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Cryptic 21-Hydroxylase Deficiency in Families of Patients with Classical Congenital Adrenal Hyperplasia^*

Division of Pediatric Endocrinology New York, New York 10021
Department of Pediatrics, The New York Hospital-Cornell Medical Center, and the Tissue Typing Laboratory New York, New York 10021
Sloan-Kettering Institute for Cancer Research New York, New York 10021
Clinica Pediatrica dell'Universita 40138 Bologna, Italy
Instituto di Semeiotica Medica Padova, Italy
Dell'Universita di Padova Padova, Italy
Centro di Endocrinologica Infantile 20157Milano, Italy
Clinica Pediatrica III, Dell'Universita di Milano, Ospedale "L. Sacco," 20157 Milano, Italy
Universita Degli Studi di Parma 43100 Parma, Italy
Instituto di Clinica Pediatrica 43100 Parma, Italy
Clinica Pediatrica 60100 Ancona, Italy
Dell'Universita Degli Studi di Ancona, Ospedale Salesi 60100 Ancona, Italy
Universita di Cagliari 09100 Cagliari, Italy
La Clinica Pediatrica, Centro di Endocrinologica Pediatrica 09100 Cagliari, Italy
Ospedale Borgonuovo Verona, Italy
Clinica Pediatrica Verona, Italy
Ospedale Provinciale Specializzato Bologna, Italy
M. Malpighi, Laboratorio di Analisi Cliniche Bologna, Italy

Address requests for reprints to: Dr. Lenore S. Levine, Department of Pediatrics, Division of Pediatric Endocrinology, New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, New York 10021.

Serum androgens and 17-hydroxyprogesterone concentrations and HLA genotypes were determined in 124 families of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH). In 8 pedigrees, we discovered 16 pubertal or postpubertal family members of either sex who had biochemical evidence of 21-hydroxylase deficiency but were without clinical symptoms of excess virilism, amenorrhea, or infertility. We designated these family members as individuals with cryptic 21-hydroxylase deficiency. Within each generation, the family members with cryptic 21-hydroxylase deficiency were HLA identical.

It is proposed that these family members are genetic compounds, having 21-hydroxylase deficiency as a result of two recessive gene defects: 1) a severe 21-hydroxylase gene defect present in the index case with classical CAH (21-OH^CAM) and 2) a mild 21-hydroxylase gene defect (21-OH^CRYPTIC). Thus, the CAH genotype in the family members with cryptic 21-hydrox-ylase deficiency is 21-OH^CAf/21-OH^CRYPTIC.

Lod score analysis for linkage between the cryptogenic 21-OH trait and HLA gave a combined Lod score for males and females of = 0.00 of 3.409. Close genetic linkage between HLA and 21-OH^CRYPTIC was thus established.

This study provides support for the previously reported heterogeneity of 21-hydroxylase deficiency which may result from allelic variability at the locus for steroid 21-hydroxylase.

^* This work was supported in part by USPHS, NIH Grants HD-00072 and HD-5895 from the NICHHD; CA-22507, CA-08748, and CA-19267 from the NCI; and AICA-16093 from the NIAID and a grant (RR-47) from the General Clinical Research Centers Program of the Division of Research Resources, NIH. This investigation was also aided by a grant from the Fairchild Foundation, and travel grants from the Mary W. Harriman Foundation and The New York Hospital-Cornell Medical Center Urologic Research Fund under the direction of Dr. David T. Mininberg.

Received April 28, 1980.

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