NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Permanent Neonatal Diabetes Mellitus

, MD and , MD.

Author Information

Initial Posting: ; Last Update: July 29, 2016.

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 multi-gene panel, and more comprehensive genomic testing.

Serial single-gene testing

  • Individuals with one parent with diabetes mellitus:
    1.

    Sequence analysis of KCNJ11

    2.

    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:
    1.

    Sequence analysis of ABCC8 and KCNJ11 first (as identification of pathogenic variants changes management)

    2.

    If no pathogenic variants are identified, sequence analysis of GCK and INS

  • Individuals with pancreatic insufficiency or agenesis without extra-pancreatic abnormalities:
    1.

    Sequence analysis of PDX1

    2.

    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 multi-gene 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 and the sensitivity of multi-gene panels vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

More comprehensive genomic testing (when available) including whole-exome sequencing (WES) and whole-genome sequencing (WGS) may be considered if serial single-gene testing (and/or use of a multi-gene 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 issues to consider in interpretation of genomic test results, click 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.
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 that may be used 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.
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].

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). 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). 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) 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) 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) 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), 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) 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) 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 MODY 5). 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). 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 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members — Autosomal Dominant Inheritance

Table 2.

Autosomal Dominant PNDM – Risk to Parents of a Proband by Gene

GenePercent of Probands with an Affected ParentPercent of Probands with a De Novo Pathogenic Variant
ABCC8~10% 1Most reported cases 2
INS27%73%
KCNJ11~10%90%
1.

A parent may have type 2 diabetes despite having the same ABCC8 pathogenic variant as their child with neonatal diabetes mellitus [Babenko et al 2006].

2.

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, his or her family members may be at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

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.

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.

Carrier (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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Diabetes Genes
    Diabetesgenes.org aims to provide information for patients and professionals on research and clinical care in genetic types of diabetes.
    United Kingdom
  • International Society for Pediatric and Adolescent Diabetes (ISPAD)
    Germany
    Phone: +49 (0)30 24603-210
    Fax: +49 (0)30 24603-200
    Email: secretariat@ispad.org
  • American Diabetes Association (ADA)
    Phone: 1-800-DIABETES (800-342-2383)
    Email: AskADA@diabetes.org
  • Diabetes UK
    United Kingdom
    Phone: 0345 123 2399
    Fax: 020 7424 1001
    Email: info@diabetes.org.uk
  • Neonatal Diabetes Registry
    University of Chicago, Kovler Diabetes Center
    5841 South Maryland Avenue
    MC1027
    Chicago IL 60637
    Phone: 773-795-4454
    Email: neonataldiabetes@uchicago.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Permanent Neonatal Diabetes Mellitus: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Permanent Neonatal Diabetes Mellitus (View All in OMIM)

138079GLUCOKINASE; GCK
176730INSULIN; INS
600509ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 8; ABCC8
600733PANCREAS/DUODENUM HOMEOBOX PROTEIN 1; PDX1
600937POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 11; KCNJ11
606176DIABETES MELLITUS, PERMANENT NEONATAL; PNDM

ABCC8

Gene structure. ABCC8 is located 4.5 kb centromeric to KCNJ11 on chromosome 11p15.1. The gene spans approximately 84 kb of genomic DNA and is made up of 39 exons. The shorter transcript variant NM_000352.4 is 4935 bp. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 25 different ABCC8 variants have been associated with permanent neonatal diabetes (see Table 3). In addition, several other variants in compound heterozygotes have been associated with PNDM. (See Flanagan et al [2009] for variants in ABCC8 that cause both neonatal diabetes mellitus and persistent hyperinsulinemic hypoglycemia of infancy.)

Table 3.

Selected ABCC8 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReferencesReference Sequences
c.215A>Gp.Asn72SerEllard et al [2007]NM_000352​.3
NP_000343​.2
c.257T>Cp.Val86AlaEllard et al [2007]
c.257T>Gp.Val86GlyEllard et al [2007]
c.394T>Gp.Phe132ValEllard et al [2007]
c.394T>Cp.Phe132LeuProks et al [2006]
c.404T>Cp.Leu135ProEllard et al [2007]
c.627C>Ap.Asp209GluEllard et al [2007],
Flanagan et al [2007]
c.631C>Ap.Gln211LysEllard et al [2007]
c.638T>Gp.Leu213ArgBabenko et al [2006]
c.674T>Cp.Leu225Phe
c.1144G>Ap.Glu382LysEllard et al [2007]
c.3554C>Ap.Ala1185GluEllard et al [2007]
c.4270A>Gp.Ile1424ValBabenko et al [2006],
Masia et al [2007a]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

For more information see Patch et al [2007], Figure 2 (full text) and Edghill et al [2010], Figures 2 and 3 (full text).

Normal gene product. The transcript variant NM_000352.4 encodes ATP-binding cassette transporter sub-family C member 8 protein (SUR1) (NP_000343.2), which has 1581 amino acids. See KCNJ11, Normal gene product.

