Ambiguous External Genitalia Research Articles

Etiology and clinical profile of children and adolescents with disorders of sex development (DSD) presenting with ambiguous external genitalia

Results 42 patients (age-neonate to 18 years, 14 (46 XX DSD), 26(46XY DSD) and 2(sex chromosome DSD) were evaluated.46 XX DSD was due to Congenital Adrenal Hyperplasia (CAH) (12/14) and SyndromicDSD(2/14). All presented with clitoromegaly and labioscrotal fusion. 5/12presented in infancy, with Adrenal crisis and severe (prader stage ≥3) virilization(Salt Wasting CAH), 7 had Simple VirilizingCAH. Hypospadias was the most common presentation in 46XY DSD. Partial Androgen Insensitivity syndrome (PAIS) (8/26, 30%) was the most common etiology.4 had 5 alpha reductase deficiency, (1 had isolated micropenis and1 cryptorchidism with PraderWilli Syndrome while other 2 had hypospadias). 4 patients had Complete Androgen insensitivity Syndrome, 2(Pure Gonadal dysgenesis), 1 (SyndromicDSD),1 (CAH, 21 hydroxylase deficiency with peripheral precocious puberty), 1 (Vanishing testis syndrome). 5 patients had inconclusive biochemical profile. 6 patients presented with virilization at puberty. Though gender identity prior to puberty was female, history suggestive of conflict regarding the gender role was present. 4/6 were reassigned a male gender, while 2 continued as females. 1 patient of Sex Chromosome DSD, had Ovotesticular DSD with rare mosaic karyotype of 46XX(p-)(P21-23)/45X 80%/20%, while other had 46XY/46XX 58%/42%chimerism.

Etiologies of 46,XY disorders of sex development (DSD): a collaborative study in Hong Kong

Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. In 46, XY DSD, the genotype is XY, but the external genitalia is incompletely virilised, ambiguous, or completely female. The objectives of this prospective study are to evaluate the testicular Sertoli and Leydig cell functions, to establish the genetic basis and to determine the relative prevalence of etiologies in Chinese patients with 46,XY DSD in Hong Kong. All patients with 46,XY DSD (either new or known) presented to five paediatric departments in Hong Kong from July 2009 till June 2011 were recruited. They were assessed by paediatric endocrinologists. Comprehensive evaluation of testicular and adrenal functions was performed using serum hormonal assays and urine steroid profiling. Based on the hormonal results, mutational analyses of the candidate genes by polymerase chain reaction and direct DNA sequencing were conducted to delineate the genetic basis of the etiologies. Sixty-five patients (54 male and 11 female) with 46,XY DSD were recruited. Their age ranged from birth to 27 years. Sixty-one (94%) patients presented with ambiguous external genitalia, two presented with delayed puberty and one each with primary amenorrhoea and inguinal hernia. Definitive diagnoses were made in 25 (38%) patients. Eleven (17%) patients had 5-alpha reductase 2 deficiency. Androgen insensitivity was confirmed by genetic analysis in eight (12%) patients. There was one patient with each of the following etiologies: Swyer syndrome, SF-1 mutation, Frasier syndrome, cholesterol side-chain cleavage deficiency, persistent Mullerian duct syndrome and mixed gonadal dysgenesis. Genetic basis of the etiologies was delineated in 23 (35%) patients. A total of 10 novel mutations were identified. The longest follow up period was 27 years, none of the patients requested change of gender sex so far. In conclusion, 46,XY DSD is a heterogeneous group with diverse etiologies. Although 5-alpha reductase 2 deficiency is believed to be rare, it is not uncommon in Hong Kong.

