenting sign.

Case presentation

We report the case of a 70-year-old man admitted to the Urgency Department for severe asthenia associated with abdominal pain and severe anemia. An urgent upper endoscopic examination showed antral hyperemic streaks and vascular ectasias extending from the pyloric ring to the gastric body as well as signs of recent bleeding. Histological results demonstrated the pathognomonic features of GAVE.

Clinical discussion

The first line treatment is considered argon plasma coagulation (APC), given its wider availability, safety, efficacy and cost-effectiveness. In current literature, other therapies and different types of endoscopic treatments have been proposed, such as EBL, RFA and Yag: laser. To date, there is no specific recommendation that privileges one method over another in the treatment of GAVE, although APC has proven effective and even better in terms of complications and costs than the other techniques.

In our experience, endoscopic coagulation with APC probes is a relatively easy-to-use technique with low cost, minimal invasiveness and provides immediate results.

On the other hand, a standardized algorithm is also required concerning to the different subtypes to give the best treatment in every case.

• • Gastric Antral Vascular Ectasia is a rare disorder that causes up to 4% of severe acute gastro-intestinal bleeding.
• • A 70-year-old man was admitted to the Urgency Department for abdominal pain and severe anemia. The urgent upper endoscopic examination and the histological results demonstrated the pathognomonic features of GAVE.
• • APC probes is a relatively easy-to-use technique with low cost, minimal invasiveness and provides immediate results.
• • A standardized algorithm is also required in relation to the different subtypes in order to give the best treatment in every case.

1. Introduction

Firstly, described by Rider JA et al. as “an erosive type of gastritis with marked veno-capillary ectasia”, gastric antral vascular ectasia ( GAVE ) is a rare disorder that causes up to 4 % of severe acute Gastrointestinal ( GI ) bleeding. GAVE is also called “watermelon stomach” [1] and it affects especially elderly females with iron deficiency anemia (89 % of patients) due to chronic blood loss as a common presenting sign [2] , [3] .

This condition is often associated with cirrhosis, which is found in up to 30 % of patients, or other systemic diseases such as autoimmune connective tissue disorders (62 %) or Raynaud's phenomenon (31 %). Less frequent associated conditions are chronic kidney disease, hypertension, familial Mediterranean fever, valvular heart disease, bone marrow transplantation and acute myeloid leukemia [4] . The GAVE typical presentation is a transfusion-dependent chronic iron-deficiency anemia from occult GI bleeding.

The diagnosis of GAVE can be both endoscopic and histological, but one of the safest ways to diagnose is through biopsy. The hyperplasia of the mucosa, capillary ectasia and thrombosis and oedematous submucosa with dilated vessels are the typical histologic features due to chronic inflammation.

In 1989, Gilliam et al. proposed a scoring system for the diagnosis of GAVE, which considered two criteria: the co-presence of ectasia and/or fibrin thrombi and spindle cell proliferation (Gilliam's score). Subsequently, a third parameter, fibrohyalinosis, was added to improve sensibility and specificity and this score was called the “GAVE score”.

This latter score is used to make a differential diagnosis between GAVE to Portal Hypertensive Gastropathy ( PHG ) and it showed a higher diagnostic accuracy, up to 80 % ( Table 1 ).

Histological score system for GAVE.

GAVE Score > 3: diagnostic for GAVE.

Sometimes GAVE is confused with PHG, an apparently similar condition, but, indeed, a deeply different entity. A correct biopsy is of utmost importance since it can distinguish GAVE from PHG, which Payen et al. established as distinct entities with different treatments since 1995.

Unlike GAVE, which occurs only in 2 % of patients on the transplant list and in 3 % of patients with HCV and advanced fibrosis, PHG has a prevalence between 20 and 80 % of patients with cirrhosis and/or portal of hypertension of other nature and its pathogenesis is not completely understood [5] , [6] .

As well explained by Gjeorgjievski M and colleagues, PHG and GAVE affect different gastric locations, as PHG involves the proximal stomach, with a mosaic-like pattern surrounding polygonal areas of erythema (whereas GAVE shows erythema most commonly arranged linearly along folds in the antrum). Apart from the gastric involvement, these two entities show differences also in terms of pathological features and response to the therapies, thus configuring two distinguished entities. Moreover, the endoscopic approach plays an insignificant role in PHG bleeding, where the only recommended treatments for reducing the bleeding are Transjugular intrahepatic portosystemic shunt ( TIPS ) or more aggressive surgical approaches (i.e. portosystemic shunt) [7] , [8] , [9] .

Concerning GAVE, it has histological, endoscopic and clinical pathognomonic findings. Its typical clinical presentation is a transfusion-dependent chronic iron-deficiency anemia or, less frequently, severe acute upper GI bleeding. Overall, GAVE accounts for 4 % of all nonvariceal upper GI bleeding cases.

1.1. Diagnosis

As previously explained, diagnosis is a combination of different criteria, including clinical, histological and endoscopic findings.

Concerning the clinic, patients usually experience iron deficiency anemia, thus requiring treatments with blood transfusions and iron supplementation; less frequently, acute gastrointestinal bleeding occurs with hematemesis or melena.

Table 2 summarizes the differences between GAVE and PHG.

GAVE vs PHG.

However, endoscopic diagnosis is very important since the GAVE lesions are mainly focal and the diagnostic biopsy can be negative if it is taken in a non-affected area. As a consequence of that, if the biopsy is negative, GAVE cannot be excluded [10] .

2. Presentation of case

We report the case of a 70-year-old man with a history of ischemic heart disease, congestive heart failure, diabetes, dyslipidemia, pulmonary hypertension, chronic kidney injury, arterial hypertension and atrial fibrillation. The patient was admitted to the Urgency Department of Careggi University Hospital for severe asthenia with abdominal pain.

The patient did not report any alcohol consumption. No history of rectal bleeding, melena or hematemesis was reported even if he was under anticoagulant therapy. A few weeks before he underwent a gastroscopy, colonoscopy and video-capsule endoscopy for indeterminate gastrointestinal bleeding with anemia: non-specific antral gastritis was detected (maybe related to biliary duodenal-gastric reflux).

Heart rate and blood pressure showed normal ranges and no postural hypotension was detected.

Blood examination revealed severe anemia (Hb value 7 g/dl) with serum iron and ferritin deficiency.

The mean corpuscular volume was normal. The International Normalized Ratio (INR) was 1.9. No leukocytosis nor platelet alterations were reported. Urea and creatinine levels were respectively 64 mg/dL and 2.1 mg/dL.

An urgent upper endoscopic examination showed antral hyperemic streaks and vascular ectasias extending from the pyloric ring to the gastric body, together with signs of recent bleeding. Histological results of biopsies taken during the gastroscopy demonstrated the pathognomonic features of GAVE: hyperplastic foveolar (serrated) gastric epithelium, fibrohyalinosis, thrombosis in venules and spindle-cell proliferation.

Abdominal- CT scan excluded additional causes of gastrointestinal bleeding. After a multidisciplinary team evaluation, the patient was referred to an endoscopic treatment attempt.

Procedure was carried out with a forward-viewing endoscope (GIF-XTQ160 scope, Olympus Medical System, Co. Ltd., Tokyo, Japan) by an experienced endoscopist who has completed his learning curve (FS), with >5000 EGDS /life. Patients underwent a deep sedation with propofol and ketamine, according to the hospital guidelines; left side position was adopted.

A watermelon stomach, extending 360-degrees from the pyloric ring to the sub-angular region was detected ( Fig. 1 , Fig. 2 A). A progressive coagulation of the mucosal vascular network was carried out with an APC probe (Erbe FiAPC Sonde 2200A – Erbe USA Inc., Marietta, Georgia, USA) ( Fig. 2 B). The patient tolerated this procedure well, no bleeding or other intraoperative complications occurred; operative time was measured at 52 min.

Endoscopic appearance of gastric antral vascular ectasia (GAVE).

Gastric antral vascular ectasia before (a) and after (b) APC coagulation.

The initial postoperative course in the intensive care unit was uneventful, so the patient was transferred to the ordinary ward on the second postoperative day.

The patient did not experience pain and oral feeding was well tolerated, so that on the fourth postoperative day he was discharged.

The one-month control gastroscopy described the complete disappearance of the previously described vascular ectasia and no residual signs of mucosal bleeding were detected ( Fig. 3 ).

One month follow up after APC coagulation.

