Association Between Cleft Lip and Sex Chromosome Abnormalities
Cleft lip and/or cleft palate can occur as part of broader syndromic presentations that include sex chromosome aneuploidies, but sex chromosome abnormalities are not established as common causal causes of isolated cleft lip. [1], [2], [3]
Turner Syndrome and Orofacial Clefting
In a population-based United States cohort of 1,872 individuals with Turner syndrome, cleft lip with cleft palate occurred in 0.2% (4 cases total across karyotype groups in the “core birth defects” dataset), and cleft lip alone occurred in 0.2% (3 cases total). [1] Cleft palate alone occurred in 0.4% (8 cases total) in the same dataset. [1]
Klinefelter Syndrome and Orofacial Clefting
Klinefelter syndrome has been reported in association with cleft palate in case reports, including variant Klinefelter presentations (for example, 49,XXXXY with submucous cleft palate and 49,XXXXY with cleft palate). [4], [5] Additional case material describes cleft palate in variant Klinefelter syndrome with cytogenetic confirmation, supporting occurrence as a rare syndromic manifestation rather than a common phenotype. [6]
Epidemiology of Cleft Lip/Cleft Palate as a Multifactorial Trait
Cleft lip with or without cleft palate is considered a complex condition influenced by both genetic susceptibility and environmental exposures, which is consistent with a multifactorial etiology for most nonsyndromic cases. [2], [3] Sex-associated clefting patterns exist at the population level, but this does not establish sex chromosome aneuploidy as a frequent underlying mechanism for cleft lip. [3]
Clinical Implications for Genetic Workup
Sex chromosome aneuploidy testing is most directly supported when cleft lip and/or cleft palate is accompanied by other clinical features suggestive of a chromosomal syndrome rather than as routine testing for isolated cleft lip alone. [2], [4], [6]
Key Takeaway on Strength of Association
Available evidence supports that sex chromosome aneuploidies, including Turner syndrome and (variant) Klinefelter syndrome, can be associated with cleft lip and/or cleft palate, but the frequency appears low and the association does not indicate a common causal relationship for isolated cleft lip. [1], [4], [5], [6]
References to Consider During Counseling
NIDCR and CDC provide population-level cleft epidemiology and note that clefts can occur alone or as part of inherited disease or syndromes, which supports consideration of syndromic etiologies in selected clinical scenarios. [7], [8]