The enigma of a late-unveiled diagnosis: a case report of Kabuki syndrome

Abstract

Case Presentation: An 8-year-old female, born to non-consanguineous parents, was referred to medical genetics due to congenital heart disease, neonatal hypotonia, polyhydramnios, and macrocephaly. During the prenatal period, Noonan syndrome was suspected. She was born prematurely at 33 weeks and presented with hypotonia and neonatal pneumonia, requiring prolonged hospitalization. She subsequently exhibited significant global developmental delay, acquiring speech at 20 months and independent walking at 2 years of age. She also demonstrated learning and socialization difficulties and was diagnosed with attention-deficit/hyperactivity disorder and generalized anxiety disorder. On physical examination, she presented with short stature (Z-score:-3), microcephaly, prominent cup-shaped ears, thick arched eyebrows, a short philtrum, simplified nasolabial folds, a high nasal root, eversion of the lower eyelids, long palpebral fissures, generalized hypotonia, scoliosis, and strabismus. At the initial evaluation, Kabuki syndrome (KS) was suspected. Whole-exome sequencing identified a heterozygous likely pathogenic variant in KMT2D (p.Pro1607Hisfs*115), confirming the diagnosis of KMT2D-related KS. Discussion: KS is a rare genetic condition caused by pathogenic variants in KMT2D or KDM6A, the latter being X-linked. The phenotype typically includes characteristic facial features, minor skeletal anomalies, mild-to-moderate intellectual disability, postnatal growth deficiency, and congenital heart defects, with an increased susceptibility to seizures in some individuals. Immunological abnormalities, such as humoral immunodeficiency and recurrent infections, as well as endocrine alterations and hearing impairment, may also occur. Behavioral manifestations may include attention-deficit/hyperactivity disorder, anxiety, and sleep disturbances. Variable expressivity and phenotypic evolution frequently hinder early recognition of the syndrome. Although suggestive findings may be present prenatally, the absence of a fully established phenotype early in life often complicates etiological suspicion. Neurological manifestations are particularly relevant for clinical suspicion, as hypotonia and global developmental delay constitute diagnostic criteria for the syndrome. Final Comments: This report highlights the importance of genetic evaluation and careful syndromic integration of clinical findings to reduce diagnostic delays in rare diseases. The phenotypic heterogeneity of KS may hinder early recognition and lead to alternative diagnostic hypotheses. Delayed diagnosis may compromise appropriate therapeutic guidance, genetic counseling, surveillance for associated comorbidities, and the implementation of early interventions, which are essential for optimizing neurodevelopmental outcomes and quality of life. Careful analysis of clinical and dysmorphic features therefore remains fundamental to reduce the diagnostic odyssey in rare diseases.