A Diagnostic Dilemma: Concurrent Diagnosis of Cystic Fibrosis and Definitive Kabuki Syndrome Type 1

TL;DR

A 9-year-old girl was diagnosed with Kabuki syndrome and had CFTR gene variants, but they did not cause cystic fibrosis.

Contribution

The study confirms coexistence of Kabuki syndrome and non-pathogenic CFTR variants through molecular genetic analysis.

Findings

The patient had a pathogenic KMT2D variant consistent with Kabuki syndrome type 1.

The patient had two CFTR gene variants inherited from parents but with preserved CFTR function.

The patient’s unaffected sister had the same CFTR genotype but no clinical symptoms.

Abstract

The article presents a clinical case involving a patient with presumptive coexistence of two hereditary disorders, confirmed by molecular genetic analyses. Clinical evaluation of the proband, a 9-year-old girl, revealed features characteristic of Kabuki syndrome, including a typical “Kabuki makeup” facial phenotype, short stature, intracranial hypertension, and diffuse muscular hypotonia. Additional clinical findings included chronic right-sided otitis media, conjunctivitis, recurrent pneumonia, bilateral conductive hearing loss, astigmatism, and primary adenitis. Clinical assessment and molecular genetic testing were performed. High-throughput sequencing identified a previously reported pathogenic heterozygous variant in the KMT2D gene, NM_003482.4:c.15142C>T p.Arg5048Cys, and two known heterozygous variants in the CFTR gene: NM_000492.4:c.1521_1523delCTT p.Phe508del and c.3454G>C p.Asp1152His, classified as pathogenic and of variable clinical significance, respectively. Segregation analysis demonstrated that the KMT2D variant most likely arose in the proband de novo, whereas the CFTR variants were inherited from each of the parents. Notably, the proband’s clinically unaffected elder sister carried the same CFTR genotype. Based on the clinical presentation and molecular genetic findings, the diagnosis of Kabuki syndrome type 1 was conclusively established in the patient. Functional assessment of CFTR demonstrated its preserved function, which did not support a diagnosis of CF or CFTR-related disorders.

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