Lenore S. Levine

CLOSE GENETIC LINKAGE BETWEEN HLA AND CONGENITAL ADRENAL HYPERPLASIA (21-HYDROXYLASE DEFICIENCY)

Congenital adrenal hyperplasia (C.A.H.) with 21-hydroxylase deficiency is an autosomal recessive disease. HLA genotyping of parents and children in six families in which more than 1 child had C.A.H. established that the gene responsible for 21-hydroxylase deficiency is closely linked to HLA. One patient had inherited a maternal HLA-A/B recombinant haplotype and studies in this family indicated that the abnormal gene is close to the HLA-B locus. The findings provide a method for identification of C.A.H. carriers and for prenatal diagnosis of affected children.

Genetic Mapping of the 21-Hydroxylase-Deficiency Gene within the HLA Linkage Group

To document further the proposed genetic linkage between congenital adrenal hyperplasia due to 21-hydroxylase deficiency and HLA, 34 unrelated families from New York and Zurich, with a total of 48 patients, 48 siblings and their parents, were studied. All patients were HLA genotypically different from the healthy sibs; when two or more children were affected in the same sibship they were always HLA-B identical. The gene for 21-hydroxylase deficiency was separated by genetic recombination from the HLA-A locus and from the locus for glyoxalase I-polymorphism. No HLA-A, HLA-B or HLA-C antigen was selectively increased among the 34 unrelated patients. Lod-score analysis for HLA-B:21-hydroxylase deficiency gave a peak for theta approximately 0.00 at 5.20 for females and 4.30 for males, giving a total peak lod score of 9.5 at theta approximately 0.00 when male and female lod scores were combined. Close genetic linkage between HLA-B and 21-hydroxylase deficiency was thus established.

Long-term endocrine sequelae after treatment of medulloblastoma: Prospective study of growth and thyroid function

Endocrine evaluations were performed prospectively in 22 patients with medulloblastoma (ages 2 1/2 to 23 1/2 years at diagnosis), after craniospinal radiation with or without adjuvant chemotherapy. The mean craniospinal hypothalamic-pituitary). and thyroid radiation doses were 3600 and 2400 rads, respectively. Fourteen (73%) of 19 patients who had not yet completed their growth experienced a decrease in growth velocity. However, only three of 10 of these children, who underwent growth hormone stimulation tests, had evidence of deficient growth hormone responses, suggesting that growth hormone secretory or regulatory dysfunction, rather than absolute growth hormone deficiency, is present in the majority of these children. Elevated thyroid-stimulating hormone levels were noted in 15 of 22 patients; one patient had hypothalamic hypothyroidism. Thus, the late effects of therapy for medulloblastoma include frequent endocrine morbidity involving hypothalamic-pituitary and thyroid dysfunction.

PRENATAL DIAGNOSIS OF CONGENITAL ADRENAL HYPERPLASIA (21-HYDROXYLASE DEFICIENCY) BY HLA TYPING

Congenital adrenal hyperplasia (C.A.H.) due to 21-hydroxylase deficiency is an HLA-linked recessive disorder. HLA-A and B antigens are expressed on amniotic cells. Prenatal diagnosis of C.A.H. by HLA typing of families and amniotic cells was attempted in two at-risk families. In one family HLA typing indicated that the fetus would have C.A.H., and this prediction was confirmed after birth. In the second family, HLA typing indicated that the fetus would be an unaffected, phenotypically normal carrier of the disease gene, and this prediction was also confirmed after birth.

Depressed serum somatomedin activity in β-thalassemia

We have found bioassayable somatomedin activity to be subnormal in 20 of 32 children and adults with beta-thalassemia. The levels were comparable to values reported in growth hormone-deficient subjects. Since patients with thalassemia are not growth hormone deficient, the data suggest the possibility of defective hepatic biosynthesis of somatomedin. Increased iron stores in these patients, who have secondary hemosiderosis of many organs, including the liver, may depress somatomedin activity. Therapy for one year with daily subcutaneous infusions of the iron-chelating agent deferoxamine had no effect on mean bioassayable serum somatomedin activity.

An update of congenital adrenal hyperplasia.

