Severe 46,XY virilization deficit due to 17beta-hydroxysteroid dehydrogenase deficiency

BACKGROUND: 17beta hydroxysteroid dehydrogenase deficiency is a presumable rare cause for a severe virilization disorder in children with 46,XY karyotype due to a defect in the testicular testosterone biosynthesis from androstenedione. PATIENT: We report on a 14 year old child with 46,XY karyotype with a predominantly female phenotype. RESULTS: Hormonal analysis showed low values for androstenedione and testosterone before and after stimulation with human chorionic gonadotropin, however, the androstenedione/testosterone ratio was elevated. Molecular genetic analysis proved the diagnosis of 17beta-hydroxysteroid dehydrogenase deficiency due to a homozygous mutation (325+4 A-T) in the HSD17B3-gene, which leads to an aberrant splicing process. CONCLUSIONS: This case demonstrates that in addition to a meticulous steroid analysis a direct molecular genetic analysis can be helpful in the diagnosis of 17beta-hydroxysteroid dehydrogenase deficiency.     

Familial Miller-Dieker syndrome and (15;17) chromosome translocation

Two siblings with familial lissencephaly presented with the clinical and neuropathological features of the Miller-Dieker syndrome. High resolution caryotype demonstrated a 46,XX,-17+der(17)t(15;17)pat translocation with partial deletion of the short arm of chromosome 17 in one patient and a balanced 46,XY,t(15;17)(q2600;p1300) translocation in the father. Review of the literature uncovered 14 additional patients with Miller-Dieker syndrome and partial deletion of the short arm of chromosome 17. A cytogenetic study should be done in all cases of lissencephaly for genetic counselling.     

以严重高血压就诊的17α-羟化酶缺乏症

患儿,女（社会性别）,14岁,因发现高血压11 d入院。患儿无月经来潮。查体：血压146/90 mm Hg,肤色略黑,乳腺未发育,可见大阴唇,未见小阴唇、阴蒂、阴道及处女膜。实验室检测发现低肾素、低皮质醇、高促肾上腺皮质激素,低性激素、高促性腺激素,血钾、醛固酮未见异常;影像学提示骨龄落后,无卵巢、子宫,双侧肾上腺皮质增生,双侧腹股沟区隐睾。染色体核型46,XY。全基因组测序提示：CYP17A1外显子区域2个纯合突变,c.985T > C（胸腺嘧啶突变为腺嘌呤）和c.987delC （缺失突变）,父母存在上述2个位点的杂合突变。确诊为先天性肾上腺皮质增生症17α-羟化酶缺乏症。给予氢化可的松治疗2个月后血压恢复正常,ACTH下降,继续氢化可的松治疗,并应患儿及父母要求按女性治疗,加用雌激素替代,手术切除隐睾。儿童高血压的鉴别诊断也应注意儿童性发育情况,筛查ACTH和皮质醇,以免误诊;对低肾素性高血压伴性发育落后者应注意鉴别罕见病17α-羟化酶缺乏症。     

Familial male pseudohermaphroditism

Familial male pseudohermaphroditism (MPH) due to 17, 20-desmolase deficiency is rare. Here we present two siblings with MPH possibly due to 17, 20-desmolase deficiency. The first patient presented with unambiguous female external genitalia and hypergonadotrophic hypogonadism. Chromosomal analysis revealed 46 XY. Ultrasound evaluation of pelvis revealed gonads in the inguinal canal, and no uterus. These findings were confirmed on laparotomy. Histology revealed the gonads to be testes. The second patient had ambiguous genitalia (perineoscrotal hypospadias, bifid scrotum with palpable gonads) with a 46 XY chromosomal pattern. Both patients had high plasma 17-hydroxy progestrone (17 OHP), low normal dehydro epiandrosterone sulphate (DHEAS) and low plasma testosterone. Plasma testosterone and DHEAS showed no response to ACTH or HCG. These features are compatible with the diagnosis of 17, 20-desmolase deficiency.     

