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 26 weeks) that does not resolve over time. Clinical manifestations at the time of diagnosis include intrauterine growth retardation (IUGR); hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. Therapy with insulin corrects the hyperglycemia and allows for catch-up growth. The course of PNDM varies by genotype. Approximately 20% of individuals with mutations in KCNJ11 have associated neurologic findings, called the DEND syndrome (developmental delay, epilepsy, and neonatal diabetes mellitus); a milder form without seizures and with less severe developmental delay is called intermediate DEND syndrome. Pancreatic hypoplasia caused by homozygous PDX1 mutations results in severe insulin deficiency and exocrine pancreatic insufficiency.
Persistent hyperglycemia (plasma glucose concentration >150-200 mg/dL) in infants younger than age six months establishes the diagnosis of PNDM. The five genes currently known to be associated with nonsyndromic PNDM are KCNJ11 (~30% of PNDM), ABCC8 (~19%), INS (~20%), GCK (~4%), and PDX1 (<1%). Molecular genetic testing is available on a clinical basis for all genes.
The mode of inheritance of PNDM is autosomal dominant for mutations in KCNJ11, autosomal dominant or autosomal recessive for mutations in ABCC8 and INS, and autosomal recessive for mutations in GCK and PDX1. Individuals with autosomal dominant PNDM may have an affected parent or may have a de novo mutation. Each child of an individual with PNDM inherited in an autosomal dominant manner has a 50% chance of inheriting the mutation. The parents of a child with autosomal recessive PNDM are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes (carriers) for mutations in GCK and PDX1 have a mild form of diabetes mellitus known as GCK-familial monogenic diabetes (formerly known as MODY2) and PDX1-familial monogenic diabetes (formerly known as MODY4). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (or of having familial monogenic diabetes), and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at increased risk for most forms of PNDM is available if the disease-causing mutation(s) in the family are known.