Cryptic Genomic Rearrangements in Three Patients with 46,XY Disorders of Sex Development

Background46,XY disorders of sex development (46,XY DSD) are genetically heterogeneous conditions. Recently, a few submicroscopic genomic rearrangements have been reported as novel genetic causes of 46,XY DSD.Methodology/Principal FindingsTo clarify the role of cryptic rearrangements in the development of 46,XY DSD, we performed array-based comparative genomic hybridization analysis for 24 genetic males with genital abnormalities. Heterozygous submicroscopic deletions were identified in three cases (cases 1–3). A ∼8.5 Mb terminal deletion at 9p24.1–24.3 was detected in case 1 that presented with complete female-type external genitalia and mental retardation; a ∼2.0 Mb interstitial deletion at 20p13 was identified in case 2 with ambiguous external genitalia and short stature; and a ∼18.0 Mb interstitial deletion at 2q31.1–32 was found in case 3 with ambiguous external genitalia, mental retardation and multiple anomalies. The genital abnormalities of case 1 could be ascribed to gonadal dysgenesis caused by haploinsufficiency of DMRT1, while those of case 3 were possibly associated with perturbed organogenesis due to a deletion of the HOXD cluster. The deletion in case 2 affected 36 genes, none of which have been previously implicated in sex development.Conclusions/SignificanceThe results indicate that cryptic genomic rearrangements constitute an important part of the molecular bases of 46,XY DSD and that submicroscopic deletions can lead to various types of 46,XY DSD that occur as components of contiguous gene deletion syndromes. Most importantly, our data provide a novel candidate locus for 46,XY DSD at 20p13.

A Rare Adolescent Case of Female Pseudohermaphroditism With Adrenocortical Carcinoma and Synchronous Teratoma

A patient with female pseudohermaphroditism is chromosomally and gonadally a female individual but has male or ambiguous external genitalia. In this paper, we report a 12-year-old Chinese girl who was diagnosed with female pseudohermaphroditism characterized by clitoridauxe, hirsutism, acne, hypertension, and karyotype 46 XX. Computed tomography scan revealed a huge left abdominal mass with distant metastases to bilateral lungs and a concomitant pelvic teratoma. Because the left abdominal mass was unresectable, the patient underwent a biopsy of the abdominal mass and a radical resection of the pelvic teratoma. Histopathology confirmed that the left abdominal mass was an adrenocortical carcinoma (ACC) and the pelvic teratoma was a mature cystic teratoma originating from the left ovary. After surgery, the patient received a transcatheter arterial chemoembolization of ACC, combined with 2 g mitotane daily for systemic treatment. It was a pity that she died 8 months later after diagnosis. So far, as we know, the simultaneous occurrence of pseudohermaphroditism, ACC, and ovarian teratomas has not been reported in the literatures before.

Ambiguous external genitalia due to defect of 5-α-reductase in seven Iraqi patients: Prevalence of a novel mutation

We report on seven Iraqi patients with 46,XY karyotype and ambiguous genitalia characterized by perineo-scrotal hypospadias, bifid scrotum, clitoris like phallus, palpable testes in inguinal canal and pseudovagina. Patients were raised five as females and two as males. They are all unrelated with the exception of two couples of brothers. The diagnosis of 5-α-reductase-2 deficiency syndrome was first hypothesized on clinical grounds and then confirmed by molecular analysis. Direct sequencing analysis of the SRD5A2 gene revealed in five patients a novel homozygous frame-shift mutation (c.453delC) and in two related patients a previous reported missense mutation. The presence of the same mutation in unrelated patients of the same population suggests a possible founder effect. This report brings the 5-α-reductase-2 deficiency syndrome to the attention of clinical geneticists and child surgeons and discusses the appropriate clinical and surgical strategies for treating these patients.

Prenatal diagnosis of ring chromosome 2 with lissencephaly and 2p25.3 and 2q37.3 microdeletions detected using array comparative genomic hybridization

We present rapid aneuploidy diagnosis of ring chromosome 2 with 2p25.3 and 2q37.3 microdeletions by aCGH using uncultured amniocytes in a fetus with IUGR, microcephaly, lissencephaly and ambiguous external genitalia. Our case adds lissencephaly to the list of CNS abnormalities in ring chromosome 2 with 2p25.3 and 2q37.3 microdeletions. We discuss the consequence of haploinsufficiency of HDAC4, KIF1A, PASK, HDLBP, FRAP2 and D2HGDH on 2q37.3, and haploinsufficiency of MYT1L, SNTG2 and TPO on 2p25.3 in this case.

