Clinical Diagnosis

Permanent neonatal diabetes mellitus (PNDM) is defined as diabetes mellitus diagnosed in the first six months of life that does not resolve over time.

Testing

Laboratory testing. Diagnosis of PNDM is based on evidence of persistent hyperglycemia (plasma glucose concentration >150-200 mg/dL) in infants younger than age six months.

Other typical laboratory findings of diabetes mellitus (e.g., glucosuria, ketonuria, hyperketonemia) may be present.

Pancreatic imaging. Imaging of the pancreas with ultrasound or CT is used to determine its presence and size.

Molecular Genetic Testing

Genes. The five genes in which mutations are currently known to cause nonsyndromic permanent neonatal diabetes are KCNJ11, ABCC8, INS, GCK, and PDX1.

• KCNJ11. Approximately 30% of PNDM is attributed to activating mutations of KCNJ11, the gene encoding one of the two components of the beta-cell plasma membrane ATP-dependent potassium channel [Ellard et al 2007].
• ABCC8. Approximately 19% of PNDM is attributed to activating mutations of ABCC8, the gene encoding the second of the two components of the beta-cell plasma membrane ATP-dependent potassium channel [Babenko et al 2006].
• INS. Approximately 20% of PNDM is attributed to mutations in INS, the gene encoding insulin [Støy et al 2007, Polak et al 2008].
• GCK. Rarely, PNDM is attributed to inactivating mutations of GCK, the gene encoding glucokinase (hexokinase IV) [Njolstad et al 2001, Njolstad et al 2003]. Carrier parents have mild diabetes mellitus or glucose intolerance (GCK-familial monogenic diabetes, previously known as MODY2).
• PDX1. Rarely, PNDM is attributed to inactivating mutations of PDX1 [Stoffers et al 1997a]. Carrier parents have mild, adult-onset diabetes mellitus (PDX1-familial monogenic diabetes, previously known as MODY4).

Note: Rare syndromic forms of neonatal diabetes can be caused by mutations in FOXP3, PTF1A, GLIS3, NEUROD1, RFX6, NEUROG3, and EIF2AK3 (see Differential Diagnosis).

Clinical testing

• Sequence analysis. Clinical testing by sequencing of coding regions of the following genes is available: KCNJ11, ABCC8, GCK, INS, and PDX1.
• Deletion/duplication analysis is available clinically for ABCC8 and GCK. However, the usefulness of such testing has not been demonstrated, as no deletions or duplications involving ABCC8 or GCK as causative of permanent neonatal diabetes mellitus have been reported.

Table 1. Summary of Molecular Genetic Testing Used in Permanent Neonatal Diabetes Mellitus

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Gene Symbol	Estimated Proportion of PNDM Attributed to Mutations in This Gene	Test Method	Mutations Detected	Test Availability
KCNJ11	30% 1	Sequence analysis	Sequence variants 2	Clinical
ABCC8	19% 3	Sequence analysis	Sequence variants 2	Clinical
		Deletion / duplication analysis 4	Exonic and whole-gene deletions
INS	20% 5	Sequence analysis	Sequence variants 2	Clinical
GCK	4% 6	Sequence analysis	Sequence variants 2	Clinical
		Deletion / duplication analysis 4	Exonic and whole-gene deletions
PDX1	<1% 7	Sequence analysis	Sequence variants 2	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Approximately 30% of PNDM is attributed to activating mutations of KCNJ11, the gene encoding one of the two components of the beta-cell plasma membrane ATP-dependent potassium channel [Ellard et al 2007].

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Approximately 19% of PNDM is attributed to activating mutations of ABCC8, the gene encoding the second of the two components of the beta-cell plasma membrane ATP-dependent potassium channel [Babenko et al 2006].

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH. 

5. Approximately 20% of PNDM is attributed to mutations in INS, the gene encoding insulin [Støy et al 2007, Polak et al 2008].

6. Rarely, PNDM is attributed to inactivating mutations of GCK, the gene encoding glucokinase (hexokinase IV) [Njolstad et al 2001, Njolstad et al 2003]. Carrier parents have mild diabetes mellitus or glucose intolerance (GCK-familial monogenic diabetes, previously known as MODY2).

