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Male pseudohermaphroditism caused by steroid 5alpha-reductase deficiency is an autosomal recessive disorder. The enzyme steroid 5alpha-reductase 2 (encoded by the SRD5A2 gene) catalyses the conversion of testosterone to dihydrotestosterone, which is required for normal differentiation of the external male genitalia. This report describes the molecular analysis of the 5alpha-reductase type 2 gene in a Brazilian patient who was raised as a female, underwent a reversal of gender role behavior, and is now a married man. This patient is a compound heterozygote bearing an A-->G mutation within exon 2, changing codon 126 from Glu to Arg on one allele and a novel single base deletion (418delT) causing a frameshift mutation at codon 140 in the same exon, on the other allele. This last mutation probably leads to the synthesis of a truncated protein, because a premature termination signal is created at codon 159.

Background Congenital perineal lipoma is extremely rare and may lead to a misdiagnosis of ambiguous genitalia. Case reports We report on two girls referred to our service for ambiguous genitalia. Patient 1 (17 days old) and patient 2 (2 months old) had unremarkable gestational and perinatal histories. Both had normal female external genitalia and a 46,XX karyotype. Patient 1 had a polypoid, protruding 3.0 x 2.0 x 1.5-cm phallic-like mass arising at the inferior border of the left labium majora, and patient 2 had a similar mass of 1.5 x 1.5 x 1.0 cm at the same site and an imperforate anus. In both cases the mass was removed and found to be a lipoma. Discussion To our knowledge, perineal lipoma has been reported only in eleven girls, nine of them with associated anorectal malformation. Migration and fusion of the labioscrotal folds and formation of the urorectal septum are simultaneous developmental events occurring in the same region, which may explain the association of perineal lipoma and anorectal malformations.

ContextLoss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R, have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH).ObjectiveTo investigate KISS1R defects in patients with absent or delayed puberty.PatientsWe investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP).MethodsThe entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification.ResultsOne novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position −2 to −4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 3′ splice acceptor site of intron 2 of KISS1R. The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP.ConclusionLoss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.

Although autoimmune thyroid disease (AITD) is frequent in Turner's syndrome (TS), followup studies are scant, and there are none regarding subclinical thyroiditis. We investigated thyroid function and morphology in 17 patients with TS (mean age 14.6 years) with transient and asymptomatic variations of TSH and/or thyroid hormones. Our 2-year follow-up included measurements of TSH, free T4, T3 and TPO and Tg antibodies, ultrasound (US) (first and last evaluations) and scintigraphy (first evaluation). Thyroid volume was evaluated relative to the patients' stature. Fourteen had abnormal hormones, including four with hypothyroidism and one with hyperthyroidism, ten had positive antibodies, and all had abnormalities on US; uptake was normal in 14/16. Abnormal hormones were independent of antibodies, number of US findings, age, time of disease and volume. At the end of the follow-up, antibodies were associated with a high number of abnormal US features, particularly heterogeneous texture. Our results indicate that recurring thyroid hormone variations in TS are due to chronic AITD.

The SRY gene (sex-determining region of the Y chromosome) initiates the process of male sex differentiation in mammalians. In humans mutations in the SRY gene have been reported to account for 10-15% of the XY sex reversal cases. We describe here two novel missense mutations in the SRY gene after the screening of 17 patients, including 3 siblings, with 46,XY gonadal dysgenesis and 4 true hermaphrodites. One of the mutations, an A to C transversion within the HMG box, causes the N65H substitution and it was found in a patient presenting 46,XY pure gonadal dysgenesis. The Escherichia coli expressed SRY(N65H) protein did not present DNA-binding activity in vitro. The other mutation, a G to T transversion, causes the R30I substitution. This mutation was found in affected and nonaffected members of a family, including the father, two siblings with partial gonadal dysgenesis, a phenotypic female with pure gonadal dysgenesis, and three nonaffected male siblings. The G to T base change was not found in the SRY sequence of 100 normal males screened by ASO-PCR. The R30I mutation is located upstream to the HMG box, within the (29)RRSSS(33) phosphorylation site. The E. coli expressed SRY(R30I) protein was poorly phosphorylated and consequently showed reduced DNA-binding capacity in vitro.

Investigation of the origin of sexual ambiguity is complex. Although testicular function has traditionally been assessed only by examining the steroidogenic capacity of Leydig cells and spermatogenesis, it has recently been shown that the measurement of serum anti-Mullerian hormone (AMH) as a marker of Sertoli cell function may also help clinicians. The aim of this study was to evaluate both Leydig and Sertoli cell functions in 46,XY patients with intersex states in order to establish biochemical patterns that would help to reach an etiologic diagnosis. We measured serum androgens, AMH and gonadotropins in 24 patients with sexual ambiguity and XY karyotype: 8 with gonadal dysgenesis (GD), 3 with 3beta-hydroxysteroid dehydrogenase deficiency (3betaHSD), 5 with androgen insensitivity syndrome (AIS), 4 with 5alpha-reductase 2 (SRD5A2) deficiency, and 4 were of unknown origin or idiopathic. Our results showed that while testosterone was low and gonadotropins elevated in patients with either GD or 3betaHSD, AMH was low in the former and high in the latter. Serum AMH and gonadotropins were normal or high in patients with 3betaHSD or AIS, but these could be distinguished by testosterone levels. Serum testosterone and gonadotropins were normal or high in AIS and SRD5A2 deficiency patients; however, while AMH was elevated in AIS, it was not the case in SRD5A2 deficiency patients, indicating that testosterone is sufficient to inhibit AMH within the testis. In idiopathic cases gonadotropins and testosterone were normal, and AMH was normal or low. We conclude that the combined measurement of androgens, AMH and gonadotropins helps to establish the diagnosis in intersex patients.

