Normal Male External Genitalia Research Articles

Effects of Androgen Treatment on Growth in Patients with 5-α-Reductase Type 2 Deficiency.

Patients with 5-α-reductase type 2 deficiency (5αRD2) require androgen treatment for the growth of normal male external genitalia. Since limited research has been conducted on the effects of androgen treatment on height in individuals with 5αRD2, we investigated the effect of androgen treatment on bone age (BA) and the height status in children with 5αRD2. Of the 19 participants who were followed up for an average of 10.6 years, 12 received androgen treatment. BA and height standard deviation scores (SDS) were compared between the treatment and non-treatment groups, as well as between the dihydrotestosterone (DHT) and testosterone enanthate (TE) treatment groups. Despite the above-average height of the 19 patients with 5αRD2, the height SDS relative to BA (htSDS-BA) was below average, particularly in the androgen treatment group. DHT treatment did not lead to an increase in BA or htSDS-BA, whereas TE treatment resulted in BA advancement and decreased htSDS-BA, especially in the prepubertal period. DHT treatment is more favorable for height than TE treatment in patients with 5αRD2, particularly during the prepubertal period. Therefore, age and the type of androgen used should be carefully considered to minimize the risk of height reduction in these patient groups.

Abstract 97: Lipoid congenital adrenal hyperplasia in a boy with primary adrenal insufficiency with normal male external genitalia

Background: Lipoid congenital adrenal hyperplasia (CAH) commonly manifests as atypical genitalia or apparent female external genitalia in 46, XY whereas rarely, it may present with normal male external genitalia. Hence, we report the first Indian case of lipoid CAH with normal male external genitalia.Case Presentation: A 8-year-old boy born of a third-degree consanguineous marriage, presented in 2018 with generalized hyper-pigmentation. Serum 8:00 am cortisol was 2.78 μg/dl and plasma 8:00 am ACTH was 1260 pg/ml. He was diagnosed to have primary adrenal insufficiency and started on oral hydrocortisone 12 mg/m2/d and fludrocortisone (100 μg/d). He had developed hypokalemia on 100 μg/d and also, on 50 μg/d susequently. Hence, his fludrocortisone had been stopped. On review visit after 3 years (at present), his height and weight were appropriate for age and Tanner's sexual maturity rating was P3, SPL-7 cm and TV-15 cc bilateral. His ACTH-stimulated steroid profile showed low serum cortisol (0.15 μg/dL) and aldosterone (3.48 ng/dL) whereas direct renin concentration was elevated (167.5 μIU/mL). Subsequent genetic analysis revealed homozygous pathogenic variant c.574C>T (p.Arg192Cys) in STAR. The patient was restarted on fludrocortisone 25 μg/d.Conclusion: We report the first genetically-proven case of lipoid CAH in a boy with normal male external genitalia in India presenting with primary adrenal insufficiency. The case emphasizes that the diagnostic possibility of lipoid CAH can not be excluded in 46,XY primary adrenal insufficiency with normal male external genitalia.

34. Chromosomal microarray characterization of a prenatal case of 46,XX SRY-positive Disorder of Sex Development (DSD)

Nonsyndromic SRY-positive testicular 46,XX disorder of sex development (DSD) is most frequently de novo. Affected individuals often have normal male external genitalia and present as adults with infertility, or come to clinical attention after puberty due to signs of undermasculinization. Genital anomalies range from small testes to cryptorchidism, micropenis, and/or hypospadias to presence of both testicular and ovarian tissue (ovotesticular DSD or true hermaphroditism). Diagnosis is typically made by chromosome analysis showing a 46,XX karyotype and metaphase fluorescence in situ hybridization (FISH) demonstrating an SRY signal translocated to a derivative X chromosome.

Direct Visual Internal Urethrotomy in Supine Position in a Patient with Complex Deformities of Both Lower Limbs and Neurogenic Bladder: A Case Report