Cytogenic and molecular analyses of 46,XX male syndrome with clinical comparison to other groups with testicular azoospermia of genetic origin

XX male is a rare sex chromosomal disorder in infertile men. The purpose of this study was to distinguish the clinical and genetic features of the 46,XX male syndrome from other more frequent, testicular-origin azoospermic causes of male infertility. To study 46,XX male syndrome, we compared clinical and endocrinological parameters to other groups with testicular-origin azoospermia, and to an age-matched group of healthy males and females as normal control. Fluorescent in situ hybridization for detection and localization of the sex-determining region of the Y gene (SRY), array-based comparative genomic hybridization screening, and real-time qualitative polymerase chain reaction of FGF9, WT1, NR5A1, and SPRY2 genes were performed in this genetic investigation. Our three patients with 46,XX male syndrome had a much higher follicular-stimulating hormone level, lower body height, lower testosterone level, and ambiguous external genitalia. One of the three patients with 46,XX male syndrome was SRY-negative. A further genetic study, including a comparative genomic hybridization array and real-time polymerase chain reaction, showed a gain of FGF9 copy numbers only in the SRY-negative 46,XX male. The genetic copy number of the FGF9 gene was duplicated in that case compared to the normal female control and was significantly lower than that of the normal male control. No such genomic gain was observed in the case of the two SRY-positive 46,XX males. Similar to clinical manifestations of 46,XX male syndrome, genetic evidence in this study suggests that FGF9 may contribute to sex reversal, but additional confirmation with more cases is still needed.

Prenatal findings of omphalocele–exstrophy of the bladder–imperforate anus–spinal defects (OEIS) complex

Omphalocele-exstrophy of the bladder (cloaca)-imperforate anus-spinal defects (OEIS) complex describes a rare grouping of more commonly occurring component malformations. We report two cases of OEIS complex diagnosed prenatally by ultrasound and magnetic resonance imaging (MRI). In both cases, OEIS complex was suspected by conventional sonography in the second trimester, and fetal MRI was performed at 27 and 32 weeks of gestation. Conventional sonography revealed low abdominal wall mass, spina bifida, absent bladder and ambiguous genitalia, but those findings were inconclusive. Using fetal MRI, we were able to detect omphalocele, imfraumbilical mass connected to gut tract, absent bladder, ambiguous external genitalia and spinal defect. Our findings suggest that fetal MRI is a useful tool for prenatal diagnosis of OEIS complex. MRI helps prenatal counseling and planning of postnatal early treatment strategy.

Role of 5α-reductase inhibitors in benign prostatic diseases

Testosterone is the most abundant androgen in serum. Intracellularly, testosterone is converted to dihydrotestosterone, the preferred ligand for androgen receptor transactivation, by the enzyme 5α-reductase. Three 5α-reductase isozymes have been discovered and they are expressed ubiquitously in human tissues. Testosterone and dihydrotestosterone have different but complimentary functions. Dihydrotestosterone has 2-5 times higher binding affinity for the androgen receptor than testosterone, and 10-fold higher potency of inducing androgen receptor signaling than testosterone. The role of dihydrotestosterone was discovered after the description of 5α-reductase type 2 deficiency in 1974, where affected males have normal internal but ambiguous external genitalia. Neither BPH nor prostate cancer has been reported in these patients. Currently, two 5α-reductase inhibitors are available for clinical use. This review will discuss the important clinical trials of 5α-reductase inhibitors in the treatment of benign prostatic diseases.

