21-Hydroxylase Deficient Congenital Adrenal Hyperplasia Due to Maternal Uniparental Isodisomy

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD CAH) is an autosomal recessive genetic condition that results from pathogenic variants in the CYP21A2 gene. Noncarrier parents are found in a small percentage of cases, typically due to de novo variants. However, uniparental disomy (UPD) should also be considered. UPD is generally suspected when an individual with an autosomal recessive condition is found to be homozygous for a rare pathogenic variant and consanguinity has been ruled out. However, UPD in CYP21A2 may be hard to recognize because homozygous genotypes are not uncommon. We present the case of a 19-month-old male born preterm who presented to pediatric endocrinology after a positive newborn screen for CAH. He was small for gestational age, with a history of adrenal crisis and elevated 17-hydroxyprogesterone (17-OHP). Genetic testing revealed homozygosity for two common pathogenic CYP21A2 variants: c.293-13C >G and c.1360C >T (p.Pro454Ser), both variants were found in the heterozygous state in the mother while the father's CYP21A2 molecular testing was negative. UPD testing was pursued and the results were consistent with the patient having maternal isodisomy of chromosome 6. In cases of patients with CAH due to homozygous CYP21A2 variants, suspicion for UPD may be increased if the child also presents with intrauterine growth restriction (IUGR), or transient neonatal diabetes (TNDM) mellitus, associated with maternal and paternal UPD of chromosome 6, respectively.