Complex 45,X/46,XY Isochromosome Yp Mosaicism Presenting With Atypical Genitalia and an Incidental CYP21A2 Mutation: A Case Report
Year: 2026
Type: article
Study design: Case Report
Abstract: Differences of sex development (DSD) encompass a heterogeneous group of congenital conditions characterized by atypical development of chromosomal, gonadal, or anatomical sex. Mosaicism involving 45,X/46,XY cell lines is a rare cytogenetic variant that presents with a broad phenotypic spectrum ranging from complete male or female phenotypes to mixed gonadal dysgenesis and atypical genitalia. We report a neonate, the product of a twin pregnancy, born at 36 weeks of gestation who presented at birth with atypical genitalia, including a phallus with ventral chordee, penoscrotal hypospadias, and an asymmetric, nonpalpable right gonad. Initial imaging demonstrated bilateral intra-abdominal/inguinal gonads alongside persistent, hypoplastic Müllerian structures (uterus, cervix, and upper vagina). Cytogenetic evaluation revealed a complex four-cell-line mosaicism: 46,XY, monosomy X, isochromosome Yp, and 47,XY,i(Y)(p10). Whole-exome sequencing confirmed the DSD diagnosis and additionally identified a coincidental heterozygous carrier status for two pathogenic alleles localized in cis with a normal CYP21A2 gene copy. Biochemical evaluation, including 17-hydroxyprogesterone, adrenocorticotropic hormone, cortisol, and serum electrolytes, showed no evidence of active congenital adrenal hyperplasia. Human chorionic gonadotropin stimulation testing demonstrated a robust testosterone response, supporting preserved Leydig cell function. Following a comprehensive multidisciplinary assessment and counseling with the family, an individualized plan for sex of rearing and long-term clinical follow-up was established. This case highlights the importance of distinguishing disease-causing enzymatic defects from incidental carrier states when evaluating complex DSD. Integrating cytogenetic findings with biochemical and functional endocrine assessment can help clarify the underlying diagnosis and gonadal function, thereby providing individualized multidisciplinary care, including appropriate surveillance and consideration of future surgical and gonadal management.
Source: Cureus
Institution: King Hamad University Hospital
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7214618181