Müllerian Remnant Malignancy

Mixed gonadal dysgenesis is a disorder of sexual differentiation, characterized by mosaicism, ambiguous external genitalia, and both Wolffian and Müllerian internal genitalia. These patients are at a known increased risk of germ cell cancer, specifically gonadoblastoma; however, in this report we describe a case of adenocarcinoma of a remnant Müllerian structure.

Disorders of Sex Development

The birth of a new baby is one of the most dramatic events in a family, and the first question is usually "is it a boy or a girl?" The newborn infant with ambiguous external genitalia often comes as a surprise for the doctors as well as the parents and is sometimes described as an endocrine emergency situation presenting a problem of sex assignment. The nomenclature such as 'intersex', 'hermaphrodite', and 'pseudohermaphrodite' is out of date as well as confusing, and many urologists are concerned that these confusing terms could be perceived to be pejorative by some affected families. In response to concerns regarding outdated and controversial terms, the Chicago Consensus held in 2005 recommended new terminology based on the umbrella term disorders of sex differentiation (DSDs). The term DSD has a comprehensive definition including any problem noted at birth in which the genitalia are atypical in relation to the chromosomes or gonads. The karyotype is used as a prefix defining the classification of DSD. DSDs are rare and complex. The optimal management of patients with DSD must be individualized and multidisciplinary, considering all aspects, including psychological care and full disclosure of alternatives relating to surgery type and timing. Although further studies are necessary to confirm guidelines and recommendations fitting for the individual patients with DSD, this article is an attempt to provide a balanced perspective for new taxonomy, clinical evaluation, and medical, surgical, and psychological management of DSD.

A Case of Ambiguous External Genitalia in a Thoroughbred Male Horse with the 63,XO/64,XY Mosaic Karyotype

A Thoroughbred colt with ambiguous external genitalia was presented for clinical and histological examinations. The colt had a short penis that faced backward between his hind limbs. The measurements of luteinizing hormone, follicle stimulating hormone, testosterone and ir-inhibin showed a tendency to increase gradually from April. Both the sex-determining region of the Y chromosome and amelogenin gene fragments were detected by the PCR method. A cytogenetic analysis revealed the 63,XO/64,XY mosaic karyotype (ratio 83:17). In autopsy, immature symmetrical subcutaneous testes were found in the inguinal regions. The testes and other accessory sex organs were histologically normal. These results add to our knowledge of chromosomal abnormality and information concerning disorders of sex development in the horse.

The 5 Alpha-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases

Despite the discovery of 5 alpha-reduction as an enzymatic step in steroid metabolism in 1951, and the discovery that dihydrotestosterone is more potent than testosterone in 1968, the significance of 5 alpha-reduced steroids in human diseases was not appreciated until the discovery of 5 alpha-reductase type 2 deficiency in 1974. Affected males are born with ambiguous external genitalia, despite normal internal genitalia. The prostate is hypoplastic, nonpalpable on rectal examination and approximately 1/10th the size of age-matched normal glands. Benign prostate hyperplasia or prostate cancer does not develop in these patients. At puberty, the external genitalia virilize partially, however, secondary sexual hair remains sparse and male pattern baldness and acne develop rarely. Several compounds have been developed to inhibit the 5 alpha-reductase isozymes and they play an important role in the prevention and treatment of many common diseases. This review describes the basic biochemical properties, functions, tissue distribution, chromosomal location, and clinical significance of the 5 alpha-reductase isozyme family.

