Masculinization Of Genitalia Research Articles

Raritná kombinácia Turnerovho syndrómu a kongenitálnej adrenálnej hyperplázie s deficitom 21-hydroxylázy: kazuistika

Combination of Turner syndrome (TS) and classic congenital adrenal hyperplasia (CAH) is rare. Globally, the incidence of CAH, autosomal recessive disorder caused by enzyme defect of steroidogenic pathway, is very low (1 : 10 000-16 000). 90 % of CAH cases are caused by 21-hydroxylase gene mutation (CYP21A2). Globally, the incidencie of Turner syndrome reaches 1 : 2 500. Phenotypically, females with TS may render wide spectrum of clinical features. Dominant symptoms are lowered terminal height and gonadal dysgenesia, ultimately leading to absence of puberty and infertility. Virilisation may be evident among TS women with chromosome Y 45, X/46, XY. We present a 57 year old woman suffering from both TS 45, X/46, XX and 21-hydroxylase deficiency. Based on the intersex, she was misdiagnosed as a male after the birth. Dominant signs were intrauterine growth retardation and Prader 5 virilisation of the external genitalia. Testes were not palpable. Laparoscopy at the age of 6 showed uterus and ovaries. After this examination, clitoroplasty and vaginoplasty was performed. Karyotyping revealed a 45, X/46, XX pattern. The presence of virilising features at the time of puberty however could not be explained with the diagnosis of Turner syndrome. Laboratory tests revealed elevated level of 17-hydroxyprogesterone, dehydroepiandrosterone with low cortisol concentration and elevated ACTH. With the genomic analysis CYP21A2 gene, namely IN2G (IVS 2-13 A/C>G), large deletion/conversion was detected. Glucocorticoid treatment was initiated. Due to increased plasma renin concentration, fludrocortisone therapy was also initiated. Within this therapy, patient´s state improved significantly.Key words: congenital adrenal hyperplasia - CYP21A2 - Turner syndrome - 21-hydroxylase deficiency.

Psychological impact of congenital adrenal hyperplasia on adolescent and young girls in Saudi Arabia

Background: Congenital adrenal hyperplasia (CAH) consists of a family of defects in the synthesis of steroid hormone in the adrenal cortex which results in high androgen levels. The androgen excess is present from early embryogenesis and results in varying degrees of virilization of the external genitalia. It can lead to major medical and psycho-social consequences. Design and Setting: Eight Saudi adolescent and young women whose age ranged between 15 to 25 y with variable severity of CAH were studied to determine the psychosocial impact at the endocrine service, King Khalid University Hospital (KKUH) Riyadh, Saudi Arabia in the period July 2017 to June 2018. Objective: The aim of this study was to determine the psychological impact of CAH on adolescent and young women who were diagnosis and appropriately reared in the early life. Methods: Eight Saudi adolescent and young women with similar clinical characteristics where chosen from a cohort of sixty four patients with CAH. Psychosocial information were gathering during a clinic visits from both participant and parents. Participants were interviewed by the primary treating endocrinologist (principal author NJ) to facilitate trust and confidence, utilizing the child behaviour checklist (CBCL) questioner. Results: There were significant differences between females with CAH diagnosed early in life and reared as females with higher incidence of anxiety, depression (25%), withdrawn/depressed behaviour (25%) and somatic complaints (75%), which depend on the variation of the severity. Conclusion: Psychological adjustment is variable in females with CAH who were diagnosed and properly reared in early life. Adjustment depends on the severity of the disease. Future multicentre studies involving CAH patients in Saudi Arabia are needed to ensure large sample size. In addition, further researchers should concentrate on various aspects of psychosocial issues of CAH.

