ESPEYB16 2. Antenatal and Neonatal Endocrinology Neonatal Hypoglycaemia (5 abstracts)
2.2. Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 9 affected individuals
Yap KL , Johnson AEK , Fischer D , Kandikatla P , Deml J , Nelakuditi V , Halbach S , Jeha GS , Burrage LC , Bodamer O , Benavides VC , Lewis AM , Ellard S , Shah P , Cody D , Diaz A , Devarajan A , Truong L , Greeley SAW , De Leon DD , Edmondson AC , Das S , Thornton P , Waggoner D & Del Gaudio D
To read the full abstract: Genet Med. 2019 Jan;21(1):233–242.
This study documented the clinical features and molecular diagnoses of 9 infants with persistent hyperinsulinism and Kabuki syndrome via a combination of sequencing and copy-number profiling methodologies.
KS is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Recognition of the dysmorphic features in the neonatal period may be difficult.
More than 75% of patients with KS harbor pathogenic variants in KMT2D located at 12q13.13 that typically occur de novo and in rare cases may be inherited (autosomal dominant Kabuki syndrome 1, KS1), and 5– 8% have pathogenic variants in KDM6A located at Xp.11.3 that are most frequently de novo (X-linked dominant Kabuki syndrome 2, KS2) (Adam et al.). KS patients can present with hypoglycemia in the newborn period due to various causes, including hyperinsulinism. In this study on 11 patients with KS and HH, five pathogenic variants (45.5%) were found in KDM6A suggesting that patients with KS harboring pathogenic KDM6A variants (KS2) may have an increased likelihood of presenting with HH as compared with patients with KS who harbor pathogenic variants in KMT2D (KS1). KS patients with a history of HH did not appear to have any additional specific phenotypic features that would differentiate them from patients without HH.
The authors recommend an increased awareness among clinicians of KS in patients with HH in the newborn period as the dysmorphic features may be subtle. KS should be considered in the differential diagnosis of persistent HH and also include comprehensive evaluation (sequencing and deletion/duplication analysis) of the KS-associated genes, KMT2D and KDM6A, during genetic testing for HH. Early diagnosis may inform appropriate follow-up and treatment of the hypoglycemic events in patients with KS, since these patients are likely to respond to diazoxide therapy. As with Soto syndrome discussed in 2.3, patients with KS have an increased incidence of HH and should have full genetic evaluation. The roles of KMT2D and KDM6A in pancreatic beta-cell physiology need further study.
Reference: Adam MP, Banka S, Bjornsson HT, Bodamer O, Chudley AE, Harris J, Kawame H, Lanpher BC, Lindsley AW, Merla G, Miyake N, Okamoto N, Stumpel CT, Niikawa N. Kabuki Syndrome Medical Advisory Board. Kabuki syndrome: international consensus diagnostic criteria. J Med Genet. 2019 Feb;56(2):89–95.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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