17-Beta Hydroxysteroid Dehydrogenase Iii Deficiency

A number sign (#) is used with this entry because 17-beta hydroxysteroid dehydrogenase III deficiency, resulting in male pseudohermaphroditism or polycystic ovary disease, is caused by homozygous or compound heterozygous mutation in the HSD17B3 gene (605573) on chromosome 9q22.

Description

HSD17B3 deficiency is an autosomal recessive disorder that manifests, in males, as undermasculinization characterized by hypoplastic-to-normal internal genitalia (epididymis, vas deferens, seminal vesicles, and ejaculatory ducts) but female external genitalia and the absence of a prostate. This phenotype is caused by inadequate testicular synthesis of testosterone, which, in turn, results in insufficient formation of dihydrotestosterone in the anlage of the external genitalia and prostate during fetal development. At the expected time of puberty, there is a marked increase in plasma leuteinizing hormone and, consequently, in testicular secretion of androstenedione. Hence, a diagnostic hallmark of this disorder is a decreased plasma testosterone-to-androstenedione ratio. Significant amounts of the circulating androstenedione are, however, converted to testosterone, in peripheral tissues, thereby causing virilization (summary by Lindqvist et al., 2001).

Clinical Features

Saez et al. (1971) reported 2 brothers with male pseudohermaphroditism and gynecomastia, in whom metabolic studies led to the conclusion that a defect in 17-ketosteroid reductase limited to the testis was the 'cause.' The parents were apparently nonconsanguineous. Seven brothers and 5 sisters were living and apparently well.

Goebelsmann et al. (1973) described this disorder in a 46-year-old phenotypic female of first-cousin parents. She was a seemingly normal girl until puberty when she developed breasts, masculinized, and failed to menstruate. Givens et al. (1974) demonstrated that gynecomastia is not necessarily present.

Imperato-McGinley et al. (1979) reported the case of a 31-year-old male who had been raised as a girl from birth to age 14 years but had switched easily to living as a male after puberty.

Kohn et al. (1981) documented a high frequency of male pseudohermaphroditism due to 17-beta-hydroxysteroid dehydrogenase deficiency in a highly inbred Arab community in Israel. In a single kindred, 24 affected persons, ranging in age from a few months to 80 years, were identified. The external genitalia were usually female at birth, although mild to moderate ambiguity was occasionally present. Gonads were palpable in the inguinal canals or labial folds. Although raised as females, all affected persons developed male body habitus and normal male secondary sexual characteristics at puberty. The pedigree of this extensively affected Arab family living in the Gaza strip was presented by Kohn et al. (1985). More than 60 affected persons had been identified in that population.

Eckstein et al. (1989) studied the basis of the paradox of lack of intrauterine male sexual differentiation but marked virilization after puberty. (This situation is somewhat similar to that of hemophilia B(Leyden) in which the levels of factor IX (300746) are very low before puberty but after puberty rise to levels about 50% of normal; see 306900.) They found that the severity of 17-ketoreductase deficiency changes with age. While the enzyme is nonfunctional until puberty, there is progressive restoration of the activity during adulthood. Testosterone production increases almost to normal, and plasma concentrations are sufficient to gradually induce marked genital virilization. Although surgical repair of external genitalia achieved good cosmetic and functional results, all affected individuals remained infertile.

Lanes et al. (1983) reported a Venezuelan sibship of 9 in which 2 males had pseudohermaphroditism, 2 males and a female had congenital hypothyroidism, and 1 male had both. 17-KSR activity is absent in testicular tissue but normal in nongonadal tissue in this disorder. Only 1 of the 3 with pseudohermaphroditism had gynecomastia. Patients with 17-KSR deficiency have female-appearing genitalia at birth and are usually reared as females. However, they invariably develop wolffian structures. Thus, the metabolism of delta(4)-A to testosterone must produce enough testosterone for this function but not enough to serve as a precursor for dihydrotestosterone and adequate masculinization of the external genitalia. At puberty, patients with 17-KSR deficiency virilize normally. Since the 3 brothers with 17-KSR deficiency had different HLA haplotypes, close linkage with HLA was excluded. The nature of the hypothyroidism was not clear but was thought to be a dyshormogenesis, possibly an iodide concentration defect. The diagnosis of 17-KSR deficiency is made on the basis of an abnormally high delta(4)-A to T ratio in plasma.

