Alternative titles; symbols
SNOMEDCT: 54470008; ORPHA: 418, 90791; DO: 0050811;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p12 | Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency | 201810 | Autosomal recessive | 3 | HSD3B2 | 613890 |
A number sign (#) is used with this entry because of evidence that congenital adrenal hyperplasia (CAH) due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency is caused by homozygous or compound heterozygous mutation in the HSD3B2 gene (613890) on chromosome 1p12.
Classic 3-beta-hydroxysteroid dehydrogenase deficiency is an autosomal recessive form of CAH characterized by a severe impairment of steroid biosynthesis in both the adrenals and the gonads, resulting in decreased excretion of cortisol and aldosterone and of progesterone, androgens, and estrogens by these tissues. Affected newborns exhibit signs and symptoms of glucocorticoid and mineralocorticoid deficiencies, which may be fatal if not diagnosed and treated early, especially in the severe salt-wasting form. Moreover, male newborns exhibit pseudohermaphroditism with incomplete masculinization of the external genitalia due to an impairment of androgen biosynthesis in the testis. In contrast, affected females exhibit normal sexual differentiation or partial virilization (summary by Rheaume et al., 1992).
Virilization is much less marked or does not occur in this type, suggesting that the gene-determined defect involves the testis as well as the adrenal. Males with the defect have hypospadias. Indeed, this form of adrenal hyperplasia can cause male pseudohermaphroditism. Salt loss is a frequent cause of death. Death may occur even with adequate adrenal replacement therapy, perhaps because of the enzyme deficiency in other organs. Zachmann et al. (1979) concluded that estrogen replacement (at a bone age of about 12 years) is required because of the involvement of the ovaries as well as the adrenal. This disorder was first reported by Bongiovanni in the early 1960s (see Bongiovanni, 1962).
Cravioto et al. (1986) referred to the enzyme deficient in these cases as 3-beta-hydroxysteroid dehydrogenase-isomerase. They described a brother and sister with an unusual form of 3-beta-HSD deficiency. The brother, aged 19 years, had a history of repeated episodes of acute adrenal crisis. The affected sister was 6 years old. A brother born between them had died of acute adrenal crisis. The findings concerning steroid levels at rest and after ACTH or hCG stimulation, coupled with normal phenotypic development and onset of puberty in the 2 patients, indicated intact C-19 steroid 3-beta-HSD activity.
Mendonca et al. (1987) described 2 adult cousins with male pseudohermaphroditism due to 3-beta-HSD deficiency without clinical salt-losing. Both patients had been reared as females since birth. One patient presented at age 17 with perineal hypospadias, virilization without gynecomastia, and a female-to-male gender role change at puberty. The second patient had undergone bilateral orchidectomy in childhood and presented 'primary amenorrhea,' absence of virilization, and a female gender role at the age of 24. Nishi and Tezuka (1992) studied 7 girls and 1 boy, of whom 3 were sibs, with accelerated growth and premature pubarche and/or hirsutism between the ages of 7 and 9.5 years. They concluded that the children had a mild form of 3-beta-hydroxysteroid dehydrogenase deficiency.
To test their hypothesis that the hormonal phenotype of HSDB3 deficiency in hyperandrogenic females is related to insulin-resistant polycystic ovary syndrome (PCOS; see 184700), Carbunaru et al. (2004) compared insulin sensitivity and gonadotropin secretion in 6 hyperandrogenic females with compromised adrenal HSDB3 phenotype despite normal HSDB3 genes to those in 9 hyperandrogenic females with classic PCOS of similar ages (14 to 36 years). The same was examined in girls with premature pubarche, 4 with and 5 without the compromised HSDB3 phenotype. The authors found that insulin sensitivity and gonadotropin data in both hyperandrogenic females with the compromised HSDB3 phenotype and classic PCOS indicated significant insulin resistance and LH (see 152780) hypersecretion in both. They concluded that the compromised HSDB3 phenotype in hyperandrogenic females is associated with a variant of insulin-resistant PCOS.
