Spectrum of Congenital Malformations in Sex Chromosome Tetrasomies and Pentasomies: A Systematic Review

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Abstract

Sex chromosome aneuploidies represent a heterogeneous group of chromosomal conditions, in which phenotypic complexity generally increases with the number of supernumerary sex chromosomes. While Turner syndrome and sex chromosome trisomies are relatively well characterized, less is known about congenital malformations in sex chromosome tetrasomies and pentasomies. This systematic review synthesizes published data on congenital malformations reported in individuals with sex chromosome tetrasomies and pentasomies, applying a standardized organ-system-based classification according to the International Classification of Diseases, Tenth Revision (ICD-10). A comprehensive literature search of PubMed and Embase identified 134 eligible publications comprising 369 individuals with at least one reported congenital malformation. Most studies were case reports (n = 105). The majority of individuals had karyotypes 48, XXYY (n = 147) and 49, XXXXY (n = 186), whereas 48, XXXX, 48, XXXY, 48, XYYY, 49, XXXXX, 49, XXXYY, 49, XXYYY, and 49, XYYYY were less frequently described. Across karyotypes, congenital malformations demonstrated a broad multisystem distribution. Musculoskeletal anomalies were most frequently reported, followed by genital and cardiac malformations. A stepwise increase in the mean number of reported malformations per individual was observed with increasing numbers of supernumerary X chromosomes (1.8 in 48, XXYY, 2.5 in 49, XXXXY, and 3.3 in 49, XXXXX), which may be compatible with, but does not establish a gene-dosage effect. Compared with population-based birth cohorts, the proportional distribution of malformations differed, suggesting redistribution across organ systems rather than a uniform increase in overall burden. Although prevalence cannot be inferred from this selected case-based evidence, this review provides the first structured synthesis of congenital malformations in these rare karyotypes and supports an organ-directed approach at clinical evaluation. Population-based studies with standardized phenotyping are needed to define absolute risks and the full phenotypic spectrum.

Abstract as published, via PubMed.