Tatton-Brown-Rahman Syndrome

A number sign (#) is used with this entry because Tatton-Brown-Rahman syndrome (TBRS) is caused by heterozygous mutation in the DNMT3A gene (602769) on chromosome 2p23.

Description

Tatton-Brown-Rahman syndrome is characterized by tall stature, a distinctive facial appearance, and intellectual disability (Tatton-Brown et al., 2014).

Clinical Features

Tatton-Brown et al. (2014) reported 13 unrelated patients with a similar phenotype characterized by tall stature (mean of +3.0 SD), large head circumference (mean of +2.5 SD), and a facial gestalt manifest as round face, heavy horizontal eyebrows, and narrow palpebral fissures. Intellectual disability was described as moderate in 11 patients and mild in 2 patients. Less common and variable features included atrial septal defects, seizures, umbilical hernia, and scoliosis. None of the patients had a hematologic malignancy. Tatton-Brown et al. (2014) proposed the term 'DNMT3A overgrowth syndrome' to refer to the disorder.

Kosaki et al. (2017) reported a 6-year-old girl, born of healthy nonconsanguineous parents, with Tatton-Brown-Rahman syndrome. Her characteristic features at birth included hypotonia, ventricular septal defect, umbilical hernia, sacral cyst, and Chiari type I anomaly. She had a round face, hypertelorism, narrow palpebral fissures, short upturned nose, deep philtrum, protruding upper lip, and short columella. At age 6 years, she exhibited overgrowth (+3 SD) and intellectual disability.

Shen et al. (2017) reported 3 additional patients with Tatton-Brown-Rahman syndrome. Patients 1 and 2 had characteristic features of the disorder, including moderate intellectual disability (IQ, 40 and 50), tall stature, and a long oval-shaped face with heavy eyebrows and narrow palpebral fissures. Patient 3 had atypical features, including severe intellectual disability, short stature, and coarse facies with long palpebral fissures, low-set ears and a prominent chin. The authors suggested that the atypical presentation of patient 3 may have resulted from his complicated prenatal history (maternal diabetes, polyhydramnios, premature rupture of membranes, preterm delivery) and hydrocephaly in early infancy.

Molecular Genetics

In 13 unrelated patients with tall stature, distinctive facies, and intellectual disability, Tatton-Brown et al. (2014) identified 13 different de novo heterozygous mutations in the DNMT3A gene (see, e.g., 602769.0001-602769.0005). The first 2 mutations were found by exome sequencing of 10 patients with an overgrowth disorder, and the subsequent 11 mutations were found by sequencing the DNMT3A gene in 152 patients with an overgrowth disorder. The mutations altered residues in functional domains of the protein, and protein modeling suggested that they may interfere with domain-domain interactions and histone binding, thereby disrupting de novo methylation. However, in vitro functional studies were not performed.

In a 6-year-old girl with TBRS, Kosaki et al. (2017) identified a heterozygous missense mutation (R882H; 602769.0006) in the DNMT3A gene. The authors noted that the arg882 residue is a somatic mutation hotspot for acute myelogeneous leukemia (AML; see 601626).

In 3 unrelated patients with TBRS, Shen et al. (2017) identified 2 different heterozygous mutations at the arg882 residue in the DNMT3A gene: R882H and R882C (602769.0007). Shen et al. (2017) stated that there were 23 known mutations in the DNMT3A gene in patients with TBRS, including 6 recurrent mutations.