Permanent Neonatal Diabetes Mellitus

CLINICAL CHARACTERISTICS

Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life (mean age: 7 weeks; range: birth to age 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and history of intrauterine growth deficiency. Therapy with insulin and/or oral hypoglycemic medications (in some molecular causes of PNDM) can correct the hyperglycemia and result in dramatic catch-up growth. The course of PNDM varies by genotype.

DIAGNOSIS/TESTING: The diagnosis of PNDM is established in an infant with diabetes mellitus diagnosed in the first six months of life that does not resolve over time. Molecular genetic testing is recommended, as identification of a specific molecular cause of PNMD can guide treatment.

MANAGEMENT

Oral sulfonylureas after initial management with insulin in those with - or -related PNDM. Rehydration and intravenous insulin infusion promptly after diagnosis; subcutaneous insulin therapy when the infant is stable and tolerating oral feedings; high caloric diet to achieve weight gain; developmental and educational support in those with -, -, -, or -related PNDM; anti-seizure medication as needed in those with DEND syndrome (evelopmental delay, pilepsy, and eonatal iabetes mellitus); pancreatic enzyme replacement therapy in those with exocrine pancreatic insufficiency. Frequent blood glucose monitoring; urinalysis for microalbuminuria and cystatin C measurement annually beginning at age ten years to screen for kidney manifestations of persistent hyperglycemia; ophthalmologic examination for retinopathy annually beginning at age ten years; developmental evaluation annually or as needed in those with -, -, -, or related PNDM; neurology evaluation and EEG in those with related DEND syndrome; evaluation of pancreatic exocrine function in those with symptoms of malabsorption; serum concentrations of fat-soluble vitamins every six months in those with known exocrine pancreatic insufficiency. In general, avoid rapid-acting insulin preparations (lispro and aspart) as well as short-acting (regular) insulin preparations (except as a continuous intravenous or subcutaneous infusion), as they may cause severe hypoglycemia in young children. Evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and treatment of hyperglycemia. Pregnant women with PNDM should be managed by an endocrinologist and maternal-fetal medicine specialist; high-resolution ultrasonography and fetal echocardiography should be offered during pregnancy to screen for congenital anomalies in the fetus.

GENETIC COUNSELING

The mode of inheritance of PNDM varies by gene: - and -related PNDM are inherited in an autosomal dominant or an autosomal recessive manner; -, -, and -related PNDM are inherited in an autosomal dominant manner; -, -, -, , -, -, -, -, -, -, and -related PNDM are inherited in an autosomal recessive manner. The majority of individuals with autosomal dominant PNDM caused by a heterozygous pathogenic variant in , , or have the disorder as the result of a pathogenic variant. Each child of an individual with PNDM inherited in an autosomal dominant manner has a 50% chance of inheriting the PNDM-related pathogenic variant. The parents of an individual with PNDM caused by biallelic pathogenic variants are presumed to be heterozygous for a PNDM-related pathogenic variant. The heterozygous parents of a child with autosomal recessive PNDM may or may not have diabetes mellitus. If both parents are known to be heterozygous for a PNDM-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. The heterozygous sibs of a proband with autosomal recessive PNDM may or may not have diabetes mellitus. Heterozygote testing for at-risk relatives requires prior identification of the PNDM-related pathogenic variants in the family. Once the PNDM-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for PNDM are possible.