A Descriptive Study on Children with Congenital Adrenal Hyperplasia Attending Assiut University Children Hospital

Introduction: Congenital adrenal hyperplasia is a group of autosomal recessive disorders that result from the deficiency of one of several enzymes involved in the steroidogenic pathway for cortisol biosynthesis. The most common cause of CAH, accounting for 90% of cases, is 21- hydroxylase deficiency resulting from mutations or deletions in the CYP21A gene [1]. Less common causes of CAH are deficiencies in the enzymes 11β-hydroxylase, 3β- hydroxysteroid dehydrogenase, 17α-hydroxylase, steroidogenic acute regulatory protein, cholesterol sidechain cleavage enzyme and P450-oxidoreductase [2]. The symptoms of disease vary depending on the nature and severity of the enzyme deficiency as well as the sex of the individual. Approximately 75% of infants with classical CAH have the severe salt-wasting form of the disease with shock, dehydration, hyponatremia, and hyperkalemia leading to death [3]. Affected females have varying degrees of virilization of the external genitalia. The remaining 25% have the simple virilizing form of disease which is less severe. Non-classical CAH is generally late onset with symptoms such as hirsutism, infertility, acne and alopecia arising from androgen excess [4]. Untreated babies with classic CAH could experience a life threatening adrenal crisis. However, treatment in the form of replacement hormone therapy (hydrocortisone or dexamethasone to replace cortisol and fludrocortisone to replace aldosterone) corrects the hormone deficiencies [3]. Life-long medication is required to prevent the return of symptoms in individuals with classic CAH. In addition, newborns with ambiguous genitalia in CAH should undergo an appropriate work-up by a medical team consisting of a pediatric endocrinologist, urologist, surgeon, geneticist, and psychologist who should assist parents in making fully informed decisions regarding gender assignment and treatment options such as genital reconstructive surgery [5]. Patients and methods: A descriptive study included children from 1 day to 18 years of age with congenital adrenal hyperplasia attending Assiut University Children Hospital over one year in the period from the 1st of June, 2016 to the 30th of May, 2017. Full thorough history and clinical examination were done to all cases: name, age, sex, residence, consanguinity, history of similar cases in the family, history of previous death due to neglected similar disease, methods of presentation as poor weight gain, poor feeding, persistent vomiting, dehydration and/or shock, convulsions, weight, height, blood pressure, signs of ambiguous genitalia, signs of dehydration, hyperpigmentation and signs of precocious puberty. All cases had been subjected to the following investigations: blood sugar, Na+, K+, blood gases, kidney function tests, karyotyping, hormonal analysis(17 OH progesterone, cortisol a.m and p.m testosterone, ACTH), pelvi-abdominal ultrasonography and magnetic resonanse imaging of the abdomen and pelvis. Results: 34 cases of congenital adrenal hyperplasia were included, of whom 8 cases were newly diagnosed on admission while 26 cases were previously diagnosed and came for follow up, 41.2% were males, 58.8% were females.

A Single Nucleotide Variant in the Promoter Region of 17β-HSD Type 5 Gene Influences External Genitalia Virilization in Females with 21-Hydroxylase Deficiency

Background: In 21-hydroxylase deficiency (21-OHD), there is an influence of genotype on the severity of external genitalia virilization. However, females carrying mutations predicting a similar impairment of enzymatic activity present a wide variability of genital phenotypes. In such cases, interindividual variability in genes related to the sex steroid hormone pathway could play a role. Objective: To evaluate the influence of POR, HSD17B5 and SRD5A2 variants on the severity of external genitalia virilization in 21-OHD females. Design and Patients: Prader stages were evaluated in 178 females with 21-OHD from a multicenter study. The 21-OHD genotypes were divided into two groups according to their severity: severe and moderate. The influences of the POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants on the degree of external genitalia virilization were analyzed. Results: The POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants were found in 25, 33, 17, 1, and 31% of the alleles, respectively. In uni- and multilinear regression, HSD17B5 c.-210A>C has a significant influence on the degree of external genitalia virilization. This variant was also identified with a higher frequency in the most severely virilized females. Conclusion: We demonstrated that a variant in the promoter region of HSD17B5 related to fetal androgen synthesis influences the genital phenotype in 21-OHD females.

Gender of rearing and psychosocial aspect in 46 XX congenital adrenal hyperplasia.