Direct visual internal urethrotomy (DVIU) is a minimally invasive treatment for urethral stricture and is usually done in lithotomy position. We presented a case of a 35-year-old man with complex deformities of both lower limbs from birth. The lower limbs were severely wasted with ankylosis of the hips, flexion of the knee joints and dorsiflexion at the ankle joints. He had a history of progressively worsening difficult in urination characterized by frequency, urgency, urgency incontinence, nocturia, poor urinary stream (improved by straining), intermittency and feeling of incomplete bladder emptying. He had occasional dysuria and total hematuria. He was not a known hypertensive or diabetic patient. No history of trauma, previous urethral instrumentation, and no history of purulent urethral discharge before the onset of problems. On presentation, his abdomen was full with slight suprapubic distention. The anal sphincter was spastic and the prostate was not enlarged. He had normal non-circumcised male external genitalia. There was no spinal deformity and the upper limbs were normal. White cell count was 14,000 cells/ mm3 with a differential neutrophil of 85.5% and urine culture showed moderate growth of coliforms. Abdominopelvic ultrasound showed a thickened bladder wall with mild hydronephrosis bilaterally and a retrograde urethrography and micturating cystourethrography showed 3 short segment bulbar urethral strictures. There was also a Christmas tree appearance of the bladder. A diagnosis of bladder outlet obstruction secondary to multiple short segment idiopathic bulbar urethral strictures on background neurogenic bladder was made. He had intravenous antibiotics for 48 hours and subsequently a DVIU under spinal anesthesia and in the supine position. Catheter was removed on the 7th day post procedure and he started clean intermittent catheterization (CIC) with 12 French catheters. Seven months post procedure, patient is still satisfied with the outcome of his treatment. We concluded that DVIU can be done safely in the supine position and CIC can help improve post procedure outcome and in managing comorbid neurogenic bladder.

Laparoscopic Management of Persistent Müllerian Duct Syndrome

Persistent Mullerian duct syndrome (PMDS) is characterized by persistence of Mullerian derivatives in a phenotypically and genotypically normal male. These patients have 46 XY karyotype with normal male external genitalia, virilization, and internal Mullerian duct structures. Typically, these patients have unilateral or bilateral undescended testes, bilateral fallopian tubes, a uterus, and an upper vagina draining into a prostatic utricle, as reported by Diamond and Uy (n.d.). We report a case of PMDS in a 25-year-old male, which present with primary infertility with bilateral cryptorchidism.

89] Robot-assisted hysterectomy and bilateral orchidopexy for a patient with persistent Müllerian duct syndrome

ObjectiveTo demonstrate robot-assisted hysterectomy and bilateral orchidopexy in a patient with persistent Müllerian duct syndrome (PMDS). PMDS is a relatively rare disorder of sexual development, patients have a 46, XY karyotype and normal male external genitalia, but internal Müllerian duct structures. Usually these phenotypic males have unilateral or bilateral undescended testes, bilateral fallopian tubes, a uterus, and an upper vagina draining into a prostatic utricle.

Genetic defects in pediatric-onset adrenal insufficiency in Japan.

Most patients with pediatric-onset primary adrenal insufficiency (PAI), such as 21-hydroxylase deficiency, can be diagnosed by measuring the urine or serum levels of steroid metabolites. However, the etiology is often difficult to determine in a subset of patients lacking characteristic biochemical findings. To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients. We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. The pathogenicities of rare variants were assessed based on in silico analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics. We identified genetic defects in 50 (85%) families: STAR in 19, NR0B1 in 18, SAMD9 in seven, AAAS in two, NNT in two, MC2R in one and CDKN1C in one. NR0B1 defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. STAR defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with STAR defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency. Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as NR0B1 defects are presumed based on phenotypes, while others with broad phenotypic variability, such as STAR defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients.

Analysis of clinical features and related genes variation in five patients with 46, XX male syndrome

Objective: To explore the clinical manifestations and molecular features of 46, XX male syndrome. Method: The clinical and molecular data of five 46, XX male syndrome cases treated in the Department of Pediatrics of Shanghai Ruijin Hospital form August 2010 to August 2014 were retrospectively analyzed. Result: The five patients were all sociopsychologically males and came to hospital respectively for short stature, ambiguous genitalia or gynecomastia. They were all below the normal male's average height, and their karyotype was all 46, XX. One case in five was verified as sex determining region of Y chromosome (SRY gene) positive revealed no abnormality in their external genitalia. He had short stature since childhood, whose SRY gene fragments were shown by FISH transferred to the ends of X chromosome. Three cases in four were SRY gene negative with ambiguous genitalia of cryptorchidism and testicular dysplasia to different degrees. The copy number variations of SOX9 gene was found in one case, the loss of heterozygosity area in DHH gene of one case. Another SRY gene negative patient who had normal male external genitalia, came to the hospital due to puberty gynecomastia, that of SOX9 gene and its upstream gene both increased. Conclusion: The main clinical characteristics of 46, XX male syndrome are male phenotype, 46, XX karyotype, gonad of testis or ovotestis and no uterus. In addition, short stature, ambiguous genitalia or gynecomastia can be one reason for hospital visits. SRY gene translocation, SOX9 gene and its upstream gene copy number increase all can lead to 46, XX male syndrome. The cause of some may play an important role in 46, XX male syndrome, but has not yet been determined.

