Transient neonatal diabetes

Alternate names

TNDM1; TNDM; DMTN; Diabetes mellitus, transient neonatal; Chromosome 6-associated transient diabetes mellitus; Diabetes mellitus, 6q24-related transient neonatal

Clinical features

This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Affected individuals have slow growth before birth followed by hyperglycemia, dehydration and failure to thrive in infancy.

Types

Type	OMIM	Gene	Locus	Description
TNDM1	Online Mendelian Inheritance in Man (OMIM) 601410	ZFP57, PLAGL1	6p22.1, 6q24.2
TNDM2	Online Mendelian Inheritance in Man (OMIM) 610374	ABCC8	11p15.1	Due to the mutations of the other subunit of the KATP channel, SUR1, which is encoded by the ABCC8 gene.
TNDM3	Online Mendelian Inheritance in Man (OMIM) 610582	KCNJ11	11p15.1

Epidemiology

Between 1 in 215,000 and 1 in 400,000 babies are born with diabetes mellitus. In about half of these babies, the diabetes is transient. Researchers estimate that approximately 70 percent of transient diabetes in newborns is caused by 6q24-related transient neonatal diabetes mellitus.

Cause

6q24-related transient neonatal diabetes mellitus is caused by the overactivity (overexpression) of certain genes in a region of the long (q) arm of chromosome 6 called 6q24. People inherit two copies of their genes, one from their mother and one from their father. Usually both copies of each gene are active, or "turned on," in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person's father; others are active only when inherited from a person's mother. This phenomenon is known as genomic imprinting.

The 6q24 region includes paternally expressed imprinted genes, which means that normally only the copy of each gene that comes from the father is active. The copy of each gene that comes from the mother is inactivated (silenced) by a mechanism called methylation.

Overactivity of one of the paternally expressed imprinted genes in this region, PLAGL1, is believed to cause 6q24-related transient neonatal diabetes mellitus. Other paternally expressed imprinted genes in the region, some of which have not been identified, may also be involved in this disorder.

There are three ways that overexpression of imprinted genes in the 6q24 region can occur. About 40 percent of cases of 6q24-related transient neonatal diabetes mellitus are caused by a genetic change known as paternal uniparental disomy (UPD) of chromosome 6. In paternal UPD, people inherit both copies of the affected chromosome from their father instead of one copy from each parent. Paternal UPD causes people to have two active copies of paternally expressed imprinted genes, rather than one active copy from the father and one inactive copy from the mother.

Another 40 percent of cases of 6q24-related transient neonatal diabetes mellitus occur when the copy of chromosome 6 that comes from the father has a duplication of genetic material including the paternally expressed imprinted genes in the 6q24 region.

The third mechanism by which overexpression of genes in the 6q24 region can occur is by impaired silencing of the maternal copy of the genes (maternal hypomethylation). Approximately 20 percent of cases of 6q24-related transient neonatal diabetes mellitus are caused by maternal hypomethylation. Some people with this disorder have a genetic change in the maternal copy of the 6q24 region that prevents genes in that region from being silenced. Other affected individuals have a more generalized impairment of gene silencing involving many imprinted regions, called hypomethylation of imprinted loci (HIL).

About half the time, HIL is caused by mutations in the ZFP57 gene. Studies indicate that the protein produced from this gene is important in establishing and maintaining gene silencing. The other causes of HIL are unknown. Because HIL can cause overexpression of many genes, this mechanism may account for the additional health problems that occur in some people with 6q24-related transient neonatal diabetes mellitus.

It is not well understood how overexpression of PLAGL1 and other genes in the 6q24 region causes 6q24-related transient neonatal diabetes mellitus and why the condition improves after infancy. The protein produced from the PLAGL1 gene helps control another protein called the pituitary adenylate cyclase-activating polypeptide receptor (PACAP1), and one of the functions of this protein is to stimulate insulin secretion by beta cells in the pancreas. In addition, overexpression of the PLAGL1 protein has been shown to stop the cycle of cell division and lead to the self-destruction of cells (apoptosis). Researchers suggest that PLAGL1 gene overexpression may reduce the number of insulin-secreting beta cells or impair their function in affected individuals.