17 beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population

Eighty-five males with 17 beta-HSD3 were identified among a highly inbred Arab population in Israel and 57 studied over a period of 25 years. The founders of this defect originated in the mountainous regions of present Lebanon and Syria, but most of the families now live in Jerusalem, Hebron, the Tel-Aviv area and, in particular, in Gaza, where the frequency of affected males is estimated at 1 in 100 to 150. Affected individuals are born with ambiguity of the external genitalia and reared as females until puberty. Thereafter marked virilization occurs, leading in many cases to the spontaneous adoption of a male gender identity and role. Adults develop a male habitus with abundant body hair and beard and the phallus and testes enlarge to adult proportions. Gender reassignment in infancy was only possible when enough erectile tissue was present at birth and developed into a normal size penis with testosterone. 17 beta-HSD3 deficiency can be reliably diagnosed by endocrine evaluation and mutation analysis. In adults the defect is characterized by markedly increased concentrations of androstenedione (A) with borderline low to normal testosterone (T) levels and a high A/T ratio. 5a-dihydrotestosterone (DHT) concentrations are moderately decreased, normal or high and dehydroepiandrosterone (DHEA) levels are high. The estrogen pathway is also impaired, even though both estrone (E-1) and estradiol-17 beta (E-2) levels are high. Children have low basal levels of all androgens, but the defect may be demonstrated after prolonged stimulation with human chorionic gonadotropin (HCG). LH and FSH levels are very high after puberty and normal in childhood. 17 beta-HSD3 isozyme is encoded by the chromosome 9q22 17 beta-HSD3 gene and expressed exclusively in testes. A point mutation in exon 3, codon 80 of the 17 beta-HSD3 gene, R80Q, caused by a single base substitution from CGG ( arginine) to CAG ( glutamine) was identified in both alleles of 24 individuals from 9 extended Arab families from Gaza, Jerusalem and Lod-Ramle. Twenty-one homozygote males (46,XY) were MPH with testicular 17 beta-HSD3 deficiency whereas the three homozygote females (46,XX) were asymptomatic, had normal internal and external genitalia, normal sexual development and revealed no biochemical evidence of 17 beta-HSD3 deficiency. The molecular pattern is compatible with an autosomal recessive mode of inheritance, sex dependent.     

Molecular analysis of the AR and SRD5A2 genes in patients with 46,XY disorders of sex development

The aim of this study was to assess the clinical and endocrinological features, and to analyze AR and SRD5A2 genes in patients with 46,XY disorders of sex development (DSD). This study included 20 patients from 19 families showing clinical features of 46,XY DSD. Molecular analysis was performed of the AR and SRD5A2 genes, as well as endocrinological evaluations, such as 17a-hydroxyprogesterone, plasma renin activity, aldosterone, adrenocorticotropic hormone and hCG stimulation test. Out of 20 patients with 46,XY DSD, only one (5%) displayed androgen insensitivity syndrome (AIS), and four (20%) were 5alpha-reductase deficient by mutation analysis. The patient with AIS revealed significant elevation of serum testosterone following hCG stimulation. The patient with 5alpha-reductase deficiency with a homozygous p.R246Q mutation had a low basal dihydrotestosterone level. The patient with p.Q6X/p.R246Q mutations showed a moderately elevated testosterone/dihydrotestosterone ratio following hCG stimulation. Endocrinological tests are not reliable for the etiological diagnosis of AIS and 5alpha-reductase deficiency due to variable reference ranges of hormonal profiles according to the age and the severity of the enzyme defect. DNA analysis may be employed as a tool for the early and precise diagnosis of patients with 46,XY DSD, and genetic counseling can be used for families at risk.     

Choice of gender in 5alpha-reductase deficiency: a moving target

Steroid 5alpha-reductase deficiency is a rare, male-limited autosomal recessive disorder caused by mutation in the SRD5A2 gene resulting in a deficiency of dihydrotestosterone (DHT) during fetal development. Here we report an affected 46,XY adolescent who was born with incompletely virilized genitalia and was raised in the female gender. At 12 years of age, the patient requested feminizing genital surgery. Surgery was withheld and psychiatric counseling was instituted. At 14 years of age, the patient's gender identity and role appeared to be in transition from a female to an increasingly male gender. This case demonstrates that in patients with disorders such as 5alpha-reductase deficiency, in which significant prenatal androgen exposures are combined with postnatal virilization, adult gender identity and gender role may be a dynamic process that is not complete until well after adolescence.     

Studies in a phenotypic female with 17-alpha-hydroxylase deficiency.

