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 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include intrauterine growth restriction, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth. The course of PNDM varies by genotype.

Diagnosis/testing.

Persistent hyperglycemia (plasma glucose concentration >150-200 mg/dL) in infants younger than age six months establishes the diagnosis of PNDM. Molecular testing is recommended: identification of pathogenic variant(s) in ABCC8 or KCNJ11 can guide treatment.

Management.

Treatment of manifestations: Start rehydration and intravenous insulin infusion promptly after diagnosis. When the infant is stable and tolerating oral feedings begin subcutaneous insulin therapy. Children with pathogenic variants in ABCC8 or KCNJ11 can be treated with oral sulfonylureas; all others require long-term insulin therapy. High caloric intake is necessary for appropriate weight gain. Pancreatic enzyme replacement therapy is required for those with exocrine pancreatic insufficiency.

Prevention of secondary complications: Aggressive treatment and frequent monitoring of blood glucose concentrations to avoid acute complications such as diabetic ketoacidosis and hypoglycemia and reduce the long-term complications of diabetes mellitus.

Surveillance: Lifelong monitoring of blood glucose concentrations at least four times a day; periodic developmental evaluations. After age ten years, annual screening for chronic complications of diabetes mellitus including urinalysis for microalbuminuria and ophthalmologic examination for retinopathy.

Agents/circumstances to avoid: 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.

Genetic counseling.

The mode of inheritance of PNDM is autosomal dominant for mutation of KCNJ11, autosomal dominant or autosomal recessive for mutation of ABCC8 and INS, and autosomal recessive for mutation of GCK and PDX1.

Individuals with autosomal dominant PNDM may have an affected parent or may have a de novo pathogenic variant. Each child of an individual with autosomal dominant PNDM has a 50% chance of inheriting the pathogenic variant.

The parents of a child with autosomal recessive PNDM are obligate heterozygotes and therefore carry one pathogenic variant. Heterozygotes for pathogenic variants 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 is possible if the pathogenic variant(s) in the family are known.

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 >150-200 mg/dL) in infants younger than age six months
• 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

Note: Measurement of hemoglobin A1c is not suitable for diagnosing diabetes mellitus in infants younger than age six months because of the higher proportion of fetal hemoglobin compared to hemoglobin A.

Radiographic features

• Pancreatic hypoplasia identified on ultrasound, CT, or MRI examination
  Note: Visualization of the pancreas in neonates may be difficult; biochemical evidence of pancreatic insufficiency (e.g., low fecal elastase, high stool fat) may help with the diagnosis in these infants.

Establishing the Diagnosis

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 testing is recommended: identification of pathogenic variant(s) in one of the genes listed in Table 1 can guide treatment (see Management).

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing

• Individuals with one parent with diabetes mellitus:
  • Sequence analysis of KCNJ11 first.
  • If no KCNJ11 pathogenic variant is found, sequence analysis of ABCC8 and INS
• Individuals whose parents both have diabetes mellitus: sequence analysis of GCK and PDX1
• Individuals without a family history of diabetes mellitus:
  • Sequence analysis of ABCC8 and KCNJ11 first (as identification of pathogenic variants changes management)
  • If no pathogenic variants are identified, sequence analysis of GCK and INS
• Individuals with pancreatic insufficiency or agenesis without extra-pancreatic abnormalities:
  • Sequence analysis of PDX1 first.
  • If no pathogenic variants are identified, consider sequence analysis of PTF1A [Houghton et al 2016].
• Individuals with syndromic PNDM: the extrapancreatic characteristics should guide genetic testing (see Genetically Related Disorders and Differential Diagnosis).

Note: Deletion/duplication analysis of GCK, INS, PDX1, and PTF1A (and for genes associated with syndromic PNDM) should be considered when sequencing is negative, as homozygous deletions in these genes can be associated with permanent neonatal diabetes mellitus.

A multigene panel that includes ABCC8, GCK, INS, KCNJ11, and PDX1 and other genes of interest (see Differential Diagnosis) may also be considered. Notes: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes ABCC8, GCK, INS, KCNJ11, and PDX1) fails to confirm a diagnosis in an individual with features of PNDM. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life with a mean age at diagnosis of seven weeks (range: birth to 26 weeks) [Gloyn et al 2004b].

The diabetes mellitus is associated with partial or complete insulin deficiency.

Clinical manifestations at diagnosis include intrauterine growth restriction (IUGR; a reflection of insulin deficiency in utero), hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive.

Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth.

Phenotype Correlations by Gene

The course of PNDM is highly variable depending on the genotype.

