A Novel Homozygous HSD3B7 Frameshift Variant Causing Congenital Bile Acid Synthesis Disorder Type 1 Presenting in Mid-Childhood with Malabsorption-Dominant Phenotype and Renal Microcysts: A Case Report

Technical Summary: A Novel Homozygous HSD3B7 Frameshift Variant in Mid-Childhood CBAS1

Problem Statement
Congenital bile acid synthesis disorder type 1 (CBAS1), caused by a deficiency in the enzyme 3β-hydroxy-Δ5-C27-steroid oxidoreductase (encoded by HSD3B7), classically presents in the neonatal period with cholestatic jaundice, hepatomegaly, and progressive liver disease. However, the recognition of attenuated, late-presenting phenotypes remains a significant diagnostic challenge. Clinicians often overlook CBAS1 in children presenting in mid-childhood with non-specific gastrointestinal symptoms (such as steatorrhoea) and subtle biochemical liver abnormalities, particularly when there is no history of neonatal cholestasis. This diagnostic delay leads to prolonged morbidity, including preventable fat-soluble vitamin deficiencies and progressive hepatic injury. Furthermore, the molecular spectrum of HSD3B7 variants associated with these milder phenotypes is not fully characterized, and the extent of extra-hepatic involvement (specifically renal) in older children remains under-explored.

Methodology
The study presents a detailed case report of a 7-year-old girl of consanguineous Pakistani descent referred for evaluation of chronic fatigue, iron-deficiency anaemia, and persistent mild transaminase elevation. The investigation followed a multi-modal approach:

• Clinical Assessment: Evaluation of growth parameters, physical examination (noting splenomegaly and xerosis), and a review of family history (consanguinity and paternal gastrointestinal symptoms).
• Biochemical Analysis: Serial monitoring of liver function tests (AST, ALT, bilirubin, GGT), coagulation profiles (INR, Prothrombin Time), and inflammatory markers (ESR). Comprehensive fat-soluble vitamin levels (A, D, E, K) were assessed.
• Metabolic Profiling: Urinary bile acid analysis was performed using electrospray tandem mass spectrometry (ESI-MS/MS). This included precursor-ion scanning to identify specific conjugated bile acid patterns.
• Genetic Analysis: Targeted next-generation sequencing (NGS) using a cholestasis gene panel was conducted to identify causative variants. Sanger sequencing confirmed the zygosity of the identified variant in the patient and carrier status in the parents.
• Imaging: Abdominal ultrasound was utilized to assess hepatic and renal morphology.
• Therapeutic Trial: The patient was treated with oral cholic acid (15 mg/kg/day) and fat-soluble vitamin supplementation, with biochemical and clinical parameters re-evaluated at six weeks.

Key Results

• Clinical Presentation: The patient presented with a malabsorption-dominant phenotype characterized by steatorrhoea, growth faltering (height dropping to the 3rd centile), and signs of fat-soluble vitamin deficiency (pruritus, xerosis, bruising, delayed wound healing). Notably, she had no history of neonatal cholestasis or jaundice.
• Biochemical Findings: Liver biochemistry showed only mild, isolated transaminase elevation (AST 58 U/L, ALT 49 U/L) with normal bilirubin and GGT. Significant deficiencies in vitamins A, D, and E were confirmed, along with coagulopathy (elevated INR).
• Metabolic Profile: Urinary bile acid profiling revealed a pathognomonic pattern for CBAS1: markedly elevated glycine- and sulphate-conjugated dihydroxy- and trihydroxycholenoic acids, with a total urinary bile acid concentration of 9.8 mmol/L.
• Genetic Findings: NGS identified a novel homozygous frameshift variant in HSD3B7 (NM_025195.4:c.714_725del, p.(His238Profs*1)). This 12-nucleotide deletion predicts a premature truncation of the protein, resulting in the loss of the C-terminal catalytic domain. The variant was absent from population databases (e.g., gnomAD) and fulfilled ACMG criteria for likely pathogenicity (PVS1, PM2).
• Imaging Findings: Abdominal ultrasound incidentally identified bilateral renal microcysts and echogenic foci, a finding previously associated with bile acid disorders but rarely documented in school-age children with mild phenotypes.
• Treatment Response: Initiation of cholic acid therapy resulted in substantial biochemical improvement within six weeks, including normalization of coagulation, ESR, and transaminases, alongside significant replenishment of vitamins D and E and resolution of steatorrhoea symptoms.

Key Contributions
The paper makes three distinct contributions to the literature on CBAS1:

1. Molecular Expansion: It identifies a novel homozygous frameshift variant in HSD3B7 not previously reported in literature or population databases. This expands the known molecular spectrum of CBAS1, reinforcing the observation that truncating variants can present with attenuated, late-onset phenotypes rather than solely severe neonatal disease.
2. Phenotypic Characterization: It documents a specific "malabsorption-dominant" phenotype in mid-childhood that lacks neonatal antecedents. This presentation is frequently missed by clinicians, leading to years of diagnostic uncertainty. The case highlights that unexplained fat malabsorption with even subtle hepatic abnormalities warrants metabolic investigation regardless of neonatal history.
3. Renal Involvement Evidence: It provides evidence that renal microcysts are an authentic component of the CBAS1 phenotype that can persist into or manifest in mid-childhood, challenging the notion that renal involvement is restricted to the neonatal or early infantile period.

Significance and Claims
The authors assert that this case supports a shift in clinical practice regarding the investigation of pediatric malabsorption. Specifically, the paper claims:

• Diagnostic Urgency: Any child presenting with unexplained fat malabsorption and subtle hepatic biochemical abnormalities should undergo targeted urinary bile acid analysis via tandem mass spectrometry, irrespective of their neonatal history. This non-invasive test is highly sensitive and specific for CBAS.
• Therapeutic Implication: Early identification allows for the initiation of bile acid replacement therapy (cholic acid), which is disease-modifying. It prevents progressive hepatic injury and reverses the complications of fat-soluble vitamin deficiency, as demonstrated by the rapid response in this patient.
• Comprehensive Assessment: Renal imaging should be included in the initial assessment of children with suspected CBAS1, as renal manifestations may be present beyond infancy.

The paper concludes that the phenotypic continuum of CBAS1 is broader than classical descriptions suggest, and that diagnostic delays carry real, preventable risks of irreversible hepatic fibrosis and metabolic bone disease.