Lack of sufficient insulin results in the signs and symptoms of diabetes mellitus. In individuals with 6q24-related transient neonatal diabetes mellitus, these signs and symptoms are most likely to occur during times of physiologic stress, including the rapid growth of infancy, childhood illnesses, and pregnancy. Because insulin acts as a growth promoter during early development, a shortage of this hormone may account for the intrauterine growth retardation seen in 6q24-related transient neonatal diabetes mellitus.

Inheritance

Most cases of 6q24-related transient neonatal diabetes mellitus are not inherited, particularly those caused by paternal uniparental disomy. In these cases, genetic changes occur as random events during the formation of reproductive cells (eggs and sperm) or in early embryonic development. Affected people typically have no history of the disorder in their family.

Sometimes, the genetic change responsible for 6q24-related transient neonatal diabetes mellitus is inherited. For example, a duplication of genetic material on the paternal chromosome 6 can be passed from one generation to the next.

When 6q24-related transient neonatal diabetes mellitus is caused by ZFP57 gene mutations, it is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

People with 6q24-related transient neonatal diabetes mellitus experience very slow growth before birth (severe intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration), usually beginning in the first week of life. Signs and symptoms of this form of diabetes are transient, which means that they gradually lessen over time and generally disappear between the ages of 3 months and 18 months. Diabetes may recur, however, especially during childhood illnesses or pregnancy. Up to half of individuals with 6q24-related transient neonatal diabetes mellitus develop permanent diabetes mellitus later in life.

Other features of 6q24-related transient neonatal diabetes mellitus that occur in some affected individuals include an unusually large tongue (macroglossia); a soft out-pouching around the belly-button (an umbilical hernia); malformations of the brain, heart, or kidneys; weak muscle tone (hypotonia); deafness; and developmental delay.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of the pancreatic islet cells
• Dehydration
• Failure to thrive(Faltering weight)
• Glycosuria(Glucose in urine)
• Hyperglycemia(High blood sugar)
• Hypovolemia(Depleted blood volume)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Transient neonatal diabetes mellitus
• Weight loss

30%-79% of people have these symptoms

• Arthrogryposis multiplex congenita
• Bilateral ptosis(Drooping of both upper eyelids)
• Contractures of the joints of the lower limbs
• Downturned corners of mouth(Downturned corners of the mouth)
• Global developmental delay
• Intellectual disability(Mental deficiency)
• Ketonuria
• Motor delay
• Prominent metopic ridge

5%-29% of people have these symptoms

• Abnormal heart morphology(Abnormality of the heart)
• Apraxia
• Bilateral tonic-clonic seizure(Grand mal seizures)
• Coma
• Generalized myoclonic seizure
• Hearing impairment(Deafness)
• Muscular hypotonia(Low or weak muscle tone)
• Neonatal onset
• Renal tubular dysfunction(Abnormal function of filtrating structures in kidney)
• Steatorrhea(Fat in feces)

1%-4% of people have these symptoms

• Type II diabetes mellitus(Noninsulin-dependent diabetes)

Diagnosis

Diagnosis of 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) should be suspected in individuals with the following clinical features:

• Severe intrauterine growth restriction
• Diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months. Presentation includes the following:
• Hyperglycemia
• Dehydration
• Plasma insulin concentrations that are low in the presence of high serum glucose concentrations
• Absence of ketoacidosis. Ketones are usually not present in the urine.
• Absence of islet cell antibodies
• Presence of a pancreas

Transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the PLAGL1 TSS alt-DMR, through one of the following mechanisms:

• Partial or complete paternal uniparental disomy of chromosome 6
• Paternal duplication of 6q24
• Hypomethylation of the maternal PLAGL1 TSS alt-DMR

Biallelic pathogenic variants in ZFP57 identified on molecular genetic testing.

Treatment

Treatment of manifestations: Rehydration and IV insulin are usually required at the time of diagnosis; subcutaneous insulin is introduced as soon as possible and used until blood glucose levels stabilize. Later recurrence of diabetes may require diet modifications alone, oral agents, or insulin.

Prevention of secondary complications: Prompt treatment of dehydration to avoid sequelae.

Surveillance: Periodic glucose tolerance tests (abnormalities suggest future recurrence); monitoring of growth and development.

Agents/circumstances to avoid: Factors that predispose to late-onset diabetes or risk factors for cardiovascular disease.

NIH genetic and rare disease info

• NIH info on Transient neonatal diabetes

Transient neonatal diabetes is a rare disease.

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