6q24-related transient neonatal diabetes mellitus
6q24-related transient neonatal diabetes mellitus is an infant-onset form of diabetes caused by the overactivity of specific genes on chromosome 6, typically resolving within the first 18 months of life.
Overview
This condition is characterized by high blood sugar levels (hyperglycemia) due to a shortage of insulin. Infants often experience severe intrauterine growth retardation and, beginning in the first week of life, hyperglycemia and excessive fluid loss (dehydration). While symptoms generally disappear between 3 and 18 months of age, diabetes may recur during childhood illnesses or pregnancy, and up to half of affected individuals develop permanent diabetes later in life.
Additional Features
Some individuals may also exhibit:
- An unusually large tongue (macroglossia).
- A soft out-pouching around the belly-button (umbilical hernia).
- Malformations of the brain, heart, or kidneys.
- Weak muscle tone (hypotonia), deafness, and developmental delay.
Causes
The disorder is caused by the overactivity (overexpression) of paternally expressed imprinted genes in the 6q24 region of chromosome 6, particularly the PLAGL1 gene. Normally, these genes are active only when inherited from the father, while the maternal copy is silenced by methylation. Overexpression occurs via three mechanisms:
- Paternal uniparental disomy (UPD): Inheriting both copies of chromosome 6 from the father.
- Paternal duplication: A duplication of the 6q24 region on the paternal chromosome.
- Maternal hypomethylation: Impaired silencing of the maternal copy of the genes, sometimes linked to ZFP57 gene mutations.
Inheritance
Most cases are not inherited and occur as random events. However, some cases involving paternal duplications can be passed through generations. When caused by ZFP57 mutations, the condition is inherited in an autosomal recessive pattern, where both parents are typically asymptomatic carriers.