Virilizing Adrenal Hyperplasia; A Genetic and Hormonal Study 1

Abstract

It is not at all unusual to find other affected children among the brothers and sisters of patients with virilizing adrenal hyperplasia. Such familial aggregations of affected children suggest, at least, a genetic basis for the condition at hand, and when the affected individuals are distributed in one generation only, there is a possibility that the condition is due to a mutant gene which finds obvious expression in the homozygote. This mode of inheritance for a possible gene responsible for virilizing adrenal hyperplasia has been suggested (1-3). Knudson (2) obtained information on 8 families, including 11 affected children. To these he added 26 families taken from the literature in which there were 32 affected children. Comparison of the observed number of affected sibs of index cases with that expected indicated sufficient agreement to favor the hypothesis of a recessive gene. All of Knudson's cases, however, were patients who showed evidence of electrolyte disturbance, and there appears to be no study which includes all types of cases which fall into this syndrome. This paper consists of information pertaining to a possible genetic etiology of this disease, obtained from 56 families containing one or more affected individuals, and an hormonal study of a group of parents of affected children. An exhaustive review of the literature is not relevant here, since our interpretations are based only upon the results of the analysis of our own data and not upon information from families that has been presented in other articles. MATERIALS AND METHODSThe data were obtained from the families of all patients with virilizing adrenal hyperplasia who were examined and diagnosed in the endocrine clinic of the Harriet Lane Home since 1945. Diagnostic criteria are those given by Wilkins (4). In each instance the information was given by the mother or responsible parent, and in a few cases by the patient himself. Some questions were put by means of a questionnaire which was mailed to all families, but since in some cases parents failed to answer the questionnaire and were otherwise unavailable, the data are in certain aspects incomplete.The data consist of information pertaining to: disease in sibs and other relatives, together with intra-family characteristics of the disease; age of sibs, their sex, maternal age at birth, birth order, death, age, cause, and place of death; maternal gestation and parturition; parental consanguinity; and size of the families of both parents.In some families all affected children were patients of the endocrine clinic, but there were 12 sibs of endocrine clinic patients who are presumed to have or have had the disease, who have never been seen in the Harriet Lane Home. Of these, 3 are still living, and detailed inquiry reveals that a firm diagnosis has been made on all three. The remaining 9 were dead by the time the index case was seen here. A diagnosis, either during life or at autopsy, was made elsewhere on 5 of these. This leaves 4 cases who were dead and who were not diagnosed as patients ...

Neonatal Screening for Congenital Adrenal Hyperplasia Using a Microfilter Paper Method for 17-α-Hydroxyprogesterone Radioimmunoassay

“…From our investigation a frequency of CAH with and without salt loss in the Emilia-Romagna Re gion of 1/5,556 can be calculated. This corre sponds to a heterozygote frequency of 1/37, CAH being transmitted as an autosomal re cessive trait [14,15], The 4 cases we detected (3 females and 1 male) include two forms with salt loss (table I, cases 1 and 4), one form without salt loss (table I, case 2) and 1 case (table I. case 3) that might be described ery 5.556 children born. This corresponds to one heterozygote every' 300 subjects, for as a late [16,17] or acquired [18] or cryptic form [ 19] of CAH based on the high values of 17-OH-P and the absolute absence of clinical signs.…”

“…The reported incidence of CAH varies inter nationally from 1:490 in the Eskimos of Al aska to 1:67,000 in one of the American States [9][10][11][12][13][14]. The lack of a screening proce dure makes an estimation of the incidence questionable.…”

Aldosterone hypersecretion in “non-salt-losing” congenital adrenal hyperplasia

“…Furthermore, it appears clear that the two syndromes are genetically -distinct from each other ( 17) although there are reports which tend to question this conclusion (18). It has been suggested that the difference between the two syndromes is one of degree of block in 21-hydroxylation, the sodium-losing variety representing the more severe block (2,8).…”

High Frequency of Nonclassical Steroid 21-Hydroxylase Deficiency

“…The classical form of congenital adrenal hyperplasia with steroid 21-hydroxylase deficiency is transmitted by an autosomal recessive gene [1] and is closely linked to the HLA-B locus on the short arm of chromosome 6 [2] with peak total lod scores as high as 9.5 [3] and 15.65 [4] for 0 (recombinant fraction) = 0. Linkage disequilibrium with the HLA-Bw47;DR7 haplotype segment has been demonstrated [5][6][7], and more recently the gene has been further localized to the C4 region of the HLA supergene by molecular genetic techniques [8,9].…”