Permanent Neonatal Diabetes Mellitus

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Summary

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 retardation, 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.

Diagnosis

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 at the most reasonable cost 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.

Table 1.

Molecular Genetic Testing Used in Permanent Neonatal Diabetes Mellitus

Gene 1Proportion of Permanent Neonatal Diabetes Mellitus Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detectable by This Method
Sequence
analysis 3		Gene-targeted deletion/duplication analysis 4
ABCC819% 5100%None reported 7
GCK4% 8100%None reported 7
INS20% 9>99%1 family 10
KCNJ1130% 11100%None reported 7
PDX1<1% 12100%None reported 7
Unknown 13NA
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

Attributed to activating pathogenic variants of ABCC8 [Babenko et al 2006]

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

No deletions or duplications involving ABCC8, GCK, KCNJ11, or PDX1 have been reported to cause permanent neonatal diabetes mellitus. Note that the KCNJ11 and ABCC8 defects are activating pathogenic variants and therefore must be missense. Duplication/deletion analysis would not identify ABCC8 and KCNJ11 defects.

8.

Njølstad et al [2001], Njølstad et al [2003]. Note: Carrier parents have mild diabetes mellitus or glucose intolerance (GCK-familial monogenic diabetes, previously known as MODY2).

9.

Støy et al [2007], Polak et al [2008]

10.

A 646-bp deletion in INS was reported in individuals with neonatal diabetes [Raile et al 2011, Garin et al 2010, Støy et al 2010]; see Table 5.

11.

Attributed to activating pathogenic variants in KCNJ11 [Ellard et al 2007]

12.

Attributed to inactivating pathogenic variants [Stoffers et al 1997a]. Note: Carrier parents have mild, adult-onset diabetes mellitus (PDX1-familial monogenic diabetes, previously known as MODY4).

13.

The genetic causes of approximately 30% of PNDM remain unknown [Rubio-Cabezas et al 2014].

Clinical Characteristics

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 retardation (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 KATP 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 KATP 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].

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.

6q24-related TNDM is defined as transient neonatal diabetes mellitus caused by overexpression of the imprinted genes at 6q24 (PLAGL1 and HYMAI). The cardinal features are: severe intrauterine growth retardation, 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 are often present. In the subset of children with ZFP57 pathogenic variants, other manifestations can include structural brain abnormalities, developmental delay, and congenital heart disease. Diabetes mellitus usually starts within the first week of life and 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. Recurrence in adolescence is more akin to type 2 diabetes mellitus. Relapse in women during pregnancy is associated with gestational diabetes mellitus.

The two most common causes of transient neonatal diabetes are 6q24-related TNDM and pathogenic variants in ABCC8 or KCNJ11. In 50 children presenting with neonatal diabetes, Metz et al [2002] failed to demonstrate clear clinical indicators to differentiate 6q24-related TNDM from other causes. However, the clinical presentation may be slightly different: neonates with 6q24-related TNDM have more severe intrauterine growth retardation, present earlier, remit earlier, and relapse later than KATP-related TNMD. The presence of other distinguishing features of 6q24-related TNDM may guide the approach to genetic testing, such macroglossia (seen in 1/3 of patients) and umbilical hernia [Rubio-Cabezas et al 2014].

  • For infants presenting in the first two weeks of life, it is reasonable to test for 6q24-related aberrations first, followed by testing for KCNJ11 and ABCC8 pathogenic variants.
  • For infants presenting from the third week of life onward, it may be more appropriate to test for KCNJ11 and ABCC8 pathogenic variants first, followed by testing for 6q24-related aberrations.
  • In infants presenting between age six and 12 months or later who are antibody negative or have a family history consistent with autosomal dominant inheritance, evaluation for pathogenic variants in INS should be considered first.

For infants with associated extra-pancreatic features or consanguineous parents, other genetic analysis may be appropriate.

