ESPE Abstracts

Introduction: De novo and inherited cases of 16p11.2 microdeletion and duplication syndromes have a spectrum of clinical manifestations, with incomplete penetrance and variable expressivity.

16p11.2 copy number variants have shared phenotypic features (autism, developmental delay). Mirror phenotypes have also been described: deletions – obesity, hyperphagia, macrocephaly; duplications – underweight, feeding/eating disorders, microcephaly. Congenital anomalies, more common in duplications, have not had a predilection for a specific organ/system.

Two cases of 16p11.2 microdeletion syndrome that presented with diazoxide-responsive hyperinsulinaemic hypoglycaemia from the first weeks of life have recently been reported.(1)

To our knowledge, this is the first description of hyperinsulinaemic hypoglycaemia in a patient with 16p11.2 duplication syndrome.

Case: A full-term normosomic male born via assisted vaginal delivery due to failure to progress and foetal distress experienced neonatal hypoglycaemia requiring intravenous dextrose for 24 hours. Right grade IV vesicoureteric reflux and a bifid right collecting system was detected at 7 weeks. At 11 months he presented with hyperinsulinaemic hypoglycaemia during a gastrointestinal illness. He was diazoxide-responsive and at 8.5 years, continues at a dose of 6.5 mg/kg/day.

His phenotype includes developmental delays, learning difficulties and anxiety, with diagnoses of Autistic Spectrum Disorder and Attention Deficit Hyperactivity Disorder. He has had low postnatal weight and BMI, with selective and restrictive eating behaviours. Cardiac surveillance due to diazoxide use identified a dilated aortic root (17 gene aortopathy panel negative).

Targeted next-generation sequencing of the coding regions and exon/intron boundaries of 16 genes (KCNJ11, ABCC8, AKT2, GLUD1, GCK, GPC3, HADH, HNF4A, INSR, KDM6A, KMT2D, SLC16A1, CACNA1D, PMM2, TRMT10A, HNF1A) in which mutations are reported to cause hyperinsulinaemic hypoglycaemia was performed. No pathogenic variants were identified.

Single nucleotide polymorphism (SNP) array detected a heterozygous interstitial duplication of approximately 551Kb (Chr16:29,647,342-30,198,151dup) at chromosome 16p11.2 containing at least 30 known genes confirming a diagnosis of chromosome 16p11.2 duplication syndrome. The duplication was not maternally inherited. Paternal DNA was not available.

Discussion: Our case expands the clinical spectrum of phenotypic abnormalities observed in the 16p11.2 duplication syndrome. The two reported cases of hyperinsulinaemic hypoglycaemia in 16p11.2 microdeletion syndrome were diagnosed neonatally and ceased Diazoxide within 15 months.(1) In one of these patients, it was postulated that SH2B1 deletion, associated with developmental delay, obesity and insulin resistance may have been contributory. However, in our case, SH2B1 was not within the duplicated region. Hence the biological mechanisms are unclear.

(1) Kostopoulou E et al. Clinical Endocrinology 2019