Pediatric Sneddon syndrome presenting with early-onset liver fibrosis: a rare case report.

Introduction

Sneddon syndrome (SS) is a rare chronic thrombotic vasculopathy associated with cerebrovascular disease and livedo racemosa (LR) [ 1 ]. The estimated yearly incidence is 4 per 1 million, predominantly affecting women aged 20–42 [ 2 ]. It is typically linked to risk factors such as female gender, hormonal influences, and hypertension, with some familial cases demonstrating autosomal dominant inheritance [ 2 ]. The ADA2 gene CECR1 (cat eye syndrome chromosome region, candidate 1) has also been implicated in familial cases, highlighting a genetic component in systemic vasculopathy [ 3 ].

SS is characterized by dermatological abnormalities, particularly LR, and neurological manifestations such as transient ischemic episodes, strokes, cognitive impairment, and seizures, all of which severely impact quality of life [ 2 ]. Diagnosis is clinical, requiring imaging studies and skin biopsies for confirmation [ 4 ]. Treatment focuses on managing coagulation abnormalities, with anticoagulation and antiplatelet therapy showing benefits [ 5 ]. However, the use of immunosuppressant remains debated [ 2 ].

Although previous case reports and literature have provided insight into its clinical features and treatment, knowledge gaps remain in understanding the optimal therapeutic strategies. This case report aims to contribute to the existing literature by presenting a rare manifestation of SS, providing further insights into its clinical presentation, diagnostic challenges, and therapeutic approach.

Notably, recent studies have identified monogenic forms of SS-like vasculopathy, particularly deficiency of adenosine deaminase 2 (DADA2), which shares clinical features with SS but follows distinct molecular pathways [ 6 ]. This case expands this paradigm by reporting concurrent DADA2 and LDLR mutations.

Case presentation

A 17-month-old female with no prior medical history presented with an insidious onset of abdominal distension, irritability, persistent constipation, and oliguria. She was born at 37 weeks of gestation to a 32-year-old multigravida woman via normal vaginal delivery without any complications. Her parents are non-consanguineous. Examination revealed a well-developed child with a weight of 12 kg, placing her in the 60th percentile; a height of 78 cm, placing her in the 48th percentile; and a head circumference of 47 cm, placing her in the 60th percentile, with normal developmental milestones. The abdomen was distended with dilated superficial veins. Urinalysis showed positive nitrites, WBCs, and bacteria, but the urine culture was negative. Kidney function tests were normal.

Abdominal ultrasound detected multiple ‘target signs’ in the mid-right abdomen, suggesting possible early ileocolic intussusception, later ruled out by repeated ultrasounds. Imaging (x-rays, contrast-enhanced CT) revealed hepatosplenomegaly (HSM), with liver and spleen spans of 10 cm and 8.1 cm, respectively. ( Fig. 1 ) Liver function tests and lipid profile were elevated, prompting further metabolic and functional liver disorder testing, all of which were negative. Liver biopsy confirmed advanced fibrosis and biliary cirrhosis. ( Fig. 2 ).

She had electrolyte imbalances (Na 131 mmol/L, K 2.9 mmol/L, Cl 95.8 mmol/L) and was treated with IV fluids, potassium chloride, oral potassium, and magnesium sulfate. A month later, she developed worsening jaundice, watery diarrhea, and decreased oral intake. Celiac markers and stool elastase were negative. She was treated with IV methylprednisolone (10 mg/day for 5 days), then transitioned to oral prednisone (6 mg/day), along with ursolit (80 mg three times daily), paracetamol, vitamin K, iron supplements, and a low-fat diet.

At two years old, despite treatment, her condition deteriorated with recurrent fevers, petechial rash, livedo racemosa, multiple oral ulcers, severe gingivitis, and periodontitis, suggesting a systemic inflammatory process. ANA profile and rheumatoid factor were normal, but immunoglobulin levels were high. Dihydrorhodamine testing was negative.

Whole Exome Sequencing (WES) identified a heterozygous c.144dupG mutation in the ADA2 gene (linked to DADA2) and a homozygous ACE I/D polymorphism. She was also heterozygous for an LDLR mutation associated with FH. Two cousins had DADA2 with serious hematologic complications. WES confirmed her father and two healthy sisters carried the ADA2 mutation, while the LDLR mutation was found in her father and one sister.

She was monitored regularly due to elevated transaminases and inflammatory markers. Prednisone was adjusted, but her condition did not improve long-term. She received etanercept (8 mg/week for 3 months), leading to initial improvement, but symptoms returned, and necessitating further treatment modifications. Steroids were tapered, and she was started on IVIG (20 g/month) and oral azathioprine (1 mg/day).

Despite these interventions, a few months later, she developed portal vein thrombosis (confirmed by ultrasound) and generalized edema, worsening her clinical state. She was treated with daily albumin (1 g/kg), furosemide (1 mg/kg), and spironolactone (3 mg/kg/day) until stabilization. Given her deteriorating liver function, liver transplantation was considered as a potential final treatment option.

Discussion

Sneddon syndrome (SS) is a rare neurocutaneous disorder initially described by Ehrmann in 1907 and later defined more comprehensively by Sneddon in 1965 [ 7 ]. It is traditionally categorized into antiphospholipid antibody (aPL)-positive and aPL-negative subtypes [ 8 ]. Our patient, although aPL-negative, exhibited hallmark features of SS, including livedo racemosa, suggesting a genetic rather than autoimmune etiology that is consistent with familial SS. Genetic analysis revealed a heterozygous c.144dupG mutation in the CECR1 (ADA2) gene, which has recently been associated with systemic vasculopathy and familial forms of SS [ 6 ]. This finding supports emerging evidence that deficiency of adenosine deaminase 2 (DADA2), a monogenic vasculopathy, can clinically overlap with SS even in the absence of aPL—characterized by features such as livedo racemosa, hepatosplenomegaly, and elevated inflammatory markers [ 6 , 9 ]. Additionally, the presence of a concurrent LDLR mutation in our patient raises the possibility of an interaction between metabolic dysregulation and inflammatory vasculopathy within the SS spectrum.