Publisher Summary Congenital adrenal hyperplasia (CAH) is a family of disorders of adrenal steroidogenesis resulting from an inherited deficiency of one of several enzymes necessary for normal steroid synthesis. This chapter describes the recent advances in congenital adrenal hyperplasia. These advances have come from the interdisciplinary collaboration of embryologists, teratologists, enzymologists, immunogeneticists, population geneticists, steroid endocrinologists, and gender psychologists. The chapter describes asimplified scheme of adrenal steroidogenesis. It provides an overview of the additional evidence that supports the concept that the adrenal fasciculate and glomerulosa function as two separate glands. This has been gained from the recent study of patients with 21-hydroxylase deficiency. New data shows that in CAH, there is a 21-hydroxylation defect in the zona fasciculata of simple virilizers and salt wasters, whereas zona glomerulosa is defective in salt wasters and not in simple virilizers. The data suggest that there is one enzyme involved in the 21-hydroxylation of the 17-hydroxy and 17-deoxy pathways of adrenal steroidogenesis in zona fasciculata.

Late onset 21-hydroxylase deficiency and HLA in the Ashkenazi population: A new Allele at the 21-hydroxylase locus

Abstract The congenital form of 21-hydroxylase deficiency (21-OH-def), which results in virilization at birth from intrauterine exposure to testosterone, results from the inheritance of an HLA-linked recessive disease allele from each parent a t the 21-OH locus (the 21-OH 0 allele). In this study we establish a relationship between intermediate and late onset 21-OH-def and HLA. In studies of five Ashkenazi families, we concluded that these syndromes can be caused by either of two combinations of genes at the 21-OH locus: They can occur in individuals who carry the 21-OH 0 allele on one baplotype and who in addition inherit a “susceptibility” 21-OH-def gene (21-OH 8 ) from their other parent (genotype = 21-OH 0 /21-OH 3 ; or they can occur in individuals who are homozygous for the “susceptibility” 21-OH-def allele (21-OH 8 /21-OH 3 ). The biochemical abnormality in late onset 21-OH-deficiency is characterized by elevated basline levels of plasma 17-hydroxyprogesterone (17-OH-P) and urinary pregnanetriol and/or relatively high 17-OH-P following ACTH stimulation. Although clinical symptoms are not always present in all family members with this biochemical abnormality, the abnormality appears to behave as a simple autosomal recessive trait that is linked to HLA. Among the five probands studied, eight of the eight haplotypes from five nonconsaguinous families assumed to carry the 21-OH 3 allele had the HLA antigens B14 and DRwl and also had the factor B (Bf) S (Slow) variant. The two remaining disease haplotypes were assumed from biochemical data to carry 21-OH 0 alleles. The results suggest that the biochemical abnormality in these syndromes is linked to HLA and that the 21-OH 3 allele has nonrandom association with the particular HLA haplotype B14, DRwl, BfS in the Ashkenazi population.

Hormonal Phenotype and HLA-Genotype in Families of Patients with Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Summary: The response of 17-hydroxyprogesterone (17-OHP) and cortisol (F) to a 6-hr ACTH stimulation in families of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency was studied. These studies demonstrated that siblings who should be heterozygous carriers of the 21-hydroxylase deficiency gene based on HLA genotyping are hormonally different from the general population.In pre- and early pubertal children predicted to be heterozygous carriers of the gene based on HLA genotyping, the 17-OHP level (13.1 ± 4.5 ng/ml), the rate of increase of 17-OHP (0.03 ± 0.01), and the ratio of 17-OHP/F at 6 hr (0.27 ± 0.07) were significantly higher (P < 0.001) than in the control population, (3.9 ± 1.9, 0.009 ± 0.005, and 0.08 ± 0.04 ng/ml, respectively). In late and postpubertal males, these hormonal parameters in the heterozygotes (17 ± 9.7, 0.04 ± 0.026, 0.42 ± 0.33 ng/ml, respectively) were significantly higher (P < 0.001) than in the general population (5.3 ± 1.6, 0.009 ± 0.004, and 0.1 ± 0.03 ng/ml, respectively).In postmenarchal females, the mean hormone responses in the heterozygotes (12.1 ± 9.7, 0.03 ± 0.02, and 0.27 ± 0.24 ng/ml, respectively) were significantly higher (P < 0.005, < 0.01, < 0.005, respectively) than in the general population (5.2 ± 2.5, 0.01 ± 0.007, and 0.1 ± 0.04 ng/ml, respectively). However, the overlapping values did not permit a clear differentiation of the hormonal responses in these two groups.Another (ACTH) stimulation in one family demonstrated that a father of a patient probably is a previously unrecognized homozygous affected patient and, thus, revision of the congenital adrenal hyperplasia (CAH) genotype for this family was required.Speculation: In families of patients with CAH due to 21-hydroxylase deficiency, siblings predicted to be heterozygous carriers of the gene for 21 hydroxylase deficiency based on HLA genotyping, will express a mild enzyme deficiency by hormonal testing.