Background:In congenital adrenal hyperplasia (CAH) with ambiguous genitalia, assigning gender of rearing can be complex, especially If genitalia is highly virilized. Apart from karyotype, prenatal androgen exposure, patient's gender orientation, sociocultural, and parental influences play a role. The aim of this study was to assess gender dysphoria and psychosocial issues in patients of CAH raised as males and females.Materials and Methods:This is a cross-sectional study that includes patients (old and new) with CAH who were treated by us in the last 6 months. A semi-structured interview proforma was used to elicit history and psychosocial background of the patients. The clinical and biochemical details were noted. For psychological analysis, patients were screened for gender dysphoria using Parent Report Gender Identity Questionnaire for children <12 years and Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults.Results:We analyzed 22 46 XX CAH patients among which, 3 were reared as males and 19 as females. Among the 19 patients reared as females, 17 patients showed no gender dysphoria. Two patients revealed gender dysphoria as indicated by their marginally low scores on the gender dysphoria assessment. However, in view of current literature and the age groups of the patients, behavior of the 6-year-old patient can be best understood as being tomboyish. Gender dysphoria in the 22-year-old can be explained by the dominance of psychosocial factors and not hormones alone. Among the three patients reared as males, two prepubertal were satisfied with their male gender identity. The third patient, aged 32 years, had gender dysphoria when reared as a male that resolved when gender was reassigned as female and feminizing surgery was done.Conclusion:Gender assignment in 46 XX CAH is guided by factors such as degree of virilization of genitalia, gender orientation, patient involvement, sociocultural, and parental influences.

Characterization of the molecular genetic pathology in patients with 11β‐hydroxylase deficiency

Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Nonclassic or mild 11OHD appears to be a rare condition. Our study assessed the residual CYP11B1 function of detected mutations, adding to the spectrum of mild 11OHD, and illustrates the variability of the clinical presentation of 11OHD. Five patients presented with mild to moderate 11OHD. Two women presented with mild hirsutism and in one case with secondary amenorrhoea. Two men presented with precocious pseudopuberty, gynaecomastia and elevated blood pressure. One 46,XX female patient was diagnosed with virilization of the external genitalia 2 years after birth. Direct DNA sequencing was carried out to perform CYP11B1 mutation analysis. The CYP11B1 mutations were functionally characterized using an in vitro expression system. CYP11B1-inactivating mutations were detected in all patients. Two novel missense mutations (p.P42L and p.A297V) and the previously characterized p.R143W mutation had residual CYP11B1 activities between 10% and 27%. A novel p.L382R and the previously uncharacterized p.G444D mutation both caused complete loss of CYP11B1 enzymatic activity. Mutations causing partial impairment of 11β-hydroxylase activity (residual activity of 10% or above) are associated with a less severe clinical presentation of 11OHD, which can be classified as a nonclassic form. Our data demonstrate that patients with nonclassic 11OHD can present with androgen excess, precocious pseudopuberty and increased blood pressure. Timely diagnosis of nonclassic 11OHD and consequently initiation of personalized treatment is essential to prevent co-morbidities caused by androgen excess and hypertension.

Characterization of a novel CYP19A1 (aromatase) R192H mutation causing virilization of a 46,XX newborn, undervirilization of the 46,XY brother, but no virilization of the mother during pregnancies

BackgroundP450 aromatase (CYP19A1) is essential for the biosynthesis of estrogens from androgen precursors. Mutations in the coding region of CYP19A1 lead to autosomal recessive aromatase deficiency. To date over 20 subjects have been reported with aromatase deficiency which may manifest during fetal life with maternal virilization and virilization of the external genitalia of a female fetus due to low aromatase activity in the steroid metabolizing fetal–placental unit and thus high androgen levels. During infancy, girls often have ovarian cysts and thereafter fail to enter puberty showing signs of variable degree of androgen excess. Moreover, impact on growth, skeletal maturation and other metabolic parameters is seen in both sexes. Objective and hypothesisWe found a novel homozygous CYP19A1 mutation in a 46,XX girl who was born at term to consanguineous parents. Although the mother did not virilize during pregnancy, the baby was found to have a complex genital anomaly at birth (enlarged genital tubercle, fusion of labioscrotal folds) with elevated androgens at birth, normalizing thereafter. Presence of 46,XX karyotype and female internal genital organs (uterus, vagina) together with biochemical findings and follow-up showing regression of clitoral hypertrophy, as well as elevated FSH suggested aromatase deficiency. Interestingly, her older brother presented with mild hypospadias and bilateral cryptorchidism and was found to carry the same homozygous CYP19A1 mutation. To confirm the clinical diagnosis, genetic, functional and computational studies were performed. Methods and resultsGenetic analysis revealed a homozygous R192H mutation in the CYP19A1 gene. This novel mutation was characterized for its enzymatic activity (Km, Vmax) in a cell model and found to have markedly reduced catalytic activity when compared to wild-type aromatase; thus explaining the phenotype. Computational studies suggest that R192H disrupts the substrate access channel in CYP19A1 that may affect binding of substrates and exit of catalytic products. ConclusionR192H is a novel CYP19A1 mutation which causes a severe phenotype of aromatase deficiency in a 46,XX newborn and maybe hypospadias and cryptorchidism in a 46,XY, but no maternal androgen excess during pregnancy.

