Minor hypospadias: the "tip of the iceberg" of the partial androgen insensitivity syndrome.

Background: Androgens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS).

Objective: The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR.

NR5A1 (SF-1) gene variants in a group of 26 young women with XX primary ovarian insufficiency.

Objective: To determine whether NR5A1 (SF-1) variants are a cause of primary ovarian insufficiency (POI) in 26 young women with similar genetic background.

Design: Genetic and functional mutation study.

Setting: University hospitals.

Screening of MAMLD1 mutations in 70 children with 46,XY DSD: identification and functional analysis of two new mutations.

More than 50% of children with severe 46,XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Besides gonadal dysgenesis, defects in androgen biosynthesis, and abnormalities in androgen sensitivity, the Mastermind-like domain containing 1 (MAMLD1) gene, which was identified as critical for the development of male genitalia, may be implicated. The present study investigated whether MAMLD1 is implicated in cases of severe 46,XY DSD and whether routine sequencing of MAMLD1 should be performed in these patients.

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

Objective: 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.

Subjects: 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.

Predominant Sertoli cell deficiency in a 46,XY disorders of sex development patient with a new NR5A1/SF-1 mutation transmitted by his unaffected father.

Objective: To further investigate the molecular mechanism by which NR5A1/SF-1 mutation led to gonadal dysgenesis with predominant Sertoli cell defect.

Design: Genetic and functional mutation study.

Setting: University hospital.

Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients.

Context: 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.

Objective: 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.

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.

Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration.

Background: Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence.

Methods: We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations.

Mother-to-son transmission of a luteinizing hormone receptor activating mutation in a prepubertal child with testotoxicosis.

Aim: To identify the LHR gene mutation in a prepubertal child with testotoxicosis.

Methods: Standard RIA procedure was used for estimating LH, FSH and testosterone levels. Molecular analysis was done by standard PCR using different sets of primers and reaction conditions specific for the LHR gene.

Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen receptor gene: an international collaborative report of 13 new mutations.

Objective: To confirm the clinical diagnosis of complete androgen insensitivity syndrome (CAIS) by molecular genetic analysis and to determine the prevalence of exon 1 mutations in the androgen receptor (AR) transactivation defects of a large series of CAIS patients.

Design: International retrospective study.

Setting: University Hospital of Montpellier, Department of Hormonology.

Mutations of CXorf6 are associated with a range of severities of hypospadias.

Objective: Mutations in chromosome X open reading frame 6 (CXorf6), a recently described candidate gene involved in the development of male genitalia, have been found in patients with complex 46,XY disorders of sexual development (46,XY DSD) including micropenis, bifid scrotum, and penoscrotal hypospadias. The objective of this work was to identify genomic variants of CXorf6 in patients with isolated hypospadias, severe or non-severe.

Design And Methods: Forty-one patients with glandular to perineal hypospadias and thirty controls were studied.

Molecular diagnosis of 5alpha-reductase-2 gene mutation in two Indian families with male pseudohermaphroditism.

Aim: To identify the genotype of two Indians with male pseudohermaphroditism.

Methods: Standard radioimmunoassay procedure was used for estimating hormonal levels. Conventional cytogenetic analysis was carried out for diagnosing the genetic sex in these subjects with genital ambiguity.

Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study.

BACKGROUND Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis and reproduction. Recently, haploinsufficiency of SF1 has been described in several 46,XY individuals with mild gonadal dysgenesis and impaired androgenization, but normal adrenal function, suggesting that dosage-sensitive or domain-specific effects of SF1 action are important in human testicular development and function. Our objective was to investigate whether partial defects in SF1 function might be associated with milder male reproductive phenotypes, such as bilateral anorchia ('vanishing testis syndrome') and micropenis.

Association between androgen receptor gene polymorphism and bone density in older women using hormone replacement therapy.

Objective: The objective of this study was to investigate the relationship between bone mineral density (BMD) and both CAG repeat polymorphism of the androgen receptor (AR) gene and skewed X chromosome inactivation (SI) in postmenopausal women.

Methods: BMD was measured by DEXA. Both the number and the X-weighted biallelic mean of the CAG repeats of AR were analysed by PCR, before and after DNA digestion with methylation-sensitive HpaII in 192 healthy Caucasian postmenopausal women.

Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor?

Context: Conflicting data have been reported regarding the presence of a constitutive activation of Galphas in ovarian granulosa cell tumors (OGCTs). Although the precise role of this mutation in the transformation of ovarian cells into malignant cells remains debatable, it has been demonstrated in other tissues that the rate of cell proliferation and invasiveness can be influenced by the gsp oncogene.

Objective: The objective of this study was to determine whether activating mutations of Galphas or Galphai are present in juvenile OGCTs and, if so, whether these mutations are significant prognostic factors.

Association between androgen receptor gene CAG repeat polymorphism and plasma testosterone levels in postmenopausal women.

Objectives: The biologic action of androgens in target cells depends on plasma androgen levels and receptor transcriptional activity. We investigated the relationship between androgen receptor (AR) CAG repeat polymorphism, serum androgen levels, and anthropometric, metabolic, and hormonal variables in 39 postmenopausal women, taking into consideration the patterns of X-chromosome inactivation.

Methods: Genomic DNA was extracted from peripheral leukocytes.

Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling.

Androgen insensitivity syndrome (AIS) is caused by numerous mutations of the androgen receptor (AR) gene. The phenotype may range from partial AIS (PAIS) with ambiguous genitalia to complete AIS (CAIS) with female genitalia. In 70% of the cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo.

An N-terminal WT1 mutation (P181S) in an XY patient with ambiguous genitalia, normal testosterone production, absence of kidney disease and associated heart defect: enlarging the phenotypic spectrum of WT1 defects.

Objective: This study reports the clinical and molecular data of an XY patient with a very unusual phenotype due to a Wilms' tumor-suppressor (WT1) gene mutation. The genotype-phenotype relationship of different WT1 mutations is then discussed.

Patient: The patient presented at birth with micropenis, severe hypospadias and cryptorchidism.