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Divergent Phenotype of Two Siblings Human Leukocyte Antigen Identical, Affected by Nonclassical and Classical Congenital Adrenal Hyperplasia Caused by 21-Hydroxylase Deficiency

Departments of Internal Medicine (O.P., V.C., M.M., E.D.N., G.F.) and Biopathology and Diagnostic Imaging (E.G.), University of Rome "Tor Vergata," 00133 Rome, Italy; Immunogenetics Laboratory (M.A., M.T.), Mediterranean Institute of Hematology (MIH) Foundation, 00133 Rome, Italy; Endocrinology and Diabetology Unit and Research Laboratory (M.C., G.F.), Bambino Gesù Children’s Hospital, 00165 Rome, Italy; and Division of Paediatrics B. Trambusti (A.A., L.C.), University of Bari, 70126 Bari, Italy

Address all correspondence and requests for reprints to: Ottavia Porzio, M.D., Department of Internal Medicine, University of Rome "Tor Vergata," Via di Montpellier 1, 00133 Rome, Italy. E-mail: porzio{at}uniroma2.it.

Context: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders most often caused by enzyme 21-hydroxylase deficiency. Most mutations causing enzymatic deficiency are generated by recombinations between the active gene CYP21 and the pseudogene CYP21P. Only 1–2% of affected alleles result from spontaneous mutations. The phenotype of CAH varies greatly, usually classified as classical or nonclassical, depending on variable degree in 21-hydroxylase activity. Here we report a divergent phenotype of two human leukocyte antigen identical siblings, affected by nonclassical and classical CAH caused by 21-hydroxylase deficiency due to different genotype.

Patients and Methods: Using direct sequencing method and Southern blot, we studied two children (one male and one female), affected, respectively, by nonclassical and classical CAH and their parents.

Results: The mother was heterozygous for the Q318X mutation, and the father was heterozygous for the V281L mutation. The brother was a compound heterozygote for the mutations V281L and Q318X, whereas the proband was compound heterozygote for the Q318X mutation and a large conversion. The two children are human leukocyte antigen identical (A*02;B*14;DRB1*01/A*33;B*14;DRB1*03).

Conclusions: Different phenotype of the proband is the result of compound heterozygosity for the maternal mutation Q318X and a de novo large conversion.

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