ABCC8 and KCNJ11. Most individuals with PNDM caused by pathogenic variants in ABCC8 and KCNJ11 are diagnosed before age three months, but a few present in childhood or early adult life. The majority of affected infants have low birth weight resulting from lower fetal insulin production. The typical presentation is symptomatic hyperglycemia, and in many individuals, ketoacidosis.

Although most individuals with pathogenic variants in KCNJ11 have isolated diabetes, 20% have associated neurologic features, called DEND syndrome (developmental delay, epilepsy, and neonatal diabetes mellitus) [Hattersley et al 2006]. A milder form, called intermediate DEND syndrome, presents with less severe developmental delay and without epilepsy. In individuals with KCNJ11 pathogenic variants, treatment with sulfonylureas corrects the hyperglycemia [Pearson et al 2006] and may reverse some of the neurologic manifestations [Hattersley & Ashcroft 2005, Slingerland et al 2006]. Neurologic manifestations might be prevented by early treatment with these agents [Greeley et al 2010] (see Management).

GCK. PNDM caused by biallelic GCK pathogenic variants is characterized by IUGR, insulin-requiring diabetes from the first day of life, and hyperglycemia in both parents.

INS. Individuals with PNDM caused by heterozygous INS pathogenic variants or biallelic deletions of INS present with diabetic ketoacidosis or marked hyperglycemia. Most newborns are small for gestational age [Støy et al 2007, Polak et al 2008]. The median age at diagnosis is nine weeks, but some children present after age six months [Edghill et al 2008].

PDX1. Pancreatic hypoplasia caused by biallelic PDX1 pathogenic variants results in a more severe insulin deficiency than in ABCC8, GCK, or KCNJ11-related neonatal diabetes as shown by a lower birth weight and a younger age at diagnosis. These individuals also have exocrine pancreatic insufficiency.

Genotype-Phenotype Correlations

ABCC8. For neonatal diabetes caused by pathogenic variants in ABCC8, genotype-phenotype correlations are less distinct [Edghill et al 2010]. Children with neonatal diabetes associated with 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 [Babenko et al 2006].

INS. The relationship between genotype and phenotype is beginning to emerge for NDM caused by pathogenic variants in INS. The diabetes mellitus in persons who are homozygous or compound heterozygous for pathogenic variants in INS can be permanent or transient. The variants c.-366_343del, c.3G>A, c.3G>T, c.184C>T, c.-370-?186+?del (a 646-bp deletion) and c.*59A>G appear to be associated with PNDM, whereas the variants c.-218A>C and c.-331C>A or c.-331C>G have been identified in persons with both PNDM and TNDM as well as persons with type 1b diabetes mellitus [Støy et al 2010].

KCNJ11. Clear genotype-phenotype correlations exist for those forms of PNDM associated with KCNJ11 pathogenic variants.

Genotype-phenotype studies correlate KCNJ11 pathogenic variants and phenotype with the extent of reduction in K_ATP channel ATP sensitivity.

Some KCNJ11 pathogenic variants are associated with transient neonatal diabetes mellitus (TNDM); others are associated with PNDM; and two variants, p.Val252Ala and p.Arg201His, are associated with both disorders [Colombo et al 2005, Girard et al 2006]. Furthermore, functional studies have shown some overlap between the magnitude of the K_ATP channel currents in TNDM- and PNDM-associated pathogenic variants [Girard et al 2006].

The location of the KCNJ11 pathogenic variant appears to predict the severity of the disease (isolated diabetes mellitus, intermediate DEND syndrome, DEND syndrome), however, there are some exceptions. Pathogenic variants in residues that lie within the putative ATP-binding site (Arg50, Ile192, Leu164, Arg201, Phe333) or are located at the interfaces between Kir6.2 subunits (Phe35, Cys42, and Gu332) or between Kir6.2 and SUR1 (Gly53) are associated with isolated diabetes mellitus. See Molecular Genetics, KCNJ11, Normal gene product for a discussion of Kir6.2 and ABCC8, Normal gene product for Sur1.

The severity of PNDM along the spectrum of isolated diabetes mellitus, intermediate DEND syndrome, and DEND syndrome correlates with the genotype [Proks et al 2004]. KCNJ11 variants that cause additional neurologic features occur at codons for amino acid residues that lie at some distance from the ATP-binding site (Gln52, Gly53, Val59, Cys166, and Ile296) [Hattersley & Ashcroft 2005].

