Isolated congenital asplenia with cryptogenic liver fibrosis and a novel SON variant: A case report

Abstract

BACKGROUND

Isolated congenital asplenia (ICA) is a rare life-threatening condition with an elusive genetic etiology. We report a patient with ICA carrying a novel heterozygous SON gene variant, which may provide a hypothesis-generating clue regarding the genetic basis of ICA.

CASE SUMMARY

A 33-year-old man presented with bilateral leg edema. Imaging indicated liver cirrhosis, ascites, and incidental absence of the spleen without a history of splenectomy. Extensive etiological evaluation was unremarkable. Whole-exome sequencing identified a novel heterozygous SON variant of uncertain significance (VUS) that had not been previously associated with asplenia. Liver biopsy showed fibrosis without definitive features of advanced cirrhosis. Notably, the patient did not experience life-threatening infections despite marked asplenia, suggesting possible adaptive immune compensation; however, this remains speculative.

CONCLUSION

This case identifies a novel SON gene VUS associated with ICA; however, its pathogenicity remains uncertain. This finding should be interpreted as a hypothesis-generating clue and does not establish a causal relationship between SON and ICA. Further functional studies and long-term follow-up are required to clarify the underlying mechanisms.

Key Words: Isolated congenital asplenia; Liver cirrhosis; SON gene variant; Whole-exome sequencing; Immune regulation; Case report

Core Tip: This case report describes a 33-year-old man with isolated congenital asplenia (ICA) who carries a novel heterozygous SON gene variant, providing a hypothesis-generating clue regarding the genetic basis of ICA. This case highlights the critical challenge of interpreting novel genetic findings in rare congenital anomalies and underscores the need for further studies to elucidate the potential biological significance of SON variants in human disease.

INTRODUCTION

Isolated congenital asplenia (ICA) is a rare developmental disorder characterized by complete absence of the spleen without other major organ anomalies. Its estimated incidence is approximately 1 in 2 million live births, with fewer than 100 cases reported worldwide[1]. As a key organ in host defense against encapsulated bacteria, the spleen plays an important role in immune surveillance. It also contributes to portal circulation, accounting for a proportion of portal venous blood flow[2]. ICA is typically diagnosed in infancy due to severe infections; however, some patients remain asymptomatic until adulthood and are diagnosed incidentally on imaging or autopsy[1,3]. ICA represents a rare model for studying splenic development and immune system organization[4]. However, the genetic basis of sporadic ICA cases remains incompletely understood.

Here, we report a patient with ICA and cryptogenic liver fibrosis carrying a novel SON gene variant of uncertain significance (VUS). To our knowledge, this is one of the few reported cases in which a SON variant is identified in the context of ICA; however, a definitive causal association remains speculative. This case highlights the importance of cautious interpretation of novel genetic findings in rare congenital anomalies and underscores the need for further studies to elucidate the potential biological significance of SON variants in human disease.

CASE PRESENTATION

Chief complaints

A 33-year-old man presented to the Department of Gastroenterology with a 4-year history of intermittent bilateral lower-limb edema.

History of present illness

Over the past 4 years, the patient developed progressive liver dysfunction, which was ultimately diagnosed as cryptogenic liver fibrosis. Notably, he had no documented history of severe or recurrent infections, and radiologic imaging had revealed the absence of splenic tissue. The patient denied any history of alcohol consumption, and there was no evidence of parasitic infection based on clinical evaluation and imaging findings.

History of past illness

The patient had no relevant past medical history.

Personal and family history

The patient’s father died of an unknown cause. His mother is alive and well, with no known history of liver disease or splenic abnormalities. No additional family history of congenital anomalies was reported.

Physical examination

On admission, vital signs were stable: Temperature 36.3 °C, blood pressure 118/70 mmHg, heart rate 80 beats/minutes, and respiratory rate 15 breaths/minutes. The abdomen was distended with normal bowel sounds. Shifting dullness and fluid wave tests were positive, consistent with ascites. Mild abdominal rigidity was noted without tenderness or rebound tenderness.

Laboratory examinations

Laboratory findings are summarized in Table 1. A comprehensive etiological workup for chronic liver disease, including viral hepatitis (hepatitis B virus, hepatitis C virus, hepatitis A virus, and hepatitis E virus), autoimmune liver diseases (antinuclear antibodies, anti-smooth muscle antibodies, antimitochondrial antibodies, antineutrophil cytoplasmic antibodies, and immunoglobulin G4), and viral infections (cytomegalovirus, Epstein-Barr virus), was negative. Although common etiologies were excluded, the lack of a full evaluation of several rare causes-including non-alcoholic fatty liver disease (NAFLD)-related genetic susceptibility, celiac disease serologies (tTG-IgA, EMA), and glycogen storage disorders-is a limitation of this study.

