Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome.

Perrault syndrome is a recessive disorder characterized by ovarian dysgenesis in females, sensorineural deafness in both males and females, and in some patients, neurological manifestations. No genes for Perrault syndrome have heretofore been identified. A small family of mixed European ancestry includes two sisters with well-characterized Perrault syndrome. Whole-exome sequencing of genomic DNA from one of these sisters revealed exactly one gene with two rare functional variants: HSD17B4, which encodes 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4), also known as D-bifunctional protein (DBP). HSD17B4/DBP is a multifunctional peroxisomal enzyme involved in fatty acid beta-oxidation and steroid metabolism. Both sisters are compound heterozygotes for HSD17B4 c.650A>G (p.Y217C) (maternal allele) and HSB17B4 c.1704T>A (p.Y568X) (paternal allele). The missense mutation is predicted by structural analysis to destabilize the HSD17B4 dehydrogenase domain. The nonsense mutation leads to very low levels of HSD17B4 transcript. Expression of mutant HSD17B4 protein in a compound heterozygote was severely reduced. Mutations in HSD17B4 are known to cause DBP deficiency, an autosomal-recessive disorder of peroxisomal fatty acid beta-oxidation that is generally fatal within the first two years of life. No females with DBP deficiency surviving past puberty have been reported, and ovarian dysgenesis has not previously been associated with this illness. Six other families with Perrault syndrome have wild-type sequences of HSD17B4. These results indicate that Perrault syndrome and DBP deficiency overlap clinically; that Perrault syndrome is genetically heterogeneous; that DBP deficiency may be underdiagnosed; and that whole-exome sequencing can reveal critical genes in small, nonconsanguineous families.

Loss of cytochrome P450 17A1 protein expression in a 17alpha-hydroxylase/17,20-lyase-deficient 46,XY female caused by two novel mutations in the CYP17A1 gene.

17alpha-Hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia caused by mutations in the CYP17A1 gene. This condition shows considerable clinical and biochemical variation. Molecular characterization of novel mutations in the CYP17A1 gene and detailed study of their structural, enzymatic, and clinical consequences are required to fully understand enzyme behavior. Here, we present the first molecular characterization of two novel mutations in CYP17A1 in a 15-year-old female Mexican mestizo 46,XY female with primary amenorrhea and lack of pubertal development and severe hypertension that manifested only after surgery. A complete clinical and biochemical evaluation was compatible with 17OHD. Structural anomalies in the CYP17A1 gene were discovered by direct automated sequencing, which revealed a novel compound heterozygous K110X/R362H mutation that leads to a complete lack of enzyme activity. Immunohistochemical analyses performed to determine protein expression and localization showed that cytochrome P450 17A1 was completely absent in the patient's testicular tissue. Studies of novel mutations, such as those described here, provide important information that allows us to better understand the effect of a given mutation on enzyme function and to observe the impact of the mutation on clinical phenotype.

Deficiency of 17 alpha-hydroxylase associated with absent gonads.

A phenotypic female presented initially at the age of 17 years with amenorrhoea and delay of sexual development. Karyotype was male, 46 XY, and as gonads were absent, a diagnosis of congenital anorchia was made. The patient was treated with oestrogen. At the age of 23 years, she re-presented with tall stature and hypertension. She then had normal female habitus but absent pubic and axillary hair. Re-investigation showed that sex steroids and cortisol were absent and established the diagnosis as 17 alpha-hydroxylase deficiency. Treatment with hydrocortisone rapidly corrected the hypertension. Ultrasound examination confirmed the absence of gonads but showed that a small uterus was present. Measurement of serum cortisol is important for recognition of such patients, but further measurements of sex steroids, particularly progesterone, are needed to prove the diagnosis. We have found no previous reports of absent gonads in 17 alpha-hydroxylase deficiency. The association remains unexplained.

The prevalence of 5 alpha-reductase deficiency in children with ambiguous genitalia in the Dominican Republic.

