Congenital hyperinsulinism (CHI) is the leading cause of persistent hypoglycemia in infants, causing neurodevelopmental and cognitive delays in up to 25–50% of affected children . Early recognition and appropriate treatment are important to prevent such adverse outcomes.
The estimated incidence of CHI is reported to be as low as 1/50,000 live births in Holland to as high as 1/2500 in geographic areas where consanguinity is highly frequent, such as Saudi Arabia . CHI is caused by genetic defects that cause disease through changes in channels expression/activity, transcription factors expression and disturbed enzyme activities. More frequently is increased activity rather than enzymes deficiency All these defects cause the common finding of recurrent episodes of hyperinsulinemic hypoglycemia due to an inappropriate secretion of insulin by the pancreatic beta-cells .
In 2016, there were 11 genes known to be associated with monogenic forms of CHI (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, and PGM1) [4, 5]. Variants in the ABCC8 and KCNJ11 genes together comprise approximately 90% of the identified cases of diazoxide-unresponsive CHI . These genes encode SUR-1 and Kir6.2, respectively, which comprise two subunits of KATP-HI, the beta-cell plasma dependent membrane ATP-potassium channel [7, 8]. Most pathogenic variants in these 2 genes are recessive and cause loss of function; however, some cases of dominantly inherited inactivating mutations have been reported. In the past, clinical phenotype of patients with dominant variants was different from those with recessive variants but the biochemical phenotype was not different . However, in 2013 Snider et al. published a large cohort of 417 children with CHI whose genotype-phenotype correlations were most successful if they have GLUD1, GCK, and recessive KATP mutations . Many of these correlations were challenging due to the high frequency of novel missense KATP mutations because these defects might be either recessive or dominant and if dominant these could be either responsive or unresponsive to diazoxide. In these cases, mutation analysis including parental testing should be considered. However, the existence of novel KATPmissense mutations variability (recessive/dominant) in adult carriers is typically unknown because they are frequently asymptomatic unless challenged with fasting or protein tolerance test [6, 9, 10].
Diazoxide, the first-line treatment for CHI, acts by opening the KATP-channel and decreasing insulin secretion . The effect of the gene variant on KATP-channel expression determines the clinical phenotype and the response to diazoxide . Octreotide, a second-line agent, is a long-acting somatostatin analog that decreases insulin secretion through hyperpolarization of the beta-cells and inhibition of calcium channels but has been associated with treatment failure due to tachyphylaxis and fatal necrotizing enterocolitis .
There are two distinct histologic forms of CHI: focal and diffuse. In a published cohort of 52 infants with CHI treated from 1985 to 1998, twenty-two had focal CHI and the rest had diffuse CHI. Only one neonate with focal HI and two with diffuse HI responded to treatment with diazoxide. All the other infants require pancreatic surgery to achieve cure .
Variants in a third gene, HNF4A, are associated with transient CHI in early infancy, despite also causing maturity-onset diabetes of the young (MODY 1) . HNF4A variants are typically rare and the incidence varies per population but have been described as the third most common cause of diazoxide-responsive CHI in a large cohort of 300 patients with CHI from United Kingdom [14, 15].
The infants of diabetic mothers (IDM) born with macrosomia typically present frequent metabolic complications including hypoglycemia, jaundice, respiratory distress, asphyxia and are in greater need of intensive care as reported by Looreda-Garcia et al. in a large cohort of 18,005 newborns where 10% were infants of diabetic mothers . The hyperinsulinemic hypoglycemia seen in IDMs occurs secondary to transient hyperinsulinism but it does not last longer than 2 or 3 days .
The current 2011 American Academy of Pediatrics guidelines for postnatal glucose homeostasis in healthy late-preterm and term infants mandate that persistent hypoglycemia, lower than 25 mg/dL from birth to 4 h of age, or lower than 35 mg/dL from 4 to 24 h of age after attempts to reefed, requires treatment with intravenous (IV) glucose . These prior AAP guidelines focused on when to screen infants for hypoglycemia and when to provide treatment but did not address the etiology work up procedure for prolonged and recurrent neonatal hypoglycemia. The Pediatric Endocrine Society recommendations published in 2015 considered the interpretation and response to plasma glucose (PG) concentration during the first 2 days of life is controversial however the mean PG concentration in normal newborns increases with time and by 72 h of age is similar to those in older infants and children. Therefore, these guidelines suggest delaying diagnostic evaluations until 2–3 days after birth .
Here we report 2 cases of IDMs with rare genetic variants of CHI whose final diagnoses of CHI were complicated and delayed because the patients were IDMs and had concomitant challenging medical conditions.