Abnormal gene product. Pathogenic variants in ABCC8 result in nonfunctional or dysfunctional KATP channels. The increased activity of KATP channels resulting from pathogenic variants in ABCC8 is caused by an increase in the magnesium-dependent stimulatory action of SUR1 on the pore [Babenko et al 2006, Masia et al 2007a], or by alteration in the inhibitory action of ATP on a mutant SUR1 channel [Proks et al 2006].

GCK

Gene structure. GCK spans more than 45 kb of genomic DNA; the transcript variant NM_000162.3, which encodes the isoform expressed specifically in pancreatic islet beta cells, has ten exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. At least ten variants of GCK have been reported in association with PNDM (see Table 4). These are nonsense, missense, or frameshift variants.

Table 4.

Selected GCK Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReferencesReference Sequences
c.629T>Ap.Met210LeuNjølstad et al [2001]NM_000162​.3
NP_000153​.1
c.683C>Tp.Thr228Met
c.790G>Ap.Gly264SerNjølstad et al [2003]
1133C>Tp.Ala378Val
c.1190G>Tp.Arg397LeuPorter et al [2005]
c.1505+2T>G
(IVS8+2T>G)
NANjølstad et al [2003]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA= not applicable

1.

Variant designation that does not conform to current naming conventions

Normal gene product. The isoform NP_000153.1, expressed specifically in pancreatic islet beta cells, has 465 amino acid residues. Glucokinase is a hexokinase that serves as the glucose sensor in pancreatic beta cells and appears to have a similar role in enteroendocrine cells, hepatocytes, and hypothalamic neurons. In beta cells, glucokinase controls the rate-limiting step of glucose metabolism and is responsible for glucose-stimulated insulin secretion [Matschinsky 2002].

Abnormal gene product. The reported pathogenic missense variants alter the kinetics of the enzyme: the glucose S0.5 is raised and the ATP Km is increased. The overall result for inactivating pathogenic variants is a decrease in the phosphorylating potential of the enzyme, which extrapolates to a marked reduction in beta-cell glucose usage and hyperglycemia. Splice site pathogenic variants are predicted to lead to the synthesis of an inactive protein.

INS

Gene structure. The INS transcript variant NM_000207.2 has three exons. Exon 2 encodes the signal peptide, the B chain, and part of the C peptide; exon 3 encodes the reminder of the C peptide and the A chain. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 25 variants have been described in association with PNDM [Støy et al 2007, Polak et al 2008, Støy et al 2010]. See Table 5 and Genotype-Phenotype Correlations.

See Støy et al [2010] for variants in INS that cause diabetes mellitus.

Table 5.

Selected INS Pathogenic Variants

DNA Nucleotide Change 1Predicted Protein ChangeReferencesReference Sequences
c.-366_343del 2, 3NAStøy et al [2007], Polak et al [2008], Støy et al [2010]NM_000207​.2 4
NP_000198​.1
c.-370-?186+?del 2, 3, 5, 6
c.-331C>A 2, 3, 7, 8
c.-331C>G 2, 3, 4, 9
c.-218A>C 2, 3, 7, 10
c.3G>A 2p.0? 11
c.3G>T 2p.0? 11
c.71C>Ap.Ala24Asp
c.94G>Ap.Gly32Ser
c.94G>Cp.Gly32Arg
c.127T>Gp.Cys43Gly
c.140G>Tp.Gly47Val
c.143T>Gp.Phe48Cys
c.184C>T 2p.Gln62Ter
c.265C>Tp.Arg89Cys
c.268G>Tp.Gly90Cys
c.287G>Ap.Cys96Tyr
c.323A>Gp.Tyr108Cys
c.*59A>G 2, 12NA

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

1.

Negative number indicates the number of base pairs preceding the A of the ATG start codon. An asterisk indicates a position in the 3’UTR; the number is the position relative to the first base past the stop codon.

2.

A 646-bp deletion. See Table 1 (footnote 10) and Genotype-Phenotype Correlations.

3.
4.

Reference sequences of the insulin preproprotein (or preproinsulin)

5.

Denotes an exon deletion starting at an unknown position in the promoter of coding DNA nucleotide -370 and ending at an unknown position in the intron 3’ of the coding DNA nucleotide 186 [Støy et al 2010]

6.
7.
8.

-94 relative to transcription initiation site

9.

-93 relative to transcription initiation site

10.

A+20 relative to transcription initiation site

11.

p.0? = effect unknown; probably no protein is produced

12.

59 nucleotides 3' of the termination codon (in the 3'UTR)

Normal gene product. The insulin preproprotein NP_000198.1 encoded by transcript NM_000207.2 has 110 amino acids. Insulin is synthesized by the pancreatic beta cells and consists of two dissimilar polypeptide chains, A and B, which are linked by two disulfide bonds. Chains A and B are derived from a 1-chain precursor, proinsulin. Proinsulin is converted to insulin by enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain. This segment is called the C peptide.

