Permanent Neonatal Diabetes Mellitus

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 age 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and history of intrauterine growth deficiency. Therapy with insulin and/or oral hypoglycemic medications (in some molecular causes of PNDM) can correct the hyperglycemia and result in dramatic catch-up growth. The course of PNDM varies by genotype.

Diagnosis/testing.

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 genetic testing is recommended, as identification of a specific molecular cause of PNMD can guide treatment.

Management.

Targeted therapy: Oral sulfonylureas after initial management with insulin in those with ABCC8- or KCNJ11-related PNDM.

Supportive care: Rehydration and intravenous insulin infusion promptly after diagnosis; subcutaneous insulin therapy when the infant is stable and tolerating oral feedings; high caloric diet to achieve weight gain; developmental and educational support in those with KCNJ11-, MNX1-, NEUROD1-, or NKX2-2-related PNDM; anti-seizure medication as needed in those with DEND syndrome (developmental delay, epilepsy, and neonatal diabetes mellitus); pancreatic enzyme replacement therapy in those with exocrine pancreatic insufficiency.

Surveillance: Frequent blood glucose monitoring; urinalysis for microalbuminuria and cystatin C measurement annually beginning at age ten years to screen for kidney manifestations of persistent hyperglycemia; ophthalmologic examination for retinopathy annually beginning at age ten years; developmental evaluation annually or as needed in those with KCNJ11-, MNX1-, NEUROD1-, or NKX2-2-related PNDM; neurology evaluation and EEG in those with KCNJ11-related DEND syndrome; evaluation of pancreatic exocrine function in those with symptoms of malabsorption; serum concentrations of fat-soluble vitamins every six months in those with known exocrine pancreatic insufficiency.

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.

Evaluation of relatives at risk: Evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and treatment of hyperglycemia.

Pregnancy management: Pregnant women with PNDM should be managed by an endocrinologist and maternal-fetal medicine specialist; high-resolution ultrasonography and fetal echocardiography should be offered during pregnancy to screen for congenital anomalies in the fetus.

Genetic counseling.

The mode of inheritance of PNDM varies by gene: ABCC8- and INS-related PNDM are inherited in an autosomal dominant or an autosomal recessive manner; GATA6-, HNF1B-, and KCNJ11-related PNDM are inherited in an autosomal dominant manner; EIF2AK3-, GCK-, GLIS3-, MNX1-, NEUROD1-, NKX2-2-, PDX1-, PTF1A-, RFX6-, SLC2A2-, and SLC19A2-related PNDM are inherited in an autosomal recessive manner.

Autosomal dominant inheritance: The majority of individuals with autosomal dominant PNDM caused by a heterozygous pathogenic variant in ABCC8, INS, or KCNJ11 have the disorder as the result of a de novo pathogenic variant. Each child of an individual with PNDM inherited in an autosomal dominant manner has a 50% chance of inheriting the PNDM-related pathogenic variant.

Autosomal recessive inheritance: The parents of an individual with PNDM caused by biallelic pathogenic variants are presumed to be heterozygous for a PNDM-related pathogenic variant. The heterozygous parents of a child with autosomal recessive PNDM may or may not have diabetes mellitus. If both parents are known to be heterozygous for a PNDM-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. The heterozygous sibs of a proband with autosomal recessive PNDM may or may not have diabetes mellitus. Heterozygote testing for at-risk relatives requires prior identification of the PNDM-related pathogenic variants in the family.

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

Suggestive Findings

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

Laboratory features

• Persistent hyperglycemia (plasma glucose concentration >250mg/dL) in infants younger than age six months that lasts for longer than seven to ten days [Lemelman et al 2018]
• Features typical of diabetes mellitus (e.g., glucosuria, ketonuria, hyperketonemia)
• Low or undetectable plasma insulin and C peptide relative to the hyperglycemia
• Low fecal elastase and high stool fat in infants with pancreatic aplasia or hypoplasia due to pancreatic exocrine insufficiency [Greeley et al 2022]

Note: Measurement of hemoglobin A1c (HgA1c) 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.

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 (or likely pathogenic) variant(s) in one of the genes listed in Table 1 can guide treatment (see Management).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a variant(s) of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

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

Clinical Description

Diabetes mellitus. 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 age 26 weeks) [Gloyn et al 2004b]. Clinical manifestations at diagnosis include intrauterine growth restriction (IUGR; a reflection of insulin deficiency in utero), hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and poor weight gain.