Mutation Analysis of NR5A1 Encoding Steroidogenic Factor 1 in 77 Patients with 46, XY Disorders of Sex Development (DSD) Including Hypospadias

BackgroundMutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum of 46,XY DSD (Disorder of Sex Development) phenotypes including severe forms of hypospadias.Methodology/Principal FindingsWe evaluated the frequency of NR5A1 gene mutations in a large series of patients presenting with 46,XY DSD and hypospadias. Based on their clinical presentation 77 patients were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external genitalia without uterus (n = 33) or hypospadias (n = 33). We identified heterozygous NR5A1 mutations in 4 cases of ambiguous external genitalia without uterus (12.1%; p.Trp279Arg, pArg39Pro, c.390delG, c140_141insCACG) and a de novo missense mutation in one case with distal hypospadias (3%; p.Arg313Cys). Mutant proteins showed reduced transactivation activity and mutants p.Arg39Pro and p.Arg313Cys did not synergize with the GATA4 cofactor to stimulate reporter gene activity, although they retained their ability to physically interact with the GATA4 protein.Conclusions/SignificanceMutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias. Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo heterozygous missense mutation, thus extending the range of phenotypes associated with NR5A1 mutations and suggesting that this group of patients should be screened for NR5A1 mutations.

Laparoscopic Gonadectomy in Two Intersex Warmblood Horses

Two phenotypically female Warmblood horses were presented at the Clinic for Horses owing to stallion-like behavior. One mare had an enlarged clitoris, whereas the other one showed no signs of ambiguous external genitalia. In both cases, intra-abdominal testicles were removed by laparoscopy. Hormone status, cytogenetic evaluation, and histopathological examination of the gonads were performed. One animal was diagnosed as having XX disorder of sexual development; the other one, as male pseudohermaphrodite.

Chromosome 1p32-p31 deletion syndrome: Prenatal diagnosis by array comparative genomic hybridization using uncultured amniocytes and association with NFIA haploinsufficiency, ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction

Objective To present prenatal diagnosis of chromosome 1p32-p31 deletion syndrome with NFIA haploinsufficiency, ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction and to review the literature. Materials, Methods, and Results A 26-year-old, primigravid woman was referred for amniocentesis at 30 weeks of gestation because of hydrocephalus and short limbs. Prenatal ultrasound showed macrocephaly, prominent forehead, ventriculomegaly, corpus callosum hypogenesis, micrognathia, and ambiguous external genitalia. Amniocentesis was performed, and array comparative genomic hybridization using uncultured amniocytes revealed a 22.2-Mb deletion of 1p32.3-p31.1 [arr cgh 1p32.3p31.1 (55,500,291 bp–77,711,982 bp)×1] encompassing the genes of NFIA, GPR177, and 89 additional genes. Cytogenetic analysis revealed a karyotype of 46,XX,del(1)(p31.1p32.3)dn. At 33 weeks of gestation, a dead fetus was delivered with a body weight of 1536 g (<5 th centile); relative macrocephaly; a broad face; prominent forehead; hypertelorism; anteverted nostrils; micrognathia; low-set ears; and abnormal female external genitalia with labial fusion, labial hypertrophy, absence of vaginal opening, and clitoral hypertrophy. Polymorphic DNA marker analysis determined a paternal origin of the deletion. Conclusion Prenatal diagnosis of ventriculomegaly with an abnormal corpus callosum should alert subtle chromosome aberrations and prompt molecular cytogenetic investigation if necessary. Fetuses with chromosome 1p32-p31 deletion syndrome and haploinsufficiency of the NFIA gene may present ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction in the third trimester.

Disgenesia gonadal parcial XY. Diagnóstico en edad adulta

We report the case of a 24-year-old adult with ambiguous external genitalia, who had never been studied or treated, but who was labelled as a hermaphrodite in the country of origin. These cases are usually evaluated at birth, the most frequent diagnosis being congenital adrenal hyperplasia. We present a case of one of the least common of these disorders, 46XY partial gonadal dysgenesis.

