Differential Diagnosis
Permanent neonatal diabetes mellitus (PNDM) vs transient neonatal diabetes mellitus (TNDM). When diabetes mellitus is diagnosed in the neonatal period, it is difficult to determine if it is likely to be transient or permanent. The most common causes of TNDM are 6q24-related TNDM and ABCC8- or KCNJ11-related TNDM. • 6q24-related TNDM is caused by overexpression of the imprinted genes at 6q24 (PLAGL1 and HYMAI). The cardinal features are severe intrauterine growth restriction, hyperglycemia that begins in the neonatal period in a term infant and resolves by age 18 months, dehydration, and absence of ketoacidosis. Macroglossia and umbilical hernia may be present. 6q24-related TNDM associated with a multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, macroglossia, neurologic features including epilepsy, and kidney malformations. Diabetes mellitus lasts on average three months but can last more than a year. Although insulin is usually required initially, the need for insulin gradually declines over time. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Diabetes mellitus may recur in adolescence or later in adulthood. Women who have had 6q24-related TNDM are at risk for relapse during pregnancy. • Activating pathogenic variants in ABCC8 and KCNJ11 with less severe effects on beta cell KATP channel function have been found to cause TNDM that is similar to the biphasic course seen in 6q24-related TNDM. Typically, infants with ABCC8- or KCNJ11-related TNDM present before age six months, go into remission between ages six and 12 months, and are likely to relapse during adolescence or early adulthood . For infants with PNDM and extra-pancreatic features, consideration of syndromic PNDM may be appropriate . Table 4. Syndromic Permanent Neonatal Diabetes Mellitus
Gene | Disorder | MOI | Distinctive Features (in addition to neonatal DM) |
|---|
CNOT1 | Holoprosencephaly ± pancreatic agenesis (OMIM 618500) | AD | PNDM; Pancreatic agenesis; Holoprosencephaly; Gallbladder agenesis |
CTLA4 | Immune dysregulation w/autoimmunity, immunodeficiency, lymphoproliferation (OMIM 616100) | AD | PNDM; Lymphoproliferative syndrome; Enteropathy; Cytopenias |
Thyroiditis EIF2B11 | Neonatal/early-onset DM transient hepatic dysfunction | AD | PNDM; Transient hepatitis FOXP3 |
IPEX syndrome | XL | Enteropathy; Dermatitis | — |
GATA4 | GATA4-related PNDM2 | AD | Pancreatic exocrine insufficiency/agenesis; Cardiac abnormalities |
IER3IP1 | Neonatal DM, microcephaly, lissencephaly, epileptic encephalopathy (OMIM 614231) | AR | — |
IL2RA | Neonatal DM immune dysfunction (OMIM 606367) | AR | PNDM; Congenital hypothyroidism |
Sepsis3 ITCH4 | Neonatal DM systemic autoimmunity | AR | PNDM; Dysmorphic facies; Widespread autoimmunity ... |
Source: GeneReviews — "Permanent Neonatal Diabetes Mellitus"
