ESPE Yearbook of Paediatric Endocrinology

J Hum Genet. 2025 Mar 70(3):177-179.doi: 10.1038/s10038-024-01312-y

Brief summary: The question asked by these investigators is how often patients with identified sex chromosome aneuploidies (SCA) need to have further genetic workups. While severe, atypical phenotypes are always a red flag, the increasing numbers of patients coming to prenatal diagnosis has lead to increased understanding of phenotypic variability, and physicians may be less likely to refer. This retrospective study evaluated 54 pediatric patients over 9 years with cytogenetically diagnosed SCA. Twelve (22%) of these were identified as having discordant or severe phenotypes, and 11 patients went for further testing. Five of these 11 patients (41.7 %) were found to have a second genetic syndrome, based on next-generation sequencing and array comparative genomic hybridization. In all of these 5, there were phenotypic similarities in the two diagnoses, but with the second diagnosis explaining the unusual findings for the specific SCA. These children included: 1) Monosomy Turner Syndrome, found to have situs inversus totalis, with compound heterozygosity for 2 pathogenic variants in DNAH5 (associated with primary ciliary dyskinesia 3 +/- situs inversus; 2) Turner Syndrome with an isodicentric Xp11.22q28 with cleft lip and palate, aural atresia and anterior displacement of the anus, with a likely homozygous pathogenic variant in TXNL4Acausing Burn-McKeown Syndrome; 3) Klinefelter 47,XXY with developmental delay, seizures, central sleep apnea, and mitral insufficiency, with a 1.28 Mb deletion of 2p23.3 encompassing the gene associated with Tatton-Brown-Rahman Syndrome (DNMT3A); 4) Triple X Syndrome, with an unusually severe neurologic phenotype including epilepsy, with a pathogenic variant in a SET-domain binding protein,SETD1B explaining her neurodevelopmental disorder; 5) Triple X Syndrome with macrocephaly and overgrowth, also with a SET-related disorder.

A key message is that we can no longer assume that uncomplicated SCA fully explains atypical phenotypes. Inordinately long referral time to genetic specialists despite the presence of atypical phenotypes might have been avoided for these 5 patients, leading to better care. The authors would like to see atypical findings in any patient with SCA be added to the list of the American College of Medical Genetics Guidelines¹, which already recommends exome or genomic sequencing as first-line testing for pediatric patients with congenital anomalies, intellectual disability and developmental delay. And, of course, a very good history and physical examination must always be done to document all observed findings.

Reference: 1. Manickam K et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(11):2029-2037. doi: 10.1038/s41436-021-01242-6.