Balducci et al. (1985) described 3 sisters with this disorder. Because of the female phenotype and 46,XY karyotype, they were thought to have the testicular feminization syndrome. At puberty, however, the 2 older patients developed signs of virilization and gynecomastia. In these patients the ratio of plasma androstenedione to testosterone was 20 to 25 times higher than normal. In the prepubertal sister, however, it was normal but became 6 times the normal value after hCG stimulation. The enzyme 17-ketosteroid reductase converts the precursor hormone androstenedione to the product hormone testosterone and converts estrone to estradiol in adrenal and gonadal tissue. Deficiency of 17-ketosteroid reductase is rarely diagnosed at birth. More frequently, it is discovered at or after puberty in genetic males who are raised as males during assessment of gynecomastia and incomplete male genital development. In those genetic males raised as females, severe hirsutism, which develops at puberty because of the sudden increase in testicular androstenedione secretion, and primary amenorrhea lead to the diagnosis. Diagnosis before puberty allows early treatment by removal of the abnormal testes which should prevent the usual presenting clinical signs of marked masculinization and hirsutism at puberty.

Castro-Magana et al. (1993) defined a 'late-onset deficiency of testicular 17-ketosteroid reductase.' They studied 48 males, aged 14 to 26 years, who had idiopathic pubertal gynecomastia. In 3 unrelated subjects, aged 16, 17, and 26 years, the serum concentrations of gonadal and adrenal steroid hormones before and after administration of corticotropin and after the combined administration of chorionic gonadotropin and dexamethasone for 3 days suggested partial deficiency of testicular 17-ketosteroid reductase. In addition to gynecomastia, the 3 subjects had decreased libido and impotence. The concentrations of androstenedione and estrone in spermatic venous serum were 19 times higher and 73 times higher, respectively, than in normal men. Castro-Magana et al. (1993) stated that 'the disorder is presumably congenital, but could be acquired.' All 3 subjects were of normal height and weight, with normal body proportions and body-hair growth. Their external genitalia were normal, as was testicular volume. One of them had a 6-year-old sister and a 9-year-old brother who had premature adrenarche.

The phenotype in male pseudohermaphroditism caused by mutations of testicular 17-beta-hydroxysteroid dehydrogenase-3 is closely similar to that of 5-alpha-reductase-2 deficiency (264600) in that both have male wolffian duct-derived internal genitalia but external genitalia that are almost always female in character. However, 17-beta-HSD deficiency is distinguished from 5-alpha-reductase-2 deficiency by elevated serum levels of androstenedione, the substrate of the 17-beta-HSD enzyme. In both disorders, virilization occurs at puberty, presumably because of cross-specificity and/or induction of isozymes of the enzymes that are the site of the primary defect. In both conditions, it is puzzling that wolffian duct structures develop, since these are thought to be under the control of testosterone.

Boehmer et al. (1999) reported on a nationwide study of male pseudohermaphroditism among all pediatric endocrinologists and clinical geneticists in the Netherlands. In this study, 18 HSD17B3-deficient index cases were identified, 12 of whom initially had received the tentative diagnosis of androgen insensitivity syndrome (AIS). In genotypically identical cases, phenotypic variation for external sexual development was observed. Gonadotropin-stimulated serum testosterone/androstenedione ratios in HSD17B3-deficient patients were discriminative in all cases and did not overlap with ratios in normal controls or with ratios in AIS patients.