Table 1 Laboratory test results.

Parameter	Value (reference)	Significance
ANA/ASMA/AMA/ANCA/IgG4	Negative	Exclude autoimmune diseases
Ferritin and transferrin saturation	Within normal limits	Exclude hemochromatosis
Hemoglobin	88 g/L (130-175)	Anemia
Platelets	354 × 109/L (125-350)	Reactive thrombocytosis
Albumin	27.6 g/L (40–55)	Hypoalbuminemia
ALT/AST	71/77 U/L (9-50/15-40)	Hepatocellular injury
Fasting plasma glucose	Within normal limits	Normal glucose metabolism
Serum lipids	Within normal limits	Normal lipid profile
eGFR	71.6 mL/minutes/1.73 m² (> 90)	Stage 2 CKD
Urine protein–creatinine ratio	224.46 μg/mg (≤ 78.24)	Nephrotic-range proteinuria
D-dimer	5.4 μg/mL (< 0.5)	Hypercoagulable state
Urine protein electrophoresis (micro-total urinary protein)	2115 mg/L (< 150.00)	Renal injury

ALT: Alanine aminotransferase; AMA: Antimitochondrial antibody; ANA: Antinuclear antibody; ANCA: Antineutrophil cytoplasmic antibodies; ASMA: Anti-smooth muscle antibody; AST: Aspartate aminotransferase; eGFR: Estimated glomerular filtration rate; IgG4: Immunoglobulin G4; CKD: Chronic kidney disease.

Imaging examinations

Magnetic resonance cholangiopancreatography demonstrated features suggestive of chronic liver disease with ascites and the absence of splenic tissue without prior splenectomy (Figure 1). Computed tomography further confirmed hepatic morphological changes consistent with fibrosis and asplenia, along with ascites, gallbladder wall edema, and portal hypertension-related changes, including varices and bowel wall edema. Computed tomographic portal venography additionally demonstrated esophagogastric varices and features consistent with portal hypertensive gastroenteropathy (Figure 2). No imaging evidence of infectious lesions, inflammatory masses, or focal abscess formation was identified. Renal ultrasonography showed normal kidney morphology and size without hydronephrosis, and intrarenal vascular flow patterns were unremarkable. Overall, imaging findings were consistent with chronic liver fibrosis complicated by portal hypertension and ICA, without evidence of infection or structural inflammatory disease.

Figure 1 Magnetic resonance cholangiopancreatography findings in isolated congenital asplenia. A: Axial T1-weighted image shows absence of the spleen, with no history of splenectomy; B: Axial T2-weighted image further confirms splenic agenesis, without evidence of accessory splenic tissue or other focal splenic lesions.

Figure 2 Portal vein computed tomography venography in isolated congenital asplenia. A: Arterial phase computed tomography (CT) image demonstrates hepatic cirrhosis, absence of the spleen, and gallbladder wall edema with pericholecystic fluid; B: Venous phase CT image confirms portal hypertension, esophageal and gastric varices, and ascites, with no evidence of splenic tissue.

MULTIDISCIPLINARY EXPERT CONSULTATION

Histopathological findings

An ultrasound-guided liver biopsy revealed mild hepatocellular degeneration with scattered spotty necrosis and focal chronic inflammatory infiltration. Portal tracts showed fibrous expansion with mild lymphocytic infiltration. Focal fibrous septa formation was observed; however, no definite pseudolobule formation or interface hepatitis was identified. Overall, the histopathological features were consistent with grade II inflammation and stage II fibrosis (Figure 3), without evidence of established cirrhosis.

Figure 3 Pathological findings of ultrasound-guided liver biopsy. A: Hematoxylin and eosin (H&E) staining (× 40); B: H&E staining (× 200).

Genetic sequencing

Whole-exome sequencing identified a heterozygous variant in the SON gene (chromosome 21: 34927155, NM_138927.1: C.5618G>A, p.Ser1873Asn), classified as a VUS. This variant has not been previously reported in association with ICA. Mitochondrial genome analysis did not identify pathogenic variants relevant to the clinical phenotype (Figure 4).

Figure 4 Genetic sequencing of a variant in the SON gene (chromosome 21 34927155, NM_138927.1: C.5618G>A, p.Ser1873Asn).