Abnormal gene product. The diabetes-associated pathogenic variants lead to the synthesis of a structurally abnormal preproinsulin or proinsulin protein. The variants associated with PNDM disrupt proinsulin folding and/or disulfide bond formation. Some reported variants disrupt normal disulfide bonds (p.Cys43Gly and p.Cys96Tyr) or add an additional unpaired cysteine residue (p.Arg89Cys and p.Gly90Cys) at the A-chain C-peptide cleavage site. The variant p.Tyr108Cys may cause mispairing of cysteines in a critical region close to a disulfide bond [Støy et al 2007]. All of the pathogenic variants are likely to act in a dominant manner to disrupt insulin biosynthesis and induce endoplasmic reticulum (ER) stress. The exact mechanism by which these unpaired cysteines disrupt ER function remains unclear [Izumi et al 2003]. Three other pathogenic variants (p.Gly32Ser, p.Gly32Arg, and p.Gly47Val) are located in a residue that is invariant in both insulin and the insulin-like growth factors and must play an important structural role. It is believed that these glycine variants also act similarly to impair proinsulin folding and thereby induce ER stress via the unfolded protein response.

KCNJ11

Gene structure. KCNJ11 is located 4.5 kb telomeric to ABCC8 on chromosome 11p15.1. The gene spans approximately 3.4 kb of genomic DNA and has a single exon. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 20 different pathogenic variants in KCNJ11 have been reported in association with neonatal diabetes mellitus (see Table 6). The two common hot spots for recurrent mutation are at amino acid residues Val59 and Arg201 [Hattersley & Ashcroft 2005]. (See Flanagan et al [2009] for variants in KCNJ11 that cause both neonatal diabetes mellitus and persistent hyperinsulinemic hypoglycemia of infancy.)

Table 6.

Selected KCNJ11 Variants

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.67G>Ap.Glu23Lys 1NM_000525​.3
NP_000516​.3
Pathogenicc.103T>Gp.Phe35Val
c.103T>Cp.Phe35Leu
c.124T>Cp.Cys42Arg
c.149G>Cp.Arg50Pro
c.155A>Gp.Gln52Arg
c.157G>Cp.Gly53Arg
c.157G>Ap.Gly53Ser
c.158G>Ap.Gly53Asp
c.175G>Ap.Val59Met
c.176T>Gp.Val59Gly
c.497G>Tp.Cys166Phe
c.497G>Ap.Cys166Tyr
c.499A>Cp.Ile167Leu
c.509A>Gp.Lys170Arg
c.510G>Cp.Lys170Asn
c.544A>Gp.Ile182Val
c.602G>Ap.Arg201His
c.601C>Tp.Arg201Cys
c.602G>Tp.Arg201Leu
c.755T>Cp.Val252Ala
c.886A>Cp.Ile296Leu
c.886A>Gp.Ile296Val
c.964G>Ap.Glu322Lys
c.989A>Gp.Tyr330Cys
c.997T>Ap.Phe333Ile
c.1001G>Ap.Gly334Asp

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Associated with type 2 diabetes mellitus; see Genetically Related Disorders.

Normal gene product. The transcript variant NM_000525.3 encodes the 390-amino acid isoform known as Kir6.2 (NP_000516.3). KCNJ11 and ABCC8 encode the proteins ATP-sensitive inward rectifier potassium channel 11 (Kir6.2) and ATP-binding cassette transporter sub-family C member 8 (SUR1), respectively; both are components of the beta-cell KATP channel. The KATP channel is a hetero-octameric complex with four Kir6.2 subunits forming the central pore, coupled to four SUR1 subunits. The KATP channels couple the energy state of the beta cell to membrane potential by sensing changes in intracellular phosphate potential (the ATP/ADP ratio). Following the uptake of glucose and its metabolism by glucokinase, there is an increase in the intracellular ATP/ADP ratio results in closure of the KATP channels, depolarization of the cell membrane, and subsequent opening of voltage-dependent Ca2+ channels. The resulting increase in cytosolic Ca2+ concentration triggers insulin release.

Abnormal gene product. Pathogenic variants in either ABCC8 or KCNJ11 result in nonfunctional or dysfunctional KATP channels. In either case, channels do not close, and thus glucose-stimulated insulin secretion does not happen. All pathogenic variants in KCNJ11 studied to date produce marked decrease in the ability of ATP to inhibit the KATP channel when expressed in heterologous systems. This reduction in ATP sensitivity means the channel opens more fully at physiologically relevant concentrations of ATP, leading to an increase in the KATP current and hyperpolarization of the beta-cell plasma membrane with subsequent suppression of Ca2+ influx and insulin secretion [Hattersley & Ashcroft 2005].

PDX1

Gene structure. The PDX1 transcript NM_000209.3 has 2573 bp and comprises two exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. At least four PDX1 variants have been described in association with pancreatic agenesis and PNDM:

Table 7.