Although the precise pathophysiology of SS remains unclear, aPL-positive cases are typically associated with thrombotic vascular changes. In contrast, aPL-negative cases—particularly those without known coagulation abnormalities—are thought to involve nonvasculitic dysfunction of small- to medium-sized arteries, which likely contributes to the observed cutaneous and cerebrovascular manifestations [ 10 ].

SS is characterized by neurological symptoms and skin lesions, most notably LR, a violaceous, net-like discoloration caused by localized arteriolar blockage. LR results from reactive venular dilation and hypoxia due to arteriolar obstruction [ 8 ]. Stroke, often ischemic in the middle or posterior cerebral artery zones, is another hallmark, presenting with hemiparesis, visual deficits, aphasia, or sensory issues, although most strokes are mild. Headache is the most common nonspecific symptom, with other manifestations including dementia, hypertension, heart valvulopathy, and ophthalmologic complications [ 2 , 7 ].

The diagnosis of SS cannot be made using a particular biologic marker [ 8 ]. Patients with solely LR at first should be tested to rule out other livedo etiologies. Table 1 summarizes the differential diagnosis of LR.

To diagnose SS, patients should undergo a comprehensive evaluation, including a skin biopsy, brain MRI, cerebral angiography, blood tests, and cardiovascular assessment. Blood tests should screen for circulating immune complexes, coagulation factors, thrombocytopenia, leukopenia, VDRL, IgG and possibly IgM anti-cardiolipin antibodies, ANA, anti-dsDNA, and lupus anticoagulant [ 2 ]. The primary diagnostic criteria include focal neurological symptoms and generalized LR with histological confirmation from a skin biopsy. Additional supportive findings include small bright foci on T2-weighted MRI and a history of transient ischemic attacks or strokes [ 2 ].

The rarity of SS poses challenges for clinical trials, and no definitive management guidelines exist. Treatment focuses on symptom management and preventing further ischemic damage to the cutaneous, cerebral, and extracerebral vasculature. Nifedipine may help alleviate pain from skin lesions [ 2 ].

Antiplatelet therapy and oral anticoagulants remain the mainstay for preventing cerebrovascular complications [ 11 ]. Some studies have found that azathioprine, cyclophosphamide, and corticosteroids are ineffective in treating SS [ 12 ]. However, one case reported improvement in neurological and cognitive function after eight months of monthly intravenous cyclophosphamide treatment [ 13 ].

Some studies have shown that elevated levels of circulating ADA2 are associated with liver fibrosis in nonalcoholic fatty liver disease (NAFLD) [ 14 , 15 ]. However, in this case, the patient presented with DADA2 alongside advanced liver fibrosis, highlighting the complexity and rarity of the condition.

A comprehensive search of PubMed, Google Scholar, and the Cochrane Library using the terms ‘Sneddon syndrome,’ ‘pediatric,’ and ‘liver fibrosis’ did not identify any comparable cases, underscoring the novelty of this report. To the best of our knowledge, this is the first documented case of Sneddon syndrome presenting with a DADA2 (ADA2 gene) mutation concurrent with an LDLR gene mutation associated with familial hypercholesterolemia (FH), along with early-onset liver cirrhosis in a toddler. While DADA2 is known to cause systemic vasculopathy and hematologic abnormalities, hepatic involvement of this severity and at such a young age is extremely rare. This unique presentation highlights the need for further research to explore the potential interaction between ADA2 and LDLR mutations in the pathogenesis of liver disease.

Conclusion

This case underscores the complex interplay of genetic mutations in rare diseases like SS. The co-occurrence of DADA2 with an LDLR mutation, associated with FH and advanced liver fibrosis, highlights the importance of thorough genetic and clinical evaluations in patients presenting with atypical symptoms and systemic manifestations. This case also raises the possibility of a novel link between ADA2 and LDLR mutations in the pathogenesis of liver disease, warranting further investigation.

Acknowledgements

The authors express profound gratitude to the Polytechnic Medical Students’ Research Association (PMRA) for their invaluable contributions and unwavering support that significantly enriched every stage of the research journey. Also, the authors express their gratitude to the patient’s family for their great contribution.

Contributor Information

Qutaiba N Awad, Faculty of Medicine, Palestine Polytechnic University, Wadi Al-Hariyah Street, Hebron 9020000, Palestine.

Taha Z Makhlouf, Faculty of Medicine, Palestine Polytechnic University, Wadi Al-Hariyah Street, Hebron 9020000, Palestine.

Mohammad F Zhour, Faculty of Medicine, Palestine Polytechnic University, Wadi Al-Hariyah Street, Hebron 9020000, Palestine.

Sami Bannoura, Department of pathology, Makassed Hospital, Ruba el-Adawiya Street, Jerusalem 91000, Palestine.

Wesam Abu hussein, Faculty of Medicine, Palestine Polytechnic University, Wadi Al-Hariyah Street, Hebron 9020000, Palestine; Department of Pediatrics, Mohammad Ali Al-Mohtaseb Governmental Hospital, Al-Sahla Street, Hebron 9020000, Palestine.

Conflict of interest

None declared.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval

This case report is exempt from ethical approval in our institute, Palestine Polytechnic University.

Informed consent

Written informed consent was obtained from the patient’s family 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.

Data availability

The data used to support the findings of this study are included.

References

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Associated Data

Data Availability Statement

The data used to support the findings of this study are included.