7. Rarely, PNDM is attributed to inactivating mutations of PDX1 [Stoffers et al 1997a]. Carrier parents have mild, adult-onset diabetes mellitus (PDX1-familial monogenic diabetes, previously known as MODY4).

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Individuals with one parent with diabetes mellitus should first be tested for mutations in KCNJ11 and then ABCC8 and INS because heterozygotes can manifest diabetes mellitus.
• Individuals with neurologic findings suggestive of developmental delay, epilepsy, and neonatal diabetes mellitus (DEND) syndrome should first be tested for mutations in KCNJ11.
• Individuals whose parents both have diabetes mellitus should first be tested for mutations in GCK and PDX1, as individuals heterozygous for a mutation in these genes can have mild diabetes mellitus (GCK-familial monogenic diabetes and PDX1-familial monogenic diabetes, respectively) with onset in adolescence or early adulthood.
• Individuals with pancreatic insufficiency or agenesis should be tested for mutations in PDX1.
• For individuals with syndromic PNDM, the extrapancreatic characteristics should guide genetic testing. Individuals with PNDM and:
  • Enteropathy and dermatitis should be tested for mutations in FOXP3 (IPEX syndrome);
  • Cerebellar involvement should be tested for mutations in PTF1A;
  • Congenital hypothyroidism should be tested for mutations in GLIS3;
  • Cerebellar hypoplasia, sensorineural deafness, and visual impairment should be tested for mutations in NEUROD1;
  • Pancreatic hypoplasia, intestinal atresia, and gall bladder hypoplasia should be tested for mutations in RFX6;
  • Congenital malabsorptive diarrhea should be tested for mutations in NEUROG3.
• Molecular genetic testing to diagnose individuals with PNDM or transient neonatal diabetes mellitus (TNDM) as a result of mutations of KCNJ11 and ABCC8 can guide treatment as individuals with these mutations may respond to therapy with oral sulfonylureas. Oral sulfonylureas are associated with fewer episodes of hypoglycemia than traditional treatment with insulin and may, in addition to treating the diabetes, improve neurologic manifestations if present [Hattersley et al 2006, Pearson et al 2006, Slingerland et al 2006] (see Management).
• Molecular genetic testing to diagnose individuals with mutations of GCK, INS, and PDX1 can be used to confirm the diagnosis of NDM and for prognostication regarding need for treatment and risk for exocrine pancreatic insufficiency.

For autosomal recessive PNDM,* carrier testing for relatives at risk of being carriers (i.e., heterozygous for a mutation that is not disease-causing) requires prior identification of the disease-causing mutations in the family.

*The mode of inheritance of PNDM is autosomal recessive for mutations in GCK and PDX1 and can be either autosomal dominant or autosomal recessive for mutations in ABCC8 and INS.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation(s) in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

KCNJ11, ABCC8, and GCK. Mutations in KCNJ11, ABCC8, and GCK are known to be associated with familial hyperinsulinism (FHI). FHI is characterized by hypoglycemia that ranges from severe difficult-to-manage neonatal-onset disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to one to two days after birth; childhood-onset disease manifests during the first months or years of life.

FHI-K_ATP, caused by mutations in either KCNJ11 or ABCC8, is most commonly inherited in an autosomal recessive manner and less commonly in an autosomal dominant manner.

• Infants with autosomal recessive FHI-K_ATP tend to be large for gestational age and usually present with severe refractory hypoglycemia in the first 48 hours of life; they usually respond only partially to medical management (i.e., diazoxide therapy) and thus may require pancreatic resection.
• The two distinct histologic forms of FHI-K_ATP- are diffuse hyperinsulinism and focal hyperinsulinism:
  • In diffuse hyperinsulinism, beta cells throughout the pancreas are functionally abnormal; approximately 2%-5% of cells have characteristic enlarged nuclei [De León & Stanley 2007].
  • Focal hyperinsulinism accounts for approximately 40%-60% of all cases. In focal hyperinsulinism, a somatic reduction to homozygosity (or hemizygosity) of a paternally inherited mutation of KCNJ11 or ABCC8 and a specific loss of maternal alleles of the imprinted chromosome region 11p15 result in a focal lesion composed of hyperplastic islet cell clusters of clonal origin (focal adenomatosis) [De León & Stanley 2007]. Focal pancreatic lesions can be cured by surgical resection.