Complement C4 allotypes in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Further evidence for different allelic variants at the 21-hydroxylase locus

Abstract The gene frequencies and haplotype frequencies for the alleles of the C4A and C4B loci were determined in a population of 39 unrelated Italian patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OH) deficiency and compared with the frequencies of the C4 alleles and C4 haplotypes present on the normal parental HLA haplotypes (i.e., the parental HLA haplotypes which did not carry the 21-OH deficiency allele). There was a decrease in the C4A ∗ QO (null) allele among the patients (uncorrected P C4A ∗ 4 allele. The gene frequencies of the C4B locus were similar in the two groups. The very rare C4B ∗ 3 allele occurred in one patient. Overall, the C4A;C4B haplotypes were very similar in the two groups. In the patient group there was a slight increase in the frequency of the C4A ∗ 3; B ∗ QO haplotype and the C4A ∗ 4; B ∗ 2 haplotype, whereas the C4A ∗ QO; B ∗ 1 and C4A ∗ QO; B ∗ 2 haplotypes were decreased or absent. One patient had the very rare haplotype C4A ∗ QO;B ∗ 3 , and was positive for the low frequency HLA-Bw47 determinant on the same haplotype. Seven patients with classical CAH and two patients with late onset 21-OH deficiency, who had the Bw47 antigen, were also found to have the unique complotype C4A ∗ QO; B ∗ 3; BF ∗ F: C2 ∗ C . Eleven additional patients with the HLA-B14, DR1-associated disease variant late onset 21-OH deficiency and four individuals with cryptic, asymptomatic 21-OH deficiency were also typed for the C4 electrophoretic variants. The 19 haplotypes with B14;DR1 all had the complotype C4A ∗ 2;B ∗ 2;BF ∗ S;C2 ∗ C . The rare C2 ∗ B allele of the C2 locus was found on 10 haplotype with 21-OH deficiency. The complotype on eight of these was C4A ∗ 4;B ∗ 2;BF ∗ S; C2 ∗ B . The C2 ∗ B was found only once on the normal parental HLA haplotypes. This study provides additional evidence for the hypothesis that the mutation on the 21-OH locus associated with HLA-Bw47 is unique and different from the mutation on the 21-OH locus resulting in the late onset or cryptic 21-OH deficiency allele associated with B14. It is likely that many independent mutations have acted on the 21-OH locus and that the clinical and biochemical heterogeneity of the 21-OH deficiency syndromes reflect heterogeneity in the DNA assaults.

IS SALT‐WASTING IN CONGENITAL ADRENAL HYPERPLASIA DUE TO THE SAME GENE AS THE FASCICULATA DEFECT?

Clinical studies in patients with 21‐hydroxylase deficiency congenital adrenal hyperplasia (CAH) were designed to ascertain the genetics of the salt‐wasting component of the disorder. The gene controlling aldosterone biosynthesis may not be the same gene that controls 21‐hydroxylase in the adrenal zona fasciculata. This we infer from the following clinical observations: (1) concordance for salt‐wasting is not observed in all HLA‐identical sibs with CAH; (2) the defect in aldosterone biosynthesis does not persist throughout life as does the fasciculate defect; (3) there is a significantly increased gene frequency of B40 and Bw47 in salt‐wasting CAH; (4) obligate heterozygote parents of patients with salt‐wasting CAH do not express a partial defect in aldosterone biosynthesis, as they do in the fasciculata. These observations cast doubt on the accepted concept of the autosomal recessive transmission of the glomerulosa 21‐hydroxylase deficiency.