Das adrenogenitale Syndrom beim Mädchen/junger Frau

With a mean global incidence of 1:14500, congenital adrenal hyperplasia (CAH) is the most common disorder of sexual differentiation (DSD). In case of female karyotype, the prenatal surplus of androgens causes virilization of the external genitalia. This includes clitoral hypertrophy and an increasing higher confluence of the urethra and normal developed proximal vagina, creating the urogenital sinus. Internal genitalia are female. Until recently feminizing surgery was performed within the first 18 months of life, at least concerning clitoroplasty. Though the cosmetic result of this kind of surgery is quite good, functional shortcomings like clitoral hyposensibility were often reported. The latest discussion about treatment of intersex patients resulted in recommendations to prevent early surgery and observe the development of the child, until the child can decide for itself, if and in what direction it wants to undergo surgery. Though CAH patients are seen as a special group within intersex disorders, these recommendations should also be considered for them. The appropriateness of this change in treatment strategy is supported by publications concerning the long-term follow-up of patients, who finally chose a gender that was different from what physicians and parents had expected.

Novel nucleotide insertions in two unrelated Indian patients with 5α reductase 2 deficiency leading to premature termination of SRD5A2 enzyme

T is converted to a more potent androgen, DHT by the action of microsomal membrane enzyme 5α reductase 2. Defects in 5α reductase 2 isozyme results in incomplete virilisation of external male genitalia. Mutations in SRD5A2 gene leads to diminished enzyme activity, thus hampering DHT synthesis from T. We describe two unrelated patients from India with 5αRD2 due to novel insertion of nucleotides in the exon 1 of SRD5A2 gene that lead to premature termination of protein. Master S (case 1; III.8) was 3years old at initial evaluation, had perineoscrotal hypospadias, microphallus and both testes were palpable in the inguinal region. Master P (case 2; III.9) was born as normal full term baby. He had primary complaint of microphallus, penoscrotal hypospadias and gonads in the inguinal region. Diagnosis of 5αRD2 was made, as T/DHT ratio in the two cases was 41 and 131.2 respectively. Sequence analysis of SRD5A2 gene showed an insertion of nucleotides TA in exon 1 (c.188_189). This resulted in premature termination of the protein due to stop codon at amino acid position 7. The protein formed is drastically truncated and inadequate protein synthesized explains the phenotypic characteristics of our patients.

Severity of Virilization Is Associated with Cosmetic Appearance and Sexual Function in Women with Congenital Adrenal Hyperplasia: A Cross-Sectional Study

Women with the classical form of congenital adrenal hyperplasia (CAH) are born with different degrees of virilization of the external genitalia. Feminizing surgery is often performed in childhood to change the appearance of the genitalia and to enable penile-vaginal intercourse later in life. There are suggestions that this affects sexual functioning. The aim is to study the anatomical, surgical, cosmetic, and psychosexual outcomes in women with CAH. Forty women with CAH, aged over 15 years, from two referral centers for management of Disorders of Sex Development in the Netherlands were included. Physical and functional status were assessed by a gynecological interview and examination. Sexual functioning was assessed with the Female Sexual Function Index and Female Sexual Distress Scale-Revised scales and compared with a reference group. Surgery performed, anatomy, cosmetic score, sexual function and distress. Thirty-six of the 40 women had undergone feminizing surgery; 25 women (69%) underwent more than one operation. Resurgery was performed in seven of the 13 (54%) women who had had a single-stage procedure. Anatomical assessment showed reasonable outcomes. Multiple linear regression showed that only level of confluence had a significant effect on cosmetic outcome, the impact depending on the number of surgeries performed. Cosmetic evaluations did not differ between the women and the gynecologists. Only 20 women had experience of intercourse. Eight women reported dyspareunia; seven women reported urinary incontinence. The women's perceived sexual functioning was less satisfactory than in the reference group, and they reported more sexual distress. The level of confluence was the major determinant for cosmetic outcome; the impact depended on the number of surgeries performed. Fifty-four percent of the women required resurgery after a single-stage procedure in childhood. Anatomical assessment showed reasonable outcomes. The women evaluated their sexual functioning and functional outcome less favorable than the reference group, and they experienced less often sexual intercourse.