The diabetes mellitus is associated with partial or complete insulin deficiency. Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth. Many individuals with ABCC8- or KCNJ11-related PNDM have improved glycemic control with sulfonylureas alone or combined with insulin treatment. Long-term follow-up studies of infants diagnosed with ABCC8- or KCNJ11-related PNDM showed that most individuals had good glycemic control on sulfonylureas with HgA1c averaging 5.9%-6.0% and minimal hypoglycemia with an average follow-up time of five to ten years [Bowman et al 2018, Warncke et al 2022].

Reports of microvascular complications vary among cohorts, with 4%-19% of affected individuals reported to have microalbuminuria and 6% reported to have retinopathy. There was no strong evidence that treatment with sulfonylureas was less effective over time, but there was a trend that later initiation of sulfonylurea treatment was associated with the need for combined treatment with insulin.

Phenotype Correlations by Gene

The course of PNDM is highly variable depending on the causative gene. Additional phenotypic features are associated with pathogenic variants in specific genes (see Table 2).

Table 2.

Permanent Neonatal Diabetes Mellitus: Phenotypes by Gene

Genotype-Phenotype Correlations

No genotype-phenotype correlations for EIF2AK3, GATA6, GCK, GLIS3, HNF1B, MNX1, NEUROD1, NKX2-2, PDX1, RFX6, SLC2A2, or SLC19A2 have been identified.

ABCC8. For neonatal diabetes caused by pathogenic variants in ABCC8, genotype-phenotype correlations are less distinct [Edghill et al 2010]. Children with neonatal diabetes associated with autosomal dominant ABCC8 pathogenic variants may have a parent with the same ABCC8 variant and type 2 diabetes, suggesting that the severity of the phenotype and age of onset of diabetes is variable among individuals with ABCC8 pathogenic variants [Babenko et al 2006].

INS. The relationship between genotype and phenotype is beginning to emerge for neonatal diabetes mellitus 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 childhood-onset monogenic diabetes, also called type 1b diabetes mellitus [Støy et al 2010] due to features including absence of evidence of beta cell autoimmunity, low serum C peptide, and insulin dependency.

KCNJ11. Some KCNJ11 pathogenic variants are associated with TNDM; others are associated with PNDM; and two variants, p.Val252Ala and p.Arg201His, are associated with both disorders [Colombo et al 2005, Girard et al 2006]. Furthermore, functional studies have shown some overlap between the magnitude of the K_ATP channel currents in TNDM- and PNDM-associated pathogenic variants [Girard et al 2006, Ashcroft 2023].

The location of the KCNJ11 pathogenic variant can partially predict the severity of the disease, i.e., isolated diabetes mellitus, intermediate DEND (developmental delay, epilepsy, and neonatal diabetes mellitus) syndrome, DEND syndrome; however, there are some exceptions. Studies have evaluated reduction in K_ATP channel ATP sensitivity and its effect on phenotype. 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.

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, Ashcroft 2023].

• 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.Cys166Phe, p.Ile296Val [Gloyn et al 2006], p.Gly334Asp [Masia et al 2007], 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.

PTF1A. Biallelic null variants are associated with pancreatic and cerebellar agenesis. Biallelic pathogenic variants involving the downstream enhancer region are associated with isolated pancreatic agenesis.

Penetrance

Reduced penetrance has been reported in ABCC8- and KCNJ11-related PNDM [Flanagan et al 2007]. Limited data is available regarding the penetrance for other molecular causes of PNDM [De Franco et al 2020c].

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 neonatal diabetes mellitus ranges from 1:90,000 to 1:260,000 live births, 50% being PNDM [Kanakatti Shankar et al 2013, Zhang et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PNDM, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Permanent Neonatal Diabetes Mellitus: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

Permanent Neonatal Diabetes Mellitus: Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

Permanent Neonatal Diabetes Mellitus: Recommended Surveillance

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

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and treatment of hyperglycemia. (Hyperglycemia may be asymptomatic.) Evaluations can include:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Screening with HbA1c or fasting or post-prandial glucose levels may be used to assess for abnormalities in glycemic control if the pathogenic variant(s) in the family are not known. Rarely an oral glucose tolerance test is needed. Continuous glucose monitors to track glucose patterns in relatives of individuals with monogenic forms of diabetes have been used.