In a 19-year-old phenotypic female (46, XY) with hypertension and hypokalemia, studies confirmed 17-alpha-hydroxylase deficiency. Prior to diagnosis she had been considered to have testicular feminization. Increased plasma progesterone and urinary pregnanediol levels were present before treatment. Increased secretion rates of deoxycorticosterone and corticosterone and abnormally low production of cortisol and aldosterone were present. Following treatment with hydrocortisone, plasma progesterone, serum potassium, and urinary pregnanediol levels and DOC and B secretions were normal. Aldosterone secretion six months after treatment remained low. Normal blood pressure measurements were achieved during treatment with hydrocortisone and oral estrogen with the patient at rest; however, mild elevations in blood pressure (130/90 mm Hg) have been noted despite continued hydrocortisone therapy.     

Myelodysplastic Syndrome with Partial Deletion of the Long Arm of Chromosome 5: First Report of a Case in a Child

A childhood case of myelodysplastic syndrome (MDS) with a deletion of the long arm of chromosome 5 (5q-) is reported. The patient was an 8 year old boy who has recurrent angina. Laboratory evaluation revealed the following: hemoglobin 8.1 gm/dl, white blood cell count 4.9 × 10³/l with 3% atypical lymphocytes, and platelet count 17.7 × 10⁴/l. A bone marrow aspirate revealed 20% blast cells and dysmyelopoietic changes involving all three marrow cell lines. Karyotype analysis of marrow cells revealed 46,XY,5q- in 100% of the metaphases.
These findings led to a diagnosis of MDS with 5q-, which is most commonly found in adult MDS. This case seems to represent an exceedingly rare childhood case of MDS with 5q-.     

17alpha-hydroxylase/17,20-Lyase deficiency due to novel compound heterozygote mutations: treatment for tall stature in a female with male pseudohermaphroditism and spontaneous puberty in her affected sister

We report on two German sisters with deficiency in the 17alpha-hydroxylase/17,20-lyase enzyme corresponding to typical hormone profile. A paternal nonsense mutation R388X in exon 7 and a maternal missense mutation P428L in exon 8 of the CYP17 gene have been identified in both girls. Residual in vitro 17alpha-hydroxylase activity for the conversion of [3H]-Preg to [3H]-17OH-Preg has been detected in transfected 293-cells expressing P428L mutant enzyme; however, no 17,20-lyase activity was observed converting [3H]-17OH-Preg into [3H]-DHEA. The 46,XX-sister spontaneously entered puberty. The 46,XY-sister with a predicted adult height of 203 cm was treated with a high dose of conjugated estrogens and resulted with a final height of 186.9 cm. The present data suggest that compound heterozygous 46,XX females bearing a P428L allele may develop spontaneous onset of puberty. Furthermore, in 46,XY females with tall stature, treatment with conjugated estrogens may lead to a significant reduction of their predicted adult height.     

MALE PSEUDOHERMAPHRODITISM DUE TO DEFICIENCY OF TESTICULAR 17-KETOSTEROID REDUCTASE

ABSTRACT. A 12.9 year-old girl, genotypically 46, XY, and considered to have a testicular feminization syndrome, developed signs of virilization and gynaecomastia. Very high androstenedione concentrations (10-fold the mean of the reference interval in boys) in relation to low normal testosterone in peripheral serum indicated a 17-ketosteroid reductase deficiency. In addition to androstenedione, the basal peripheral levels of 17-hydroxyprogesterone and estrone were increased, being 5- and 3-fold the mean of the reference interval, respectively, whereas pregnenolone, progesterone, dehydroepiandrosterone, 5α-dihydrotestosterone and estradiol concentrations were within pubertal stage-appropriate reference intervals. The total spermatic vein serum steroid concentrations were about 5-fold the mean in old men, and androstenedione, estrone and dehydroepiandrosterone were particularly elevated, whereas estradiol was normal and testosterone subnormal by a factor of 1/8. In the testis tissue, the concentration of androstenedione was extremely high, whereas that of testosterone tended to be relatively low. Our patient was obviously producing testicular steroids at her maximal rate, because no response to hCG administration was observed. This state was assiociated with a high-normal circulating LH concentration. The concentration of testicular LH/hCG receptors was only one-fifth of that seen in old men, which may have resulted from receptor down-regulation associated with a high degree of stimulation.     

