[[File:Autosomal dominant - en.svg|thumb|right|Diagram of autosomal dominant inheritance, which is relevant for some genetic causes of TNDM.]]
'''Transient Neonatal Diabetes Mellitus''' (TNDM) is a rare form of diabetes that occurs in newborns. It is characterized by hyperglycemia that typically resolves within the first few months of life, although it may recur later in life. TNDM is distinct from [[Permanent Neonatal Diabetes Mellitus]] (PNDM), which does not resolve.
==Clinical features==
== Causes ==
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.
TNDM is often caused by genetic abnormalities. The most common genetic cause is an abnormality in the [[imprinting]] of chromosome 6q24. This can involve paternal uniparental disomy, duplication of the paternal allele, or loss of maternal methylation. Other genetic mutations, such as those affecting the [[KCNJ11]] or [[ABCC8]] genes, can also lead to TNDM.
Affected individuals have slow growth before birth followed by [[hyperglycemia]], dehydration and failure to thrive in infancy.
==Types==
== Symptoms ==
Symptoms of TNDM include:
{| class="wikitable"
* Hyperglycemia
|-
! Type
! [[OMIM]]
! Gene
! Locus
! Description
|-
| TNDM1
| {{OMIM|601410||none}}
| [[ZFP57]], [[PLAGL1]]
| 6p22.1, 6q24.2
|
|-
| TNDM2
| {{OMIM|610374||none}}
| [[ABCC8]]
| 11p15.1
| Due to the mutations of the other subunit of the K<sub>ATP</sub> channel, SUR1, which is encoded by the [[ABCC8]] gene.<ref name="pmid18497752">{{cite journal |vauthors=de Wet H, Proks P, Lafond M, etal |title=A mutation (R826W) in nucleotide-binding domain 1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes |journal=EMBO Rep. |volume= 9|issue= 7|pages= 648–54|date=May 2008 |pmid=18497752 |doi=10.1038/embor.2008.71 |pmc=2475326}}</ref>
|-
| TNDM3
| {{OMIM|610582||none}}
| [[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.
* 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
* Dehydration
* Plasma [[insulin]] concentrations that are low in the presence of high serum glucose concentrations
* Failure to thrive
* Absence of [[ketoacidosis]]. Ketones are usually not present in the urine.
* Glycosuria
* 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''' ==
These symptoms typically appear within the first week of life.
'''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.
== Diagnosis ==
Diagnosis of TNDM is based on clinical presentation and laboratory tests showing elevated blood glucose levels. Genetic testing can confirm the diagnosis by identifying abnormalities in chromosome 6q24 or other related genetic mutations.
'''Surveillance:''' Periodic glucose tolerance tests (abnormalities suggest future recurrence); monitoring of growth and development.
== Treatment ==
Management of TNDM involves controlling blood glucose levels, often with insulin therapy. The condition usually resolves spontaneously within the first few months of life, but monitoring is essential to manage any recurrence of diabetes later in life.
'''Agents/circumstances to avoid:''' Factors that predispose to late-onset diabetes or risk factors for cardiovascular disease.
== Prognosis ==
The prognosis for infants with TNDM is generally good, as the condition resolves in most cases. However, there is a risk of developing type 2 diabetes or other forms of diabetes later in life, so long-term follow-up is recommended.
Diagram of autosomal dominant inheritance, which is relevant for some genetic causes of TNDM.
Transient Neonatal Diabetes Mellitus (TNDM) is a rare form of diabetes that occurs in newborns. It is characterized by hyperglycemia that typically resolves within the first few months of life, although it may recur later in life. TNDM is distinct from Permanent Neonatal Diabetes Mellitus (PNDM), which does not resolve.
Causes
TNDM is often caused by genetic abnormalities. The most common genetic cause is an abnormality in the imprinting of chromosome 6q24. This can involve paternal uniparental disomy, duplication of the paternal allele, or loss of maternal methylation. Other genetic mutations, such as those affecting the KCNJ11 or ABCC8 genes, can also lead to TNDM.
Symptoms
Symptoms of TNDM include:
Hyperglycemia
Dehydration
Failure to thrive
Glycosuria
These symptoms typically appear within the first week of life.
Diagnosis
Diagnosis of TNDM is based on clinical presentation and laboratory tests showing elevated blood glucose levels. Genetic testing can confirm the diagnosis by identifying abnormalities in chromosome 6q24 or other related genetic mutations.
Treatment
Management of TNDM involves controlling blood glucose levels, often with insulin therapy. The condition usually resolves spontaneously within the first few months of life, but monitoring is essential to manage any recurrence of diabetes later in life.
Prognosis
The prognosis for infants with TNDM is generally good, as the condition resolves in most cases. However, there is a risk of developing type 2 diabetes or other forms of diabetes later in life, so long-term follow-up is recommended.