Selected PDX1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.188_189delCp.Pro63ArgfsTer60NM_000209​.3
NP_000200​.1
c.492G>Tp.Glu164Asp
c.532G>Ap.Glu178Lys
c.533A>Gp.Glu178Gly

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The pancreas/duodenum homeobox protein 1 or transcription factor insulin promoter factor 1 (PDX1) is a master regulator of pancreatic development and of the differentiation of progenitor cells into the beta-cell phenotype.

During embryogenesis in the mouse, pdx1 expression initiates on commitment of the foregut endoderm to a pancreatic fate. In the adult organism, pdx1 expression is limited to the beta cell and its importance in maintaining beta-cell phenotype is illustrated by multiple animal models. In mature beta cells, pdx1 regulates the expression of critical genes including insulin, glucokinase, and the glucose transporter Glut2 [Habener et al 2005].

Abnormal gene product. The single-nucleotide deletion c.188_189delC predicts the formation of a truncated, inactive protein (p.Pro63ArgfsTer60), whereas the mutated proteins p.Glu164Asp or p.Glu178Lys undergo increased degradation leading to a reduction in protein levels and ultimately to decreased transcriptional activity. The p.Glu178Gly variant reduces PDX1 transactivation.

References

Literature Cited

  1. American Diabetes Association. Children and adolescents. Diabetes Care. 2016a;39 Suppl 1:S86–S93. [PubMed: 26696687]
  2. American Diabetes Association. Diabetes care in the hospital. Diabetes Care. 2016b;39 Suppl 1:S99–S104. [PubMed: 26696689]
  3. Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355:456–66. [PubMed: 16885549]
  4. Babiker T, Vedovato N, Patel K, Thomas N, Finn R, Männikkö R, Chakera AJ, Flangan SE, Shepherd MH, Ellard S, Ashcroft FM, Hattersley AT. Successful transfer to sylfonylureas in KCNJ11 is determined by the mutation and duration of diabetes. Diabetologia. 2016;59:1162–6. [PMC free article: PMC4869695] [PubMed: 27033559]
  5. Bonnefond A, Lomberk G, Buttar N, Busiah K, Vaillant E, Lobbens S, Yengo L, Dechaume A, Mignot B, Simon A, Scharfmann R, Neve B, Tanyolaç S, Hodoglugil U, Pattou F, Cavé H, Iovanna J, Stein R, Polak M, Vaxillaire M, Froguel P, Urrutia R. Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. J Biol Chem. 2011;286:28414–24. [PMC free article: PMC3151084] [PubMed: 21592955]
  6. Colombo C, Delvecchio M, Zecchino C, Faienza MF, Cavallo L, Barbetti F. Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation. Diabetologia. 2005;48:2439–41. [PubMed: 16205880]
  7. D’Amato E, Giacopelli F, Giannattasio A, D’Annunzio G, Bocciardi R, Musso M, Lorini R, Ravazzolo R. Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis. Diabet Med. 2010;27:1195–200. [PubMed: 20854389]
  8. De Franco E, Shaw-Smith C, Flanagan SE, Shepherd MH, International NDM. Consortium, Hattersley AT, Ellard S. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency. Diabetes. 2013;62:993–7. [PMC free article: PMC3581234] [PubMed: 23223019]
  9. Dimitri P, Warner JT, Minton JA, Patch AM, Ellard S, Hattersley AT, Barr S, Hawkes D, Wales JK, Gregory JW. Novel GLIS3 mutations demonstrate an extended multisystem phenotype. Eur J Endocrinol. 2011;164:437–43. [PubMed: 21139041]
  10. Durocher F, Faure R, Labrie Y, Pelletier L, Bouchard I, Laframboise R. A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome. Clin Genet. 2006;70:34–8. [PubMed: 16813601]
  11. Edghill EL, Bingham C, Slingerland AS, Minton JA, Noordam C, Ellard S, Hattersley AT. Hepatocyte nuclear factor-1beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development. Diabet Med. 2006;23:1301–6. [PubMed: 17116179]
  12. Edghill EL, Flanagan SE, Ellard S. Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11. Rev Endocr Metab Disord. 2010;11:193–8. [PubMed: 20922570]
  13. Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, MacDonald MJ, Støy J, Steiner DF, Philipson LH, Bell GI., Neonatal Diabetes International Collaborative Group. Hattersley AT, Ellard S. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes. 2008;57:1034–42. [PubMed: 18162506]
  14. Edghill EL, Gloyn AL, Goriely A, Harries LW, Flanagan SE, Rankin J, Hattersley AT, Ellard S. Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J Clin Endocrinol Metab. 2007;92:1773–7. [PubMed: 17327377]
  15. Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ, Shield JP, Hattersley AT, Ashcroft FM. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet. 2007;81:375–82. [PMC free article: PMC1950816] [PubMed: 17668386]
  16. Flanagan SE, Clauin S, Bellanné-Chantelot C, de Lonlay P, Harries LW, Gloyn AL, Ellard S. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat. 2009;30:170–80. [PubMed: 18767144]