The effect of fetal androgen metabolism‐related gene variants on external genitalia virilization in congenital adrenal hyperplasia

The 21-hydroxylase deficiency (21OHD) is caused by CYP21A2 mutations resulting in severe or moderate enzymatic impairments. 21OHD females carrying similar genotypes present different degrees of external genitalia virilization, suggesting the influence of other genetic factors. Single nucleotide variants (SNVs) in the CYP3A7 gene and in its transcription factors, related to fetal 19-carbon steroid metabolism, could modulate the genital phenotype. To evaluate the influence of the 21OHD genotypes and the CYP3A7, PXR and CAR SNVs on the genital phenotype in 21OHD females. Prader scores were evaluated in 183 patients. The CYP3A7, PXR and CAR SNVs were screened and the 21OHD genotypes were classified according to their severity: severe and moderate groups. Patients with severe genotype showed higher degree of genital virilization (Prader median III, IQR III-IV) than those with moderate genotype (III, IQR II-III) (p < 0.001). However, a great overlap was observed between genotype groups. Among all the SNVs tested, only the CAR rs2307424 variant correlated with Prader scores (r(2) = 0.253; p = 0.023). The CYP21A2 genotypes influence the severity of genital virilization in 21OHD females. We also suggest that the CAR variant, which results in a poor metabolizer phenotype, could account for a higher degree of external genitalia virilization.

M499 REPRODUCTIVE FUNCTION OF WOMEN WITH GENITAL ANOMALIES

I. Gonadal dysgenesys: Streak gonad, Ovaryan and Testicular dysgenesys, Ovotestis. II. Uterovaginal anomalies: 1. vaginal aplasia: utero-vaginal aplasia (MRKH syndrome) 2. compete cervico-vaginal aplasia and partial vaginal aplasia 3. unicornuate uterus: with functional uterine horn, unfunctional uterine horn, without horn 4. uterus duplex: symmetric form with duplication of vagina, asymmetric with aplasia of hemivagina 5. bicornuate uterus: complete, incomplete forms and arcuate uterus 6. septate uterus: complete septum with vaginal duplication, incomplete septum 7. fallopian tubes anomaly: absence of tube, additional fimbria. III. External genitalia virilization: I-V degree by Von Prader. Conclusions: The systematic analysis of all clinical cases, allows to suggest new systematyzation and upgrade clinico-morphological classification for optimize the appropriate surgical correction of female patients with various genital malformations.

Prenatal Treatment of Congenital Adrenal Hyperplasia—Not Standard of Care

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common autosomal recessive disorder due to mutations in the CYP21A2 gene. Since genetic counselors play a crucial role in educating families about inherited disorders, they need to have thorough knowledge regarding the pathophysiology of CAH especially the effects on the fetus, the complex genetics of this disorder, and the controversies surrounding experimental prenatal dexamethasone treatment. Affected female fetuses may have varying degree of virilization of the external genitalia. Starting in the 1980's, supraphysiologic glucocorticoid treatment was used to decrease the virilization of the external genitalia of affected female fetuses. However, recent clinical observations, animal studies and greater awareness of the details of human fetal adrenal physiology raise concerns regarding the safety of this prenatal treatment. We review the pathophysiology of CAH, the safety and ethical considerations of prenatal dexamethasone treatment and the views of multiple medical societies that conclude that this experimental therapy should only be done in prospective trials approved by ethical review boards.

