Endocrine Abstracts

We present two families illustrating complex management issues introduced by mutational analysis in CAH.

Family 1. A female index case presented at birth with ambiguous genitalia and was diagnosed with severe salt losing CAH. She is a compound heterozygote with two severe mutations: 659G (intron 2 splice site mutation) from her mother and CYP21 deletion from her father. Mother and mother's identical twin sister have compound heterozygosity for the mild mutation 1688G>T and the severe mutation 659G, but are clinically well untreated, despite biochemistry consistent with late onset CAH. They had early adrenarche and puberty, and normal height. The duplication of the functional 21B gene at the site of the 1688G>T may have allowed compensation in them.

In mother's 2nd pregnancy, prenatal testing identified a compound heterozygote boy with a CYP21 deletion from his father, and the mild mutation 1688G>T from his mother, with the potentially protective 21B duplication. Initial biochemistry was abnormal with raised 17OHP, an exaggerated response to stimulation, and a borderline cortisol response. Subsequently 17OHPs normalised. He remains well untreated.

Family 2. A male index case presented at aged 9yrs with advanced bone age, tall stature and virilisation. Biochemistry was consistent with late onset CAH. On mutational analysis, he is a compound heterozygote for two mild mutations 1004T>A and 1688G>T.

His father has the same genotype but is asymptomatic with normal fertility, puberty and stature. The mother is a carrier of 1688G>T (mild) mutation and is clinically unaffected. The sister is homozygous positive for 1688G>T and remains asymptomatic. Two brothers tested positive for 1004>T but negative for 1688G>T. They are carriers of late onset CAH and are unaffected. All the siblings are untreated.

These kindreds illustrate the importance of family history, biochemistry and mutational analysis when formulating a management plan for treatment of CAH.