3. Review of the literature

A screening of the literature available for all the English language papers in the electronic databases (Medline, PubMed, Google Scholar, SCOPUS, and the Cochrane Controlled Trials Register) was performed until January 2021. The following keywords were used as free text terms or Medical Subject Headings (MeSH): “GAVE”, “watermelon stomach”, “angiodysplasia”, “vascular ectasia of the stomach”, “endoscopic”, “treatment”. Major variations of these keywords were used to improve search results. Since the available literature on the subject is limited, we have used even generic keywords to expand our research fields, also individually examining the references to selected studies to increase our performance. Data were collected from the abstract, main manuscript, tables, supplementary material, or graphs. Only human adult subject studies whose outcomes of interest were retrievable were included in the analysis. Therapeutic modalities included in this review are APC, neodymiumdoped yttrium aluminum garnet (Nd:YAG), endoscopic band ligation ( EBL ), and radiofrequency ablation ( RFA ). To evaluate the effectiveness of the treatment, we included studies that examined at least one of our primary established outcomes as needed for transfusion, increased hemoglobin levels, and/or re-bleeding data for the techniques studied. For complications, we included case series with at least 5 patients, evaluating adverse events such as therapeutic failure, perforations and mortality. In total, 24 studies were included. Of these, 12 studies (5 prospective and 7 retrospective) collect the results of treatment with APC, 6 studies show the outcomes in the use of EBL, 5 studies (4 prospective and 1 retrospective) describe the experience in the use of RFA. One study compares APC and RFA. Table 3 , Table 4 , Table 5 show the patient characteristics and the results reported in the included studies.

Results for the use of APC for the treatment of GAVE [2] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [24] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] .

Results for the use of EBL for the treatment of GAVE [15] , [27] , [28] , [29] , [31] , [40] .

Results of the use of RFA for the treatment of GAVE [21] , [30] , [41] , [42] , [43] , [44] .

4. Discussion

Treatment of GAVE is predominantly symptomatic. The aim is to correct the blood loss with fluid resuscitation and/or blood transfusions and iron supplementation. Before endoscopic therapy, the gold standard treatment was the gastric antrectomy. Modern guidelines advise endoscopic ablation as the preferred treatment of GAVE since surgery is associated with higher mortality and it should be reserved only for unresponsive or refractory patients [4] , [7] , [11] , [12] . Only GAVE lesions with symptoms due to blood loss should be treated [13] .

Endoscopic treatment consists of multiple techniques. Current treatment options include nonthermal (endoscopic band ligation) and thermal (APC, laser, and RFA) techniques. Some others, like cryotherapy and Nd:YAG laser are of limited use, because of a higher complication rate and the reduced diffusion.

Unlike in patients with GAVE, the endoscopic approach plays a small role in the treatment of PHG bleeding. The only treatment that might be recommended for prophylaxis is non-selective B-blockers while TIPS and surgery (portosystemic shunt) are used to reduce the severity of PHG.

The first line treatment is considered the argon plasma coagulation (APC), given its wider availability, safety, efficacy and cost-effectiveness. APC is a non-contact electro-coagulation technique that uses an ionized argon jet to apply a monopolar current on the target zone [14] .

Twelve studies collected the results of the treatment with APC, seven retrospective and five prospective. Probst et al. reported the longest follow-up time of 30.4 months, the maximum number of patients enrolled was reached by the prospective study from Batthi et al. with 50 cases and a mean 8.5 months follow-up. Two sessions were found to be required with this technique. APC is shown to be equally effective in both diffuse and stripy patterns [4] . In the literature, most of the authors report excellent results in terms of reducing the need for blood transfusions and increasing hemoglobin levels [15] , [16] , [17] , [18] , [19] , [20] . Its clinical success rate varies between 100 % and 40 %, as reported respectively by St.Romain et al. and Garg et al. [21] , [22] . The good control of the depth of penetration of the coagulation with APC is one of the benefits that allows us to avoid excessive blood loss. It also does not create adhesions and secondary bleeding [23] . No complications or at least a limited bleeding was found with APC except for Fuccio et al., which reports a 90 % treatment success with abdominal pain and bloating in 80 % of the cases. Chaves et al. described postprocedural bleeding in 35 % of patients. Chiu et al. also reported an 80 % recurrence of bleeding during follow-up. Its long-term efficacy is still under discussion and this may not sufficiently support its exclusive use in GAVE [24] .

Endoscopic band ligation (EBL), which was initially used when APC was not available or as rescue therapy in case of inefficient APC, became a helpful alternative thanks to its ability to treat a larger area at once and to safely treat the deep vascular plexus, which has been shown to play a role in symptom recurrence [25] , [26] .

This technique is supported by a limited number of studies [27] , [28] , [29] , [30] , showing a low complication rate. The method has wide availability, and the short procedure time makes it more tolerated. It can also be used for lesions deeply involving mucosa and submucosa and appears to be effective even with a reduced number of sessions compared to APC; apparently, no important difference was found in the influence on hemoglobin level elevation and on the need for transfusion [31] , [32] . This could suggest that an earlier referral of patients presenting GAVE to an EBL may improve the outcomes, reducing the probability of recurrence. Zepeda-Gomez et al. 2019 reported an 81.8 % success in a cohort of 33 patients with a mean follow-up of 35.9 months, showing no significant complications. Fábián et al. and O'Morain et al. reported that the baseline hemoglobin level might possibly reflect of the likelihood response to EBL. It also seems that patients with a good response to EBL show a longer survival. Despite an initial good response, Keohane et al. found a recurrence-bleeding rate from 35 % to 78.9 %. In case of recurrence, patients can be treated again with EBL and in some cases, APC may be complementary. APC may be particularly useful in case of previous banding, where the scar tissue is difficult to suction, in order to achieve a correct banding. Patients treated with EBL with chronic renal failure, which promotes neovascularization from chronic ischemia, seem to have a higher rate of recurrence of GAVE [32] .

The most common adverse events were ulcers, epigastric pain and mild bleeding. Although the efficacy of these techniques has not been universally identified for all the subtypes of GAVE, APC is still considered the first choice in linear GAVE, while EBL may be more useful in widespread and severe GAVE [14] . Recent studies suggest that more severe cases may be preferentially selected for EBL given the deeper penetration of this technique than APC. The differentiation of the subtypes of GAVE may help to find an effective therapeutic algorithm which could be useful in patient's selection [33] .

On the other hand, Radiofrequency ablation (RFA) uses an alternating electrical high-frequency current locally delivered on tissue or mucosa with a controlled thermal coagulative necrosis depth. This approach has also achieved encouraging results, thanks to a uniform ablation depth, although it is not an easy-to-use technique and requires longer training. There is limited long-term data for RFA ( Table 5 ). We evaluated six studies: no significant complications were reported, despite the mean 8 months follow-up. A retrospective study by St. Romain et al. shows no complications in 28 treated cases with a mean 18 months follow-up in 28 treated cases. Another retrospective work by Raza et al. shows good outcomes with 67 % of clinical success in a mean 11 months follow-up.

However, the available evidence suggests that it is equally effective and tolerable compared with APC requiring fewer sessions [29] . Moreover, RFA seems to be effective also on patients with APC-refractory GAVE. More controlled trials are necessary to evaluate its efficacy, safety, and reliability [29] , [33] .

Another tool for endoscopic therapy is the Nd:YAG laser. Recent literature has confirmed the rationality of this endoscopic thermal therapy in reducing or in some cases avoiding the need for blood transfusions up to 50–80 % of cases. Some authors would particularly indicate Nd:YAG laser therapy for GAVE when associated with heart valve diseases, cirrhosis, chronic renal failure, and connective tissue diseases [34] . However, in the literature, there are few studies that have evaluated the effectiveness.

Nonetheless, APC proved to be just as effective, and even better in terms of complications and cost [21] , [22] , while more APC sessions are generally required to achieve the same efficacy in terms of bleeding reduction [35] .

Currently, there is no specific recommendation that privileges one method over another in the treatment of GAVE.

5. Conclusion

APC has been widely used in recent years and the technology is still improving. In our experience, endoscopic coagulation with APC probes is a relatively easy-to-use technique with low cost, minimal invasiveness and provides immediate results. We believe that it is safer and more effective when performed by experienced endoscopists.

On the other hand, a standardized algorithm is also required concerning the different subtypes, to give the best treatment in every case.

In conclusion, further studies are needed before any definitive conclusions are reached regarding the treatment.

Abbreviations

Declaration of competing interest.

Authors declare that they have no competing interests.

Acknowledgements

The authors thank Dr. Edda Russo PhD for English revision.

