Partial Androgen Insensitivity Syndrome Research Articles

Challenges in clinical and laboratory diagnosis of androgen insensitivity syndrome: a case report

IntroductionAndrogen is a generic term usually applied to describe a group of sex steroid hormones. Androgens are responsible for male sex differentiation during embryogenesis at the sixth or seventh week of gestation, triggering the development of the testes and penis in male fetuses, and are directed by the testicular determining factor: the gene SRY (sex determining region on Y chromosome) located on the short arm of chromosome Y. The differentiation of male external genitalia (penis, scrotum and penile urethra) occurs between the 9th and 13th weeks of pregnancy and requires adequate concentration of testosterone and the conversion of this to another more potent androgen, dihydrotestosterone, through the action of 5α-reductase in target tissues.Case presentationThis report describes the case of a teenage girl presenting with a male karyotype, and aims to determine the extension of the mutation that affected the AR gene. A Caucasian girl aged 15 was referred to our laboratory for genetic testing due to primary amenorrhea. Physical examination, karyotype testing and molecular analysis of the androgen receptor were critical in making the correct diagnosis of complete androgen insensitivity syndrome.ConclusionsSex determination and differentiation depend on a cascade of events that begins with the establishment of chromosomal sex at fertilization and ends with sexual maturation at puberty, subsequently leading to fertility. Mutations affecting the AR gene may cause either complete or partial androgen insensitivity syndrome. The case reported here is consistent with complete androgen insensitivity syndrome, misdiagnosed at birth, and consequently our patient was raised both socially and educationally as a female. It is critical that health care providers understand the importance of properly diagnosing a newborn manifesting ambiguous genitalia. Furthermore, a child with a pseudohermaphrodite phenotype should always undergo adequate endocrine and genetic testing to reach a conclusive diagnosis before gender is assigned and surgical interventions are carried out. Our results show that extreme care must be taken in selecting the genetic tools that are utilized for the diagnosis for androgen insensitivity syndrome.

Androgen Insensitivity Syndrome with Male Sex-of-Living

Recent articles (Kulshreshtha et al., 2009; Meyer-Bahlburg, 2009, 2010; Nourizadeh& Hashemzadeh,2008; T’Sjoenetal., 2011)regardingmalegender identity incompleteandrogeninsensitivity syndrome (CAIS) prompt me to report my own similar history of male upbringing in spite of Quigley grade 5 (i.e., close to CAIS in phenotype, but with slight clitoral enlargement and partial labial fusion) (Quigley et al., 1995), partial androgen insensitivity syndrome (PAIS), and change to female sex-ofliving in early adulthood. I am also seeking to clarify some minor points. MeyerBahlburg (2009) and Zucker (1999) have both written that there hadbeenapreviouscaseofCAISwithmaleupbringingreported by Money (1991). I know that this patient actually had partial AIS because I am his cousin. He (my cousin) was also described by Money and Ogunro (1974). Another minor point: Crawford et al. (1970) reported my age at mastectomy as 14 and Money (1991) reported it as 15. I was actually still age 13 at that time. I would like to offer my thoughts based on first-hand experience of a situation similar to that of the patients in the aforementioned articles with CAIS living as males. An underlying, unquestioned assumption in much writing on changes of sex-ofliving is that ‘‘gender identity’’ is an imperative, overriding psychological force. My own pediatric endocrinologist (J. D. Crawford, M.D. of Massachusetts General Hospital) told me when I was age 21 that gender identity was‘‘an unshakable conviction.’’However, he never asked me whether I experienced it that way. My actual inner experience was of gender identity as an ordinary, malleable conviction, vulnerable to changes in perception of facts. As a child, I had been told that medical authorities hadconcludedthat Iwasmale.However, later,asayoungadult, I revised this to the belief that I was actually a person with AIS who should more appropriately be living as female. Perhaps those interested in the psychology of gender identity should pause to question the belief that‘‘gender identity’’always exists as a profound, unalterable psychological force or drive. Some seem to be using as their model for gender identity the compulsion of transsexuals to live as their target gender, no matter what the impediments. If transsexuals did not have such a need, they would not be transsexuals, but it is a great leap to assume that all other persons’ experience of gender identity is of the same nature. Perhaps what clinicians perceive as‘‘core gender identity’’ is sometimes not a deep and integral component of a patient’s psychological makeup, but instead a somewhat superficial reaction and adaptation to the social and medical predicament the patient perceives himself/herself to be in. The apparent male gender identity of the patients in the Kulshreshtha et al. and T’Sjoen et al. articles might be partly, or even wholly, explicable as the product of the patients’ having been told they were, in some sense,‘‘really’’male, than having their reactions reinforced by counselors. The authors seek an explanation in chromosomes or genetics or brain differentiation, but perhaps what they are seeing is not much more than their own ideas being recycled back to them. A person’s actions may be controlled, not only through overt or inchoate coercion, but also through their being misinformed or under-informed. A child’s apparent‘‘gender identity’’may consistofhisorherperception ofan immutable reality. Children knowthat, in theordinarycourseofevents,peopledonotchoose their own sex. They may perceive the word of an authority like a physician, not merely as one human being’s opinion, but as a simple statement of an unchangeable fact. My own history indicates that clinicians are not extremely perceptive about intersex children’s gender identity and can even be complexly wrong about it. Records from when I was P. Cadet (&) White River Junction, VT 05001, USA e-mail: peggycadet@gmail.com

