Clinical and Cytogenetic Studies of Patients with Sex Chromosome Disorders of Sex Development (DSD)

Abstract

Our work aimed at studying the frequency of sex chromosome DSD among Egyptian DSD patients, phenotype-genotype correspondence of those patients with sex chromosome DSD and early detection of Y chromosome material for proper counseling of patients at risk of gonadal tumor development. Patients were collected from Clinical Genetics and Endocrinology Clinics, Medical Centre for Scientific Excellence, National Research Centre over one year. They were subjected to pedigree analysis, thorough clinical examination including pubertal staging, anthropometric measurements and genital examination. All patients were examined using karyotype. FISH analysis was done for some patients to rule out the presence of Y-specific sequence (SRY) and to characterize unidentified sex chromosome marker or ring chromosomes. Hormonal assessment and ultrasonography were performed whenever needed and laparoscopy with gonadal biopsy was carried out for selected patients. Cytogenetic studies revealed that sex chromosome DSD represented 44% of total referring DSD patients during the period of the study which is higher than previously reported. Numerical abnormalities constituted 77% which is similar to previous reports. Patients were categorized into two main groups according to their karyotypes; X chromosomal abnormalities were encountered in 56.3% which represented the most frequent abnormalities in our patients; 88.9% of them had monosomy 45,X (mosaic 45,X were 58.3% among which 21.3% had mosaicism with Y chromosome). Klinefelter syndrome was encountered in 43.8% which represented the second most frequent abnormality in our patients; 85.7% had classic 47,XXY and the remaining 14.3% were variants. By phenotype-genotype correspondence, 47,XXY karyotype asone of the commonest congenital chromosomal disorders resulting in hypogonadism and genetically-determined infertility was consistent with our studied patients presenting post pubertal. Diagnosis of 47,XXY in the prepubertal period was mostly accidental and presented with rare associations such as delayed milestones of development and dysmorphic features which needs further investigations. Other variants of Klinefelter syndrome presented with variable features of dysmorphism, genital ambiguity and hypogonadism which is similar to the previously reported in such cases. Short stature was a cardinal feature in most of patients having complete or partial X chromosome monosomy, either in pure or mosaic forms. Among patients with 45,X karyotype; Turner manifestations were more frequent. Patients with 45,X, in mosaicism with X chromosome, were all reared as females and those presented post pubertal complained of primary amenorrhea which is a typical finding as gonadal dysgenesis/ovarian failure are consistent with monosomy. Patients with 45,X, in mosaicism with Y chromosome, were three patients; all had SRY +ve signal by FISH; one patient reared as a female, presented with short stature and delayed puberty, was advised to do laparoscopy to exclude the risk of gonadoblastoma and the other two patients were reared as males presented with genital ambiguity and cryptorchidism;pathology reports confirmed the diagnosis of mixed gonadal dysgenesis in one patient and ovotesticular DSD in the other.