3β-hydroxysteroid dehydrogenase type II deficiency on newborn screening test

Area of Science:

• Endocrinology
• Genetics
• Pediatrics

Background:

• Congenital adrenal hyperplasia (CAH) encompasses a group of genetic disorders affecting adrenal steroidogenesis.
• 3β-hydroxysteroid dehydrogenase II (3β-HSD) deficiency is a rare CAH variant characterized by impaired cortisol and androgen synthesis.
• Classic 3β-HSD deficiency presents with salt-wasting crises and ambiguous genitalia in newborns.

Observation:

• Newborn screening tests for CAH can yield positive results due to elevated 17-hydroxyprogesterone (17OHP), potentially influenced by extra-adrenal conversion of 17-hydroxypregnenolone (Δ517OHP).
• A 46,XY infant with genital ambiguity and adrenal crisis showed elevated serum 17OHP and Δ517OHP, with a high Δ517OHP/cortisol ratio.
• Molecular analysis identified a homozygous p.P222Q mutation in the HSD3B2 gene in the affected infant, with heterozygous parents.

Findings:

• This case represents the first genotype-proven 3β-HSD type II deficiency detected through the Newborn Screening Program in Brazil.
• The findings confirm a strong genotype-phenotype correlation for the HSD3B2 p.P222Q mutation, leading to classic salt-wasting 3β-HSD deficiency.
• Elevated Δ517OHP levels are characteristic of 3β-HSD deficiency.

Implications:

• Early detection of 3β-HSD deficiency via newborn screening is crucial for timely intervention and management of potentially life-threatening conditions.
• Further evaluation of 17OHP assay reproducibility in newborn screening is warranted.
• Moderately elevated 17OHP levels may serve as an early indicator for diagnosing other forms of classic CAH beyond 21-hydroxylase deficiency.