Author's contributions

LF and AB were a major contributor in writing the manuscript; FS and DB reviewed and analyzed the clinical data and critically revised the manuscript; FS and DB analyzed the data and provided pictures; FG, FS and FC reviewed the final version of the manuscript.

Personal financial interests

Authors declare that they have no personal financial interests.

Authors have nothing to declare.

Other competing interests

Ethics approval and consent to participate.

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Availability of data and materials

Provenance and peer review.

Not commissioned, externally peer-reviewed.

Prof. Fabio Cianchi, Director of Digestive Surgery Unit, AOU Careggi.

Our work has been conducted the work has been reported in line with the SCARE criteria [45] .

• Case Report
• Open access
• Published: 06 May 2024

Novel SETBP1 D874V adjacent to the degron causes canonical schinzel–giedion syndrome: a case report and review of the literature

• Jing Zheng 1 , 2 ,
• Meiqun Gu 1 , 2 ,
• Shasha Xiao 1 , 2 ,
• Chongzhen Li 1 , 2 ,
• Hongying Mi 1 , 2 &
• Xiaoyan Xu 1 , 2  

BMC Pediatrics volume  24 , Article number:  309 ( 2024 ) Cite this article

252 Accesses

Metrics details

Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.

Peer Review reports

Introduction

Schinzel-Giedion syndrome (SGS, OMIM 269,150) is a rare autosomal dominant genetic disorder first reported in 1978 [ 1 ]. Clinical features of SGS include distinctive facial appearance (commonly midface retraction), profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies such as congenital heart disease, hydronephrosis, delayed neurological development, and skeletal dysplasia [ 2 ]. Liu et al. proposed revised diagnostic criteria for SGS, classifying it into three types based on clinical presentation and/or pathogenic SETBP1 variant, enabling definitive diagnosis for patients with atypical clinical phenotypes via genetic testing and broadening the phenotypic spectrum [ 3 ].

Hoischen et al. confirmed that SGS is caused by variant in the SETBP1 gene. In contrast to loss-of-function (LoF) variant leading to SETBP1 haploinsufficiency disease (SETBP1-HD), characterized by hypotonia and mild motor developmental delay/intellectual disability (MIM: #616,078), known SETBP1 variants causing SGS are gain-of-function (GoF) and located within a 12 bp hotspot region encoding SETBP1 amino acid residues 868–871, which are associated with the canonical SGS phenotype. The SETBP1 aa868-871 region functions as a degron, a signal regulating protein degradation, and pathogenic variants within the degron result in SETBP1 protein accumulation. Missense variants of residues I871 and D868 have been demonstrated to be associated with the lowest and highest levels of pathogenic SETBP1 protein, respectively, indicating a significant genotype-phenotype correlation in this region [ 4 ].

In this study, we report a patient with a typical SGS clinical presentation, who was found to carry a novel de novo heterozygous SETBP1 D874V variant. The mutated residue is located near the degron region, but the patient presents with a classical clinical phenotype that could not be explained by the currently known genotype-phenotype correlations.

Materials and methods

A female neonate who was admitted to the neonatal intensive care unit of First People’s Hospital of Yunnan Province was included in this study. She exhibited dysmorphic facial features (midface retraction, frontal bossing, and low-set ears), bilateral varus, syndactyly of the 4th and 5th toe, hydronephrosis, and congenital heart disease. We conducted follow-up for her clinical condition. The patient’s parents provided written informed consent to the study.

Genetic tests

Two milliliters of the peripheral blood collected from the patient were used (anticoagulant: EDTA), and whole-exome sequencing was performed by Beijing Chigene Translational Medicine Research Center Co., Ltd (Beijing, China). Genomic DNA was extracted using the Blood Genome Column Medium Extraction Kit (Kangweishiji, China) according to the manufactural instructions. The extracted DNA samples were subjected to quality control using Qubit 2.0 fluorimeter and electrophoresis using 0.8% agarose gel for further protocol. Protein-coding exome enrichment was performed using xGen® Exome Research Panel v1.0 (IDT, Iowa, USA) that consists of 429,826 individually synthesized and quality-controlled probes, which targets 39 Mb protein-coding region (19,396 genes) of the human genome and covers 51 Mb of end-to-end tiled probe space. After target enrichment, high-throughput sequencing was performed on Illumina NovaSeq 6000 series sequencer (PE150), which was used to perform paired-end 150 bp sequencing, with a mean sequencing depth of 100X and sequencing coverage of 99%. Raw data were processed by the fastp software for adapters removing and low-quality reads filtering [ 5 ]. The paired-end reads were aligned to the Ensemble GRCh37/hg19 reference genome using the Burrows-Wheeler Aligner (BWA) software pacakage, and the GATK software was used reads calling. Detected single nucleotide polymorphisms (SNPs) and insertions and deletions (indels) not longer than 50 bp were then annotated using the ANNOVAR software. The common variants, with minor allele frequency (MAF) > 0.05, found in the 1000 Genomes Project and the ExAC and gnomAD databases were filtered out.

The primers designed for polymerase chain reaction (PCR) were as SETBP1 -F, 5′-GGGAGCAGAAATCAAAAGAGTACC-3′ and SETBP1 -R, 5′-CCAAAACCCAAAAGGGAATACACA-3′. Sanger sequencing was performed using the ABI 2720 DNA analyzer (USA). The NCBI BLAST algorithm was used for sequence alignment.

Pathogenicity analysis of genetic variants

Computer software, including REVEL, SIFT, Polyphen2-HVAR, Polyphen2-HDIV, PROVEAN, and MutationTaster, were used to predict the deleterious effects of each variant on the protein function. Exomiser and Phenolyzer software were used to perform genotype-phenotype analysis. Homology modeling was performed using the Modeller software ( https://salilab.org/modeller/ ) to analyze changes in the three-dimensional structure, and evolutionarily conserved regions were analyzed using UGENE software ( http://ugene.unipro.ru/ ). Finally, the pathogenicity assessment and genetic interpretation of candidate gene variants were performed according to the American College of Medical Genetics and Genomics guidelines and criteria [ 5 ] for variant classification.

Review of the literature

Variants and clinical features of previously reported cases with genetically diagnosed with SGS were collected. Data on these patients were retrieved from PubMed ( http://www.ncbi.nlm.nih.gov/pubmed ) using the search terms “Schinzel–Giedion syndrome” or “SGS” and “ SETBP1 ” Only articles in English were included.

Case presentation

The patient was admitted to the hospital with " high-risk delivery”, G1P1, born by cesarean section at a gestational age of 40 + 4 weeks, with a birth weight of 3430 g and an Apgar score of 9-9-9. Her parents were healthy, not consanguineous, and had no family history of specific diseases. The examination during pregnancy revealed that the mother suffered form gallbladder polyps and hypothyroidism.The fetus displayed severe hydronephrosis, pericardial effusion, and cauda equina cysts. Her physical examination upon admission showed stable vital signs, and stable breathing. Unique facial features included midface retraction, frontal bossing, and low-set ears (Fig. 1 A). The anterior fontanelle was flat and soft, the size is 3.0 cm*3.0 cm. There wasn’t flaring of nares, nor perioral and fingertip cyanosis. The pulmonary examination showed no abnormalities, heart rate was 125 beats/min, heart rhythm was regular, and class II/6 systolic murmur could be heard in the precordial region. The abdomen was significantly enlarged (Fig.  1 B), with an abdominal circumference of 38 cm, 2–3 bowel sounds/min, increased muscle tone of the limbs, limited abduction of both upper and lower limbs, bilateral varus, syndactyly of the 4th and 5th toe and vulvar malformation (dysplasia of the labia majora). During hospitalization, the patient had normal lab results for full biochemistry profile, routine blood, urine, and stool examinations, and thyroid function tests. In addition, tandem mass spectrometry screening of blood and urine samples showed normal results. Chest radiographs revealed broad bones (Fig.  2 A). Color Doppler echocardiography showed atrial septal defect, patent ductus arteriosus, right atrial and right ventricular enlargement. Moreover, color Doppler ultrasonography of the urinary system detected bilateral severe hydronephrosis (Fig.  2 D, E). Abdominal CT showed a significant increase in the size of both kidneys and signs of severe hydronephrosis in both kidneys (Fig.  2 F). Cranial color Doppler ultrasonography showed grade II-IVH on the left side and moderate enlargement of bilateral lateral cerebral ventricles (Fig.  2 B, C). Video electroencephalogram (EEG) showed normal results. No ocular fundus abnormalities were observed. Moreover, both ears did not respond to the rapid auditory brainstem response test. Due to the deformities of the heart, kidney, bone and other organs of the child, congenital genetic metabolic diseases could not be excluded. After obtaining the consent of the family members, the Whole-Exome Sequencing was improved. The child was treated with nasal catheter oxygen and anti-infection during the hospitalization. The child had difficulty in early feeding(weak sucking reflex) and could be fully fed orally before discharge, but the sucking power was also poor. Her parents abandoned treatment and was discharged from the hospital 13 days after birth. 8 months after birth, in the outpatient follow-up, the child presented with delayed gross motor development and no seizures, and the patient’s family members refused to perform a cranial MRI.