Severe Undervirilisation in a 46,XY Case Due to a Novel Mutation in HSD17B3 Gene

17-β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an important enzyme involved in the final steps of androgen synthesis and is required for the development of normal male external genitalia. 46,XY individuals with deficiency of this enzyme present a wide clinical spectrum from a female appearance of the external genitalia through ambiguous genitalia to a predominantly male genitalia with micropenis or hypospadias. This paper reports a one-year-old 46,XY patient with 17β-HSD3 deficiency who presented with female external genitalia and bilaterally palpable gonads in the inguinal region. The low T/Δ4 ratio after human chorionic gonadotropin (hCG) stimulation suggested 17β-HSD3 deficiency. A homozygous mutation, c.761_762delAG, was determined at the intron 9/exon 10 splice site of the HSD17B3 gene. To the best of our knowledge, this mutation has not been reported thus far, but its localization and type would imply a complete disruption of the 17β-HSD3 which may explain the phenotype of our patient.

The management of the persistent Müllerian duct syndrome

ObjectivesTo report the findings and management of patients with persistent Müllerian duct syndrome (PMDS). Patients and methodsNineteen phenotypically male patients (aged 8months to 27years) presented with testicular maldescent. All of them had normal male external genitalia. Two of them had had a previous diagnosis of persistent Müllerian structures. All patients were karyotyped, and had a hormonal profile, diagnostic laparoscopy, retrograde urethrocystogram, gonadal biopsies, and surgical management according to the findings. The follow-up was based on a clinical examination, abdominal ultrasonography (US) and scrotal colour-Doppler US at 3 and 6months after surgery, and every 6months thereafter. ResultsDiagnostic laparoscopy showed the presence of persistent Müllerian structures in all 19 patients. All patients had a normal male karyotype (46XY). Ten patients had a laparoscopic excision of their Müllerian structures while the remaining nine patients had their Müllerian structures left in place. No malignant changes were found in the excised Müllerian tissues. Of the 37 gonadal biopsies taken, 31 (84%) indicated normal testes. ConclusionsThe incidence and prevalence of PMDS are not well estimated. Müllerian structures should be removed whenever possible to avoid the risk of malignant transformation. The early diagnosis of PMDS makes possible the excision of Müllerian structures and a primary orchidopexy. A long-term follow-up is needed for patients with intact Müllerian structures and magnetic resonance imaging might be a better method than US for that purpose. Most of the patients had normal testicular histology, which might allow fertility.

Epididymal polar dissociation: a previously undescribed anatomical variant.

The normal male external genitalia include the testicles with the epididymis attached posteriorly and the vas deferens arising from this. This case describes an anatomical variation of this normal anatomy not previously reported in the literature. A 17-year-old boy presented with symptoms of intermittent testicular torsion and underwent scrotal exploration. On the left side there was a bell-clapper deformity with the epididymis separated into two parts with the lower pole high in the scrotum and attached to the tunica vaginalis. A normal vas deferens was seen to arise from the isolated lower pole of the epididymis. There was no connection between the vas deferens and the testis or upper pole of epidiymis. This case reminds us of the possibility of anatomical variations and the importance of keeping them in mind to prevent complications at time of surgery.

A novel mutation of anti-Mullerian hormone gene in Persistent Mullerian Duct Syndrome presented with bilateral cryptorchidism: A case report

BackgroundWe report a novel mutation in a case of Persistent Mullerian Duct Syndrome (PMDS). PMDS is characterized by the persistence of female reproductive organs derivatives in a 46,XY subject due to the failure of the Mullerian duct to regress in utero. To date, 53 different mutations of the anti-Mullerian hormone (AMH) gene, including the present one, have been identified. Clinical caseA 2-week-old male presented with bilateral cryptorchidism and normal male external genitalia. His karyotype was 46,XY. hCG stimulation test was normal. At age 1 year and 4 months, he underwent laparoscopic surgery which revealed a uterus and fallopian tubes. The anti-Mullerian hormone (AMH) level was undetectable (<0.01 ng/mL). Diagnosis of Persistent Mullerian Duct Syndrome, probably due to an AMH mutation, was made. Genetic studiesA unique homozygous T to G base substitution was found at position 2219, near the middle of the exon 5, changing codon CTG to CGG in anti-Mullerian hormone (AMH) gene. This mutation causes leucine to be converted to arginine at position 426 belonging to a (L)RA(L)LLLKALQ highly conserved sequence in the AMH gene. Both parents are heterozygous for the mutation. ConclusionPersistent Mullerian Duct Syndrome (PMDS) is a rare cause of bilateral cryptorchidism, when in doubt the existence of Mullerian derivatives should be explored by laparoscopy. Assay of serum AMH helps to distinguish between mutations of AMH and AMH receptor. If serum AMH is very low or undetectable, sequencing of the AMH gene usually confirms the presence of a mutation.