‘Idiopathic’ partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?

46,XY disorders of sex differentiation (46,XY DSD) can be due to a testis determination defect, an androgen biosynthesis defect, or androgen resistance (complete or partial androgen insensitivity syndrome (PAIS), or 5α reductase deficiency). We aimed to evaluate the impact of a prenatal contamination by environmental xenoestrogens in 'idiopathic' PAIS-like phenotype. We investigated 28 newborn/infant males with 46,XY DSD, normal androgen production, and no androgen receptor or steroid-5αR type II enzyme (SRD5A2) gene mutations. To exclude other genetic defects, we sequenced the steroidogenic factor 1 (SF1) and mastermind-like domain-containing 1 (MAMLD1) genes, which were recently found to be associated with the PAIS-like phenotype. Parents were interviewed about their environmental/occupational exposure to endocrine disrupting chemicals (EDCs) before/during the patients' fetal life. Total estrogenic bioactivity of patient serum was analyzed by ultrasensitive bioassay. All the patients had normal SF1 sequence and one patient showed a double polymorphism of MAMLD1. Eleven (39.3%) of the 28 patients had reported parental fetal exposure to EDCs. The mean estrogenic bioactivity in these 11 patients with fetal EDC exposure (6.65 ± 8.07 pg/ml) versus 17 cases without contamination (1.27 ± 0.34 pg/ml) and controls (1.06 ± 0.44 pg/ml; P<0.05) was elevated. Our results indicate that the 'idiopathic' PAIS-like phenotype may in some cases be related to EDC contamination during fetal life.

Severe forms of partial androgen insensitivity syndrome due to p.L830F novel mutation in androgen receptor gene in a Brazilian family

BackgroundThe androgen insensitivity syndrome may cause developmental failure of normal male external genitalia in individuals with 46,XY karyotype. It results from the diminished or absent biological action of androgens, which is mediated by the androgen receptor in both embryo and secondary sex development. Mutations in the androgen receptor gene, located on the X chromosome, are responsible for the disease. Almost 70% of 46,XY affected individuals inherited mutations from their carrier mothers.FindingsMolecular abnormalities in the androgen receptor gene in individuals of a Brazilian family with clinical features of severe forms of partial androgen insensitivity syndrome were evaluated. Seven members (five 46,XY females and two healthy mothers) of the family were included in the investigation. The coding exons and exon-intron junctions of androgen receptor gene were sequenced. Five 46,XY members of the family have been found to be hemizygous for the c.3015C>T nucleotide change in exon 7 of the androgen receptor gene, whereas the two 46,XX mothers were heterozygote carriers. This nucleotide substitution leads to the p.L830F mutation in the androgen receptor.ConclusionsThe novel p.L830F mutation is responsible for grades 5 and 6 of partial androgen insensitivity syndrome in two generations of a Brazilian family.