Phenotypic variants of the patient. ( A ) Characteristic midface retraction, frontal bossing, and low-set ears at 1 day after birth; ( B ) A grossly distended abdomen

Photographs show the clinical features of the patient in this study. ( A ) Chest radiographs at 1 day after birth show wide ribsn ( B, C ) Color doppler ultrasonography at 10 days after birth shows widened bodies and anterior horns of lateral ventricles; ( D, E ) Color doppler ultrasonography at 10 days after birth shows severe hydronephrosis was found in both kidneys, bilateral pelvis and calyces were severely dilated with a “palette” appearancete ( F ) Abdominal CT at 1 day after birth shows Significant increase in the size of both kidneys, signs of severe hydronephrosis in both kidneys

Result of genetic tests

Whole-exome sequencing suggested a heterozygous variant (c.2621 A > T, p.Asp874Val) in exon 4 of SETBP1 (NM_015559). This variant was a missense variant. The detected variant was not found in many databases including the 1,000 Genomes Project, ExAC gnomAD and dbSNP databases.

Analysis of the pathogenicity of gene variant

Sanger sequencing of the genome of the patient and her parents suggested that the patient had a de novo variant; As both parents had the wild-type gene (Fig.  3 ). Some silico predictions, including REVEL, SIFT, Polyphen2-HVAR, Polyphen2-HDIV, PROVEAN, and MutationTaster, suggested the deleterious effects of this variant on protein function. There has been no previous report of such variants. This variant was classified as likely pathogenic according to American College of Medical Genetics and Genomics guidelines (the supporting evidence for likely pathogenicity was PS2 + PM1 + PM2_Supporting + PP3).

Sanger sequencing confirms de novo c.2621 A > T variant(p.Asp874Val) in the SETBP1 gene in the patient

Protein-DNA/RNA docking using HDOCK server( http://hdock.phys.hust.edu.cn/ ) (hybrid algorithm of template-based modeling and ab initio free docking) is shown in Fig.  4 A. Green represents SETBP1 protein and sky blue represents E3 ubiquitin ligase, which promotes ubiquitination and degradation of SETBP1 protein. When mutated, SETBP1 protein fails to bind to E3 ubiquitin ligase, leading to protein overexpression. As shown in Fig.  4 A: S876, D868, S869, G870, I871, G872, T873 and D874 of SETBP1 form interactions with L48, K50, G101, C103, R105, P158 and N159 of E3 ubiquitin ligase, which in turn promote SETBP1 binding to E3 ubiquitin ligase and thus ubiquitination occurs. The hotspot variants D868, S869, G870 and I871 of the SETBP1 gene significantly affect the binding of SETBP1 to E3 ubiquitin ligase, thereby affecting ubiquitination. The D874V variant(p.Asp874Val) reported in this paper is also in the vicinity of the SETBP1 gene binding E3 ubiquitin ligase, which may also affect the binding of SETBP1 protein to E3 ubiquitin ligase and thus affect SETBP1 protein ubiquitination, ultimately leading to the development of the disease.Alignment of the SETBP1 sequences revealed that the amino acid residues at position 874 were strictly conserved (Fig. 4 B).

In-silico analysis of SETBP1 c.2621 A > T/p.Asp874Val variant. ( A ) Protein-DNA/RNA docking using HDOCK server ( http://hdock.phys.hust.edu.cn/ ) (hybrid algorithm of template-based modeling and ab initio free docking). As shown in Fig.  4 A: Green represents SETBP1 protein and sky blue represents E3 ubiquitin ligase. S876, D868, S869, G870, I871, G872, T873 and D874 of SETBP1 form interactions with L48, K50, G101, C103, R105, P158 and N159 of E3 ubiquitin ligase, which in turn promote SETBP1 binding to E3 ubiquitin ligase and thus ubiquitination occurs. The hotspot variants D868, S869, G870 and I871 of SETBP1 gene significantly affect the binding of SETBP1 to E3 ubiquitin ligase, thereby affecting ubiquitination. The D874V variant reported in this paper is also in the vicinity of the SETBP1 gene binding E3 ubiquitin ligase, which may also affect the binding of SETBP1 protein to E3 ubiquitin ligase and thus affect SETBP1 protein ubiquitination, ultimately leading to the development of the disease. ( B ) Alignment of the SETBP1 sequences revealed that the amino acid residues at position 874 were strictly conserved

The aforementioned data, the patient’s clinical manifestations, and the SETBP1 variant status indicated that SGS was caused by a heterozygous variant (c.2621 A > T, p.Asp874Val) in SETBP1 .

We evaluated a total of 20 articles and 60 patients. All data were curated in Table  1 .

Discussions

Liu et al. have updated the diagnostic criteria for Schinzel-Giedion (SGS). The revised criteria now classify SGS into three distinct types based on clinical observations and the presence of the SETBP1 variant [ 3 ]. SGS type I, also known as the classic type, is characterized by the hallmark clinical features, including developmental delays and distinctive facial morphology such as a prominent forehead, midface retraction, and low-set ears, as well as the presence of hydronephrosis or two of the four characteristic skeletal anomalies, including a sclerotic skull base, wide occipital synchondrosis, increased cortical density or thickness, and broad ribs. This classification aligns with the previously proposed diagnostic criteria by Lehman and colleagues. Type II refers to as an intermediate phenotype of SGS, is diagnosed in patients with development delays and the distinctive facial features, but without the presence of hydronephrosis or typical skeletal abnormalities, with the presence of the SETBP1 variant. Type III, also known as the simple type, is diagnosed in patients with the SETBP1 variant and developmental delays, with expressive language delay being the most prominent feature. These revised criteria will aid in the accurate diagnosis and management of SGS.

As far as we know, all reported cases of classical SGS meeting the diagnostic criteria proposed by Lehman and colleagues have exhibited missense variants within a 12-basepair hotspot located in exon 4 of the SETBP1 gene (Table  1 ) [ 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. This hotspot, which encodes four amino acid residues (D868, S869, G870, and I871), known as the degron, is located within the SKI homologous region of the SETBP1 protein and is a critical site for substrate recognition by the cognate SCF-β-TrCP E3 ubiquitin ligase [ 4 , 12 ]. Variants within the degron prevent the binding of SETBP1 protein to E3 ubiquitin ligase, leading to protein overexpression [ 24 , 25 ]. Patients with missense variants in residues 862, 867, and 873 near the hotspot region exhibit a milder SGS phenotype, and the proximity of the mutated position to the degron is associated with clinical overlap with the classic SGS phenotype [ 4 , 7 ]. Notably, D874V found in this study is adjacent to the degron, which is inconsistent with the previous knowledge.

To date, 63 cases of genetically confirmed SGS have been reported, including 16 missense variants and 1 insertion variant (Table  1 ). SETBP1 D874V reported in this paper is a novel variant and the first report of SETBP1 non-hotspot variant identified in a canonical SGS case. Being highly conserved in different species, D874 might have an important biological role. In addition, protein model analysis of the variant suggests that the hotspot variants D868, S869, G870 and I871 of the SETBP1 gene significantly affect the binding of SETBP1 to E3 ubiquitin ligase, thereby affecting ubiquitination. The D874V variant reported in this paper is located in proximity of the bliding site for E3 ubiquitin ligase, which may also affect the binding of SETBP1 protein to E3 ubiquitin ligase and thus affect SETBP1 protein ubiquitination, ultimately leading to the development of the disease.