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

Pregnancy Management

Pregnant women with PNDM should be managed by an endocrinologist and maternal-fetal medicine specialist. Management should conform to the guidelines for treatment of other forms of diabetes during gestation [American Diabetes Association Professional Practice Committee 2022]. Glycemic control during gestation is important to prevent complications in the mother, fetal overgrowth, and congenital anomalies due to maternal hypo- and hyperglycemia. 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 for diabetes during pregnancy. Although there have been reports supporting the safety and efficacy of glyburide in the treatment of diabetes during pregnancy [Moretti et al 2008], a recent meta-analysis found that glyburide was associated with an increased risk of neonatal hypoglycemia [Guo et al 2019].

Therapies Under Investigation

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

Mode of Inheritance

The mode of inheritance of permanent neonatal diabetes mellitus (PNDM) varies by gene (see Table 8).

Table 8.

Permanent Neonatal Diabetes Mellitus: Mode of Inheritance

If an individual has a specific genetic syndrome associated with PNDM (e.g., Wolcott-Rallison syndrome or thiamine-responsive megaloblastic anemia syndrome), counseling for that condition is indicated.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• The majority of individuals with autosomal dominant PNDM caused by a heterozygous pathogenic variant in ABCC8, INS, or KCNJ11 have the disorder as the result of a de novo pathogenic variant:
  • Most reported individuals with autosomal dominant ABCC8-related PNDM have the disorder as the result of a de novo pathogenic variant [Patch et al 2007].
  • Approximately 73% of individuals with INS-related PNDM [Nishi & Nanjo 2011] and 90% of individuals with KCNJ11-related PNDM [Greeley et al 2022] have the disorder as the result of a de novo pathogenic variant.
• Some individuals with autosomal dominant PNDM have the disorder as the result of a pathogenic variant inherited from a parent.
  • Children with autosomal dominant ABCC8-related PNDM may have a parent diagnosed with type 2 diabetes mellitus who is heterozygous for the same ABCC8 pathogenic variant [Babenko et al 2006].
  • Children with autosomal dominant INS-related PNDM may have a parent with the same INS pathogenic variant and a history of type 2 diabetes mellitus diagnosed in adulthood (although the expected phenotype in a heterozygous parent would be PNDM) [Støy et al 2007].
• Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing.
• If a molecular diagnosis has been established in the proband, the pathogenic variant found in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant;
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Gonadal mosaicism for a pathogenic variant in KCNJ11 has been reported [Gloyn et al 2004a, Edghill et al 2007]; the overall incidence of gonadal mosaicism is unknown. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder in affected family members, reduced penetrance (ABCC8- and KCNJ11-related PNDM), and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate clinical and molecular 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 and/or is known to have the PNDM-related pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If a molecular diagnosis has been established in the proband and the PNDM-related 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 because of the possibility of parental gonadal mosaicism [Gloyn et al 2004a, Edghill et al 2007].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal 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 PNDM-related 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 and/or is known to have the PNDM-related pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with PNDM caused by biallelic pathogenic variants are presumed to be heterozygous for a PNDM-related pathogenic variant.
• Recommendations for the evaluation of parents of a proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing.
• The heterozygous parents of a child with autosomal recessive PNDM may or may not have diabetes mellitus (see Genotype-Phenotype Correlations).
  • In 43% of individuals with ABCC8-related PNDM, the condition is inherited in an autosomal recessive manner from unaffected parents with heterozygous pathogenic variants [Patch et al 2007].
  • INS-related PNDM has also been reported to be inherited in an autosomal recessive manner from unaffected parents [Garin et al 2010]. Heterozygous parents with pathogenic variants in INS that are associated with autosomal recessive PNDM may have adult-onset diabetes mellitus [Raile et al 2011].
  • Individuals who are heterozygous for a pathogenic variant in GCK or PDX1 may have milder forms of diabetes mellitus (GCK- or PDX1-related maturity-onset diabetes of the young [MODY], respectively).