Androgen Insensitivity and Liability to Drug-Induced Extrapyramidal Symptoms

Androgen insensitivity syndrome (AIS) is a disorder of sex development characterized by variable defects in virilization of individuals with 46,XY karyotype. It is caused by mutations in the X chromosome androgen receptor gene, which, depending on their specific location, result in complete or partial peripheral androgen resistance. This case report highlights a possible increased liability of patients with AIS to drug-induced extrapyramidal symptoms (EPS). A 28-year-old patient with partial AIS was admitted to the hospital because of paranoid ideation. At puberty onset, she had undergone bilateral orchiectomy; estrogen replacement therapy was prescribed but stopped 2 months later against medical advice. During her hospitalization, severe EPS manifested following initiation of risperidone 2 mg/d. She was later switched to sertindole 12 mg/d with a satisfactory response and no motor side effects. Patients with AIS may have an increased susceptibility to drug-induced EPS, which may be caused by striatal dysfunction that is possibly associated with resistance to androgens during critical periods of early brain differentiation or direct effects of androgen receptor gene mutations on nigrostriatal function and development. Clinicians should cautiously treat psychosis in patients with AIS, preferably with antipsychotic compounds that have a low risk of EPS.

550 SHOULD PROXIMAL HYPOSPADIAS WITH BILATERALLY DESCENDED GONADS BE CONSIDERED A DISORDER OF SEX DEVELOPMENT (DSD)?

You have accessJournal of UrologyPediatrics: Congenital Anomalies - Lower Urinary Tract & Genitalia1 Apr 2011550 SHOULD PROXIMAL HYPOSPADIAS WITH BILATERALLY DESCENDED GONADS BE CONSIDERED A DISORDER OF SEX DEVELOPMENT (DSD)? Rodrigo L.P. Romao, Darius J. Bagli, Armando J. Lorenzo, Walid A. Farhat, Bruno Leslie, Victor Figueroa, David Chitayat, Diane Wherrett, and Joao L. Pippi Salle Rodrigo L.P. RomaoRodrigo L.P. Romao Toronto, Canada More articles by this author , Darius J. BagliDarius J. Bagli Toronto, Canada More articles by this author , Armando J. LorenzoArmando J. Lorenzo Toronto, Canada More articles by this author , Walid A. FarhatWalid A. Farhat Toronto, Canada More articles by this author , Bruno LeslieBruno Leslie Toronto, Canada More articles by this author , Victor FigueroaVictor Figueroa Toronto, Canada More articles by this author , David ChitayatDavid Chitayat Toronto, Canada More articles by this author , Diane WherrettDiane Wherrett Toronto, Canada More articles by this author , and Joao L. Pippi SalleJoao L. Pippi Salle Toronto, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1275AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In 2006, the Chicago consensus on disorders of sex development proposed a new nomenclature that has been widely adopted for disorders previously referred to as “intersex”. The consensus included isolated perineal hypospadias (regardless of cryptorchidism) as one of the situations in clinical practice that would warrant a full workup for DSD (karyoptype, imaging studies, and hormone profiles). Our objective was to look at the impact of having a DSD workup on diagnosis, management or gender assignment for patients seen for isolated proximal hypospadias and bilateral fully descended gonads. METHODS Retrospective analysis of a single institution database containing 125 patients followed by a multidisciplinary DSD clinic. Inclusion criteria were: proximal hypospadias (defined as perineal or scrotal with bifid scrotum) and bilateral descended gonads (defined as 2 gonads palpable in a scrotal /topical position). Data collected included: karyotype, external genitalia appearance, presence of mullerian structures on abdominal ultrasound, gender assignment, final diagnosis and surgical treatment. RESULTS Undervirilization of the external genitalia was the referral diagnosis in 45 patients (45/125-36%). Of those, 17 (38%) met inclusion criteria. Two patients also had micropenis. Time of referral was before 1 year of age for all patients. Average stretched penile length was 2.2 ± 0.57 cm. Penoscrotal transposition was present in 6 (35%) patients. Karyotype was 46 XY in all of them. Abdominal ultrasound performed in 14 patients failed to show any mullerian structures in the pelvis. Laboratory profile was consistent with partial androgen insensitivity syndrome (PAIS) in all but one patient, who was diagnosed with salt-wasting congenital adrenal hyperplasia (CAH). Surgical treatment consisted of only hypospadias repair with correction of penoscrotal transposition when indicated for the entire study population. CONCLUSIONS Based on our data, isolated proximal hypospadias with bilateral descended gonads might not warrant a full workup for DSD. In the study population, all patients had a normal male karyotype and no mullerian structures were identified. Gender assignment was uniformly male and surgical management was not affected by diagnostic tests. Refining the indications for DSD workup could potentially avoid the stress and stigma imposed to patients and families by the label of “ambiguous genitalia”. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e223 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rodrigo L.P. Romao Toronto, Canada More articles by this author Darius J. Bagli Toronto, Canada More articles by this author Armando J. Lorenzo Toronto, Canada More articles by this author Walid A. Farhat Toronto, Canada More articles by this author Bruno Leslie Toronto, Canada More articles by this author Victor Figueroa Toronto, Canada More articles by this author David Chitayat Toronto, Canada More articles by this author Diane Wherrett Toronto, Canada More articles by this author Joao L. Pippi Salle Toronto, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Sex of rearing seems to exert a powerful influence on gender identity in the absence of strong hormonal influence: report of two siblings with PAIS assigned different sex of rearing