Diagnosing SGS in the neonatal period can be challenging due to the presence of non-specific symptoms, including genital abnormalities, reduced sucking ability, decreased muscle tone, and EEG waveform abnormalities, in addition to the typical clinical manifestations of SGS [ 12 ]. In a 2022 case report by Yang et al. [ 10 ], a neonatal patient with midface retraction and developmental delay was diagnosed with “non-classical” SGS based on the absence of hydronephrosis and skeletal abnormalities at birth, and the presence of a SETBP1 gene variant, S869G, according to the Lehman diagnostic criteria. However, after 18 months of follow-up, bilateral hydronephrosis was detected by color Doppler ultrasonography, leading to a revised diagnosis of classical SGS. The authors emphasize the importance of long-term follow-up to observe the evolution of phenotypes diagnosed by early molecular testing, as phenotypic changes are common, particularly in infants. Out of 56 patients with SGS exhibiting variants in the degron sequence (hotspot variants sequence), five did not have hydronephrosis. According to Yang et al.‘s case report, progressive hydronephrosis may occur in long-term survivors, albeit at a slower development rate. However, the patient reported in this study developed severe hydronephrosis in the neonatal period, underscoring the need for close monitoring of renal function during later follow-up.

The SETBP1 protein is expressed throughout the body, but its levels are highest during brain development before birth, when nerve cells undergo proliferation and migration to specific regions of the brain. Variants in the SETBP1 gene can result in severe neurological developmental abnormalities, given its critical role in this process. A study by Banfi F et al. revealed that SETBP1 variants lead to the accumulation of the SETBP1 and SET proteins and the consequent P53 inhibition in neural cells. These molecular changes promote the onset of cancer-like behavior in neural progenitors that accumulate widespread DNA damage without programmed cell death engagement [ 26 ]. Neurodevelopmental delay is a hallmark characteristic of SGS, with asphyxia, feeding difficulties, and recurrent apnea being common symptoms in the neonatal period [ 11 ]. A stud y by Wong MM et a l illustrated that the variants that carrying SETBP1 missense variants outside the degron, cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1-HD, and primarily characterised by intellectual disability, epilepsy, speech and motor impairment [ 27 ]. The incidence of developmental delay, epilepsy, and expressive language delay is extremely high with increasing age, with 97% (56/58) of reported cases of children with SGS presenting with neurological developmental abnormalities, including developmental delay and seizures. In this study, cranial color Doppler ultrasonography showed moderate enlargement of bilateral lateral cerebral ventricles and a normal EEG waveform during the neonatal period. However, the patient’s family members did not approve of performing a cranial MRI. Currently, at 8 months of age, the patient exhibits retardation of gross motor development but has not experienced epileptic seizures. Long-term follow-up visits are required to monitor the patient’s progress. These findings highlight the importance of early diagnosis and appropriate imaging studies in the management of SGS, particularly in patients with a suspected neurological developmental abnormality.

In summary, this study reports the first case of canonical SGS in a Chinese neonate caused by a novel SETBP1 non-degron region variant, D874V. This finding expands the genetic spectrum of SGS and provides a new case for investigating genotype-phenotype correlations in SGS.

Data availability

The datasets presented in this article are not readily available because of privacy restrictions (the guardians of patients are reluctant to authorize the release of all the raw data of whole-exome sequencing, but agree to contribute positive sanger-sequencing results). Requests to access the datasets should be directed to the corresponding author.

Abbreviations

• Schinzel-Giedion syndrome

Gain-of-function

Loss-of-function

Electroencephalogram

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Acknowledgements

We would like to thank the patient and their family for their participation in this study. We sincerely thank the Beijing Chgene Translational Medicine Research Center, the Beijing Kangxu Medical Inspection Institute and the Wuhan Kindstar Medical Inspection Institute provide us with essential help for genetic testing.

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ZJ, GM, and XS conceptualized and designed the study, collected data, carried out the analyses, drafted the initial manuscript, and reviewed and revised the manuscript. LC provides color ultrasound examinations for children. MH and XX conceptualized and designed the study, and critically reviewed the manuscript. All authors reviewed and approved the final version.

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Zheng, J., Gu, M., Xiao, S. et al. Novel SETBP1 D874V adjacent to the degron causes canonical schinzel–giedion syndrome: a case report and review of the literature. BMC Pediatr 24 , 309 (2024). https://doi.org/10.1186/s12887-024-04779-y

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CASE REPORT article

Systemic metastases in large cell neuroendocrine prostate cancer: a rare case report and literature review.

• Department of Urology, Chongqing General Hospital, Chongqing University, Chongqing, China

Neuroendocrine prostate neoplasms, encompassing small cell carcinoma, carcinoid, and large cell carcinoma, are infrequently observed in malignant prostate tumors. The occurrence of large cell neuroendocrine prostate cancer (LCNEPC) is exceedingly rare. In this study, the patient initially presented with a persistent dysuria for a duration of one year, accompanied by a serum prostate-specific antigen (PSA) level of 17.83ng/mL. Prostate magnetic resonance imaging (MRI) and chest computed tomography (CT) scan showed that a neoplastic lesion was considered, and prostate biopsy confirmed prostate adenocarcinoma with a Gleason score of 7 (4 + 3). Then, thoracoscopic lung tumor resection was performed, and the pathological examination revealed the presence of primary moderately differentiated invasive adenocarcinoma of the lung and metastatic prostate adenocarcinoma, the Gleason score was 8 (4 + 4). After 1 year of endocrine therapy with goserelin acetate and bicalutamide, he underwent a laparoscopic radical prostatectomy (LRP), the pathological report indicated the presence of adenocarcinoma mixed with NE carcinoma. Two months after the LRP, the patient experienced gross hematuria and sacral tail pain. Further examination revealed multiple metastatic lesions throughout the body. He also underwent transurethral resection of bladder tumor (TURBT) for bladder tumor and received etoposide+ cisplatin chemotherapy three weeks post-surgery. The patient eventually died of multi-organ failure due to myelosuppression after chemotherapy. This case report presents an uncommon instance of LCNEPC with widespread systemic metastases, while also providing a comprehensive review of existing literature to facilitate improved management and treatment strategies for similar patients in subsequent cases.

1 Introduction

Prostate cancer (Pca) exhibits the highest incidence rate among males worldwide annually and ranks as the second most prevalent cause of tumor-associated mortality ( 1 ). Neuroendocrine prostate cancer (NEPC) is an uncommon subtype of prostate malignancy, primarily originating from prostate adenocarcinoma (PRAD), and progresses to mixed neuroendocrine (NE) carcinoma-acinar adenocarcinomas ( 2 ). In 2016, the World Health Organization (WHO) categorized prostate neuroendocrine tumors as highly differentiated carcinoid tumors, small cell neuroendocrine carcinoma (SCNC), and large cell neuroendocrine prostate cancer (LCNEPC) ( 3 ). Among these subtypes, carcinoid tumors and LCNEPC are less prevalent than SCNC ( 3 , 4 ). The majority of reported cases of LCNEPC have been observed in patients with adenocarcinoma who have undergone long-term androgen deprivation therapy (ADT), indicating transdifferentiation. However, primary LCNEPC cases have also been reported in several studies ( 5 , 6 ), although they are less common than cases with adenocarcinoma transdifferentiation. LCNEPC exhibits high invasiveness and is frequently associated with extensive metastasis, resulting in a poor prognosis ( 7 , 8 ). The primary treatment for LCNEPC is chemotherapy, with the main regimen being etoposide+ platinum ( 9 ). Previous reports have indicated that the combination of etoposide with either cisplatin or carboplatin is generally effective ( 10 , 11 ). In this case, the patient initially presented with progressive dysuria, and PRAD and lung tumors were diagnosed during hospitalization. While receiving goserelin acetate and bicalutamide endocrine therapy, the patient underwent thoracoscopic lung tumor resection, and postoperative pathological diagnosis suggested primary lung adenocarcinoma along with metastases of PRAD. He subsequently received 4 cycles of sintilimab, paclitaxel, and loplatin immunotherapy combined with chemotherapy. After 1 year of ADT treatment he underwent laparoscopic radical prostatectomy (LRP) for prostate cancer and was diagnosed with LCNEPC at this time. 2 months after the operation, the patient developed bladder, lung, liver, pelvic, and multiple bone metastases and recurrence, and received etoposide and cisplatin chemotherapy. After 1 cycle of treatment, the patient died due to multi-organ dysfunction caused by severe myelosuppression.

2 Case description

The 65-year-old patient was admitted to the department of urology on March 14th, 2022 due to progressive dysuria. The patient did not exhibit symptoms such as gross hematuria or bone pain, and had no history of cardiovascular and cerebrovascular diseases, diabetes, etc. The serum total prostate-specific antigen (tPSA) level was measured at 17.83ng/mL, and a digital rectal examination(DRE) revealed the presence of a hard nodule measuring approximately 1×1cm on the right lobe. The prostate magnetic resonance imaging (MRI) enhancement showed an abnormal signal in the migratory zone 9–11 points of the prostate, T2-weighted images indicated an equal/slightly hypointense lesion, and the PI-RADS score was 3 ( Figure 1A ). Chest computed tomography (CT) showed a solid nodule in the apical segment of the upper lobe of the right lung, with unclear boundaries and adhesion to the adjacent pleura, the size of which was about 2.8cm×2.3cm, and a suspicious metastatic lesion in the middle lobe ( Figures 1B, C ). A whole body bone scan (WBBS) and brain MRI were performed, both of which showed no evidence of tumor metastasis.