Polycystic Ovary Syndrome

Pang et al. (1987) theorized that genetic females with ovarian 17-ketosteroid reductase deficiency would probably have a normal female phenotype at birth and normal pubertal breast development but would have onset at puberty of virilization and menstrual disorders due to the sudden increase of ovarian secretion of androstenedione, which may be converted to testosterone. Therefore, they investigated women with hirsutism and found 1 whose hormonal production and responses indicated ovarian 17-ketosteroid reductase deficiency. The 18-year-old woman had progressive hirsutism, secondary amenorrhea, and polycystic ovary disease (PCOD). Excess androstenedione was secreted by the ovaries. The conversion of androstenedione to testosterone was normal, apparently because of peripheral conversion of androstenedione; very little testosterone was secreted by the ovaries. The patient's 2 younger sisters with peripubertal symptoms of androgen excess also had elevated serum levels of androstenedione. In 43 patients with PCOD, who ranged in age from 18 to 38 years, Toscano et al. (1990) found 2 with a hormonal pattern suggesting ovarian 17-KSR deficiency. Two of 3 brothers of 1 patient (aged 25 and 34 years) presented with persistent pubertal gynecomastia; 1 brother also had severe oligospermia. These clinical findings and the hormonal pattern suggested a partial testicular 17-KSR deficiency. (Of the 43 patients, 5 others showed PCOD secondary to nonclassic 21-hydroxylase deficiency; in the remaining 36 patients, the precise defect could not be pinpointed.)

Diagnosis

HSD17B3 deficiency can be reliably diagnosed by endocrine evaluation and mutation analysis (Boehmer et al., 1999).

Population Genetics

Boehmer et al. (1999) found that the minimal incidence of HSD17B3 deficiency in the Netherlands was 1:147,000 with a heterozygote frequency of 1:135. They noted that the incidence of HSD17B3 deficiency is 0.65 times the incidence of AIS, which is thought to be the most frequent known cause of male pseudohermaphroditism without dysgenic gonads.

Molecular Genetics

In a study of 5 unrelated male pseudohermaphrodites, Geissler et al. (1994) identified 4 substitution and 2 splice junction mutations in the HSD17B3 gene (see, e.g., 605573.0001-605573.0005).

Andersson et al. (1996) stated that the 17-beta-HSD3 mutations characterized to that time included 10 missense mutations, 3 splice junction mutations, and 1 small deletion that results in a frameshift. Three of these mutations occurred in more than 1 family. Complementary DNAs incorporating 9 of the 10 missense mutations had been constructed and expressed in reporter cells; 8 of these 9 mutations cause almost complete loss of enzymatic activity. In 2 subjects with loss of function due to missense mutations, Andersson et al. (1996) found that testosterone levels were very low in testicular venous blood. These data suggest that the common mechanism for testosterone formation in postpubertal subjects with this disorder is the conversion of circulating androstenedione to testosterone by one or more of the unaffected 17-beta-HSD isoenzymes.

Boehmer et al. (1999) identified biallelic mutations in the HSD17B3 gene in all 18 patients with pseudohermaphroditism identified in the Netherlands. At least 4 mutations, including 655-1G-A (605573.0006) and R80Q (605573.0003), found worldwide, appeared to be ancient and originating from genetic founders. Their dispersion could be reconstructed through historical analysis. Phenotypic variation can occur between families with the same homozygous mutations.

Lindqvist et al. (2001) stated that a total of 19 mutations in the HSD17B3 gene that impair testosterone biosynthesis and cause male undermasculinization had been found. Fifteen of these molecular lesions were missense mutations, 3 were splice junction abnormalities, and 1 was a frameshift mutation. In a subject with HSD17B3 deficiency, Lindqvist et al. (2001) reported a novel cys268-to-tyr substitution mutation in exon 10 of the HSD17B3 gene (605573.0010). Reconstitution experiments with recombinant protein reveal that substitution of tyrosine for cysteine at position 268 of HSD17B3 abrogates the enzymatic activity. The authors noted that their case brought to 20 the number of mutations in the HSD17B3 gene that cause male undermasculinization.