There is an ongoing debate regarding the relative contribution of nurture over nature in development of gender identity. Patients with partial androgen insensitivity syndrome (PAIS) have ambiguous genitalia and are known to be reared as male or female. Familial cases of PAIS sharing common hormonal defects are usually reared in the same sex. Here, we describe two siblings with PAIS, one reared as a male and the other as female. These two siblings presented at adolescence. Gender identity was concordant with the sex of rearing for both. The male sibling was distressed with gynecomastia that had disrupted his social life. The sex of rearing seems to have played a predominant role in the formation of gender identity in these two patients with PAIS.

Androgen insensitivity syndrome: Risk of malignancy and timing of surgery in a paediatric and adolescent population

Management of female phenotype XY disorders poses a series of problems for the treating clinician. Even after a series of investigations and imaging modalities, there are lingering doubts about the exact nature of the disease and the correct management option. Optimal timing and necessity for removal of their testes have been a debated issue by physicians. There is a generally accepted opinion among physicians that the risk of malignancy in androgen insensitivity syndrome (AIS) is considerably lower than with other intersex disorders and occurs at a later age. The highlight of this presentation is to reinforce the value of laparoscopic gonadectomy in management of AIS in correlation with data suggesting higher risk of malignancy. A retrospective review of 11 phenotypic females with XY karyotype was carried out. The patients were evaluated by a diagnostic protocol which included clinical, hormonal, sonographic and cytogenetic examinations. Patients/parents were counselled by the team concerning the different treatment modalities and contrary to the assigned gender, laparoscopy was offered to them. Uneventful bilateral gonadectomy was performed in all the patients and gonads submitted for histopathological examination. A total of 11 patients (mean age, 10.4 ± 4.1 years), including six with complete AIS and five with partial AIS (PAIS) were reviewed. In two patients with PAIS (18.1%), histopathology revealed malignancy (bilateral seminoma and gonadoblastoma) and in an additional patient, a benign hamartoma was found. Literature evidence suggests that AIS female phenotype patients retaining their testes through puberty have a 5% chance for developing malignant tumours. Reviewing our results in correlation with literature, we found that PAIS patients may harbour a higher risk of malignancy. In complementation to hormonal tests and cytogenetic techniques, laparoscopic gonadectomy is required to complete the diagnostic work up for AIS as it also adds a final therapeutic approach with low risk and huge benefit. Since laparoscopy is now a well-tolerated and widely accepted gold standard, it should be included in routine management for patients with AIS. Risk of malignancy in PAIS should be investigated in larger cohort of these patients.

Phenotypical, Biological, and Molecular Heterogeneity of 5α-Reductase Deficiency: An Extensive International Experience of 55 Patients