By in situ hybridization, Berube et al. (1989) demonstrated that the gene for 3-beta-hydroxysteroid dehydrogenase/isomerase is located on the 1p13 band. By in situ hybridization, Morrison et al. (1991) refined the localization to 1p13.1. Bain et al. (1993) demonstrated that the genes encoding the gonadal (HSD3B2) and nongonadal (HSD3B1) forms of 3-beta-hydroxysteroid dehydrogenase are encoded by closely linked genes on mouse chromosome 3. They are located within a segment that is conserved on human chromosome 1.
To define the hormonal criteria via genotypic proof for HSDB3 deficiency in the adrenals and gonads, Lutfallah et al. (2002) investigated the type II 3-beta-HSD genotype in 55 patients with clinical and/or hormonal presentation suggesting compromised adrenal with or without gonadal HSDB3 activity. The hormonal findings in the genotype-proven patients suggested that the following hormonal criteria are compatible with HSDB3 deficiency CAH: ACTH-stimulated 17-hydroxypregnenolone in (1) neonates with ambiguous genitalia at or greater than 378 nmol/liter equivalent to or greater than 5.3 SD above the control mean level (95 +/- 53 SD nmol/liter); (2) Tanner I children with ambiguous genitalia at or greater than 165 nmol/liter equivalent to or greater than 35 SD above the control mean level (12 +/- 4.3 SD nmol/liter); (3) children with premature pubarche at or greater than 294 nmol/liter equivalent to or greater than 54 SD above Tanner II pubic hair stage-matched control mean level (17 +/- 5 SD nmol/liter); and (4) adults with at or greater than 289 nmol/liter equivalent to or greater than 21 SD above the normal mean level (25 +/- 12 SD nmol/liter).
In 3 families with the classic severe form of 3-beta-HSD deficiency, Rheaume et al. (1992) detected 2 mutations in the HSD3B2 gene, one nonsense (W171X; 613890.0001) and the other frameshift (613890.0002). The nonsense mutation was found in homozygosity in 2 of the families, which were related. The index case of the third family was a compound heterozygote for W171X and the frameshift mutation.
Welzel et al. (2008) described the functional consequences of 3 C-terminal mutations in the 3-beta-HSD protein that were found in 4 patients with the classic form of beta-3-HSD deficiency with varying degrees of undervirilization. One of these was a missense mutation (P341L; 613890.0011) and the other 2 were nonsense mutations. The P341L mutation showed a residual DHEA conversion of 6% of wildtype activity. Additional analysis of P341L, including 3-dimensional protein modeling, revealed that the mutant's inactivity predominantly originated from a putative structural alteration of the 3-beta-HSD protein and was further aggravated by increased protein degradation. The stop mutations caused truncated proteins missing the final G helix that abolishes enzymatic activity irrespective of an augmented protein degradation. Genital appearance of the mutation carriers did not correlate with the mutants' residual in vitro activity.