Tratamento cirúrgico da hipertrofia clitoriana

INTRODUÇÃO: Segundo vários autores, a hipertrofia discreta do clitóris está presente em 25% das mulheres. Quando o volume passa a incomodar no ato sexual, acompanhado ou não de distúrbios psicológicos, as pacientes buscam inicialmente ajuda de ginecologistas ou endocrinologistas e não raramente são encaminhadas à cirurgia plástica para a resolução dos problemas. MÉTODO: Nossa experiência é baseada em 9 pacientes, durante 15 anos, portadoras de genitália ambígua, submetidas a tratamento cirúrgico. Foram selecionados 3 casos para ilustrar os resultados obtidos com a técnica. Duas pacientes com hipertrofia clitoriana do tipo II de Prader foram selecionadas; uma de origem adquirida na idade adulta, e outra de origem possivelmente congênita. A terceira paciente apresentava anomalias sexuais múltiplas, de origem congênita: agenesia de vagina, hipertrofia clitoriana, presença de ovários e testículos atrofiados, pseudo-hermafroditismo feminino, catalogada como tipo V de Prader. Todos os três pacientes foram submetidas a redução do clitóris pela dissecção da cobertura músculo-cutânea (desenluvamento) e sepultamento do corpo clitoriano por sutura. RESULTADOS: Os procedimentos cirúrgicos realizados preservaram a estética e a sensibilidade, com redução das dimensões do clitóris. CONCLUSÃO: Os procedimentos apresentam relativa simplicidade, porém dentro de critérios cirúrgicos buscando a preservação das funções e da anatomia da genitália externa.

Physical, behavioral, endocrinologic, and cytogenetic evaluation of two Standardbred racehorses competing as mares with an intersex condition and high postrace serum testosterone concentrations

2 Standardbred racehorses that had been winning races while competing as mares underwent postrace drug testing and had serum testosterone concentrations above the acceptable limit for female racehorses. Initial physical examinations by the referring veterinarian revealed ambiguous external genitalia and suspected intra-abdominally located testes leading to a preliminary diagnosis of male pseudohermaphroditism. Horses were referred for further evaluation of sex. Physical examination of the external genitalia confirmed the findings of the referring veterinarian. Transrectal palpation and ultrasonography revealed gonads with an ultrasonographic appearance of testes. On cytogenetic analysis, both horses were determined to have a 64,XY karyotype and 8 intact Y chromosome markers and 5 SRY gene markers, which were indicative of a genetic male and confirmed an intersex condition. Additionally, both horses had some male-type behavior and endocrinologic findings consistent with those of sexually intact males. Taken together, these findings confirmed that both horses were male pseudohermaphrodites. Both horses returned to racing competition as males. As of October 1, 2008, the Pennsylvania Horse and Harness Racing Commissions implemented a postrace drug testing policy that included analysis of blood samples for anabolic and androgenic steroids and set maximum allowable concentrations of testosterone for racing geldings and females. Within 8 months of initiation of this drug testing policy, the 2 horses of this report were identified as having an intersex condition. This raises the possibility that intersex conditions may be more common in racing Standardbreds than was previously suspected.

Ambiguous External Genitalia in Childhood in Port Harcourt, Nigeria

Ambiguous external genitalia are a major cause of parental anxiety and a challenge to paediatricians in developing countries. Aims and objectives: This study aims to highlight the pattern of presentation and challenges in the management of ambiguous external genitalia in a developing country. Patients and methods: A prospective study of all patients with ambiguous external genitalia managed in the paediatric endocrine unit of the University of Port Harcourt Teaching Hospital between January 2008 and Dec 2010 was done. Biodata, clinical presentation, management and outcome were documented. Results: Six patients were seen with ambiguous external genitalia during the study period. Age ranged from birth to 16 years at presentation. The commonest presentation was clitoral hypertrophy in all patients. The commonest initial diagnosis was CAH. Definitive confirmation of cause of ambiguous external genitalia with a reconstructive surgery was done in only one patient due to non-availability and high cost of investigation. Three (50%) patients were lost to follow up of which 2(66.7%) have resorted to spiritual treatment. One patient who presented at 16 years of age died from an associated obstructive uropathy with chronic renal failure. Conclusion: The challenges in managing children with ambiguous external genitalia in developing countries include late presentation, high cost andnon-availability of investigations for making definitive diagnosis.