Original article

Kabuki make-up syndrome: A syndrome of mentalretardation, unusual facies, large and protruding ears, and postnatal growth deficiency

Kabuki syndrome (KS) is a multiple congenital anomaly syndrome that is characterized by postnatal growth deficiency, hypotonia, short stature, mild-to-moderate intellectual disability, skeletal abnormalities, persistence of fetal fingertip pads, and distinct facial appearance. It is mainly caused by pathogenic/likely pathogenic variants in the KMT2D or KDM6A genes. Here, we described the clinical features of nine sporadic KS patients with considerable phenotypic heterogeneity. In addition to intellectual disability and short stature, our patients presented with a high prevalence of motor retardation and recurrent otitis media. We recommended that KS should be strongly considered in patients with motor delay, short stature, intellectual disability, language disorder and facial deformities. Nine KMT2D variants, four of which were novel, were identified by whole-exome sequencing. The variants included five nonsense variants, two frameshift variants, one missense variant, and one non-canonical splice site variant. In addition, we reviewed the mutation types of the pathogenic KMT2D variants in the ClinVar database. We also indicated that effective mRNA analysis, using biological materials from patients, is helpful in classifying the pathogenicity of atypical splice site variants. Pedigree segregation analysis may also provide valuable information for pathogenicity classification of novel missense variants. These findings extended the mutation spectrum of KMT2D and provided new insights into the understanding of genotype-phenotype correlations, which are helpful for accurate genetic counseling and treatment optimization.

Major structural abnormalities of the eye in neonates include anophthalmos (no ocular tissues), microphthalmos (small, disorganized eye), nanophthalmos (small but relatively normally structured eye) and buphthalmos (whole eye is enlarged). Major eyelid defects in neonates include complete fusion of the upper and lower eyelids and a “hidden” eye (cryptophthalmos), focal fusion of the upper and lower eyelids (ankyloblepharon), focal defects in either or both eyelids (eyelid coloboma), or abnormal shape of the lower eyelid (euryblepharon). Causes of a narrowed palpebral fissure (space between the eyelids) with or without upper eyelid drooping (ptosis) in neonates include blepharophimosis, congenital ptosis, or congenital Horner syndrome. There are a number of known genetic causes for many of the above disorders, which are discussed throughout the chapter. In some cases these anomalies may occur sporadically and/or in isolation, whereas in other instances they may point to and help guide workup of a number of underlying systemic conditions. Management is challenging and case dependent. Consultation with an ophthalmologist is advisable prenatally if the condition is identified on prenatal imaging or soon after birth. Overarching principles include creating a clear visual axis to optimize visual development and restoring functional eyelids to help cover the eye and avoid corneal scarring and/or exposure.

Advances in the field of neurogenetics have practical applications in rapid diagnosis on blood and body fluids to extract DNA, obviating the need for invasive investigations. The ability to obtain a presymptomatic diagnosis through genetic screening and biomarkers can be a guide to life-saving disease-modifying therapy or enzyme replacement therapy to compensate for the deficient disease-causing enzyme. The benefits of a comprehensive neurogenetic evaluation extend to family members in whom identification of the causal gene defect ensures carrier detection and at-risk counseling for future generations. This chapter explores the many facets of the neurogenetic evaluation in adult and pediatric motor disorders as a primer for later chapters in this volume and a roadmap for the future applications of genetics in neurology.