Meshael M Alswailem1, Ohoud S Alzahrani2, Lamyaa Alghofaili1, Ebtesam Qasem1, Mai Almohanaa1, Afaf Alsagheir2, Bassam Bin Abbas2, Najya A Attia3, Adnan Al Shaikh3, Ali S Alzahrani4,5. 1. Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. 2. Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. 3. Department of Pediatrics, King Abdulaziz Medical City, Jeddah, Saudi Arabia. 4. Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. aliz@kfshrc.edu.sa. 5. Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. aliz@kfshrc.edu.sa.
Abstract
CONTEXT AND OBJECTIVES: 5-α reductase deficiency is a rare 46,XY disorder of sex development. We present detailed phenotypic and genotypic features of a cohort of 24 subjects from a highly consanguineous population of Saudi Arabia SUBJECTS AND METHODS: We studied the clinical presentation and hormonal profiles of 24 subjects diagnosed with 5-α reductase deficiency and performed genetic testing on DNA isolated from their peripheral blood using polymerase chain reaction and direct sequencing of the SRD5A2. RESULTS: All subjects had 46,XY karyotype and presented with atypical appearance of external genitalia ranging from clitoromegaly, micophallus with hypospadias, undescended testes to completely normally looking female genitalia. Thirteen (54%) of them had severe under virilization and were assigned female sex at birth. The other 11 subjects were raised as males. Stimulated Testosterone:Dihydrotestosterone ratio was high in all 16 subjects in whom it was measured. The genetic testing revealed 2 nonsense mutations (p.R103X and p.R227X) in 2 unrelated subjects, 3 missense mutations (p.P181L, p.A228T, p.R246Q) in 11 subjects and a splice site mutation (IVS1-2A > G) in 11 other subjects. There was significant phenotypic variability even in subjects with the same mutation and also within the same family. CONCLUSION: This is the first and largest report of the clinical and molecular genetics of 5-α reductase deficiency from the Middle East. It shows weak genotype/phenotype correlation and significant phenotypic heterogeneity. IVS1-2A > G mutation is the most common mutation and is likely to be a founder mutation in this part of the world.
CONTEXT AND OBJECTIVES: 5-α reductase deficiency is a rare 46,XY disorder of sex development. We present detailed phenotypic and genotypic features of a cohort of 24 subjects from a highly consanguineous population of Saudi Arabia SUBJECTS AND METHODS: We studied the clinical presentation and hormonal profiles of 24 subjects diagnosed with 5-α reductase deficiency and performed genetic testing on DNA isolated from their peripheral blood using polymerase chain reaction and direct sequencing of the SRD5A2. RESULTS: All subjects had 46,XY karyotype and presented with atypical appearance of external genitalia ranging from clitoromegaly, micophallus with hypospadias, undescended testes to completely normally looking female genitalia. Thirteen (54%) of them had severe under virilization and were assigned female sex at birth. The other 11 subjects were raised as males. Stimulated Testosterone:Dihydrotestosterone ratio was high in all 16 subjects in whom it was measured. The genetic testing revealed 2 nonsense mutations (p.R103X and p.R227X) in 2 unrelated subjects, 3 missense mutations (p.P181L, p.A228T, p.R246Q) in 11 subjects and a splice site mutation (IVS1-2A > G) in 11 other subjects. There was significant phenotypic variability even in subjects with the same mutation and also within the same family. CONCLUSION: This is the first and largest report of the clinical and molecular genetics of 5-α reductase deficiency from the Middle East. It shows weak genotype/phenotype correlation and significant phenotypic heterogeneity. IVS1-2A > G mutation is the most common mutation and is likely to be a founder mutation in this part of the world.
Entities:
Keywords:
46,XY; 5-Alpha reductase; Disorders of sex development; Mutation; Phenotype
Authors: Nasir A M Al-Jurayyan; Sharifah D A Al Issa; Abdulrahman M H Al Nemri; Hessah M N Al Otaibi; Amir M I Babiker Journal: J Pediatr Endocrinol Metab Date: 2015-09 Impact factor: 1.634
Authors: G Ocal; P Adiyaman; M Berberoğlu; E Cetinkaya; N Akar; A Uysal; T Duman; O Evliyaoğlu; Z Aycan; S Lumbroso; C Sultan; S Lumbrasso Journal: J Pediatr Endocrinol Metab Date: 2002-04 Impact factor: 1.634
Authors: A E Thigpen; D L Davis; A Milatovich; B B Mendonca; J Imperato-McGinley; J E Griffin; U Francke; J D Wilson; D W Russell Journal: J Clin Invest Date: 1992-09 Impact factor: 14.808