In 46,XY disorders of sex development, 5α-reductase deficiency is rare and is not usually the first-intention diagnosis in newborn ambiguous genitalia, contrary to partial androgen insensitivity syndrome. Yet the cause of ambiguous genitalia may guide sex assignment, and rapid, precise diagnosis of 5α-reductase deficiency is essential. The aim of the study was to describe relevant data for clinical diagnosis, biological investigation, and molecular determination from 55 patients with srd5A2 mutations identified in our laboratory over 20 yr to improve early diagnosis. The study was performed at Montpellier University Hospital. We studied a cohort of 55 patients with srd5A2 gene mutations. Genetic analysis of srd5A2 was conducted. Clitoromegaly (49.1%) and microphallus with various degrees of hypospadias (32.7%) were frequent phenotypes. Female external genitalia (7.3%) and isolated micropenis (3.6%) were rare. Seventy-two percent of patients were initially assigned to female gender; five of them (12.5%) switched to male sex in peripuberty. Over 72% of patients were considered for 5α-reductase deficiency diagnosis when the testosterone/dihydrotestosterone cutoff was 10. In 55 patients (with 20 having a history of consanguinity), we identified 33 different mutations. Five have never been reported: p.G32S, p.Y91H, p.G104E, p.F223S, and c.461delT. Homozygous mutations were present in 69.1% of cases, compound heterozygous mutations in 25.5%, and compound heterozygous mutations alone with the V89L polymorphism in 5.4%. Exons 1 and 4 were most affected, with 35.8 and 21.7% mutant alleles per exon, respectively. In the largest cohort to date, we demonstrate a wide spectrum of phenotypes and biological profiles in patients with 5α-reductase deficiency, whatever their geographical or ethnic origins.

Undervirilization in XY newborns may hide a 5α‐reductase deficiency: report of three new SRD5A2 gene mutations

The observation of ambiguous genitalia in the newborn signals a medical, surgical and psychological emergency. The most crucial decision will be the choice of sex assignment. Rapid and precise diagnosis is thus essential. In XY newborns with normal/high plasma testosterone (T), partial androgen insensitivity syndrome (PAIS) is usually the first diagnosis evoked, which implies an androgen receptor (AR) defect. The diagnosis of steroid-5-alpha-reductase deficiency is rarely considered by the paediatrician. We report three new SRD5A2 gene mutations in four newborns from France, Morocco and Turkey. The newborns presented with ambiguous genitalia and normal plasma T values and the initial diagnosis\PAIS. In all four cases, normal sequences of the complete AR gene excluded this diagnosis and raised the hypothesis of 5α-reductase deficiency. The entire coding region (5 exons) of the SRD5A2 gene was assessed by PCR and direct sequencing analysis. For patient 1, we identified a new homozygous 2bp deletion in exon 1 (c.122_123delAG). Patient 2 had a known homozygous mutation, p.G115D, in exon 2. New compound heterozygous mutations in exon 4 (p.A215V) and exon 5 (p.X255Q) were found in patient 3. Patient 4 presented a new substitution in exon 1 (p.S14R) associated with a known polymorphism (p.V89L). Our data confirm our previous experience and clearly demonstrate that a 5-α reductase defect should be considered in all XY newborns with ambiguous genitalia and normal plasma T secretion, whatever their geographic area or ethnic group; moreover, this defect was not linked to specific phenotype. Early molecular diagnosis is indispensable for the crucial decision of the newborn's sex of rearing.

Morris Syndrome: Description of a case Characterized by Partial Androgen Insensitivity

The Morris syndrome is a X-linked recessive condition due to a complete or partial insensitivity to androgens, resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete or partial depending on the amount of residual androgen receptor function. The phenotype of individuals with partial androgen insensitivity syndrome may range from mildly virilized female external genitalia to mildly undervirilized male external genitalia. We describe a case of Partial Androgen Insensitivity Syndrome in a 21–year-old patient with a 46, XY karyotype, bilateral inguinal masses, clitoral enlargement and partial posterior labial fusion. Surgical care consisted of bilateral orchiectomy and plastic surgery of external genitalia. The patient underwent estrogen replacement therapy.

Long-Term Outcome of Pituitary-Gonadal Axis and Gonadal Growth in Patients With Hypospadias at Puberty