During a 10-year period 65 children and adolescents with ambiguous genitalia from the Dominican Republic, not known through kindred studies of 5 alpha-reductase deficiency, were evaluated. Plasma androgen determinations were performed before and/or after Leydig cell stimulation of the testes with human chorionic gonadotropin. Of the children there were 24 female pseudohermaphrodites, 21 of whom had 21-hydroxylase deficiency, 1 true hermaphrodite and 40 (62 per cent) male pseudohermaphrodites. One child had a human chorionic gonadotropin response suggestive of 17-20 desmolase deficiency, and on further evaluation he also had partial deficiencies of the enzymes 21-hydroxylase and 17 alpha-hydroxylase. Five subjects had a female phenotype and subnormal androgen responses to human chorionic gonadotropin. In 5 of 33 male pseudohermaphrodites with a normal testosterone response to human chorionic gonadotropin 5 alpha-reductase deficiency was suspected by elevated plasma testosterone/dihydrotestosterone ratios before and/or after human chorionic gonadotropin stimulation. The diagnosis of 5 alpha-reductase deficiency was confirmed by elevated 5 beta/5 alpha urinary C19 and C21 steroid metabolite ratios. One subject with 5 alpha-reductase deficiency was traced to the original Dominican kindred of 38 affected subjects. Pedigree analysis of another proband revealed 3 additional affected relatives. Four subjects with a normal testosterone response to human chorionic gonadotropin had XO/XY gonadal dysgenesis. There were 25 male pseudohermaphrodites with normal plasma testosterone and dihydrotestosterone responses to human chorionic gonadotropin, who were not diagnosed by this methodology. This study reveals that 5 alpha-reductase deficiency occurs with a frequency of 13 per cent as a cause of male pseudohermaphroditism in the Dominican Republic with approximately the same frequency as XO/XY gonadal dysgenesis. Unlike female pseudohermaphrodites, the majority of male subjects with pseudohermaphroditism remain unclassified by these techniques.

[A case of 49 XXXXY gonadosomatic dysgenesis: clinical elements and biological consequences of polysomy X]. / A propos d'un cas de dysgénésie gonadosomatique 49 XXXXY: eléments cliniques et conséquences biologiques de la polysomie X.

Discovery of 49 XXXXY syndrome in a six years young boy allows description of the main clinical characteristics of this disease: hypotrophy, facial anomalies, hypogenitalism, delayed speech development and oligophrenia. Radio-cubital synostosis is quite specific in this syndrome. The hypothesis of a correlation between clinical anomalies and excess of genes induced by polysomia has been suggested. We give results of five X-linked enzymatic activities: steroid sulfatase (STS) (located on the probably noninactivated segment), Hypoxanthine Guanine Phosphoribosyl Transferase (HGPRT), Glucose 6 Phosphate Déshydrogenase (G6PD), Phospho Glycerate Kinase (PGK), Alpha Galactosidase A (Alpha GAL A). Only STS activity seems to be significatively increased.

Two cases of 17 alpha-hydroxylase deficiency--one combined with complete gonadal agenesis.

Two cases of 17 alpha-hydroxylase deficiency are described. Both patients had primary amenorrhoea, total lack of female secondary sexual characteristics, slight hypertension and hypokalaemia. One patient was of male genotype (male pseudohermaphrodite), and in addition this patient had complete gonadal agenesis. The other patient was of female genotype. In both patients the level of plasma corticosterone was markedly increased, whereas the concentration of plasma cortisol was very low and plasma aldosterone low within the normal range. Furthermore, the plasma ACTH level was significantly increased and the plasma renin activity around the lower normal limit. The urinary excretion of corticosterone metabolites was markedly increased, whereas the excretion of both cortisol metabolites and tetrahydroaldosterone was decreased. The patients had no symptoms of glucocorticoid deficiency. Treatment with dexamethasone 0.5 mg daily completely suppressed the abnormal corticosterone production and normalized both blood pressure and serum potassium. In addition, the patient of male genotype has received sequential therapy with oestrogen and gestagen for 3 years, but so far no development of the secondary sexual characteristics has occurred.

XY females with enzyme deficiencies of steroid metabolism. A brief review.

The literature on XY females with enzyme deficiencies (17 alpha-hydroxylase, 17 beta-reductase and 17, 20-desmolase) is reviewed. The main features of these individuals are briefly compared with those of XY females with pure gonadal dysgenesis and with testicular feminization.