Practical approach to steroid 5alpha-reductase type 2 deficiency

The aim of this article is to review the literature on steroid 5alpha-reductase type 2 deficiency (5α-RD2) to provide clinicians with information to guide their management of patients with this disorder. The 5alpha-reductase type 2 is encoded by the 5alpha-reductase type 2 gene (SRD5A2) on chromosome 2 and is predominantly expressed in external genital tissues and the prostate. Mutations of the SRD5A2 gene leads to an uncommon autosomal recessive disorder affecting sexual differentiation in individuals with 46,XY karyotype; their phenotype can range from almost normal female structures to a distinct male phenotype with ambiguous genitalia at birth. These phenotypes result from impaired conversion of testosterone to dihydrotestosterone due to mutations in the SRD5A2 gene. Patients exhibit virilization at puberty without breast development, which is often accompanied by gender identity change from female to male. More than 40 mutations have been reported in all five exons of the SRD5A2 gene. Phenotype–genotype correlations for 5α-RD2 have not been well established. The newborn phenotypes of male pseudohermaphrodites with 5α-RD2, partial androgen insensitivity syndrome (PAIS), or 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) enzyme deficiency may be indistinguishable. We conclude that steroid 5α-RD2 should be included in the differential diagnosis of newborns with 46,XY DSD. It is important that the diagnosis be made in infancy by biochemical and molecular studies before gender assignment or any surgical intervention because these patients should be considered males at birth.     

Proximal 3p Deletion: Case Report and Review of the Literature

A boy with severe growth and psychomotor retardation, facial dysmorphism, a large atrial septal defect, limitation of joint movement and hearing impairment is described. High-resolution banding chromosome analysis showed interstitial deletion of the proximal segment of chromosome 3: 46, XY, del(3)(p12p14.2) de novo. The deleted chromosome 3 was of paternal origin as judged from Q-banding polymorphisms. Delineation of proximal 3p deletion syndrome is proposed by summarizing the clinical and cytogenetical findings of the present and previously reported five patients.     

Pediatric disorders of sex development

The management of disorders of sexual differentiation (DSD) involves a multidisciplinary approach. The main aim of analysis was to study the phenotype-karyotype correlation in North Indian children with DSD. The records of pediatric DSD were retrieved and characteristics noted. Of total of 58 children, 43 (74.1%) and 10 (17.2%) were raised as males and females respectively. The mean age at presentation was 31.3±9 months. The karyotype was 46XY in 45 (77.6%) and 46XX in 12 (20.7%). CAH was commonest cause of DSD (36.2%), followed by gonadal dysgenesis. Of the 15 patients of 46 XY CAH, there were 5 with 17-α hydroxylase deficiency, 2 with 3-β HSD deficiency and one case of lipoid adrenal hyperplasia. There was an excess of genetic males, possibly due to prevalent socio-cultural factors and gender bias favoring males. There is a need to improve the diagnostic facilities and incorporate a team approach in management of DSD.     

SRY基因检测在儿童性发育疾病诊断中的应用

目的：应用SRY基因直接测序检测技术和外周血染色体核型分析技术对外生殖器模糊的幼儿及青春期儿童进行检查以明确诊断。方法：采用常规G显带方法分析20例外生殖器模糊的患儿染色体核型,用PCR技术扩增其SRY基因,进行基因测序,分析是否存在SRY基因及SRY基因是否存在突变情况。结果：20例患儿中SRY基因阳性的有17例,阴性3例。直接测序结果显示所有SRY基因阳性患者该基因均未发生突变。染色体核型分析中检出4例特殊核型为：46, XY, del (Y) (q12)/45, X、46, XY, add (Y) (p11)、46, XY, r (9)及46, XY, 9 qh+。结论：SRY基因检测有助于明确儿童性发育疾病的分型,具有快速检测的优越性,与常规G显带相结合分析有助于儿童性发育疾病的初步诊断。     