FINAL DIAGNOSIS

Based on the patient’s medical history and clinical investigations, the final diagnoses were ICA, cryptogenic liver fibrosis (precirrhotic stage), and stage 2 chronic kidney disease.

TREATMENT

The patient received therapeutic paracentesis, albumin infusion, diuretics, hepatoprotective therapy, and management of portal hypertension and metabolic abnormalities. Clinical symptoms improved, and the patient was discharged with multidisciplinary follow-up.

OUTCOME AND FOLLOW-UP

During a subsequent follow-up, intermittent elevations of liver enzymes, renal dysfunction, and hyperkalemia were observed. Following symptomatic supportive treatment, the patient’s condition stabilized, and no severe infections occurred during follow-up. Ongoing monitoring is actively being conducted by the gastroenterology and nephrology teams.

DISCUSSION

This case describes an adult patient diagnosed with ICA during evaluation for cryptogenic liver fibrosis. Unlike most ICA cases, which are diagnosed in infancy due to severe infections[5], this patient was identified incidentally during workup for chronic liver disease and remained free of life-threatening infections despite confirmed asplenia. The patient exhibited the characteristic diagnostic features of ICA, including radiologically confirmed absence of the spleen. The lack of severe infections is clinically noteworthy; however, it should be interpreted with caution. Although compensatory or adaptive immune mechanisms have been proposed in asplenic individuals, current evidence in humans remains limited and largely speculative[6].

From a genetic perspective, approximately half of familial ICA cases are associated with RPSA mutations, which disrupt splenic morphogenesis[7,8]. In this patient, no RPSA mutation was identified. Instead, whole-exome sequencing revealed a heterozygous SON VUS (NM_138927.1: c.5618G>A, p.Ser1873Asn). Mutations in the SON gene are linked to Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM: 617140), a multisystem developmental disorder characterized by neurodevelopmental abnormalities and congenital malformations[9]. However, the absence of corresponding phenotypic features in this patient argues against a classical ZTTK phenotype, and the clinical significance of the detected variant remains uncertain. Importantly, current data are insufficient to support a causal relationship between the SON variant and ICA. Therefore, this finding should be interpreted as hypothesis-generating only. The absence of parental genetic testing and functional studies further limits interpretation, and the inheritance pattern of this variant remains unclear.

A notable aspect of this case is the potential link between asplenia and liver fibrosis. With regard to liver involvement, the spleen contributes to portal venous circulation[2], and its absence may theoretically influence portal hemodynamics. However, direct evidence linking congenital asplenia to liver fibrosis in humans is lacking. Although experimental studies suggest that splenic immune modulation may affect hepatic inflammation and fibrogenesis[10,11], the clinical relevance of these mechanisms in this case remains uncertain. Therefore, any association between asplenia and liver fibrosis should be considered speculative rather than causal.

The renal impairment observed in this patient is of uncertain etiology and may be multifactorial, potentially related to chronic liver disease or other unrecognized factors. At present, no direct mechanistic link between ICA, the SON variant, and renal dysfunction can be established.

This study has several limitations. First, parental genetic analysis, functional validation, and in silico pathogenicity prediction were not available, which limits the interpretation of the identified SON variant and its potential inheritance pattern. Second, several uncommon causes of liver fibrosis, including NAFLD-related genetic susceptibility, celiac disease, and glycogen storage disorders, were not fully evaluated and therefore cannot be completely excluded. Third, as a single case report, the observed associations among ICA, the SON variant, liver fibrosis, and renal impairment cannot establish causal relationships.

Finally, patients with ICA require lifelong preventive care, including vaccination against encapsulated bacteria and prompt antibiotic therapy for febrile episodes[5]. Long-term multidisciplinary follow-up is essential, particularly in patients with concomitant hepatic or renal dysfunction.

CONCLUSION

We report a rare case of ICA associated with cryptogenic precirrhotic liver fibrosis and renal impairment in an adult patient without a history of severe infections. A heterozygous SON VUS was identified; however, its pathogenic relevance remains unclear, and no causal relationship was established with this finding. This case highlights the importance of cautious interpretation of rare variants detected by next-generation sequencing and suggests that the clinical significance of SON variants in ICA requires further investigation.

ACKNOWLEDGEMENTS

The authors would like to sincerely thank Li-Ping Chen and Yu-Chong Zhao for their valuable guidance and constructive suggestions throughout the clinical management and manuscript revision process. Their insights significantly improved the quality of this work. The authors also confirm that all necessary permissions have been obtained for the use of any copyrighted materials, including text and illustrations.