  17. Flanagan SE, De Franco E, Lango Allen H, Zerah M, Abdul-Rasoul MM, Edge JA, Stewart H, Alamiri E, Hussain K, Wallis S, de Vries L, Rubio-Cabezas O, Houghton JAL, Edghill EL, Patch AM, Ellard S, Hattersley AT. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man. Cell Metab. 2014;19:146–54. [PMC free article: PMC3887257] [PubMed: 24411943]
  18. Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT. Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia. 2006;49:1190–7. [PubMed: 16609879]
  19. Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL, Robinson D, Shield JP, Temple K, Ellard S, Hattersley AT. Mutations in ATP-ésitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007;56:1930–7. [PubMed: 17446535]
  20. Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004;53:1360–8. [PubMed: 15111507]
  21. Garin I, Edghill EL, Akerman I, Rubio-Cabezas O, Rica I, Locke JM, Maestro MA, Alshaikh A, Bundak R, del Castillo G, Deeb A, Deiss D, Fernandez JM, Godbole K, Hussain K, O'Connell M, Klupa T, Kolouskova S, Mohsin F, Perlman K, Sumnik Z, Rial JM, Ugarte E, Vasanthi T., Neonatal Diabetes International Group. Johnstone K, Flanagan SE, Martínez R, Castaño C, Patch AM, Fernández-Rebollo E, Raile K, Morgan N, Harries LW, Castaño L, Ellard S, Ferrer J, Perez de Nanclares G, Hattersley AT. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad Sci U S A. 2010;107:3105–10. [PMC free article: PMC2840338] [PubMed: 20133622]
  22. Girard CA, Shimomura K, Proks P, Absalom N, Castano L, Perez de Nanclares G, Ashcroft FM. Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Arch. 2006;453:323–32. [PubMed: 17021801]
  23. Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T, Temple IK, Hattersley AT, Ellard S. Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab. 2004a;89:3932–5. [PubMed: 15292329]
  24. Gloyn AL, Diatloff-Zito C, Edghill EL, Bellanne-Chantelot C, Nivot S, Coutant R, Ellard S, Hattersley AT, Robert JJ. KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. Eur J Hum Genet. 2006;14:824–30. [PubMed: 16670688]
  25. Gloyn AL, Hashim Y, Ashcroft SJ, Ashfield R, Wiltshire S, Turner RC. Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53). Diabet Med. 2001;18:206–12. [PubMed: 11318841]
  26. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004b;350:1838–49. [PubMed: 15115830]
  27. Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT. Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet. 2005;14:925–34. [PubMed: 15718250]
  28. Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003;52:568–72. [PubMed: 12540637]
  29. Greeley SA, Naylor RN, Philipson LH, Bell GI. Neonatal diabetes: an expanding list of genes allows for improved diagnosis and treatment. Curr Diab Rep. 2011;11:519–32. [PMC free article: PMC3226065] [PubMed: 21993633]
  30. Greeley SA, Tucker SE, Naylor RN, Bell GI, Philipson LH. Neonatal diabetes mellitus: a model for personalized medicine. Trends Endocrinol Metab. 2010;21:464–72. [PMC free article: PMC2914172] [PubMed: 20434356]
  31. Habener JF, Kemp DM, Thomas MK. Minireview: transcriptional regulation in pancreatic development. Endocrinology. 2005;146:1025–34. [PubMed: 15604203]
  32. Haldorsen IS, Vesterhus M, Raeder H, Jensen DK, Søvik O, Molven A, Njølstad PR. Lack of pancreatic body and tail in HNF1B mutation carriers. Diabet Med. 2008;25:782–7. [PubMed: 18644064]
  33. Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P. Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians. Diabetologia. 1998;41:1511–5. [PubMed: 9867219]
  34. Hansen T, Ambye L, Grarup N, Hansen L, Echwald SM, Ferrer J, Pedersen O. Genetic variability of the SUR1 promoter in relation to beta-cell function and Type II diabetes mellitus. Diabetologia. 2001;44:1330–4. [PubMed: 11692183]
  35. Hart LM, van Haeften TW, Dekker JM, Bot M, Heine RJ, Maassen JA. Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K(+) channel in the beta-cell. Diabetes. 2002;51:3135–8. [PubMed: 12351459]
  36. Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue K. ISPAD Clinical Practice Consensus Guidelines 2006-2007. The diagnosis and management of monogenic diabetes in children. Pediatr Diabetes. 2006;7:352–60. [PubMed: 17212604]
  37. Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes. 2005;54:2503–13. [PubMed: 16123337]
  38. Houghton JA, Swift GH, Shaw-Smith C, Flanagan SE, de Franco E, Caswell R, Hussain K, Mohamed S, Abdulrasoul M, Hattersley AT, MacDonald RJ, Ellard S. Isolated pancreatic aplasia due to hypomorphic PTF1A mutation. Diabetes. 2016. Epub ahead of print. [PMC free article: PMC5001172] [PubMed: 27284104]
