Isolated permanent neonatal diabetes mellitus (ORPHA:99885)
Permanent neonatal diabetes mellitus (PNDM) is a monogenic form of neonatal diabetes (NDM, see this term) characterized by persistent hyperglycemia within the first 12 months of life in general, requiring continuous insulin treatment.
Epidemiology
The incidence of NDM is estimated to be 1/95,000 to 1/150,000 live births. About 50% of NDM cases are permanent (PNDM) and 50% transient (TNDM, see this term). The condition has been reported in all ethnic groups and affects male and female infants equally.
Clinical description
The median age of onset of PNDM is nine weeks. Initial clinical manifestations include hyperglycemia, glycosuria, intrauterine growth retardation, osmotic polyuria, severe dehydration, and failure to gain weight. The subsequent course of the disease depends on the genetic defect underlying DM. Most patients display some degree of developmental coordination disorder (including visual-spatial dyspraxia). Manifestations depend on the type of gene mutation involved. In KCNJ11 and ABCC8-related cases, patients usually present before three months of age with symptomatic hyperglycemia, and often ketoacidosis. Approximately 25% of patients with mutations in the KCNJ11 gene have associated neurological findings, including developmental delay and epilepsy (DEND syndrome, see this term) or a milder form of DEND without seizures and with less severe developmental delay (intermediate DEND, see this term). In INS-related cases, patients present with marked hyperglycemia or diabetic ketoacidosis usually at nine weeks, but some at a much later age. GCK-related PNDM patients have permanent insulin-dependent diabetes from the first day of life. Homozygous PDX1 mutations or mutations in other genes such as GATA6, PTF1A or HNF1B are related to rare cases of pancreatic hypoplasia with severe insulin deficiency and possibly exocrine pancreatic insufficiency. Two groups can be distinguished based on pancreatic involvement: patients with abnormal pancreas development and children with a normal pancreas. Long-term complications include developmental delay, microalbuminuria, and retinopathy.
Etiology
Mutations in 10 genes have been associated with PNDM: KCNJ11 (34% of cases), ABCC8 (24%), INS (13%), GCK (4%), PDX1 (<1%), GATA6, PTF1A, HNF1B, RFX6 and MNX1. These last five genes may be associated with syndromic forms. The genetic defects result in partial or complete insulin deficiency, and for the last six in possible pancreatic hypoplasia.
Diagnostic methods
Diagnosis of PNDM is made in infants under 12 months of age with persistent hyperglycemia (plasma glucose concentration >150-200 mg/dl). Molecular genetic testing of the implicated genes confirms the diagnosis and guides management.
Differential diagnosis
Differential diagnoses include type 1 diabetes mellitus, transient neonatal diabetes mellitus (TNDM), IPEX syndrome, and Wolcott-Rallison syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is available for most forms of PNDM provided that the disease-causing mutation has been identified in the family.
Genetic counseling
The pattern of inheritance is autosomal dominant or autosomal recessive depending on the gene. Genetic counseling should be provided to affected families.
Management and treatment
Immediate treatment involves rehydration and administration of intravenous insulin. Insulin can rapidly be switched to subcutaneously administered preparations. The aim is to control hyperglycemia and to enable catch-up growth. In those with KCNJ11 or ABCC8 mutations, a complete neurological assessment is recommended. Patients with activating mutations in these two genes can be treated long-term with oral sulfonylureas (currently in research protocols as no market authorization has yet been granted in this indication), and others with long-term insulin therapy.
Prognosis
Appropriate early treatment significantly reduces the risk of long-term complications.

                            Last update: 
                            November 2014


                            - Expert reviewer(s): 
                            Pr Michel POLAK