Clinical Guidance

No clinically relevant genotype-phenotype correlations for EIF2AK3, GATA6, GCK, GLIS3, HNF1B, MNX1, NEUROD1, NKX2-2, PDX1, RFX6, SLC2A2, or SLC19A2 have been identified. ABCC8. For neonatal diabetes caused by pathogenic variants in ABCC8, genotype-phenotype correlations are less distinct . Children with neonatal diabetes associated with autosomal dominant ABCC8 pathogenic variants may have a parent with the same ABCC8 variant and type 2 diabetes, suggesting that the severity of the phenotype and age of onset of diabetes is variable among individuals with ABCC8 pathogenic variants . INS. The relationship between genotype and phenotype is beginning to emerge for neonatal diabetes mellitus caused by pathogenic variants in INS.

Source: GeneReviews — "Permanent Neonatal Diabetes Mellitus"

Penetrance

Reduced penetrance has been reported in ABCC8- and KCNJ11-related PNDM . Limited data is available regarding the penetrance for other molecular causes of PNDM .

Source: GeneReviews — "Permanent Neonatal Diabetes Mellitus"

Diagnostic Criteria

Suggestive Findings

Permanent neonatal diabetes mellitus (PNDM) should be suspected in individuals with the following laboratory and radiographic features.

Laboratory features

• Persistent hyperglycemia (plasma glucose concentration 250mg/dL) in infants younger than age six months that lasts for longer than seven to ten days

• Features typical of diabetes mellitus (e.g., glucosuria, ketonuria, hyperketonemia)

• Low or undetectable plasma insulin and C peptide relative to the hyperglycemia

• Low fecal elastase and high stool fat in infants with pancreatic aplasia or hypoplasia due to pancreatic exocrine insufficiency

Source: GeneReviews — "Permanent Neonatal Diabetes Mellitus"

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

Management Guidelines

No clinical practice guidelines for permanent neonatal diabetes mellitus (PNDM) have been published. General guidelines for treatment of neonatal diabetes are available in the ISPAD Clinical Guidelines for Permanent Neonatal Diabetes . In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PNDM, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Permanent Neonatal Diabetes Mellitus: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Diabetes mellitus

| Pediatric endocrinology eval/referral for acute long-term DM mgmt |

Kidney manifestations

| Kidney ultrasound for evidence of cystic kidney disease or dysplasia | In persons w/HNF1B-related PNDM

Developmental delay/ Neurologic features of DEND syndrome

| • Developmental eval

• Neurology eval EEG in those w/suspected seizures

| In those w/KCNJ11-, MNX1-, NEUROD1-, NKX2-2-related PNDM

Exocrine pancreatic insufficiency

| • Imaging of pancreas

• Eval of pancreatic exocrine function (fecal elastase, serum concentrations of fat-soluble vitamins)

| In those w/HNF1B-, PDX1-, PTF1A-, RFX6-related PNDM

Genetic counseling

| By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implicati...

Source: GeneReviews — "Permanent Neonatal Diabetes Mellitus"

Clinical Guidance

In general, rapid-acting insulin preparations (lispro and aspart) as well as short-acting (regular) insulin preparations should be avoided (except when used as a continuous intravenous or subcutaneous infusion), as they may cause severe hypoglycemic events in young children.

Source: GeneReviews — "Permanent Neonatal Diabetes Mellitus"

Therapies Under Investigation

Search ClinicalTrials.gov in the and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Permanent Neonatal Diabetes Mellitus"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 7. Permanent Neonatal Diabetes Mellitus: Recommended Surveillance

Source: GeneReviews — "Permanent Neonatal Diabetes Mellitus"