  39. Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M. A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet. 2003;361:301–7. [PubMed: 12559865]
  40. Hussain K. Mutations in pancreatic ß-cell Glucokinase as a cause of hyperinsulinaemic hypoglycaemia and neonatal diabetes mellitus. Rev Endocr Metab Disord. 2010;11:179–83. [PubMed: 20878480]
  41. Izumi T, Yokota-Hashimoto H, Zhao S, Wang J, Halban PA, Takeuchi T. Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. Diabetes. 2003;52:409–16. [PubMed: 12540615]
  42. Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, Wright CV. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet. 2002;32:128–34. [PubMed: 12185368]
  43. Kim YS, Kang HS, Takeda Y, Hom L, Song HY, Jensen J, Jetten AM. Glis 3 regulates neurogenin 3 expression in pancreatic ß-cells and interacts with its activator, Hnf6. Mol Cells. 2012;34:193–200. [PMC free article: PMC3465161] [PubMed: 22820919]
  44. Koster JC, Cadario F, Peruzzi C, Colombo C, Nichols CG, Barbetti F. The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy. J Clin Endocrinol Metab. 2008;93:1054–61. [PMC free article: PMC2266958] [PubMed: 18073297]
  45. Lango Allen H, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R., International Pancreatic Agenesis Consortium. Ferrer J, Hattersley AT, Ellard S. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet. 2011;44:20–2. [PMC free article: PMC4062962] [PubMed: 22158542]
  46. Masia R, De Leon DD, MacMullen C, McKnight H, Stanley CA, Nichols CG. A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Diabetes. 2007a;56:1357–62. [PubMed: 17317760]
  47. Masia R, Koster JC, Tumini S, Chiarelli F, Colombo C, Nichols CG, Barbetti F. An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes. Diabetes. 2007b;56:328–36. [PubMed: 17259376]
  48. Massa O, Iafusco D, D'Amato E, Gloyn AL, Hattersley AT, Pasquino B, Tonini G, Dammacco F, Zanette G, Meschi F, Porzio O, Bottazzo G, Crino A, Lorini R, Cerutti F, Vanelli M, Barbetti F. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat. 2005;25:22–7. [PubMed: 15580558]
  49. Matschinsky FM. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes. 2002 Dec;51 Suppl 3:S394–404. [PubMed: 12475782]
  50. Metz C, Cave H, Bertrand AM, Deffert C, Gueguen-Giroux B, Czernichow P, Polak M. Neonatal diabetes mellitus: chromosomal analysis in transient and permanent cases. J Pediatr. 2002;141:483–9. [PubMed: 12378186]
  51. Mohamadi A, Clark LM, Lipkin PH, Mahone EM, Wodka EL, Plotnick LP. Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. Pediatr Diabetes. 2010;11:203–7. [PubMed: 19686306]
  52. Moretti ME, Rezvani M, Koren G. Safety of glyburide for gestational diabetes: a metab-analysis of pregnancy outcomes. Ann Pharmacother. 2008;42:483–90. [PubMed: 18349305]
  53. Nicolino M, Claiborn KC, Senée V, Boland A, Stoffers DA, Julier C. A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency. Diabetes. 2010;59:733–40. [PMC free article: PMC2828654] [PubMed: 20009086]
  54. Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, Thorsteinsson B, Borch-Johnsen K, Hansen T, Pedersen O. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes. 2003;52:573–7. [PubMed: 12540638]
  55. Njølstad PR, Sagen JV, Bjørkhaug L, Odili S, Shehadeh N, Bakry D, Sarici SU, Alpay F, Molnes J, Molven A, Søvik O, Matschinsky FM. Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes. 2003;52:2854–60. [PubMed: 14578306]
  56. Njølstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001;344:1588–92. [PubMed: 11372010]
  57. Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S. Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabetes Obes Metab. 2007;9 Suppl 2:28–39. [PubMed: 17919176]
  58. Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355:467–77. [PubMed: 16885550]
  59. Pinney SE, Oliver-Krasinski J, Ernst L, Hughes N, Patel P, Stoffers DA, Russo P, De León DD. Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin-3 gene coding sequence. J Clin Endocrinol Metab. 2011;96:1960–5. [PMC free article: PMC3135203] [PubMed: 21490072]
  60. Polak M, Cave H. Neonatal diabetes mellitus: a disease linked to multiple mechanisms. Orphanet J Rare Dis. 2007;2:12. [PMC free article: PMC1847805] [PubMed: 17349054]
  61. Polak M, Dechaume A, Cavé H, Nimri R, Crosnier H, Sulmont V, de Kerdanet M, Scharfmann R, Lebenthal Y, Froguel P, Vaxillaire M, French ND. (Neonatal Diabetes) Study Group. Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group. Diabetes. 2008;57:1115–9. [PubMed: 18171712]