Adult women with 21-hydroxylase deficient congenital adrenal hyperplasia, surgical and psychological aspects

Congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency results in prenatal androgen exposure and virilization of the external genitalia. The surgical procedures, indications, timing, and methods used have come under debate during the past decade. The androgen effect on later behaviors adds to the complexity of the situation for these women. The purpose of this review is to update physicians on recent findings regarding the outcome of feminizing surgery, infertility, quality of life (QoL), and psychosexual aspects in women with CAH. Surgical outcome, also for the more modern techniques used today, has not been entirely satisfactory and QoL assessments paint a dark picture. All psychological effects assessed show a spectrum of severity correlating with the CYP21A2 genotype or disease severity. The prevailing recommendation for sex of rearing is to let all patients with the 46,XX karyotype grow up as girls. This notion has now been challenged regarding patients with the most extreme virilization of genitalia. There are large differences in outcome depending on the severity of the disease or CYP21A2 mutation. Care needs to be individualized and centralized to specialized multidisciplinary teams. Feminizing surgery is still not satisfactory for all patients. More studies regarding sex identity are needed.

SRD5A2 gene mutations and polymorphisms in Spanish 46,XY patients with a disorder of sex differentiation

One hundred and forty-six index patients with 46,XY DSD in whom gonads were confirmed as testes were consecutively studied for a molecular diagnosis during the period 2002-2010. AR gene was analysed in all patients as the first candidate gene, yielding a mutation in 42.5% of cases and SRD5A2 gene was analysed as the second candidate gene, resulting in the characterization of 10 different mutations (p.Y91D, p.G115D, p.Q126R, p.R171S, p.Y188CfsX9, p.N193S, p.A207D, p.F219SfsX60, p.R227Q and p.R246W) in nine index patients (6.2% of the total number of 46,XY DSD patients). One of the mutations (p.Y188CfsX9) has never been reported. In addition, we genotyped SRD5A2 gene p.V89L and c.281+15T>C polymorphisms in 46,XY DSD and in 156 normal adult males and found that patients with SRD5A2 mutations or without a known molecular diagnosis presented a higher frequency of homozygous p.L89, homozygous TT and combined CCTT genotypes compared with controls. This result suggests that 46,XY DSD patient phenotypes may be influenced by SRD5A2 polymorphism genotypes. SRD5A2 gene mutations may not be as infrequent as previously considered in 46,XY DSD patients with variable degrees of external genitalia virilization at birth and normal T production and appears to be the second aetiology in our series.

45,X/46,XY mosaicisme: Report of five cases and clinical review

Introduction The mosaicism 45, X/46, XY is a gonosomal abnormality characterized by a broad phenotypic spectrum, ranging from women with or without Turner syndrome stigmata, to men apparently normal, passing by the ambiguous phenotypes with variable virilisation of external genitalia. From the histological point of view, several situations may arise. Patients and methods We analyzed the clinical, hormonal, sonographic, and genitographics data, as well as peroperative and histological findings for five cases of mosaicism 45, X/46, XY, and we discussed treatment performed. Results The mean age of patients was 6.6 years, two had a female phenotype with clitoral hypertrophy (one of them had Turner syndrome stigmata), one had a normal male phenotype with bilateral cryptorchidism and two had an ambiguity of external genitalia assigned to male. Short stature was noted for four patients. Surgical exploration concluded to the diagnosis of mixed gonadal dysgenesis for four of our patients. No cases of gonadoblastoma have been reported, for girls a prophylactic gonadectomy was performed, for boys the streak gonad was resected and the dysgenetic testis biopsied and preserved, subject for constant monitoring. Conclusion This heterogeneity indicate the importance of an accurate clinical and histological evaluation of any patient presenting with 45, X/46,XY mosaicism.

Approach to Assigning Gender in 46,XX Congenital Adrenal Hyperplasia with Male External Genitalia: Replacing Dogmatism with Pragmatism

The goal of sex assignment is to facilitate the best possible quality of life for the patient. Factors such as reproductive system development, sexual identity, sexual function, and fertility are important considerations in this regard. Although some DSD gender assignments are relatively straightforward, those with midstage genital ambiguity and unclear gonadal function represent a major challenge. A recent major change in DSD care has been to encourage a male assignment for 46,XY infants with ambiguous genitalia who have evidence of testicular function and in utero central nervous system androgen exposure. In contrast, assignment of virilized 46,XX DSD patients remains female when ovaries and internal organs are present, regardless of the extent of virilization of the external genitalia. In this paper, we propose consideration of male assignment for these 46,XX patients who have fully developed male genitalia based on available outcome data.