Figure 1 Imaging and pathology findings at the patient’s first visit. (A) The prostate MRI at T2-weighted images revealed the presence of nodular patchy hypointense lesion in the migratory zone in the direction of points 9–11; (B) Chest CT showed a solid nodule was observed in the apical segment of the upper lobe of the right lung, which was considered a primary lesion; (C) scattered solid nodules were observed in the middle lobe of the right lung, suggesting metastasis; (D) HE staining. The glands exhibit irregular and fused, or small infiltrating glands with varying shapes and prominent nucleoli (4×); (E) Immunohistochemical staining revealed positive expression of PSA (10×). The site of the lesion was marked with a red circle.

Subsequently, the patient underwent transperineal magnetic resonance fusion color ultrasound prostate aspiration biopsy. Pathological examination showed that prostate adenocarcinoma, Gleason score was 7 (4 + 3), WHO/ISUP group 3 ( Figures 1D, E ). Then immediately began the androgen blockade treatment of goserelin acetate + bicalutamide (goserelin 3.6 mg per month and bicalutamide 50 mg daily). Simultaneously, the lung tumor was also considered malignant based on the chest CT report, and given that lung malignancies progress more rapidly than prostate cancer, the patient underwent thoracoscopic resection of the lung tumor on April 1th, 2022. Pathological examination revealed moderately differentiated invasive adenocarcinoma and metastatic prostate adenocarcinoma, the Gleason score was 8 (4 + 4). Following surgery, the patient underwent genetic sequencing, which indicated the absence of mutations in tumor suppressors such as TP53, BRCA2, PTEN, and CDKN2. Microsatellite instability (MSI) was detected as microsatellite stable (MSS), tumor mutation burden (TMB) was low, and poly (ADP-ribose) polymerase (PARP) inhibitor-related gene and PD-L1 expression tests were negative. Subsequently, the patient underwent 4 cycles of immunotherapy with sintilimab in combination with chemotherapy using paclitaxel and lobaplatin. During this period, myelosuppression occurred and recovered after timely treatment. During androgen blockade therapy, the patient underwent regular underwent PSA testing, which revealed a gradual decrease in PSA levels ( Figure 2A ). Furthermore, there was no observed increase in levels of neuron-specific enolase (NSE) ( Figure 2B ). In addition, a comprehensive evaluation including WBBS and chest CT was conducted, which did not reveal any indications of bone metastasis or recurrence of lung tumors. The patient reported only mild dysuria, without gross hematuria, bone pain, or weight loss.

Figure 2 Trends in patient PSA and NSE. (A) Total PSA; (B) NSE.

One year after receiving ADT, after the patient fully communicates with us and expresses his willingness to operate, the patient returned to the hospital for LRP. Prior to LRP, the 18F-fluorodeoxyglucose positron emission tomography/computed tomography [(18F)FDG PET/CT] scan showed increased FDG metabolism in the right lobe of the prostate, compression of the bladder’s posterior wall, and no signs of metastasis in other organs were observed. The patient underwent LRP on June 13th, 2023. A cystoscopy was conducted prior to the operation, revealing an enlargement of the prostate with protrusion of the right lobe and middle lobe toward the bladder with invasion of part of the posterior wall of the bladder. No tumor was found in the bladder. During LRP, invasion of the right wall of the bladder by the right lobe and middle lobe of the prostate was observed, and the adhesion of the prostate to denonvillier fascia (DF) was unbounded. Consequently, a partial cystectomy was performed. Subsequent routine pathological examination indicated the presence of PRAD [Gleason score 8 (4 + 4)] with LCNEPC (approximately 10%) ( Figures 3A, B ), with LCNEPC identified in the bladder wall and the right bladder neck ( Figure 3C ). Hematoxylin-eosin (HE) staining revealed the presence of palisade-like structures surrounding the cell nests, characterized by large nuclei that exhibited deep staining, coarse chromatin, evident necrosis, and excessive mitotic activity ( 8 ). IHC analysis demonstrated positive expression of CD56, CDX-2, and SSTR2 ( Figures 3D-F ), while negative expression was observed for chromogranin A (CgA), synaptophysin (Syn), and NSE ( Figures 3G–I ), Ki-67 was strongly positive expression (+ 80%) ( Figure 3J ). After surgery, the patient did not receive further androgen blockade therapy and chemotherapy for personal reasons.

Figure 3 Pathological results of the patient after LRP. HE staining (A-C) showed that the simultaneous presence of adenocarcinoma and LCNEPC components; The cells exhibited large size, with palisade-like structures surrounding cell nests. The nuclei appeared large and deeply stained, indicating high mitotic activity, a low nuclear-to-plasma ratio, and extensive cell necrosis; IHC was positive for (D) CD56, (E) CDX -2, (F) SSTR2, and negative (G-J) for (G) CgA, (H) Syn, (I) NSE, (J) Ki-67 was strongly positive (90%) (10×).

Two months after undergoing LRP, the patient was readmitted to the hospital due to the presence of gross hematuria. The tPSA level was measured at 0.59ng/mL ( Figure 2A ), while the NSE level was recorded as 35.59ng/mL ( Figure 2B ). Computed Tomography urography (CTU) revealed the presence of enlarged masses in the region of the previous prostate and bilateral seminal vesicles, and significant space-occupying lesion on the right lateral wall of the bladder, considering tumor recurrence ( Figures 4A, B ). Intrahepatic nodules of small size were observed ( Figure 4C ). The chest CT scan revealed new multiple scattered nodules in both lungs compared to the previous scan ( Figure 4D ), indicating potential metastases. A WBBS indicated the presence of new metabolically active foci in the left acetabulum, as well as new osteolytic lesions in the pubic joint and bilateral ischium, suggesting bone metastases ( Figure 4E ). Additionally, the recurrence of intravesical tumors was considered as the likely cause of gross hematuria. On August 17th, 2023, a subsequent transurethral resection of bladder tumor (TURBT) revealed the presence of a tumor measuring 8 × 6 × 6cm ( Figure 4F ) on the top wall of the bladder, visible from the 12 o’clock position. Postoperative pathological examination indicated that the tumor exhibited characteristics consistent with LCNEPC without an acinar adenocarcinoma component ( Figure 4G ). IHC results demonstrated positive staining for SSTR2 and Ki-67 (90% +) ( Figures 4H, I ), negative staining for CD56, CgA, Syn, NSE, and P504S ( Figures 4J-N ).

Figure 4 Imaging changes after patient progression, intraoperative conditions and postoperative findings. (A, B) CTU scans revealed the recurrence of bladder and pelvic tumors; (C) upper abdomen CT indicated hepatic metastasis; (D) chest CT showed multiple metastases; (E) WBBS indicated bone metastases; (F) intraoperative cystoscopy reveals tumor at 12 o’clock in the bladder; (G) typical LCNEPC presentation, no adenocarcinoma component, IHC was positive for (H) SSTR2 and (I) Ki-67 (90%), and negative for (J) CD56, (K) CgA, (L) Syn, (M) NSE and (N) P504S (10×).

Three weeks following the surgery, the patient underwent etoposide+ cisplatin chemotherapy (etoposide 150 mg daily for 3 consecutive days, and cisplatin 50mg for 3 consecutive days, and prepared to repeat every 4 weeks). The genetic sequencing report suggested that etoposide has a general effect with more pronounced side effects, while docetaxel and cisplatin exhibit greater efficacy with fewer side effects. Following thorough communication with the patient, the patient ultimately opted to proceed with the treatment plan of etoposide and cisplatin. After receiving chemotherapy, the patient developed severe myelosuppression, which was not relieved after treatment, multi-organ failure occurred, and the patient’s family refused further rescue measures. The patient was pronounced clinically dead on September 28 th , 2023 ( Table 1 ).

Table 1 Timeline of the patient process.

3 Discussion

NE cells are typically found in prostate tissue and their numbers increase during puberty. These cells are less frequently observed in acini and do not express androgen receptors (AR) or secrete PSA ( 12 ). The differentiation of NE cells in the prostate can impede the apoptosis of prostate cancer cells. Consequently, the extent of NE differentiation in the majority of prostate cancers is associated with heightened tumor invasiveness, rapid disease progression, and poor prognosis ( 13 ).

