Syndromic forms of congenital hyperinsulinism

Abstract

Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.

Hyperinsulinemic Hypoglycemia in Childhood

“…Hyperinsulinemic Hypoglycemia has been reported in syndromic channelopathies such as overgrowth syndromes (such as Beckwith-Wiedemann syndrome (BWS) and Sotos syndrome), monogenic or chromosomal developmental syndromes with postnatal growth retardation (Turner syndrome, Kabuki syndrome, etc. ), congenital glycosylation syndromes and Timoty syndrome [7].…”

“…Beckwith-Wiedemann syndrome is caused by genetic and/or epigenetic defects that alter the expression of imprinting genes on chromosome 11's short arm (11p15.5) [10]. The presence of the KATP gene on the short arm of the 11th chromosome appears to facilitate the onset of hyperinsulinism [7].…”

“…Kabuki syndrome has been linked to mutations on the X chromosome in the KMT2D (75%) and KDM6A (3-5%) genes. Both genes encode proteins that regulate histones, so they are in the group of chromatin regulation disorders [7].…”

“…Turner syndrome is a relatively common (1/2500 female birth) syndrome, characterized by short stature and ovarian insufficiency. The association of cases with Turner syndrome and HH has been reported, and when the cases in some series are evaluated, it has been predicted that HH is seen 50 times more often than the normal population [7]. Moreover, in a study in which HH was found in 9 out of 69 patients with Turner syndrome, they stated Turner syndrome as the third most common syndrome in which HH was detected [12].…”

“…In cases of Turner syndrome, KDM6A "haploinsufficiency" induced by mosaic X chromosome monosomy was assumed to be the etiology of HH. Most of the cases are responsive to diazoxide, and the need for medication usually disappears within 1 year, but cases that went to pancreatectomy have also been reported [7].…”