Prenatal treatment of mothers with fetuses at risk for congenital adrenal hyperplasia: How relevant is it to Indian context?

Management of congenital adrenal hyperplasia (CAH) from embryonic stage to adulthood is a critical challenge. We would like to comment on some of the practical difficulties in offering prenatal treatment for CAH-affected fetuses in Indian population. For initiating the prenatal dexamethasone (DEX) treatment, all members of the family need to be informed about the risks and benefits of the treatment to the mother and the fetus as well as about the available invasive diagnostic tests to determine the gender and genotype of the fetus. Prenatal sex disclosure is not routinely practiced in India due to high female feticide rate. The treatment has to be given to both unaffected and affected female fetuses until the determination of prenatal sex. Moreover, most of our populations reside in rural areas where the antenatal care is not adequate. Prenatal DEX treatment in India outruns the risks rather than the benefits, as evident from the literature on the safety of pregnant mothers and fetuses.

Pubertal development among girls with classical congenital adrenal hyperplasia initiated on treatment at different ages.

INTRODUCTION: Children with congenital adrenal hyperplasia (CAH) provide us an opportunity to study the clinical effects of androgen excess in humans. We studied the sequence of pubertal development in girls with congenital adrenal hyperplasia initiated on treatment at different ages, to assess the effects of androgen exposure on the Hypothalamic-Pituitary-Ovarian (HPO) axis. MATERIALS AND METHODS: Girls more than 18 years of age, with CAH, on follow-up at this hospital were the subjects for this study. Details of history, physical findings, laboratory evaluation, and medication were noted from their case records and verified from the patients and their / parents, in addition to assessment of their present health status. RESULT: We studied 24 patients of classical CAH (SW-2, SV-22, average age - 24.5 ± 6.6 years). All had varying degrees of genital ambiguity (Prader stage 3 (n = 13), Prader stage 2 (n = 10), Prader stage 1 (n = 1). Among them were13 girls, who were started on steroids after eight years of age. Girls who received treatment from infancy and early childhood had normal pubertal development (mean age at menarche 11.4 ± 1.7 years). Hirsutism was not a problem among them. Untreated children had progressive clitoral enlargement throughout childhood, developed pubic hair at around three to six years of age, and facial hair between nine and eleven years. Plasma testosterone ranged from 3 to 6 ng / ml prior to treatment. Six of the 13 untreated CAH girls had subtle breast development starting at ages 11 - 16 years and three had spontaneous infrequent vaginal bleeding starting at ages 11 - 17. Steroid supplementation initiated pubertal changes in older girls in two-to-six months' time. CONCLUSION: There was a delay in HPO axis maturation (as evidenced by delayed pubertal development) in the absence of treatment in girls with CAH. This could be corrected with steroid supplementation.

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. SETTING: The study was performed at Montpellier University Hospital. PATIENTS: We studied a cohort of 55 patients with srd5A2 gene mutations. MAIN OUTCOME MEASURE(S): Genetic analysis of srd5A2 was conducted. RESULTS: 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. CONCLUSIONS: 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.

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. Direct sequencing was done using the ABI Prism Dye terminator sequencing kit and the ABI 310 sequencing apparatus. RESULTS: We found a heterozygous mutation of the LHR gene in exon 11 of the second transmembrane region, Met-->Thr at the 398 position (M398T). The same mutation was also found in the proband's mother. CONCLUSION: To our knowledge, this is the first molecular characterization of maternally inherited testotoxicosis in a 5 1/2-year-old boy from the Indian subcontinent.

Gender identity of children and young adults with 5alpha-reductase deficiency.

Male pseudohermaphroditism (46,XY DSD) due to 5alpha-reductase deficiency has been recognized for the last few decades. There is scant literature on this entity in India. We compiled data on five patients with this disorder. Four of our five patients were reared as females. Our assessment of these children reveals that they had male gender identity from childhood. Three of the four reared as females chose to change gender role at adolescence, while the fourth is still prepubertal. We conclude that all these patients had male gender identity from early childhood. The parents took note of this only after the appearance of male secondary sexual characteristics at puberty, thereby giving an impression of change in gender identity and gender role.

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. Molecular analysis was carried out by standard polymerase chain reaction procedure using different sets of primers and reaction conditions specific for the 5alpha-reductase type 2 gene (SRD5A2) gene. Direct sequencing was carried out using the ABI Prism dye terminator sequencing kit and the ABI 310 sequencing apparatus. RESULTS: We found an SRD5A2 gene mutation in exon 5, where arginine is substituted with glutamine (R246Q), in two males with pseudohermaphroditism and ambiguous genitalia from unrelated families. This is the first time this mutation has been reported in individuals from India. CONCLUSION: Identification of the R246Q mutation of the SRD5A2 gene from two unrelated Indian families possibly extends the founder gene effect.

Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD).

OBJECTIVE: Mutations within the pituitary-specific paired-like homeobox gene PROP1 have been described in 50-100% of patients with familial combined pituitary hormone deficiency (CPHD). We screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 CPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1. DESIGN AND PATIENTS: Patients with congenital hypopituitarism were recruited from the London Centre for Paediatric Endocrinology as well as several national and international centres. The pituitary phenotype ranged from isolated growth hormone deficiency (IGHD) to panhypopituitarism. Clinical data, including endocrine and neuro-radiological studies were obtained from patient records, and DNA was collected and screened for mutations within PROP1 using PCR and single-stranded conformation polymorphism (SSCP) analysis. Positive results on SSCP were sequenced directly. RESULTS: The prevalence of PROP1 mutations in unselected sporadic cases of hypopituitarism was lower (1.1%) than in familial cases (29.5%). PROP1 mutations can be associated with a highly variable phenotype, and both pituitary hypoplasia and pituitary hyperplasia. We describe the waxing and waning of a pituitary mass over 20 months in association with a PROP1 mutation that is predicted to lead to complete loss of function. Additionally, we have identified a possible founder mutation in CPHD patients from the Indian subcontinent. CONCLUSIONS: PROP1 mutations are rare in sporadic cases of CPHD, although the prevalence rises if there is a positive family history or if the patients are carefully selected with respect to the endocrine and neuroradiological phenotype. There is considerable phenotypic variability in families with the same mutation, indicating the role of other genetic or environmental factors on phenotypic expression. Finally, the pituitary enlargement that is observed in patients with PROP1 mutations can wax and wane in size before eventual involution.