Reports of pubertal hormonal and gonadal status in patients with hypospadias are scarce. We evaluated the pituitary-gonadal axis and gonadal growth in patients with hypospadias at puberty. We retrospectively reviewed serum luteinizing hormone, follicle-stimulating hormone, testosterone and testicular volume at puberty (age 15 years or greater) in the medical charts of patients with hypospadias treated since 1986 and followed at our institution. Enrolled in this study were 43 patients with a mean age at evaluation of 17.6 years (range 15.1 to 22.8). Of these patients 14 and 29 were treated for mild and severe hypospadias, respectively. Six patients with severe hypospadias underwent bilateral orchiopexy for bilateral undescended testes. All patients were Tanner stage 4 to 5 at evaluation. Of 14 mild hypospadias cases we noted hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, decreased luteinizing hormone and decreased testosterone in 1 each (7% each). Of 23 severe hypospadias cases without bilateral undescended testes we noted hypergonadotropic hypogonadism, partial androgen insensitivity syndrome and decreased testosterone in 2 (9%), 1 (4%) and 1 (4%), respectively. Of 6 patients with severe hypospadias and bilateral undescended testes we noted hypergonadotropic hypogonadism in 1 (17%) and increased luteinizing hormone with normal testosterone in 2 (33%). Testicular volume less than 10 ml with increased follicle-stimulating hormone was identified in 7 of 43 patients, including 1 of 14 (7%) with mild hypospadias, 3 of 23 (13%) with severe hypospadias without bilateral undescended testes and 3 of 6 (50%) with severe hypospadias and bilateral undescended testes. Our study revealed endocrine dysfunction in patients with mild and severe hypospadias at puberty even without an undescended testis. Of these patients those with severe hypospadias and an undescended testis may be at higher risk for impaired spermatogenesis.

Incomplete androgen insensitivity (Reifenstein syndrome) - a case report

We report a 20 year old case of partial androgen insensitivity syndrome, referred to our clinic with complaints concerning external genital organs and left undescended testicle. The phenotypically male case was first evaluated for secondary sex development. Axillary hair was scanty and no pubic hair was found. There was no breast development. In the gynecological examination, the clitoris was hypertrophic (4.6 cm) and a blind vagina with intact hymen was seen. Abdominopelvic ultrasonography revealed the absence of an uterus and adnexes which was supported by magnetic resonance imaging (MRI). There was a palpable mass in the left inguinal canal (cryptorchism), seen as atrophic tissue under the skin in MRI. Although the other testis was in the labioscrotal fold, it was atrophic. The Karyotype was 46 XY after genetic investigation.

C601S mutation in the androgen receptor results in partial loss of androgen function

The present study was undertaken on a case of partial androgen insensitivity syndrome to look at the etiology of the disorder. The patient exhibited a female phenotype despite 46,XY chromosome complement. Direct DNA sequencing of coding region of the androgen receptor gene in this case revealed a 2329G>C substitution (cDNA sequence reference) in exon 3 of the gene. The substitution resulted in replacement of Cys with Ser at codon 601 of the ligand-binding domain of the protein. Analyses on 200 control samples revealed absence of this substitution(s). In vitro assays were done using COS-1 cells. The mutation resulted in partial (∼40%) loss of ligand-binding and significant (∼70%) loss of downstream transactivation function. The mutation was absent in the controls. The findings are particularly interesting since another substitution at the same codon (T GC–T TC) has been reported in association with complete androgen insensitivity syndrome.

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.

Isolated micropenis reveals partial androgen insensitivity syndrome confirmed by molecular analysis

Partial androgen insensitivity syndrome (PAIS) is the milder variant of androgen receptor (AR) defects. The subtle effects of AR mutations present in a patient with micropenis, peno-scrotal hypospadias, infertility, clitoromegaly and posterior labial fusion. We studied the association of isolated micropenis with the genetic defects resulting in androgen resistance, that is, AR gene defects and 5-alpha reductase type 2 (SRD5A2) deficiency. We describe two cases of isolated micropenis: one in a 14-year-old boy and the other in a 3-year-old boy who was followed until he was 10 years old. There were no findings of hypospadias, cryptorchidism or gynecomastia in either of these patients. Serum gonadotrophin and androgen levels were obtained and karyotyping was done. Human chorionic gonadotropin (hCG) stimulation testing assessed the functional capacity of the testes. DNA was extracted from peripheral leukocytes, and all exons of the SRD5A2 and AR genes were amplified by polymerase chain reaction and sequenced. In both patients, baseline testosterone (T) level was low and the values were elevated after hCG testing. The sequence of the SRD5A2 gene was normal in patient 1, and a heterozygous polymorphism, V89L, was found in patient 2. Two known mutations, P390S and A870V, were identified in patients 1 and 2, respectively. Mutations in the AR gene can be associated with isolated micropenis without other features of PAIS, such as hypospadias or gynecomastia. This underlines the importance of including AR gene analysis in the evaluation of isolated micropenis with normal plasma T to ensure proper management of the patient and appropriate genetic counseling for the family.