Introduction Over the last two decades, through the voices of groups including non-governmental organizations, persons bearing sex differentiation disorders have begun to question when and how one should decide in favor of or against surgical intervention following diagnosis. Method Semi-structured interviews were held with seven adult patients who showed sex differentiation disorders at birth: Two with 5-alpha-reductase type-2 deficiency and five with congenital adrenal hyperplasia. Objectives To investigate both how sexual identity is structured and the relationship between sexual identity, choice of sex object and sexual difference. Discussion There is no ideal moment to perform surgical reassignment interventions on intersex patients, since the depth of the trauma can be neither predicted nor avoided. Traumatic events and their numerous occurrences are overdetermined, and depend on how parents, medical teams and subjects themselves cope with them throughout life. This fact is closely related to the question of how and when to operate, and who makes any decision to operate in order to “normalize” “abnormal” sex organs. The subject should never be left out of this decision. This most complex discussion involves many variegated factors, including X and Y chromosomes, testosterone levels, hormone receptor sensitivities, sexual practices, the gender of partners, mannerisms, clothing, accessories, dream content and sexual fantasies, and none of them determine individuals’ identification nor their preferences for this or that sexual object. Conclusions Sex is trauma. Neither male nor female nor any other gender identification implies the choice of sex object, genders of partners or sexual practices.

We report on a 5-year-old girl with a male karyotype (46,XY), severe psychomotor and physical retardation, minor anomalies, and female external genitalia with a blindly ending vagina. She has normal adrenal function, prepubertal serum gonadotropin and testosterone levels, which did not rise after hCG stimulation. On abdominal exploration no gonads were found, and only mesonephric and Müllerian remnants. She was HY positive, and no deletion was detected in the Y chromosome using 5 different probes. Although a genetic defect is not excluded, pregnancy complications suggest an environmental insult to the developing testes.

The complexity of human sex differentiation becomes manifest in the variety of diseases associated with sex ambiguity (SA). There are a few clinical centers especially dedicated to the managament of such patients, and hence, few large series have been published. We had the oportunity to evaluate 126 cases of SA. Among them, 57 (45.2%) were male pseudohermaphrodites (MPH), 35 (27.8%) were female pseudohermaphrodites (FPH), 23 (18.3%) had anomalies of gonadal differentiation (AGD), and 11 (8.71) exhibited other genital abnormalities. Among MPH, 36 were considered idiopathic, due to our impossibility to study androgen/receptor binding in cultured fibroblasts to diagnose partial androgen resistance, 11 were syndromic, there were 5 anorchias, 3 had complete androgen resistance, 1 had mullerian persistence and 1 5-alpha-reductase deficiency. Congenital adrenal hyperplasia was the main cause of FPH (24); there were also 6 syndromic cases and 5 idiopathic cases. Among AGD, there were 10 cases of true hermaphroditism, 8 Klinefelter syndromes, 3 mixed gonadal dysgenesis and 2 testicular dysgenesis due to sex chromosome aberrations. There were also 4 cases of balano-prepucial hypospadias, 3 of cryptorchidism, 3 incarcerated ovaries and 1 idiopathic microrchidism. Such a large series could only be achieved as a result of an interdisciplinary approach to SA over approximately 5 years.

CLINICAL AND MOLECULAR STUDIES OF 21 BRAZILIAN FAMILIES WITH CLASSIC CONGENITAL ADRENAL HYPERPLASIA (CAH) DUE TO 21-HYDROXYLASE DEFICIENCY

The genetic organization of the 21-OHase (P450c21) complex in CAH is well characterized, but the literature studies vary depending on the population. This study was carried out to determine the genic alterations of the P450c21 complex in brazilian families. During 6 months, 12 families were analyzed with 15 affected individuals with classic 21-OHase deficiency. Blood samples of all family members were tested for hibridization on conventional Southern blot with TaqI digests of DNA with gene probes for P450c21 and C4. Among the 15 affected individuals (9F:6M, with positive family history and consanguinity in 5/12), 8 had the simple virilizing and 7 had the salt-wasting form. The most frequent genic alteration was the point mutation of the 21B gene with normal 21A gene (50%), a result similar to those of the literature. The absence of deletion of the 21B gene and the finding of 30% of convertion in 21B gene indicate the necessity of new studies with more patients.