• Of 24 individuals with pathogenic variants at the arginine residue, Arg201, all but three had isolated PNDM.
• The p.Val59Met variant is associated with intermediate DEND syndrome.
• The following pathogenic variants associated with DEND syndrome are not found in less severely affected individuals: p.Gln52Arg, p.Val59Gly, p.Ile296Val, p.Cys166Phe [Gloyn et al 2006], p.Gly334Asp [Masia et al 2007b], p.Ile167Leu [Shimomura et al 2007], p.Gly53Asp, p.Cys166Tyr, and p.Ile296Leu [Flanagan et al 2006].
• Improvement of the neurologic features of DEND syndrome with sulfonylurea treatment also appears to be genotype dependent: children with the variants p.Val59Met [Støy et al 2008, Mohamadi et al 2010] and p.Gly53Asp [Koster et al 2008] have been shown to respond to sulfonylureas.

Penetrance

Reduced penetrance has been seen in PNDM caused by pathogenic variants in KCNJ11 and ABCC8 [Flanagan et al 2007].

Nomenclature

Some individuals with "neonatal" diabetes mellitus may not be diagnosed until age three to six months, therefore it has been suggested that the term "diabetes mellitus of infancy" or "congenital diabetes" should replace the designation "neonatal diabetes mellitus" [Massa et al 2005, Greeley et al 2011].

Prevalence

The estimated incidence of permanent neonatal diabetes ranges from 1:215,000 to 1:260,000 live births [Stanik et al 2007, Slingerland et al 2009, Wiedemann et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with neonatal diabetes mellitus as a result of pathogenic variants in ABCC8 or KCNJ11, a complete neurologic evaluation should be performed.

To establish the extent of disease in an individual with suspected or confirmed pathogenic variants in PDX1, imaging of the pancreas and evaluation of pancreatic exocrine function (stool elastase, serum concentrations of fat-soluble vitamins) should be performed.

Consultation with a clinical geneticist and/or genetic counselor should be obtained early in the evaluation of PNDM.

Treatment of Manifestations

Initial treatment. Rehydration and intravenous insulin infusion should be started promptly after diagnosis, particularly in infants with ketoacidosis.

Long-term medical management. An appropriate regimen of subcutaneous insulin administration should be established when the infant is stable and tolerating oral feedings. Few data on the most appropriate insulin preparations for young infants are available.

• Intermediate-acting insulin preparations (neutral protamine Hagedorn [NPH]) tend to have a shorter duration of action in infants, possibly because of smaller dose size or higher subcutaneous blood flow.
• The longer-acting preparations with no significant peak-of-action effect such as Lantus^® (glargine) or Levemir^® (detemir) may work better in small infants.
• In individuals with very low insulin requirements, diluted insulin (5 or 10 U/mL) may be more appropriate if used with caution.
• Some centers recommend the use of continuous subcutaneous insulin infusion for young infants [Polak & Cave 2007] as a safer, more physiologic, and more accurate way of administering insulin.
• Caution:
  • In general, rapid-acting (lispro and aspart) and short-acting (regular) preparations (except when used as a continuous intravenous or subcutaneous infusion) should be avoided as they may cause severe hypoglycemic events.
  • Extreme caution should be observed when using a diluted insulin preparation in order to avoid dose errors.

Identification of a KCNJ11 or ABCC8 pathogenic variant is important for clinical management since most individuals with these pathogenic variants can be treated with oral sulfonylureas. Children with pathogenic variants in KCNJ11 or ABCC8 can be transitioned to therapy with oral sulfonylureas; high doses are usually required (0.4-1.0 mg/kg/day of glibenclamide). Transfer protocols are available at www.diabetesgenes.org. Treatment with sulfonylureas is associated with improved glycemic control [Hattersley & Ashcroft 2005, Pearson et al 2006, Thurber et al 2015, Babiker et al 2016].

Long-term insulin therapy is required for all other causes of PNDM, although mild beneficial effect of oral sulfonylureas in persons with GCK pathogenic variants has been reported [Turkkahraman et al 2008, Hussain 2010].

High caloric intake should be maintained to achieve weight gain.

Pancreatic enzyme replacement therapy is required in persons with exocrine pancreatic insufficiency.

Prevention of Secondary Complications

Aggressive treatment and frequent monitoring of blood glucose concentrations is essential to avoid acute complications such as diabetic ketoacidosis and hypoglycemia.

Long-term complications of diabetes mellitus can be significantly reduced by maintaining blood glucose concentrations in the appropriate range. The American Diabetes Association recommends the following glycemic goals across all pediatric age-groups [American Diabetes Association 2016a]:

• Glycemic targets for children younger than age six years:
  • 90-130 mg/dL before meals
  • 90-150 mg/dL at bedtime/overnight
• Hemoglobin A1c value < 7.5%

Surveillance

Lifelong monitoring (≥4x/day) of blood glucose concentrations is indicated to achieve the goals of therapy.