  62. Porter JR, Shaw NJ, Barrett TG, Hattersley AT, Ellard S, Gloyn AL. Permanent neonatal diabetes in an Asian infant. J Pediatr. 2005;146:131–3. [PubMed: 15644838]
  63. Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM. Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci U S A. 2004;101:17539–44. [PMC free article: PMC536014] [PubMed: 15583126]
  64. Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B, Colclough K, Hattersley AT, Ashcroft FM, Ellard S. A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet. 2006;15:1793–800. [PubMed: 16613899]
  65. Raile K, O'Connell M, Galler A, Werther G, Kühnen P, Krude H, Blankenstein O. Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals. Eur J Endocrinol. 2011;165:255–60. [PubMed: 21566073]
  66. Rigoli L, Lombardo F, Di Bella C. Wolfram syndrome and WFS1 gene. Clin Genet. 2011;79:103–17. [PubMed: 20738327]
  67. Rohayem J, Ehlers C, Wiedemann B, Holl R, Oexie K, Kordonouri O, Salzano G, Meissner T, Burger W, Schober E, Huebner A, Lee-Kirsh MA., Wolfram Syndrome Diabetes Writing Group. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care. 2011;34:1503–10. [PMC free article: PMC3120194] [PubMed: 21602428]
  68. Rubio-Cabezas O, Hattersley AT, Njølstad PR, Mlynarski W., Ellard S, White N, Chi DV, Craig ME. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2014;15:47–64. [PubMed: 25182307]
  69. Rubio-Cabezas O, Minton JA, Kantor I, Williams D, Ellard S, Hattersley AT. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes. 2010;59:2326–31. [PMC free article: PMC2927956] [PubMed: 20573748]
  70. Rubio-Cabezas O, Patch AM, Minton JA, Flanagan SE, Edghill EL, Hussain K, Balafrej A, Deeb A, Buchanan CR, Jefferson IG, Mutair A., Neonatal Diabetes International Collaborative Group. Hattersley AT, Ellard S. Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab. 2009;94:4162–70. [PMC free article: PMC2775655] [PubMed: 19837917]
  71. Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, Philippe J. Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab. 2003;88:4398–406. [PubMed: 12970316]
  72. Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, Gloyn AL, Edghill EL, Hattersley AT, Wellauer PK, Goodwin G, Houlston RS. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004;36:1301–5. [PubMed: 15543146]
  73. Senée V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougnères P, Taha D, Julier C. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet. 2006;38:682–7. [PubMed: 16715098]
  74. Senée V, Vattem KM, Delépine M, Rainbow LA, Haton C, Lecoq A, Shaw NJ, Robert JJ, Rooman R, Diatloff-Zito C, Michaud JL, Bin-Abbas B, Taha D, Zabel B, Franceschini P, Topaloglu AK, Lathrop GM, Barrett TG, Nicolino M, Wek RC, Julier C. Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes. 2004;53:1876–83. [PubMed: 15220213]
  75. Shalev SA, Tenebaum-Rakover Y, Horovitz Y, Paz VP, Ye H, Carmody D, Highland HM, Boerwinkle E, Hanis CL, Muzny DM, Gibbs RA, Bell GI, Philipson LH, Greeley SAW. Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutation in IER3IP1: insights into the natural history of a rare disorder. Pediatr Diabetes. 2014;15:252–6. [PMC free article: PMC3994177] [PubMed: 24138066]
  76. Shaw-Smith C, Flanagan SE, Patch AM, Grulich-Henn J, Habeb AM, Hussain K, Pomahacova R, Matyka K, Abdullah M, Hattersley AT, Ellard S. Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia. Pediatric Diabetes. 2012;13:314–21. [PubMed: 22369132]
  77. Shaw-Smith C, De Franco E, Lango Allen H, Batlle M, Flanagan SE, Borowiec M, Taplin CE, van Alfen-van der Velden J, Cruz-Rojo J, Perez de Nanclares G, Miedzybrodzka Z, Deja G, Wlodarska I, Mlynarski W, Ferrer J, Hattersley AT, Ellard S. GATA4 mutations are a cause of neonatal diabetes in childhood-onset diabetes. Diabetes. 2014;63:2888–94. [PubMed: 24696446]
  78. Shimomura K, Horster F, de Wet H, Flanagan SE, Ellard S, Hattersley AT, Wolf NI, Ashcroft F, Ebinger F. A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology. 2007;69:1342–9. [PubMed: 17652641]
  79. Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ. Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene. Diabetologia. 2006;49:2559–63. [PubMed: 17047922]
  80. Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A, Mlynarski W, Hattersley AT, Ellard S. Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births. Diabetologia. 2009;52:1683–5. [PMC free article: PMC2709852] [PubMed: 19499210]