FHI-GCK, caused by mutations in GCK is inherited in an autosomal dominant manner. Infants with FHI-GCK tend to be appropriate for gestational age at birth and present at about age one year (range: 2 days to 30 years).

KCNJ11 and ABCC8

• Normal variants in KCNJ11 and ABCC8, particularly the p.Glu23Lys polymorphism in KCNJ11, have been associated with type 2 diabetes mellitus [Hani et al 1998, Gloyn et al 2001, Hansen et al 2001, 't Hart et al 2002, Gloyn et al 2003, Nielsen et al 2003, Florez et al 2004].
• Activating mutations in KCNJ11 and ABCC8 with less severe effects on channel function have been found to cause TNDM that is similar to the biphasic course seen in the 6q24 phenotype. Typically, infants with TNDM caused by K_ATP channel mutations present before age six months, then go into remission between ages six and 12 months and are likely to relapse during adolescence or early adulthood [Gloyn et al 2005, Flanagan et al 2007].

ABCC8. A dominant ABCC8 mutation is associated with hyperinsulinemic hypoglycemia in the neonatal period and diabetes mellitus later in life [Huopio et al 2003].

INS. Heterozygous mutations in INS have been reported in individuals with infancy-onset diabetes, type 1b diabetes, familial monogenic diabetes and early-onset type 2 diabetes [Støy et al 2010].

GCK. Dominant inactivating mutations of GCK are associated with GCK-familial monogenic diabetes, a mild form of diabetes mellitus presenting later in life.

PDX1. Dominant inactivating mutations of PDX1 are associated with PDX1-familial monogenic diabetes, a mild form of diabetes mellitus.

Natural History

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.

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

KCNJ11 and ABCC8. Most individuals with PNDM caused by mutations in KCNJ11 and ABCC8 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 cases ketoacidosis.

Although most individuals with mutations in KCNJ11 have isolated diabetes, 20% have associated neurologic features, the most severe of which are generalized epilepsy, and marked delay of motor and social development [Hattersley et al 2006]. This syndrome is known as DEND (developmental delay, epilepsy, neonatal diabetes) [Gloyn et al 2004b]. A milder form, called intermediate DEND syndrome, presents with less severe developmental delay and without epilepsy. In individuals with KCNJ11 mutations, 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] (see Management).

INS. PNDM caused by heterozygous INS mutations presents 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].

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

PDX1. Pancreatic hypoplasia caused by homozygous PDX1 mutations results in a more severe insulin deficiency than in K_ATP or GCK-related neonatal diabetes as shown by a lower birth weight and a younger age at diagnosis. In addition these individuals have exocrine pancreatic insufficiency.

Genotype-Phenotype Correlations

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

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

Some KCNJ11 mutations are associated with TNDM; others are associated with PNDM; and two mutations, 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 mutations [Girard et al 2006].

The location of the mutation seems to predict the severity of the disease (isolated diabetes mellitus, intermediate DEND syndrome, DEND syndrome). Mutations 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 subunits.

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

• Of 24 individuals with mutations at the arginine residue, Arg201, all but three had isolated PNDM.
• The p.Val59Met mutation is associated with intermediate DEND syndrome.
• The following mutations associated with full DEND syndrome are not found in less severely affected individuals: p.Gln52Arg, p.Val59Gly, p.Ile296Val, p.Cys166Phe [Gloyn et al 2006]; p.Gly334Asp [Masia et al 2007b]; p.Ile167Leu [Shimomura et al 2007]; p.Gly53Asp, p.Cys166Tyr, p.Ile296Leu [Flanagan et al 2006] (see Table 2).
• Improvement of the neurologic features of DEND syndrome with sulfonylurea treatment also seems to be genotype dependent: children with the mutations p.Val59Met [Støy et al 2008, Mohamadi et al 2010] and p.Gly53Asp [Koster et al 2008] have been shown to respond to sulfonylureas (see Table 2).

For neonatal diabetes caused by ABCC8 mutations, genotype-phenotype correlations are less distinct [Edghill et al 2010].

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

Penetrance

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

Nomenclature

As some cases of "neonatal" diabetes mellitus may not be recognized until age three to six months, it has been suggested that the term "diabetes mellitus of infancy" should replace the designation "neonatal diabetes mellitus" [Massa et al 2005].

