DNMT3A overgrowth syndrome

DNMT3A overgrowth syndrome is a rare genetic disorder characterized by rapid pre- and post-natal growth, intellectual disability, and distinct facial features. It is caused by mutations in the DNMT3A gene, which disrupts normal DNA methylation during development.

Overview

DNMT3A overgrowth syndrome is a disorder characterized by faster than normal growth before and after birth, subtle differences in facial features, and intellectual disability.

Symptoms and Characteristics

Individuals with DNMT3A overgrowth syndrome present with a variety of physical, intellectual, and psychological features:

• Overgrowth: Affected individuals are often longer than normal at birth and remain taller than their peers throughout life. Many become overweight in late childhood or adolescence.
• Head and Facial Features: An abnormally large head size (macrocephaly), a prominent forehead, thick horizontal eyebrows, narrowed openings of the eyes (narrowed palpebral fissures), and upper front teeth that are often larger than normal.
• Intellectual and Developmental Features: Intellectual disability ranging from mild to severe. Some individuals exhibit features of autism spectrum disorder, which are characterized by impaired communication and socialization skills.
• Skeletal and Muscular Features: A rounded upper back that also curves to the side (kyphoscoliosis), flat feet (pes planus), weak muscle tone (hypotonia), and loose, highly flexible joints (joint hypermobility).
• Other Medical and Psychological Features: Heart defects and psychological disorders such as depression, anxiety, or obsessive-compulsive disorder.

Frequency

The prevalence of DNMT3A overgrowth syndrome is unknown. More than 20 affected individuals have been described in the medical literature.

Causes

Mutations in the DNMT3A gene cause DNMT3A overgrowth syndrome. The gene provides instructions for making an enzyme called DNA methyltransferase 3 alpha, which is involved in DNA methylation (the addition of methyl groups to DNA molecules).

DNA methylation is important for many cellular functions, including regulating gene activity, controlling chemical reactions, and processing neurotransmitters in the nervous system. The enzyme is particularly important for establishing DNA methylation patterns during development before birth.

Some mutations that cause this syndrome lead to a decrease in normal enzyme function, resulting in reduced DNA methylation before birth. It is unclear how other mutations affect protein function. This decreased DNA methylation likely disrupts the normal regulation of important developmental genes, though the exact mechanism causing the specific features of the syndrome remains unknown.

Associated Gene

• DNMT3A

Inheritance Pattern

This condition is inherited in an autosomal dominant pattern, meaning one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from an affected parent. Other cases result from new mutations (de novo) and occur in people with no history of the disorder in their family.

Other Names for This Condition

• Tatton-Brown-Rahman syndrome
• TBRS