Syndromic causes of permanent neonatal diabetes mellitus

  • GATA4-related PNDM. Heterozygous inactivating pathogenic variants in GATA4 are associated with pancreatic agenesis or pancreatic hypoplasia leading to PNDM and congenital heart defects [D'Amato et al 2010, Shaw-Smith et al 2014]. GATA4 is a zinc finger transcription factor closely related to GATA6. The diabetes phenotype in individual carrying pathogenic variants is quite variable, ranging from TNDM, PNDM and diabetes presenting later in life. The severity of the exocrine insufficiency is also variable. Extrapancreatic manifestations include cardiac abnormalities and neurodevelopmental delays. Inheritance is autosomal dominant, but in most reported individuals the pathogenic variants have arisen de novo.
  • GATA6-related PNDM (OMIM 600001). Heterozygous inactivating pathogenic variants in GATA6 are the most common cause of pancreatic agenesis [Lango Allen et al 2011]. Extrapancreatic features are common and include structural heart defects, biliary tract and gut anomalies, and other endocrine abnormalities. The diabetic phenotype in those with pathogenic variants in GATA6 is broad, ranging from PNDM with exocrine insufficiency to transient episodes of hyperglycemia. In the largest published series of GATA6-PNDM, the median age at diagnosis of diabetes was two days and the median birth weight was 1588 grams. Individuals with heterozygous pathogenic variants in GATA6 have also been diagnosed with diabetes at an older age [Lango Allen et al 2011, De Franco et al 2013]. Inheritance is autosomal dominant, but in most reported individuals the pathogenic variants have arisen de novo.
  • PTF1A-related PNDM (OMIM 609069). Homozygous inactivating pathogenic variants in PTF1A cause pancreatic agenesis leading to PNDM associated with cerebellar agenesis and severe neurologic dysfunction [Sellick et al 2004]. PTF1A encodes a basic helix-loop-helix protein of 48 kd. The protein plays a role in determining whether cells allocated to the pancreatic buds continue toward pancreatic organogenesis or revert back to duodenal fates [Kawaguchi et al 2002]. Infants with PTF1A-related PNDM present with severe IUGR, and very low circulating insulin and C-peptide in the presence of severe hyperglycemia. Neurologic features include flexion contractures of extremities and absence of the cerebellum demonstrated on brain imaging [Sellick et al 2004]. A recent report described an individual with PTF1A-related PNDM without neurological manifestations [Houghton et al 2016]. Exocrine pancreatic dysfunction may be present as well. Inheritance is autosomal recessive.
  • Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly as insulin-dependent diabetes mellitus. The majority of affected males have other autoimmune phenomena including Coombs-positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. Typically, serum concentration of immunoglobulin E (IgE) is elevated. The majority of affected males die within the first year of life of either metabolic derangements or sepsis. FOXP3 is currently the only gene in which mutation is known to cause IPEX syndrome. Inheritance is X-linked.
  • Wolcott-Rallison syndrome (OMIM 226980) is characterized by infantile-onset diabetes mellitus and exocrine pancreatic dysfunction (25%) as well as the extra-pancreatic manifestations of epiphyseal dysplasia (90%), developmental delay (80%), acute liver failure (75%), osteopenia (50%), and hypothyroidism (25%). In addition, older individuals with Wolcott-Rallison syndrome may develop chronic kidney dysfunction [Senée et al 2004]. The prognosis is poor. EIF2AK3, the gene encoding eukaryotic translation initiation factor 2-alpha kinase 3, is the only gene in which pathogenic variants are known to cause Wolcott-Rallison syndrome. Durocher et al [2006] observed that the severity of the manifestations and age of presentation in individuals with the same pathogenic variant may vary and concluded that no simple relationship exists between the clinical manifestation and EIF2AK3 pathogenic variants in Wolcott-Rallison syndrome. This is the most common cause of PNDM in consanguineous families [Rubio-Cabezas et al 2009]. Inheritance is autosomal recessive.
  • A syndrome of neonatal diabetes mellitus with congenital hypothyroidism (OMIM 610199) has been associated with mutation of GLIS3. GLIS3 encodes zinc finger protein GLIS3 (also known as GLI similar protein 3), a transcription factor expressed in the pancreas from early developmental stages. GLIS3 plays a role in the transcriptional regulation of neurogenin-3 and insulin [Kim et al 2012, ZeRuth et al 2013]. In addition to neonatal diabetes and congenital hypothyroidism, the syndrome can present with congenital glaucoma, hepatic fibrosis, polycystic kidneys, and dysmorphic facial features [Senée et al 2006]. Inheritance is autosomal recessive and partial gene deletions are the most common type of pathogenic variant [Dimitri et al 2011].
  • A syndrome of neonatal diabetes mellitus with pancreatic hypoplasia, intestinal atresia, and gall bladder hypoplasia (OMIM 615710) has been associated with pathogenic variants in RFX6. RFX6 is a transcription factor required for the differentiation of four of the five islet cell types and for the production of insulin. RFX6 acts downstream of the pro-endocrine factor neurogenin-3. Pancreatic exocrine function is normal [Smith et al 2010]. Inheritance is autosomal recessive.
  • A syndrome of neonatal diabetes mellitus, cerebellar hypoplasia, sensorineural deafness, and visual impairment has been associated with pathogenic variants in NEUROD1 (OMIM 601724), encoding neurogenic differentation factor 1, a transcription factor that plays an important role in the development of the endocrine pancreas. Pancreatic exocrine function is normal [Rubio-Cabezas et al 2010]. Inheritance is autosomal recessive.
  • A syndrome of congenital malabsorptive diarrhea and neonatal diabetes mellitus (OMIM 610370) has been associated with pathogenic variants in NEUROG3, encoding neurogenin-3, a basic helix loop helix transcription factor essential in the development of enteroendocrine, Paneth, goblet, and enterocyte cells in the intestine and pancreatic endocrine cells [Pinney et al 2011]. Diabetes may also present later in childhood [Wang et al 2006]. Pancreatic exocrine function may also be affected. Inheritance is autosomal recessive.
  • A syndrome of neonatal diabetes mellitus and renal abnormalities (OMIM 137920) has been associated with pathogenic variants in HNF1B. HNF1 beta is a key regulator of a transcriptional network that controls the specification, growth and differentiation of the embryonic pancreas. The diabetes phenotype in individuals heterozygous for a single pathogenic variant in HNF1B manifests more frequently later in life (renal cysts and diabetes syndrome – RCAD, or MODY5). The neonatal presentation due to biallelic pathogenic variants in HNF1B is characterized by evidence of severe insulin deficiency (low birth weight, diabetes ketoacidosis) and pancreatic exocrine insufficiency due to hypoplastic pancreas. Other manifestations include genital tract malformations, hyperuricemia and gout, as well as abnormal liver function. The inheritance is autosomal recessive but penetrance is incomplete [Yorifuji et al 2004, Edghill et al 2006, Haldorsen et al 2008, Tjora et al 2013].
  • A syndrome of neonatal diabetes with brain malformations, microcephaly, and microphthalmia has been associated with pathogenic variants in PAX6 (OMIM 607108). PAX6 is a transcription factor involved in eye and brain development that also plays a role in pituitary development and in ß-cell differentiation and function. In heterozygous individuals, diabetes presents later in life, however in individuals with biallelic pathogenic variants, the diabetes manifests in the neonatal period. The central nervous system (CNS) phenotype includes microcephaly and panhypopituitarism. The ocular phenotype includes aniridia, keratopathy, optic nerve defects, cataracts, microphthalmia and anophthalmia [Yasuda et al 2002, Solomon et al 2009].
  • Wolfram syndrome – diabetes mellitus with optic atrophy, diabetes insipidus, and/or deafness. The associated gene, WFS1, encodes an endoplasmic reticulum (ER) membrane-embedded protein involved in regulating ER stress. The earliest and most consistent phenotypic characteristic in individuals with Wolfram syndrome is diabetes, which is usually diagnosed during childhood, but it can also present in the first year of life. The inheritance is autosomal recessive [Rigoli et al 2011, Rohayem et al 2011]. See WFS1-Related Disorders.
  • A syndrome of neonatal diabetes mellitus, deafness, and thiamine-responsive megaloblastic anemia caused by pathogenic variants in SLC19A2. SLC19A2 encodes a thiamine transporter. Also known as Rogers syndrome, this syndrome can also be associated with neurologic deficits, visual disturbances, and cardiac abnormalities. The diabetes phenotype can manifests in the first six months of life or later. The inheritance is autosomal recessive [Shaw-Smith et al 2012]. See Thiamine-Responsive Megaloblastic Anemia Syndrome.
  • A syndrome of neonatal diabetes mellitus, developmental delays, sacral agenesis and imperforated anus caused by pathogenic variants in MNX1. Other manifestations include intrauterine growth retardation, hypoplastic lungs. Inheritance is autosomal recessive [Flanagan et al 2014].
  • A syndrome of neonatal diabetes mellitus, developmental delays, hypotonia, short stature and deafness caused by pathogenic variants in NKX2-2. Other manifestations include intrauterine growth retardation, cortical blindness, and impaired visual tracking. Inheritance is autosomal recessive [Flanagan et al 2014].
  • A syndrome of neonatal diabetes, microcephaly, lissencephaly, and epileptic encephalopathy caused by pathogenic variants in IER3IP1. IERI31P1 encodes a highly conserved protein with marked expression in beta cells in cerebral cortex but which function is not well known. Inheritance is autosomal recessive [Shalev et al 2014].

