ABSTRACT
Deficiency of the 5α-reductase 2 enzyme impairs the conversion of testosterone to dihydrotestosterone (DHT) and differentiation of external genitalia, seminal vesicles and prostate in males. The present study describes the phenotype, genotype and gender identity in a large cohort of patients with 5αRD2. All patients underwent detailed clinical evaluation, hormonal profile, karyotyping and molecular analysis of the SRD5A2 gene. The molecular analysis of the SRD5A2 gene showed the presence of mutant alleles in 24 patients. We found 6 novel mutations IVS(1-2) T>C, p.A52T, 188-189insTA, 904-905ins A, p.A12T and p.E57X in our patients. All patients had ambiguous genitalia and the degrees of under-virilization ranged from penoscrotal hypospadias and microphallus to clitoromegaly. The position of gonads was variable in patients with same mutation. All the patients with mutations in the SRD5A2 gene had male gender identity. Those reared as female had gender dysphoria and underwent gender reassignment. Though a specific genotype-phenotype correlation could not be established in our patient but confirming the diagnosis of 5αRD2 with assessment of the SRD5A2 gene may help in appropriate gender assignment.
Subject(s)
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/deficiency , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , Disorder of Sex Development, 46,XY/genetics , Gender Dysphoria/genetics , Gender Identity , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mutation , Adolescent , Biomarkers/blood , Child , Child, Preschool , DNA Mutational Analysis , Disorder of Sex Development, 46,XY/enzymology , Disorder of Sex Development, 46,XY/psychology , Disorder of Sex Development, 46,XY/therapy , Female , Gender Dysphoria/enzymology , Gender Dysphoria/psychology , Gender Dysphoria/therapy , Genetic Predisposition to Disease , Hormones/blood , Humans , India , Infant , Karyotype , Karyotyping , Male , Phenotype , Sex Reassignment Procedures , Surveys and QuestionnairesABSTRACT
AIMS: Wolfram syndrome, also known as DIDMOAD, is a relatively rare inherited neurodegenerative disorder, first evident in childhood as an association of juvenile-onset diabetes mellitus and optic atrophy, followed by diabetes insipidus and deafness. The aim of the study was to examine the clinical profile of patients with DIDMOAD syndrome presenting to a tertiary care hospital in north India. METHODS: Clinical presentation of juvenile-onset diabetes mellitus fulfilling the diagnosis of Wolfram syndrome was studied using a prepared standardized form. RESULTS: Subjects with juvenile-onset non-autoimmune diabetes mellitus attending the diabetic clinic at a tertiary care centre in north India were followed for 10 years and a diagnosis of fully developed Wolfram syndrome was confirmed in seven individuals. The series consisted of five male and two female patients with a mean age of 17.5 ±7.34 years. Two subjects had consanguinity and none had any other family member affected. Optic atrophy was present in all, sensorineural hearing loss in 4/7, central diabetes insipidus in 4/7 and nephrogenic diabetes insipidus in 2/7 subjects. The new associations found were: spastic myoclonus, short stature with pancreatic malabsorption, nephrogenic diabetes insipidus, cyanotic heart disease and choledocholithiasis with cholangitis. Genetic analysis revealed mutation in exon 8 of the WFS1 gene in all the cases studied. CONCLUSIONS: The present clinical series of Wolfram syndrome reveals a varied clinical presentation of the syndrome and some new associations.