Bain, P. A., Meisler, M. H., Taylor, B. A., Payne, A. H. The genes encoding gonadal and nongonadal forms of 3-beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase are closely linked on mouse chromosome 3. Genomics 16: 219-223, 1993. [PubMed: 8486361] [Full Text: https://doi.org/10.1006/geno.1993.1162]
Berube, D., Luu The, V., Lachance, Y., Gagne, R., Labrie, F. Assignment of the human 3 beta-hydroxysteroid dehydrogenase gene (HSDB3) to the p13 band of chromosome 1. Cytogenet. Cell Genet. 52: 199-200, 1989. [PubMed: 2630193] [Full Text: https://doi.org/10.1159/000132878]
Bongiovanni, A. M. The adrenogenital syndrome with deficiency of 3-beta-hydroxysteroid dehydrogenase. J. Clin. Invest. 41: 2086-2092, 1962. [PubMed: 13968789] [Full Text: https://doi.org/10.1172/JCI104666]
Carbunaru, G., Prasad, P., Scoccia, B., Shea, P., Hopwood, N., Ziai, F., Chang, Y. T., Myers, S. E., Mason, J. I., Pang, S. The hormonal phenotype of nonclassic 3-beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J. Clin. Endocr. Metab. 89: 783-794, 2004. [PubMed: 14764797] [Full Text: https://doi.org/10.1210/jc.2003-030934]
Cravioto, M. D., Ulloa-Aguirre, A., Bermudez, J. A., Herrera, J., Lisker, R., Mendez, J. P., Perez-Palacios, G. A new inherited variant of the 3-beta-hydroxysteroid dehydrogenase-isomerase deficiency syndrome: evidence for the existence of two isoenzymes. J. Clin. Endocr. Metab. 63: 360-367, 1986. [PubMed: 3088022] [Full Text: https://doi.org/10.1210/jcem-63-2-360]
Hamilton, W., Brush, M. G. Four clinical variants of congenital adrenal hyperplasia. Arch. Dis. Child. 39: 66-72, 1964. [PubMed: 14160089] [Full Text: https://doi.org/10.1136/adc.39.203.66]
Lutfallah, C., Wang, W., Mason, J. I., Chang, Y. T., Haider, A., Rich, B., Castro-Magana, M., Copeland, K. C., David, R., Pang, S. Newly proposed hormonal criteria via genotypic proof for type II 3-beta-hydroxysteroid dehydrogenase deficiency. J. Clin. Endocr. Metab. 87: 2611-2622, 2002. [PubMed: 12050224] [Full Text: https://doi.org/10.1210/jcem.87.6.8615]
Mendonca, B. B., Bloise, W., Arnhold, I. J. P., Batista, M. C., Toledo, S. P. A., Drummond, M. C. F., Nicolau, W., Mattar, E. Male pseudohermaphroditism due to nonsalt-losing 3-beta-hydroxysteroid dehydrogenase deficiency: gender role change and absence of gynecomastia at puberty. J. Steroid Biochem. 28: 669-675, 1987. [PubMed: 2826919] [Full Text: https://doi.org/10.1016/0022-4731(87)90396-7]
Morrison, N., Nickson, D. A., McBride, M. W., Mueller, U. W., Boyd, E., Sutcliffe, R. G. Regional chromosomal assignment of human 3-beta-hydroxy-5-ene steroid dehydrogenase to 1p13.1 by non-isotopic in situ hybridisation. Hum. Genet. 87: 223-225, 1991. [PubMed: 2066113] [Full Text: https://doi.org/10.1007/BF00204189]
Nishi, Y., Tezuka, T. Mild adrenal 3-beta-hydroxysteroid dehydrogenase deficiency in children with accelerated growth, premature pubarche and/or hirsutism. Europ. J. Pediat. 151: 19-23, 1992. [PubMed: 1309452] [Full Text: https://doi.org/10.1007/BF02073883]
Rheaume, E., Simard, J., Morel, Y., Mebarki, F., Zachmann, M., Forest, M. G., New, M. I., Labrie, F. Congenital adrenal hyperplasia due to point mutations in the type II 3-beta-hydroxysteroid dehydrogenase gene. Nature Genet. 1: 239-245, 1992. [PubMed: 1363812] [Full Text: https://doi.org/10.1038/ng0792-239]
Welzel, M., Wustemann, N., Simic-Schleicher, G., Dorr, H. G., Schulze, E., Shaikh, G., Clayton, P., Grotzinger, J., Holterhus, P.-M., Riepe, F. G. Carboxyl-terminal mutations in 3-beta-hydroxysteroid dehydrogenase type II cause severe salt-wasting congenital adrenal hyperplasia. J. Clin. Endocr. Metab. 93: 1418-1425, 2008. [PubMed: 18252794] [Full Text: https://doi.org/10.1210/jc.2007-1874]
Zachmann, M., Forest, M. G., De Peretti, E. 3 beta-hydroxysteroid dehydrogenase deficiency: follow-up study in a girl with pubertal bone age. Horm. Res. 11: 292-302, 1979. [PubMed: 295036] [Full Text: https://doi.org/10.1159/000179067]