Primary amenorrhea in four adolescents revealed 5α-reductase deficiency confirmed by molecular analysis

To determine the genetic cause of primary amenorrhea. Case series. Pediatric endocrinology, endocrinology, and gynecology departments of academic hospitals. Three adolescents and one young woman 46, XY patients with srd5A2 gene mutations. Genetic analysis of srd5A2. We report four srd5A2 gene mutations in three adolescents and one young woman with 46,XY primary amenorrhea. All presented clitoromegaly and two presented hypospadias; all had been reared as females. Virilization of the external genitalia was noted in the pubertal period in all four patients. Three were maintained in the female sex of rearing by personal choice, and the fourth switched gender. We identified the homozygous substitutions p.L55Q (exon 1), p.Q56R (exon 1), and p.N193S (exon 4), in patients 1, 2, and 3, respectively. Patient 4 had compound heterozygous mutations, a new c.34delG (exon 1) associated with p.R246W (exon 5). All patients had high plasma T levels (ranges, 16.2-23.2 nmol/L; normal female teenage range, 0.35-2 nmol/L). Our data clearly demonstrate that 5α-reductase deficiency should be considered in XY adolescents with primary amenorrhea and no breast development associated with virilization at puberty and high plasma T. Positive parental consanguinity should reinforce the diagnostic orientation.

Sexual Function and Surgical Outcome in Women with Congenital Adrenal Hyperplasia Due toCYP21A2Deficiency: Clinical Perspective and the Patients’ Perception

Females with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency are exposed to androgens during fetal development, resulting in virilization of the external genitalia. Little is known about how these women feel that the disease has affected their lives regarding surgery and psychosexual adaptation. Our objective was to investigate the correlation between the surgical results, the self-perceived severity of the disease, and satisfaction with sexual life and relate the results to the CYP21A2 genotype. Sixty-two Swedish women with CAH and age-matched controls completed a 120-item questionnaire, and a composite score for sexual function was constructed. The surgical outcome, including genital appearance and clitoral sensitivity, was evaluated by clinical examination. The patients were divided into four CYP21A2 genotype groups. The sexual function score, but not for genital appearance, was higher in the patients satisfied with their sexual life. This was also true of the patients who were satisfied with the surgical result. There were discrepancies between the patients' perception of the impact of the condition on their sexual life and what health professionals would assume from clinical examination. The patients in the null genotype group scored lower on sexual function and satisfaction with their sexual life and had more surgical complications, also compared with the slightly less severe I2-splice genotype group. Our data show that the null genotype group was considerably more affected by the condition than the other groups and should be regarded as a subgroup, both psychologically and from a surgical perspective. Genotyping adds clinically valuable information.

Is hypospadias a genetic, endocrine or environmental disease, or still an unexplained malformation?

Hypospadias is one of the most frequent genital malformations in the male newborn and results from an abnormal penile and urethral development. This process requires a correct genetic programme, time- and space-adapted cellular differentiation, complex tissue interactions, and hormonal mediation through enzymatic activities and hormonal transduction signals. Any disturbance in these regulations may induce a defect in the virilization of the external genitalia and hypospadias. This malformation thus appears to be at the crossroads of various mechanisms implicating genetic and environmental factors. The genes of penile development (HOX, FGF, Shh) and testicular determination (WT1, SRY) and those regulating the synthesis [luteinizing hormone (LH) receptor] and action of androgen (5alpha reductase, androgen receptor) can cause hypospadias if altered. Several chromosomal abnormalities and malformative syndromes include hypospadias, from anterior to penoscrotal forms. More recently, CXorf6 and ATF3 have been reported to be involved. Besides these genomic and hormonal factors, multiple substances found in the environment can also potentially interfere with male genital development because of their similarity to hormones. The proportion of hypospadias cases for which an aetiology is detected varies with the authors but it nevertheless remains low, especially for less severe cases. An interaction between genetic background and environment is likely.