  81. Smith SB, Qu HQ, Taleb N, Kishimoto NY, Scheel DW, Lu Y, Patch AM, Grabs R, Wang J, Lynn FC, Miyatsuka T, Mitchell J, Seerke R, Désir J, Eijnden SV, Abramowicz M, Kacet N, Weill J, Renard ME, Gentile M, Hansen I, Dewar K, Hattersley AT, Wang R, Wilson ME, Johnson JD, Polychronakos C, German MS. Rfx6 directs islet formation and insulin production in mice and humans. Nature. 2010;463:775–80. [PMC free article: PMC2896718] [PubMed: 20148032]
  82. Solomon BD, Pineda-Alvarez DE, Balog JZ, Hadley D, Gropman AL, Nandagopal R, Han JC, Hahn JS, Blain D, Brooks B, Muenke M. Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia. Am J Med Genet Part A. 2009;149A:2543–6. [PMC free article: PMC2783496] [PubMed: 19876904]
  83. Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Jancova E, Ciljakova M, Hlava P, Michalek J, Flanagan SE, Pearson E, Hattersley AT, Ellard S, Klimes I. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab. 2007;92:1276–82. [PubMed: 17213273]
  84. Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997a;17:138–9. [PubMed: 9326926]
  85. Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997b;15:106–10. [PubMed: 8988180]
  86. Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A. 2007;104:15040–4. [PMC free article: PMC1986609] [PubMed: 17855560]
  87. Støy J, Greeley SA, Paz VP, Ye H, Pastore AN, Skowron KB, Lipton RB, Cogen FR, Bell GI, Philipson LH., United States Neonatal Diabetes Working Group. Diagnosis and treatment of neonatal diabetes: a United States experience. Pediatr Diabetes. 2008;9:450–9. [PMC free article: PMC2574846] [PubMed: 18662362]
  88. Støy J, Steiner DF, Park S-Y, Ye H, Philipson LH, Bell GI. Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev Endocr Metab Disord. 2010;11:205–15. [PMC free article: PMC2974937] [PubMed: 20938745]
  89. Thurber BW, Carmody D, Tadie EC, Pastore AN, Dickens JT, Wroblewski KE, Naylor RN, Philipson LH, Greeley SAW. Age at time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes. Diabetologia. 2015;58:1430–5. [PMC free article: PMC4641523] [PubMed: 25877689]
  90. Tjora E., Wathle G, Erchinger F, Engjom T, Molven A, Aksnes L, Haldorsen IS, Dimcevski G, Raeder H, Njølstad PR. Exocrine pancreatic function in hepatocyte nuclear factor 1beta-maturity-onset diabetes of the young (HNF1B-MODY) is only moderately reduced: compensatory hypersecretion from a hypoplastic pancreas. Diabet Med. 2013;30:946–55. [PubMed: 23600988]
  91. Turkkahraman D, Bircan I, Tribble ND, Akçurin S, Ellard S, Gloyn AL. Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy. J Pediatr. 2008;153:122–6. [PubMed: 18571549]
  92. Wang J, Cortina G, Wu SV, Tran R, Cho JH, Tsai MJ, Bailey TJ, Jamrich M, Ament ME, Treem WR, Hill ID, Vargas JH, Gershman G, Farmer DG, Reyen L, Martin MG. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. 2006;355:270–80. [PubMed: 16855267]
  93. Wiedemann B, Schober E, Waldhoer T, Koehle J, Flanagan SE, Mackay DJ, Steichen E, Meraner D, Zimmerhackl LB, Hattersley AT, Ellard S, Hofer S. Incidence of neonatal diabetes in Austria-calculation based on the Austrian Diabetes Register. Pediatr Diabetes. 2010;11:18–23. [PubMed: 19496964]
  94. Yasuda T, Kajimoto Y, Fujitani Y, Watada H, Yamamoto S, Watarai T, Umayahara Y, Matsuhisa M, Gorogawa S, Kuwayama Y, Tano Y, Yamasaki Y, Hori M. PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes. 2002;51:224–30. [PubMed: 11756345]
  95. Yorifuji T, Kurokawa K, Mamada M, Imai T, Kawai M, Nishi Y, Shishido S, Hasegawa Y, Nakahata T. Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism. J Clin Endocrinol Metab. 2004;89:2905–8. [PubMed: 15181075]
  96. ZeRuth GT. Takeda Y, Jetten AM. The Krüppel-like protein Gli-similar 3 (Glis3) functions as a key regulator of insulin transcription. Mol Endocrinol. 2013;27:1692–705. [PMC free article: PMC3787130] [PubMed: 23927931]

Suggested Reading

  1. Greeley SA, John PM, Winn AN, Ornelas J, Lipton RB, Philipson LH, Bell GI, Huang ES. The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes. Diabetes Care. 2011;2011;34:622–7. [PMC free article: PMC3041194] [PubMed: 21273495]
  2. Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab. 2008;4:200–13. [PubMed: 18301398]
  3. Rubio-Cabezas O, Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options. Horm Res Paediatr. 2013;80:137–46. [PMC free article: PMC3884170] [PubMed: 24051999]
  4. Shield JP. Neonatal diabetes: new insights into aetiology and implications. Horm Res. 2000;53 Suppl 1:7–11. [PubMed: 10895036]

Chapter Notes

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 to live Web site
  • 9 August 2007 (cas) Original submission
Copyright © 1993-2016, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2016 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1447PMID: 20301620

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...