Double Trouble: Co-Occurrence of Aromatase Deficiency and Non-Classic CAH in Three Siblings

Abstract

Introduction: Aromatase deficiency (AD), an exceedingly rare autosomal recessive condition, causes virilization in females and tall stature with metabolic derangements in males. Clinical manifestations result from decreased estrogen production and androgen excess, but presentation varies based on residual aromatase activity. Non-classic CAH (NCCAH) is a relatively common disorder. Males are often asymptomatic or present with premature adrenarche (PA). Females are typically diagnosed during childhood/adolescence with PA, acne, hirsutism, or menstrual irregularities. We present three siblings with both conditions and describe their long-term follow-up. Cases: Identical twin sisters presented at birth with virilized genitalia. Evaluation revealed 46XX karyotype, transiently elevated testosterone (unchanged with hCG stimulation), normal 17OHP and normal ovarian tissue on gonadal biopsy. Due to sporadic follow-up, their diagnosis and care were delayed until age 15y when AD was confirmed with genetic testing (compound heterozygous: whole gene deletion on one allele and c.242A>G (p.tyr81cys) mutation on the other). Both girls had acne, hirsutism and clitoromegaly, but reached spontaneous menarche at 11y and height within mid-parental height (MPH). Given the genetic nature of AD, younger brother was assessed and diagnosed with AD with the same mutation in CYP19A1. He had normal height-corrected BMD, lipids and glucose. His testosterone level was high-normal with undetectable estradiol. He had height below MPH with slow growth velocity, low IGF-1 and bone age (BA) within 2SD for age (BA 14y at CA 15y). GH stimulation test with estrogen priming revealed GH peak of 4.1 ng/ml, consistent with GH deficiency. All three siblings had high baseline and stimulated 17OHP which prompted genetic testing for CAH and confirmed NCCAH due to homozygous pVal282Leu substitution in CYP21A2. Treatment for both AD and NCCAH in females is combined estrogen+progesterone (usually given as an oral contraceptive pill), to replace estrogen and suppress androgen overproduction. The twin sisters elected clitoral reduction at age 19y with a satisfactory outcome. Their brother is not on any treatment at this time. At age 18y, his BA is still 14y-14.5y, as expected in AD, but atypical for NCCAH. Conclusion: Virilized genitalia in the newborn period prompted extensive evaluation of twin sisters that led to diagnosis of AD but also prompted assessment and diagnosis of their asymptomatic brother. Elevation of 17OHP, previously not described in AD patients, prompted testing for CAH and confirmed the unique finding of both AD and NCCAH in these three siblings. We postulate that the combined AD/NCCAH caused exacerbation of androgen excess in all three siblings. The short stature in our male patient is presumably due to GH deficiency.