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, Wiedermann et al 2010].

Evaluations Following Initial Diagnosis

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

To establish the extent of disease in an individual with suspected or confirmed mutations in PDX1, imaging of the pancreas and evaluation of pancreatic exocrine function should be performed.

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 newer, longer-acting preparations with no peak-of-action effect such as Lantus^® (glargine) may work better in small infants.
• 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 mutation is important for clinical management since most individuals with these mutations can be treated with oral sulfonylureas. Children with mutations 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). Treatment with sulfonylureas is associated with improved glycemic control [Hattersley & Ashcroft 2005, Pearson et al 2006].

Long-term insulin therapy is required for all other causes of PNDM, although mild beneficial effect of oral sulfonylureas in persons with GCK mutations 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 Primary Manifestations

Several case reports have demonstrated measurable improvement in neurodevelopmental outcome in children with DEND syndrome treated with sulfonylureas. These reports raise the possibility that neurologic manifestations can be prevented by early treatment with these agents [Greeley et al 2010].

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. Given the increased risk and vulnerability to hypoglycemia in young children, the American Diabetes Association recommends the following:

• Glycemic targets for children younger than age six years:
  • 100-180 mg/dL before meals
  • 110-200 mg/dL at bedtime/overnight
• Hemoglobin A1c value between 7.5% and 8.5% [Silverstein et al 2005]

Surveillance

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

Children with PNDM, particularly those with a mutation 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:

• Screening 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.

Testing of Relatives at Risk

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

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

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

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

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

• Approximately 10% of individuals with autosomal dominant neonatal diabetes mellitus caused by mutations in KCNJ11 and 27% of individuals with autosomal dominant neonatal diabetes mellitus caused by INS have an affected parent. In contrast, no families with dominantly inherited ABCC8-related PNDM have been described [Patch et al 2007].
• A proband with autosomal dominant neonatal diabetes mellitus may have the disorder as the result of a new mutation. The proportion of cases caused by de novo mutations in KCNJ11 and INS is estimated at 90% and 73%, respectively. De novo mutations account for all reported cases of heterozygous ABCC8-related PNDM [Patch et al 2007].
• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Germline mosaicism for a mutation in KCNJ11 has been reported [Gloyn et al 2004a, Edghill et al 2007]; the overall incidence of germline mosaicism is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation in KCNJ11, ABCC8, or INS include molecular genetic testing, and clinical testing for diabetes mellitus (oral glucose tolerance testing). 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.

Note: Although approximately 10% of individuals diagnosed with PNDM inherited in an autosomal dominant manner have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

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 disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because germline mosaicism has been reported in this condition.

Offspring of a proband. Each child of an individual with PNDM inherited in an autosomal dominant manner has a 50% chance of inheriting the mutation.

Other family members of a proband. 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

• In 43% of cases, ABCC8-related PNDM is inherited in an autosomal recessive manner from unaffected parents with heterozygous mutations [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].
• The parents of a child with autosomal recessive PNDM are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) for mutations in GCK and PDX1 have a milder form of diabetes mellitus (GCK-familial monogenic diabetes and PDX1-familial monogenic diabetes, respectively). However, heterozygotes (carriers) for mutations in INS associated with recessively inherited NDM have normal glucose tolerance [Garin et al 2010].

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (or having familial monogenic diabetes, previously known as MODY), and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) for mutations in GCK and PDX1 have a milder form of diabetes mellitus (GCK-familial monogenic diabetes, previously known as MODY2, and PDX1-familial monogenic diabetes, previously known as MODY4).

Offspring of a proband. The offspring of an individual with autosomal recessive neonatal diabetes mellitus are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is available once the mutations have been identified in the family.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for permanent neonatal diabetes mellitus is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) must be identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like PNDM) do not affect intellect and have treatment available are not common. 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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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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;34:622–7. [PMC free article: PMC3041194] [PubMed: 21273495]
2. 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]
3. 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]
4. Shield JP. Neonatal diabetes: new insights into aetiology and implications. Horm Res. 2000;53 Suppl 1:7–11. [PubMed: 10895036]

Acknowledgments

The authors receive grant support from NIH grants K23-DK073663 (DDDL); and R01DK53012 and R01DK56268 (CAS).

Revision History

• 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