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Novel Presentation of Congenital Bile Acid Synthesis Defect-3 with Skeletal Abnormalities and Hypotonia

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
Congenital bile acid synthesis defect-3 (CBAS3) (OMIM #613812) is an extremely rare genetic condition with autosomal recessive inheritance, caused by a homozygous or compound heterozygous pathogenic variants in the CYP7B1 gene on chromosome 8q12.3 (OMIM #613812). Pathogenic variants lead to a deficiency of the oxysterol 7α-hydroxylase enzyme, preventing the breakdown of cholesterol into bile acid. CBAS3 is characterized by hepatomegaly, prolonged jaundice after birth, failure to thrive, elevations in abnormal bile acids, conjugated hyperbilirubinemia, diarrhea, steatorrhea, cirrhosis, and progressive intrahepatic cholestasis with liver fibrosis. Currently, there are fewer than 10 cases reported in the medical literature.

Case Presentation
This female was born at 28 weeks gestation to a 32-year-old gravida 3 para 2>3 mother and 34-year-old father of Syrian descent; the parents are consanguineous (first cousin once removed). Pregnancy was complicated by maternal COVID infection, placental abruption, and intrauterine growth restriction. New York State newborn screen was normal. Neonatal period was complicated by grade 1 intraventricular hemorrhage, retinopathy of prematurity, and acquired CMV. Infant first presented to the ED at 4-months-old for evaluation of seizure-like activity with no reported history or signs of trauma.

Diagnostic Workup
Growth parameters (adjusted for age of 4 months) include length 13th percentile, weight 40th percentile, head circumference 94th percentile. Head CT identified bilateral subdural hematomas concerning for non-accidental trauma, and dilated funduscopic exam identified unilateral intraretinal hemorrhages; neither of these findings were present on ultrasound or ophthalmologic evaluation in the neonatal period, ruling out birth-related injury. MRI brain was negative for parenchymal injury, restricted diffusion, and CNS lesion.



Labs were notable for transaminitis (ALT 166, AST 114) but were otherwise normal. Abdominal CT was negative for injury. Both initial and follow up skeletal surveys were negative for fractures but noted cupping of the distal metaphyses of the ulnae and radii. Glutaric aciduria was considered despite a normal newborn screen; urine C5-DC and plasma acylcarnitine testing were negative. The family denied any history of trauma during CPS investigation.



At genetics consultation, generalized hypotonia and ankle clonus were appreciated, as well as hypoplastic clavicles and dysplastic acetabulae on x-ray imaging. Whole exome sequencing revealed a homozygous pathogenic variant in the CYP7B1 gene, denoted c.889 A>G p. (T297A).

Treatment and Management
Gastroenterology consultation and workup are pending for persistently elevated transaminases without hyperbilirubinemia, which is concerning for a hepatic disorder.

Outcome and Follow-Up
Opthamology, neurosurgery, and neurology continue to follow. Early intervention evaluation is pending based on concern for delayed developmental milestones and referral to developmental pediatrics was placed due to risk for cerebral palsy.

Discussion
Genetic sequencing confirmed that this female infant has a homozygous recessive variant in the CYP7B1 gene consistent with CBAS3. Although she did not have hepatosplenomegaly or jaundice at birth, she does have some clinical findings typical of CBAS3, including elevated liver enzymes and early struggles to gain weight, which are improving. This infant may have a novel presentation of CBAS3 in the form of skeletal abnormalities, hypotonia, and elevated transaminases without hyperbilirubinemia, which are not typical of the disease. Furthermore, she has bilateral subdural hematomas and unilateral intraretinal hemorrhages, which are not explained by birth injury or prematurity. While the family denied any history of trauma and CPS investigation did not find any evidence of abuse, the possibility of non-accidental injury cannot be excluded.

Conclusion
The abnormal clinical presentation of this patient suggests a novel phenotype, which may be due to the confounding effects from CBAS3, pregnancy complications, and other external factors. Possible areas for further research include inducing the pathogenic variant of the CYP7B1 gene in a bone marrow cell line to observe for microanatomical changes or inducing the same variant in a mouse model and observing for any musculoskeletal abnormalities, such as hypotonia and skeletal malformations. Additionally, further observation of the child’s progress and the arise of any new findings could inform clinicians of other possible presentations of CBAS3.

 

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