Sibs of a proband

• If both parents are known to be heterozygous for a PNDM-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• The heterozygous sibs of a proband with autosomal recessive PNDM may or may not have diabetes mellitus.
  • Heterozygotes for pathogenic variants in ABCC8 may have normal glucose tolerance.
  • Heterozygotes for pathogenic variants in GCK, INS, or PDX1 may have a milder form of diabetes mellitus (e.g., GCK- or PDX1-related MODY).

Offspring of a proband. The offspring of an individual with PNDM caused by biallelic pathogenic variants are obligate heterozygotes for a PNDM-related pathogenic variant.

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

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

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Referral to a maternal-fetal medicine specialist should be considered for females with PNDM who are pregnant or considering pregnancy (see Pregnancy Management).

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

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Pathogenesis

KCNJ11 and ABCC8 encode the proteins ATP-sensitive inward rectifier potassium channel 11 (Kir6.2) and ATP-binding cassette sub-family C member 8 (SUR1), respectively; both are components of the beta cell K_ATP channel. The K_ATP channel is a hetero-octameric complex with four Kir6.2 subunits forming the central pore, coupled to four SUR1 subunits. The K_ATP 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 hexokinase-4, the increase in the intracellular ATP:ADP ratio results in closure of the K_ATP channels, depolarization of the cell membrane, and subsequent opening of voltage-dependent Ca²⁺ channels. The resulting increase in cytosolic Ca²⁺ concentration triggers insulin release.

Pathogenic variants in either ABCC8 or KCNJ11 result in nonfunctional or dysfunctional K_ATP 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 K_ATP 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 K_ATP current and hyperpolarization of the beta cell plasma membrane with subsequent suppression of Ca²⁺ influx and insulin secretion [Hattersley & Ashcroft 2005].

GCK encodes hexokinase-4 (also called glucokinase), which 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, hexokinase-4 controls the rate-limiting step of glucose metabolism and is responsible for glucose-stimulated insulin secretion [Matschinsky 2002]. GCK pathogenic missense variants alter the kinetics of the enzyme: the glucose S_0.5 is raised, and the ATP K_m 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. 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. The diabetes-associated pathogenic variants lead to the synthesis of a structurally abnormal preproinsulin or proinsulin protein. INS pathogenic variants associated with PNDM disrupt proinsulin folding and/or disulfide bond formation. All of the pathogenic variants are likely to act in a dominant manner to disrupt insulin biosynthesis and induce endoplasmic reticulum (ER) stress.

PDX1 encodes pancreas/duodenum homeobox protein 1 (also known as transcription factor insulin promoter factor 1; PDX1), a master regulator of pancreatic development and of the differentiation of progenitor cells into the beta cell phenotype. In mature beta cells, PDX1 regulates the expression of critical genes including insulin, hexokinase-4, and the glucose transporter encoded by SLC2A2 (solute carrier family 2, facilitated glucose transporter member 2) [Habener et al 2005].

Table 9.

Permanent Neonatal Diabetes Mellitus: Mechanism of Disease Causation

Gene-specific laboratory technical considerations

• PTF1A. Analysis of PTF1A should include sequencing of the downstream enhancer, which accounts for >60% of PNDM-related pathogenic variants in this gene [Demirbilek et al 2020].
• There are no gene-specific laboratory technical considerations for the other genes listed in Table 1.

Author Notes

Dr Sara Pinney (ude.pohc@syennip) is actively involved in clinical research regarding individuals with permanent neonatal diabetes mellitus (PNDM). Dr Pinney would be happy to communicate with persons who have any questions regarding diagnosis of PNDM or other considerations.

Dr Pinney is also interested in hearing from clinicians treating families affected by monogenic diabetes in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Children's Hospital of Philadelphia Monogenic and Atypical Diabetes Program
Phone: 1-215-590-3174

Acknowledgments

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

Author History

Diva D De León, MD (2008-present)
Sara E Pinney, MD, MSTR (2024-present)
Charles A Stanley, MD; Children's Hospital of Philadelphia (2008-2024)

Revision History

• 14 November 2024 (sw) Comprehensive update posted live
• 29 July 2016 (sw) Comprehensive update posted live
• 23 January 2014 (me) Comprehensive update posted live
• 5 July 2011 (me) Comprehensive update posted live
• 8 February 2008 (me) Review posted live
• 9 August 2007 (cas) Original submission

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