Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease – A Rare Case Concerning <i>PMM2</i> Gene Pleiotropy

Hyperinsulinaemic hypoglycaemia (HH) is a very rare disease with an estimated incidence of 1/50,000, 1 and includes a clinical, histological and genetic heterogeneous group of disorders characterised by hypoglycaemia, hyperinsulinism or, more specifically, increased C-peptide level and inappropriate low blood levels of ketone bodies during a hypoglycaemic event.HH is a variable condition: it can be transient or persistent; patients can present with mild symptoms or with very symptomatic hypoglycaemia with adrenergic symptoms or life-threatening neurologic symptoms; it can be congenital or secondary, mainly to overgrowth syndromes/metabolic disorders.Pancreatic lesions that can cause HH may be diffuse or focal.Both 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET)/computed tomography (CT) and genetic study are essential diagnostic tools to differentiate these types, with important management implications.Until 2017, 12 genes were described in the literature associated with HH, but still 50% of cases remain without genetic confirmation.2 Management depends on both phenotype and genotype, but all require intravenous glucose at very high infusion rate (>8 mg/kg/min) at presentation.There are different approaches for management in the non-acute phase, such as increased glucose intake (oral or intravenous), dietary modifications, exercise eviction, pharmacological treatment (such as diazoxide, octreotide or lanreotide), hormone administration (such glucagon) or surgical treatment (excision of focal lesion or almost total pancreatectomy for diffuse lesion).Polycystic kidney disease (PKD), mainly the autosomal recessive type, is a hepatorenal fibrocystic disease, 3 characterised by bilaterally enlarged, diffusely echogenic kidneys that can be found on prenatal ultrasound or after birth, and biliary ductal ectasia or signs of congenital hepatic fibrosis.It is usually more severe than the autosomal dominant type and presents earlier in life.Biallelic pathogenic variants in the PKHD1 gene are found in about 42-87% of patients.3 About 30% of these children die in the neonatal period or within the first year of life due to respiratory insufficiency consequent to oligohydramnios.4 The co-occurrence of both diseases (HIPKD) has been recently described by Cabezas et al., in a group of 17 patients from 11 families.5 It is caused by non-coding variant in the promoter region for phosphomannomutase 2 (PMM2), c.-167G>T, both in homozygous or compound heterozygous variants with deleterious coding.

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