46,XX Male Disorder of Sexual Development: A Case Report

The main factor influencing sex determination of an embryo is the sex-determining region Y (SRY), a master regulatory gene located on the Y chromosome. The presence of SRY causes the bipotential gonad to differentiate into a testis. However, some individuals carry a Y chromosome but are phenotypically female (46,XY females) or have a female karyotype but are phenotypically male (46,XX males). 46, XX male is rare (1:20 000 in newborn males), and SRY positivity is responsible for this condition in approximately 90% of these subjects. External genitalia of 46,XX SRY-positive males appear as normal male external genitalia, and such cases are diagnosed when they present with small testes and/or infertility after puberty. Herein, we report an adolescent who presented with low testicular volume and who was diagnosed as a 46,XX male. SRY positivity was demonstrated in the patient by fluorescence in situ hybridization method. Conflict of interest:None declared.

Genetic analysis of a family with complete androgen insensitivity syndrome

Androgen insensitivity causes impaired embryonic sex differentiation leading to developmental failure of normal male external genitalia in 46 XY genetic men. It results from diminished or absent biological actions of androgens, which is mediated by the androgen receptor (AR) in both the embryo and secondary sexual development. Mutations in the AR located on the X chromosome are responsible for the disease. Almost 70% of affected individuals inherit the mutation from their carrier mother. We hereby report a 10-year-old girl with all the characteristics of complete androgen insensitivity syndrome (CAIS). Similar scenario was observed in 3 maternal aunts, Sequencing of the AR gene in all the family members revealed C 2754 to T transition in exon 6. It was concluded that the C 2754 to T transition rendered the AR incapable of both ligand-binding and activating the transcription and was the cause of CAIS in the patient.

45,X/46,XY mosaicism: a cause of short stature in males

45,X/46,XY mosaicism is associated with a broad spectrum of phenotypes ranging from apparently normal male development to individuals with incomplete sexual differentiation and clinical signs of Turner syndrome in both males and females. The most common presentation among individuals with a 45,X/46,XY karyotype is sexual ambiguity, accounting for approximately 60% of cases, while the least common category of 45,X/46,XY patients consists of those with bilaterally descended testes, found in 11-12%. We report on two patients with an apparently normal male phenotype and 45,X/46,XY mosaicism who were diagnosed postnatally because of short stature. Both of these boys presented at the age of 15 years with short stature, minor Turner-like stigmata, normal male external genitalia and spontaneous pubertal development. One of them had coarctaction of the aorta with bicuspid aortic valve, an uncommon clinical feature in boys with mosaicism. The same patient underwent a trial of GH replacement therapy with poor response and his sperm analysis revealed azoospermia. Like our patients, most mosaic 45,X/46,XY children with bilateral scrotal testes go unrecognised at birth and throughout childhood unless they have somatic features of Turner syndrome or significant growth retardation. We recommend that boys with otherwise unexplained short stature, being short for their families, should be karyotyped routinely as is recommended in short-stature girls. In addition, boys with 45,X/46,XY mosaicism require a thorough clinical evaluation similar to that performed in girls with Turner syndrome and must be routinely followed up for their potential to respond favorably to GH treatment and for late onset abnormalities, such as infertility and gonadal tumors.

A child with isolated nephrotic syndrome and WT1 mutation presenting as a 46, XY phenotypic male

Mutations in the WT1 gene can lead to Denys-Drash syndrome or Frasier syndrome and can also cause isolated nephrotic syndrome (NS). Most patients with isolated NS caused by WT1 mutations present as 46, XX phenotypic females. There have been two cases with an onset age younger than 3 years with isolated NS caused by WT1 mutations presenting as 46, XY phenotypic males. We present a 46, XY phenotypic male patient with isolated NS and end-stage renal disease (ESRD) at the age of 6.3 years. He had normal male external genitalia with normal penis length and soft and normal volume of both testes. A mutation, 1051A>G (K351E), in exon 8 of WT1 was identified in the patient. After starting hemodialysis, manifestations of hypertension and renal failure improved, but he died at 6.8 years of age as a result of respiratory failure and heart failure. Our study supports the necessity of searching for mutations in WT1 in 46, XY phenotypic male patients with isolated NS and ESRD.