Adenocarcinoma is the most prevalent pathological subtype of prostate malignant tumors, and the standard treatment approach involves ADT and antiandrogenic therapy. The majority of neuroendocrine cancers, including LCNEPC, arise in the context of long-termed ADT treatment ( 5 ). Because ADT does not completely eliminate NE cells ( 14 ). According to the review of the literature, 12 cases of prostate adenocarcinoma differentiated into LCNEPC after being treated with ADT. The mean serum PSA at the time of initial diagnosis of prostate adenocarcinoma in 10 patients was 28.05 ng/mL (range 0–90ng/mL). The mean duration of ADT treatment was 3.5 years (range 2–9 years). The average time from the first diagnosis of prostate cancer to the diagnosis of LCNEPC was 4.7 years (range 2–9 years). Among the patients diagnosed with LCNEPC, chemotherapy was administered to 7 individuals, and the final outcome in 11 patients was death or loss to follow-up ( 15 ). Currently, only one patient, who harbored a somatic BRCA2 mutation, survived after receiving treatment with the Rad3-related protein (ATR) Inhibitor (M6620) in conjunction with gemcitabine, cisplatin, and etoposide, achieving a progression-free survival (PFS) of 20 months ( 16 ).

Based on the available literature, a total of 12 cases of primary LCNEC of the prostate were reported with an average overall survival of 21.5 months(range 7–54 months) ( 15 ). Patients with a diagnosis of pure LCNEPC who received a chemotherapy regimen of etoposide + cisplatin after diagnosis still had an extremely poor prognosis, with a mean survival of 7.3 months ( 5 , 17 ). Among the patients diagnosed with NE carcinoma-acinar adenocarcinoma mixed type who received chemotherapy in combination with ADT and the median survival time was significantly longer than that of pure LCNEPC patients ( 18 , 19 ). Another patient diagnosed with primary LCNEC combined with adenocarcinoma received ADT combined with chemotherapy with etoposide + cisplatin, and after terminating the chemotherapy was treated with abiraterone because of the high metastatic risk, and the patient was followed up for 20 months without progression ( 20 ). However, untreated cases of LCNEPC tend to progress rapidly, ultimately resulting in mortality ( 21 ). In an unpublished case, the tumor invaded the bladder neck and the patient was initially treated with cisplatin and etoposide, followed by the addition of pembrolizumab and Leuprolide, which did not impede the tumor’s progression. Subsequently, the patient underwent treatment with docetaxel (75 mg/m 2 ) and prednisone. After 5 cycles, imaging revealed improvement of the sclerotic lesions, and no new metastatic lesions were detected, with the PSA value measuring less than 0.01ng/mL. It shows that docetaxel and prednisone may have efficacy in the treatment of LCNEPC ( 15 ). In our case, the patient was not treated with docetaxel, making it impossible to know whether the patient would have had a better outcome and longer survival.

Two possible mechanisms have been proposed to explain the occurrence of LCNEPC based on the appealing two scenarios. Firstly, it is suggested that patients with adenocarcinoma may develop LCNEPC after long-term ADT treatment, This could be attributed to the selection pressure exerted by ADT, which affects the cloning progression of non-NE cells. Consequently, the loss of androgen receptor (AR) expression occurs, leading to the emergence of NE cells that do not express AR. This process is known as transdifferentiation ( 5 , 22 ). Additionally, in vitro studies of the prostate cancer cell line LNCaP have demonstrated a decrease in AR expression in cultured cells lacking androgens ( 22 ). RaPa et al ( 23 ) believed that the NE differentiation of prostate cancer is a dynamic process that is influenced by androgen deprivation. This process involves the participation of various cytokines and growth factors in the acquisition of neuroendocrine phenotypes. While the evidence for the transdifferentiation of LCNEPC remains uncertain, the presence of NE carcinoma-acinar adenocarcinoma mixed type serves as a strong indication of transdifferentiation ( 8 ). In this case, both adenocarcinoma and LCNEPC were detected simultaneously during LRP one year after ADT treatment, However, when a recurrent bladder tumor was resected two months later, only LCNEPC was observed. This mechanism is consistent with what has been observed in several clinical cases, including our case. The second mechanism suggests that LCNEPC can develop in the absence of prior ADT treatment through the direct malignant transformation of normal prostate NE cells, as reported in a limited number of cases ( 6 , 24 ). However, the precise mechanism underlying this process necessitates further investigation.

In this case, the patient was diagnosed with LCNEPC one year after receiving ADT, a notably shorter than any previously reported in scholarly literature. Had the patient not undergone LRP, the diagnosis of LCNEPC would have been unattainable, potentially resulting in a more unfavorable prognosis. Timely diagnosis of LCNEPC is of paramount importance, but which patients will develop into LCNEPC is unpredictable. The definitive diagnosis of LCNEPC hinges on the pathological examination. Obtaining serial biopsy samples at multiple time points between initiation of ADT and the diagnosis of NEPC can provide an in-depth insight into disease progression, and is one of the methods for early diagnosis, and guide the timely revision of the treatment strategies ( 25 ). However, executing this procedure in a clinical setting remains challenging. Through our case, we believe that detecting the changes of NSE level in the blood may also be a valuable diagnostic tool for NEPC. As illustrated in Figure 2B , there was an observable increase in patients’ NSE level in September 2022 (5 months after initiating ADT therapy). Despite remaining within the normal range, it was not taken seriously until the patient was tested again 2 months after LRP, and it was suggested that the NSE level had been significantly increased. Consequently, it is recommended that patients undergo regular monitoring of NSE level, and prompt diagnosis should be pursued upon detection of an increasing trend. In the diagnosis of LCNEPC, the following features need to be met in terms of morphology: 1) The cells are large and polygonal, with large and deeply stained nuclei, abundant cytoplasm, and low nuclear/cytoplasmic ratio; 2) Typical cell nests surrounded by a palisade-like structure; 3) A high mitotic rate and extensive cell necrosis are evident. In IHC, NE markers such as Syn, CgA, and CD56 are utilized, with at least one of these markers needing to be positive ( 8 ). However, in a reported case of SCNC of the prostate, the patient exhibited negative results for CD56, NSE, Syn, and CgA, and was finally diagnosed as SCNC according to its clinical manifestations, auxiliary examinations, and cellular morphological features ( 26 ). In our case, in the pathologic diagnosis after TURBT, the IHC results indicated negative findings for CD56, NSE, Syn, and CgA, and only positive for SSTR2. Therefore, we posit that in cases where morphology aligns with neuroendocrine carcinoma and common markers such as CgA, Syn, CD56, and NSE are negative, it is necessary to further enhance the identification of other markers, such as SSTR2 ( 27 ), CDX-2 ( 28 ), enhancer of zeste homologue 2 (EZH2) ( 29 ), heterochromatin protein 1α (HP1α) ( 30 ) and forkhead box A1 (FOXA1) ( 31 ) to further achieve a more precise diagnosis of neuroendocrine carcinoma and establish a foundation for subsequent treatment. These molecular markers that may be used in the diagnosis of NEPC.

Additionally, the expression of PSA serves as a distinguishing criterion between adenocarcinoma and neuroendocrine cancer, as NEPC rarely exhibits PSA expression ( 32 ). It is important to note that certain cases of NE carcinoma-acinar adenocarcinoma mixed type may express PSA, while high-grade acinar adenocarcinoma can also express neuroendocrine markers ( 33 ). Hence, the morphological and IHC diagnosis and differentiation are crucial for the diagnosis of NE carcinoma. In this case, the patient experienced systemic multi-organ metastases two months after undergoing LRP. Notably, the level of PSA did not increase but rather decreased compared to the pre-LRP level, and the patient did not receive ADT during this period. It is also confirmed that LCNEPC does not express AR or PSA.