Complete androgen insensitivity syndrome: diagnosis and management

Complete androgen insensitivity syndrome (CAIS) is an X-linked genetic disorder affecting 46,XY individuals, characterized by the loss of function of the androgen receptor gene resulting in complete peripheral androgen resistance. Patients have a nonambiguous female phenotype with normal female external genitalia. Gonads are undescended testes (either intra-abdominal or inguinal), there is no uterus and the length of the vagina is usually very short. Gender identity is always female. This review focuses on the importance of accurate diagnosis of CAIS versus partial androgen insensitivity syndrome and other disorders of sex development by genotyping the androgen receptor, and raises issues of the optimal management of these patients. In the era of the Consensus Statement on Management of Intersex Disorders, we provide new insights into CAIS screening, surgical management of the gonads (balancing between hormonal production and malignancy risk) and of vaginal adequacy, and the ethics concerned with the disclosure to patients and their families.

Functional Analysis of Novel Androgen Receptor Mutations in a Unique Cohort of Indonesian Patients with a Disorder of Sex Development

Mutations in the androgen receptor (AR) gene, rendering the AR protein partially or completely inactive, cause androgen insensitivity syndrome, which is a form of a 46,XY disorder of sex development (DSD). We present 3 novel AR variants found in a cohort of Indonesian DSD patients: p.I603N, p.P671S, and p.Q738R. The aim of this study was to determine the possible pathogenic nature of these newly found unclassified variants. To investigate the effect of these variants on AR function, we studied their impact on transcription activation, AR ligand-binding domain interaction with an FxxLF motif containing peptide, AR subcellular localization, and AR nuclear dynamics and DNA-binding. AR-I603N had completely lost its transcriptional activity due to disturbed DNA-binding capacity and did not show the 114-kDa hyperphosphorylated AR protein band normally detectable after hormone binding. The patient with AR-I603N displays a partial androgen insensitivity syndrome phenotype, which is explained by somatic mosaicism. A strongly reduced transcriptional activity was observed for AR-Q738R, together with diminished interaction with an FxxLF motif containing peptide. AR-P671S also showed reduced transactivation ability, but no change in DNA- or FxxLF-binding capacity and interferes with transcriptional activity for as yet unclear reasons.

P15.01: Surface rendering of external genitalia in fetus at 32 weeks of gestation affected by Partial Androgen Insensitivity Syndrome (PAIS)

P15.01: Surface rendering of external genitalia in fetus at 32 weeks of gestation affected by Partial Androgen Insensitivity Syndrome (PAIS)

Corporeal Body Grafting Using Buccal Mucosa for Posterior Hypospadias With Severe Curvature

Severe penile curvature correction by corporeal body grafting has been successfully performed using various grafts and biomaterials. We present our initial experience with buccal mucosa as a free corporeal graft to correct severe penile curvature as part of a multistage approach to posterior hypospadias repair. A total of 12 children with a mean age of 6.2 years (range 4 to 8) with posterior hypospadias and severe ventral chordee (greater than 45 degrees) necessitating ventral grafting underwent correction using buccal mucosa. Preoperative androgen supplement was given when penile and glanular size was significantly small for age. Buccal mucosa was harvested from the inner side of the cheek or the lower lip. The harvested graft was defatted, fashioned and fixed to the ventral corporeal defect. The pre-grafting penile angle, immediate post-grafting angle and penile angle at 6 months were assessed. All children had penoscrotal or perineal hypospadias, 4 had partial androgen insensitivity syndrome and 1 underwent multiple previous failed repairs. Androgen was given preoperatively in 3 children. After chordee release and urethral plate transection the penile angle was between 45 and 80 degrees. Mean graft length and width was 2.5 and 1.6 cm, respectively. All children had a straight penis at the end of the procedure and none required additive dorsal plication. At the last followup at 12 months all children had a straight penis except 2 with mild curvature (less than 10 degrees). No complications were noted with this technique. Preliminary results of the novel use of buccal mucosa as a corporeal graft for severe chordee appear satisfactory. Longer term followup is needed to further document these data.