Complex genomic rearrangement in the SOX9 5′ region in a patient with Pierre Robin sequence and hypoplastic left scapula

Pierre Robin sequence (PRS) can occur as a component of campomelic dysplasia (CD) and acampomelic CD (ACD) caused by dysfunction or dysregulation of SOX9, although it can also take place as an isolated form. Recently, genomic alterations in the far upstream and the far downstream region of SOX9 have been identified in patients with isolated PRS. Here, we report on a male patient with PRS and a heterozygous genomic rearrangement in the 5' region of SOX9. Clinical analysis revealed PRS-compatible craniofacial anomalies, mild hypoplasia of the left scapula, and normal male external genitalia. Molecular analysis identified a paracentric inversion on the long arm of chromosome 17 with breakpoints at 17q21.31 and 17q24.3, and a microdeletion spanning from -4.15 to -1.16 Mb relative to SOX9. These findings indicate that the chromosomal region more than 1.16 Mb apart from SOX9 contains at least one developmental enhancer(s) for SOX9 that plays a critical role in the development of the mandible and a relatively small role in the development of the scapula. Moreover, the concept of exclusion mapping argues that putative CD/ACD loci are located within the 1.16 Mb region closest to SOX9 coding exons, which remain intact in this Non-CD/ACD patient. This study provides a novel example for long-range cis-regulatory mutations of SOX9.

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.

Characterization of Novel StAR (Steroidogenic Acute Regulatory Protein) Mutations Causing Non-Classic Lipoid Adrenal Hyperplasia

ContextSteroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH).ObjectiveStAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported.DesignTo report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature.SettingCollaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain.PatientsTwo subjects of a non-consanguineous Caucasian family were studied. The 46,XX phenotypic normal female was diagnosed with adrenal insufficiency at the age of 10 months, had normal pubertal development and still has no signs of hypergonodatropic hypogonadism at 32 years of age. Her 46,XY brother was born with normal male external genitalia and was diagnosed with adrenal insufficiency at 14 months. Puberty was normal and no signs of hypergonadotropic hypogonadism are present at 29 years of age.ResultsStAR gene analysis revealed two novel compound heterozygote mutations T44HfsX3 and G221S. T44HfsX3 is a loss-of-function StAR mutation. G221S retains partial activity (∼30%) and is therefore responsible for a milder, non-classic phenotype. G221S is located in the cholesterol binding pocket and seems to alter binding/release of cholesterol.ConclusionsStAR mutations located in the cholesterol binding pocket (V187M, R188C, R192C, G221D/S) seem to cause non-classic lipoid CAH. Accuracy of genotype-phenotype prediction by in vitro testing may vary with the assays employed.

Craniorachischisis and omphalocele in a stillborn cynomolgus monkey (Macaca fascicularis)

Nonhuman primates have been a common animal model to evaluate experimentally induced malformations. Reports on spontaneous malformations are important in determining the background incidence of congenital anomalies in specific species and in evaluating experimental results. Here we report on a stillborn cynomolgus monkey (Macaca fascicularis) with multiple congenital anomalies from the colony maintained at the Southwest National Primate Research Center at the Texas Biomedical Research Institute, San Antonio, Texas. Physical findings included low birth weight, craniorachischisis, facial abnormalities, omphalocele, malrotation of the gut with areas of atresia and intussusception, a Meckel diverticulum, arthrogryposis, patent ductus arteriosus, and patent foramen ovale. The macaque had normal male external genitalia, but undescended testes. Gestational age was unknown but was estimated from measurements of the limbs and other developmental criteria. Although cytogenetic analysis was not possible due to the tissues being in an advanced state of decomposition, array Comparative Genomic Hybridization analysis using human bacterial artificial chromosome clones was successful in effectively eliminating aneuploidy or any copy number changes greater than approximately 3-5 Mb as a cause of the malformations. Further evaluation of the animal included extensive imaging of the skeletal and neural tissue defects. The animal's congenital anomalies are discussed in relation to the current hypotheses attempting to explain the frequent association of neural tube defects with other abnormalities.