Hypomelanosis of Ito - case report

OBJECTIVES: The authors report a case of hypomelanosis of Ito (HI), a rare neurocutaneous syndrome with neurological and chromosomal alterations associated with cutaneous involvement and recurrent pneumonia. CASE REPORT: A male patient, age 1 year and 11 months, was admitted with bilateral bronchopneumonia to the S?o Vicente de Paulo Hospital. Examination revealed hypochromic maculas on the skin, compatible with HI, and a delay in neuropsychomotor development. The patient was submitted to incisive biopsy of the abdominal skin lesions, electroencephalogram, magnetic resonance, and cytogenetic evaluation. RESULTS: Histology and immunohistochemistry evinced absence of melanin and reductio of melanocyte in focal areas of the epidermis. The electroencephalogram revealed diffuse cortico-subcortical dysfunction. Encephalic magnetic resonance imaging was compatible with arachnoid cyst in the temporal region. Karyotype showed chromosome mosaicism (46, XY) and interstitial deletion of bands 22.2 to 24.4 of the long arm of chromosome 10 (25%). CONCLUSIONS: Analysis of skin lesions is important for the etiologic definition of neuropediatric disorders.     

The earlier described mutation (c.307c > T [p.R103X]) in the SRD5A2 gene causing a 46,XY female phenotype

Deletions and mutations in the 5-alpha-reductase type 2 (SRD5A2) gene have been identified in 46,XY disorders of sexual differentiation (DSD). The clinical spectrum is heterogeneous, varying from a normal female external genital appearance to clitoromegaly and isolated micropenis or microphallus associated with hypospadias of various degrees. We describe a 46,XY DSD patient with a homozygous c.307C>T (p.R103X) mutation in the SRD5A2 gene. The case presented with a normal female external genital phenotype.     

17α羟化酶/17,20碳链裂解酶缺陷症一家系CYP17A1基因突变分析

目的 对一儿童17α羟化酶/17,20碳链裂解酶缺陷症(17OHD)先证者及其主要家系成员进行CYP17A1基因突变分析,旨在提高认识和引起重视.方法分别获取先证者及其父母、双胎姐姐的基因组DNA,应用PCR和DNA直接测序方法,进行CYP17A1基因突变检测.结果 先证者存在CYP17A1基因复合型点突变,即Exl的nt186delC和Ex6的nt1085G>A,使17α羟化酶完全失活,从而导致170HD.并在其父Exl、其母和其双胎姐姐Ex6上均发现同类型基因突变.其中nt186delC为新发现突变位点,健康对照者未发现类似基因突变.结论 异卵双胎先证者分别在CYP17A1基因的Exl和Ex6存在复合点突变,其父母和双胎姐姐均为突变携带者.开展基因诊断有助于提高临床诊治水平.     

Congenital adrenal hyperplasia in Turkey: a review of 273 patients

In this study the clinical and epidemiological characteristics of congenital adrenal hyperplasia were evaluated retrospectively from the records of 273 patients managed in our clinic over a 25-year period. 21-Hydroxylase deficiency was present in 234 patients (85.7%), simple virilizing form in 134 (110 F, 24 M), salt-losing form in 85 (71 F, 14 M) and late on-set form in 15 girls. 11β-Hydroxylase deficiency was diagnosed relatively frequently (13.5%) among our patients with congenital adrenal hyperplasia; one girl had 17α-hydroxylase deficiency and one boy had 3α-hydroxy steroid dehydrogenase deficiency. The median chronological age of diagnosis was 12 months (1 day-16.6 years) in patients with classical congenital adrenal hyperplasia. Chromosomal sex was 46, XX in a total of 221 patients and 46, XY in 52. Ninety-one girls were considered to be male before diagnosis was established and male sex was assigned in 31 of them due to development of male gender identity at diagnosis. Parental consanguinity rate among families of patients was higher than the general population in Turkey (56.4% vs 21%). Our overall figures show that the incidence of congenital adrenal hyperplasia is expected to be high due to a high rate of consanguinity in our populations and the patients remain frequently undiagnosed during the neonatal period. Therefore screening may be beneficial in our population.     

Female phenotype in a male child due to 17-alpha-hydroxylase deficiency

The discovery of testicles in a 3-year-old girl with XY karyotype led to a diagnosis of testicular feminization. Subsequently, however, hypokalaemia, hypertension, and severe prostration during a mild infection suggested adrenal involvement, and investigations showed a 17-alpha-hydroxylase deficiency. Diagnosis of testicular feminization should not be made without excluding a defect of testosterone synthesis.