The treatment approach for LCNEPC significantly differs from that of typical adenocarcinoma due to the lack of androgen receptor expression and resistance to hormone therapy exhibited by most NEPCs ( 34 ), From the studies reported to date, may only derive benefits from ADT in LCNEPC patients contains adenocarcinoma component ( 18 , 19 , 35 ). Currently, there is a lack of standardized treatment plans or guidelines for these patients. While active surgery can be performed for patients with resectable lesions, the majority of patients are diagnosed at an advanced stage of the disease, resulting in missed opportunities for surgical intervention. Consequently, chemotherapy becomes the primary treatment option. Typically, platinum-based chemotherapy regimens, with etoposide + cisplatin being the most commonly selected regimen, are employed ( 5 , 9 ). In cases where etoposide proves ineffective, regimen docetaxel, gemcitabine + platinum may be chosen as an alternative ( 11 , 36 ). In this case, the patient was diagnosed with LCNEPC following LPR, and chemotherapy was not initiated initially but was only contemplated after the occurrence of hematuria and reoperation 2 months later. Therefore, we recommend that chemotherapy or other treatments be commenced at the time of initial diagnosis in future patients presenting with similar conditions. If there is a combination of adenocarcinoma component with metastatic lesions, the consideration of ADT treatment in conjunction with novel hormonal therapies like apalutamide, rezvilutamide, darolutamide, etc., alongside the initiation of chemotherapy, is recommended. Furthermore, the initial genetic sequencing report did not identify any gene mutations, and no further genetic sequencing was performed at the time of the subsequent diagnosis of LCNEPC, so it was not possible to know whether mutations in genes such as TP53 and BRCA2 had occurred, and it was not possible to formulate a treatment strategy based on the results of the genetic sequencing. It is advised for LCNEPC patients to undergo genetic sequencing, although it is important to acknowledge that the genetic sequencing report merely serves as a treatment reference and does not dictate the selection of therapy for patients. Furthermore, it is possible for different genetic sequencing companies to yield varying results. Therefore, more studies on this disease is still needed to provide a theoretical basis for the selection of treatment options.

Meanwhile, it was mentioned earlier that a patient with the BRCA2 somatic mutation who received a combination of M6620 and etoposide + cisplatin + gemcitabine chemotherapy had a significantly better prognosis than other cases ( 16 ). M6620 is an emerging and potent ataxia telangiectasia mutated and Rad3-related protein (ATR) inhibitor ( 37 ). This case suggests that patients with neuroendocrine prostate cancer may be considered in combination with ATR inhibitors on the basis of chemotherapy, especially in patients with mutation genes involved in homologous recombination repair pathway.

The metastatic site of LCNEPC closely resembles that of PRAD, primarily involving bone, liver, lungs, and lymph nodes ( 5 ). However, instances of brain metastasis have also been reported ( 38 ), albeit as a rare occurrence. In the present case, the patient exhibited metastases in the lungs, liver, lymph nodes, and bone, as well as a recurrence of pelvic and bladder tumors, all within a mere two-months. We intended to conduct a PET/CT or brain MRI brain MRI scan to assess the presence of brain metastasis; however, the patient declined the aforementioned examination due to financial constraints. Consequently, the patient’s condition of brain remains unknown, although he did not exhibit symptoms such as headache, nausea, or blurred vision. It is worth noting that the sample size of patients is limited, and further investigation is necessary to elucidate the specific mechanisms underlying LCNEC metastasis.

LCNEC is characterized by high invasiveness and a bleak prognosis. Evans et al. ( 5 ) reported that 6 patients survived for an average of 7 months after diagnosis of LCNEPC, and Marcus et al. ( 39 ) reported a median survival duration of 10 months in patients diagnosed with NE tumors, accompanied by a 5-year overall survival rate of 12.6%. Tanaka et al. ( 40 ) reported that patients with NEPC have the following typical clinical course: 1) short survival time after recurrence; 2) PSA level does not increase after recurrence; 3) metastatic sites resembling those of adenocarcinoma. The clinical trait presented in this case is consistent with the above viewpoints. Ultimately, the patient succumbed to systemic multi-organ failure caused by post-chemotherapy myelosuppression, leading to his demise three and a half months after being diagnosed with LCNEPC.

To sum up, LCNEPC represents a rare form of prostate cancer characterized by a high level of malignancy, a propensity for early metastasis, and a poor prognosis. This study presents a case initially diagnosed as prostate adenocarcinoma, which subsequently transformed into mixed NE carcinoma-acinar adenocarcinomas following treatment with ADT and metastasized to multiple organs within two months of LCNEPC diagnosis. The patient succumbed to the disease 3.5 months later. The diagnosis of LCNEPC relies on HE+ IHC staining, and platinum-based chemotherapy serves as the primary treatment modality. Further investigation into the molecular biological characteristics of this disease is warranted. Although there are epigenetic regulators that are altered in NEPC, whether this affects genetic predisposition, including the molecular biology characterizing the disease, requires further study.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by Chongqing General Hospital, Chongqing University. The studies were conducted in accordance with the local legislation and institutional requirements. The a member of the patient's family provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

MX: Writing – review & editing, Writing – original draft, Resources, Conceptualization. WT: Data curation, Writing – review & editing. XX: Writing – review & editing. XP: Writing – review & editing. FY: Writing – review & editing, Funding acquisition, Conceptualization.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The work was supported by the Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau), grant number: 2024ZDXM018.8.

Acknowledgments

The authors would like to express their sincere appreciation to all those who have contributed in managing the patient and completing the case report.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: prostate cancer, large cell, neuroendocrine carcinoma, metastasis, transdifferentiation

Citation: Xiao M, Tong W, Xiao X, Pu X and Yi F (2024) Systemic metastases in large cell neuroendocrine prostate cancer: a rare case report and literature review. Front. Oncol. 14:1398673. doi: 10.3389/fonc.2024.1398673

Received: 12 March 2024; Accepted: 02 May 2024; Published: 15 May 2024.

Reviewed by:

Copyright © 2024 Xiao, Tong, Xiao, Pu and Yi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Faxian Yi, [email protected] ; Maolin Xiao, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Case Report, Practices Survey and Literature Review of an Under-Recognized Pediatric Vascular Disorder: The BASCULE Syndrome

Affiliations.

• 1 CHU Lenval, Hôpitaux Pédiatriques de Nice, Nice, France.
• 2 Unité de Dermatologie, Hôpital Archet-2, CHU de Nice, Nice, France.
• 3 Université Côte d'Azur, Faculté de Médecine, Nice, France.
• 4 Unité de Néphrologie et de Rhumatologie Pédiatrique, Hôpital L'Archet, CHU de Nice, Nice, France.
• 5 Unité de Médecine Vasculaire, Université Côte d'Azur, CHU Nice, Nice, France.
• 6 Unité de Médecine et d'Explorations Vasculaires, CHU Pasteur et CHU Pédiatrique Lenval, Nice, France.
• PMID: 35463901
• PMCID: PMC9021422
• DOI: 10.3389/fped.2022.849914

Introduction: Bier anemic spots, cyanosis, and urticaria-like eruption (BASCULE) syndrome is an underreported pediatric vascular disorder from the group of acrosyndromes. In children, these include paroxysmal acrosyndromes (Raynaud's phenomenon and chilblain-like lesions), permanent acrosyndromes (acrocyanosis), and transient acrosyndromes, in which their pathogeneses are associated with virus infections, Epstein-Barr virus, and, more recently, SARS-CoV-2, respectively.

Methods: We reported a case of BASCULE syndrome associated with postural orthostatic tachycardia syndrome (POTS) and provided a narrative review of case reports describing the BASCULE syndrome in children. Moreover, we presented the results of a prospective practice survey that we performed in the French medical community.

Results: A 14-years-old boy reported pruritic erythrocyanic lesions on the lower limbs, which occurred whenever he was in a standing position and fully resolved when he laid down. He reported asthenia and cramps. He presented a typical BASCULE syndrome associated with POTS confirmed by a tilt-test. Physical and vascular examinations were within the normal range. We identified 12 case reports, describing 21 pediatric cases since 2016. Most patients were adolescents between 12 and 19 years of age or were newborns. Furthermore, 20% of cases in the literature have presented POTS or orthostatic intolerance. Our survey among 95 French physicians confirmed that BASCULE syndrome is an underdiagnosed and under recognized disease in the general pediatric practice, at least in France. Among these physicians, 65% had already encountered patients with similar symptoms, but only 30% declared that they had knowledge of the BASCULE syndrome.

Conclusion: The under-recognition of the clinical manifestations leads the patients to consult emergency rooms, with multiple unnecessary investigations performed. Therefore, we suggest that the diagnosis of BASCULE syndrome is based on clinical observations, without the need for laboratory tests, to avoid unnecessary health costs. We suggest physicians to perform a tilt-test when POTS is suspected.

Keywords: BASCULE syndrome; POTS; acrosyndrome; children; orthostatic intolerance.

Copyright © 2022 Baurens, Briand, Giovannini-Chami, De Guillebon De Resnes, Hubiche, Chiaverini, Giordana, Leftheriotis and Bernardor.

Publication types

• Case Reports