Neonatal hyperinsulinemic hypoglycemia: case report of kabuki syndrome due to a novel KMT2D splicing-site mutation

Abstract

Background Persistent neonatal hypoglycemia, owing to the possibility of severe neurodevelopmental consequences, is a leading cause of neonatal care admission. Hyperinsulinemic hypoglycemia is often resistant to dextrose infusion and needs rapid diagnosis and treatment. Several congenital conditions, from single gene defects to genetic syndromes should be considered in the diagnostic approach. Kabuki syndrome type 1 (MIM# 147920) and Kabuki syndrome type 2 (MIM# 300867), can be associated with neonatal hyperinsulinemic hypoglycemia. Patient presentation We report a female Italian (Sicilian) child, born preterm at 35 weeks gestation, with persistent hypoglycemia. Peculiar facial dysmorphisms, neonatal hypotonia, and cerebellar vermis hypoplasia raised suspicion of Kabuki syndrome. Hyperinsulinemic hypoglycemia was confirmed with glucagon test and whole-exome sequencing (WES) found a novel heterozygous splicing-site mutation (c.674-1G > A) in KMT2D gene. Hyperinsulinemic hypoglycemia was successfully treated with diazoxide. At 3 months corrected age for prematurity, a mild global neurodevelopmental delay, postnatal weight and occipitofrontal circumference growth failure were reported. Conclusions Kabuki syndrome should be considered when facing neonatal persistent hypoglycemia. Diazoxide may help to improve hyperinsulinemic hypoglycemia. A multidisciplinary and individualized follow-up should be carried out for early diagnosis and treatment of severe pathological associated conditions.

Recommendations for neonatologists and pediatricians working in first level birthing centers on the first communication of genetic disease and malformation syndrome diagnosis: consensus issued by 6 Italian scientific societies and 4 parents’ associations

“…A genetic diagnosis allows the families to feel less fragile, regardless of the benefit that it may have on the clinical management. NGS techniques allowed to provide early genetic counseling [45][46][47][48]. When promptly obtained, they may support and guide clinicians to the most appropriate clinical management and communicative approach, avoiding futile and/or disproportionate treatments [32], as well as further unnecessary separations between children and their parents [49].…”

Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town

“…Most of them, including the one here described, involve the SCNN1A gene [ 18 ]. These are mainly deletions, insertions, or splicing mutations, which may cause abolition or severe malfunctioning of the encoded protein (subunit of ENaC) [ 1 , 3 , 19 , 20 ]. Correlations between missense mutations and milder forms of disease are hypothesized.…”

“…NGS techniques allowed the identification of SCNN1A gene mutations in present patients (homozygous), as well as in their parents and in the aunt of one of them (heterozygous). Indeed, detection of genetic variants in affected subjects and healthy carriers may be relevant for suggesting new elements of the genotype-phenotype correlations, and for a precise reproductive counselling, also in view of primary and/or secondary prevention of disease [ 20 , 26 , 27 ]. Our report may broaden the knowledge of the genetic and molecular bases of PHA1, improve its clinical characterization and provide useful indications for the treatment of patients.…”

Recommendations on the first communication of genetic disease and malformation syndrome diagnosis: consensus issued by 6 Italian Scientific Societies and 4 Parents’ Associations

“…The neonatologist/pediatrician is often the rst to observe complex syndromic pictures, not always identi ed in the prenatal period. He must be aware of all aspects around the genetic diseases, including communication, bioethics, and law [17][18][19][20][21][22][23][24][25][26] in view of a multidisciplinary care of the affected newborns and children.…”