Testing strategy for syndromic permanent neonatal diabetes mellitus. Individuals with PNDM and:

  • Pancreatic exocrine insufficiency or agenesis and cardiac abnormalities should be tested for pathogenic variants in GATA4 and GATA6;
  • Enteropathy and dermatitis should be tested for pathogenic variants in FOXP3 (IPEX syndrome);
  • Cerebellar involvement should be tested for pathogenic variants in PTF1A;
  • Congenital hypothyroidism should be tested for pathogenic variants in GLIS3;
  • Cerebellar hypoplasia, sensorineural deafness, and visual impairment should be tested for pathogenic variants in NEUROD1;
  • Pancreatic hypoplasia, intestinal atresia, and gall bladder hypoplasia should be tested for pathogenic variants in RFX6;
  • Congenital malabsorptive diarrhea should be tested for pathogenic variants in NEUROG3;
  • Skeletal abnormalities and liver dysfunction should be tested for pathogenic variants in EIF2AK3 (WRS - Wolcott-Rallison syndrome);
  • Megaloblastic anemia and deafness should be tested for pathogenic variants in SLC19A2 (TRMA; thiamine-responsive megaloblastic anemia);
  • Renal and genital abnormalities should be tested for pathogenic variants in HNF1B;
  • Brain malformations, microcephaly and microphthalmia should be tested for pathogenic variants in PAX6;
  • Optic atrophy, diabetes insipidus and deafness should be tested for pathogenic variants in WFS1 (Wolfram syndrome).

Management

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 www.ClinicalTrialsRegister.eu 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.