Children with PNDM, particularly those with a pathogenic variant in KCNJ11 or ABCC8, should undergo periodic developmental evaluations.

Yearly screening for chronic complications associated with diabetes mellitus should be started after age ten years and should include the following:

• Urinalysis for microalbuminuria
• Ophthalmologic examination to screen for retinopathy

Agents/Circumstances to Avoid

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.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The management of pregnant women with PNDM should conform to the guidelines for treatment of other forms of diabetes during gestation [American Diabetes Association 2016b]. Glycemic control during gestation is not only important to prevent complications in the mother, but also to prevent fetal overgrowth (due to fetal hyperinsulinemia triggered by the excess of maternal glucose crossing the placenta) and associated complications. Referral to a maternal-fetal medicine specialist should be considered. In addition, high resolution ultrasonography and fetal echocardiography should be offered during pregnancy to screen for congenital anomalies in the fetus.

Until recently, insulin was the mainstay of therapy of diabetes during pregnancy; however, emerging data support the safety and efficacy of glyburide in the treatment of diabetes during pregnancy [Moretti et al 2008]. Thus, in women with PNDM treated with glyburide before pregnancy, it is reasonable to continue this treatment if appropriate glycemic control can be achieved.

Therapies Under Investigation

Search ClinicalTrials.gov in the US 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.

Mode of Inheritance

The mode of inheritance of permanent neonatal diabetes mellitus (PNDM) varies by gene:

• ABCC8 and INS. Autosomal dominant or autosomal recessive
• GCK and PDX1. Autosomal recessive
• KCNJ11. Autosomal dominant

Autosomal Dominant Inheritance ‒ Risk to Family Members

Parents of a proband (see Table 2)

• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant in ABCC8, INS, or KCNJ11 include molecular genetic testing and clinical testing for diabetes mellitus (oral glucose tolerance testing).
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism for a pathogenic variant in KCNJ11 has been reported [Gloyn et al 2004a, Edghill et al 2007]; the overall incidence of germline mosaicism is unknown.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the ABCC8, INS, or KCNJ11 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with PNDM inherited in an autosomal dominant manner has a 50% chance of inheriting the ABCC8, INS, or KCNJ11 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Autosomal Recessive Inheritance ‒ Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive PNDM are obligate heterozygotes and therefore have one PNDM-related pathogenic variant.
• The parents of a child with autosomal recessive PNDM may or may not be affected (see Genotype-Phenotype Correlations).
  • ABCC8. In 43% of affected individuals, ABCC8-related PNDM is inherited in an autosomal recessive manner from unaffected parents with heterozygous pathogenic variants [Patch et al 2007].
  • INS-related PNDM has also been reported to be inherited in an autosomal recessive manner from unaffected parents [Garin et al 2010]. Heterozygotes for pathogenic variants in INS associated with recessively inherited NDM may have adult onset diabetes [Raile et al 2011].
  • GCK and PDX1. Heterozygotes for pathogenic variants in GCK and PDX1 have milder forms of diabetes mellitus (GCK-familial monogenic diabetes and PDX1-familial monogenic diabetes, respectively).

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not heterozygous.
• Heterozygotes for pathogenic variants in GCK, INS, or PDX1 have a milder form of diabetes mellitus (e.g., GCK-familial monogenic diabetes, previously known as MODY2, or PDX1-familial monogenic diabetes, previously known as MODY4). Heterozygotes for pathogenic variants in ABCC8 have normal glucose tolerance. See MODY Overview.

Offspring of a proband. The offspring of an individual with autosomal recessive neonatal diabetes mellitus are obligate heterozygotes for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a PNDM-related pathogenic variant.

Heterozygote detection. Carrier testing for at-risk relatives requires prior identification of the PNDM-related pathogenic variants in the family.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PNDM-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for PNDM are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Acknowledgments

The authors receive grant support from NIH grants R01DK098517 and R01FD004095 (DDDL); and R37DK056268 (CAS).

Revision History

• 29 July 2016 (sw) Comprehensive update posted live
• 23 January 2014 (me) Comprehensive update posted live
• 5 July 2011 (me) Comprehensive update posted live
• 4 March 2008 (cd) Revision: sequence analysis and prenatal diagnosis available for INS mutations
• 8 February 2008 (me) Review posted live
• 9 August 2007 (cas) Original submission

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