SNOMEDCT: 768843007; ORPHA: 404443; DO: 0112339;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p23.3 | Tatton-Brown-Rahman syndrome | 615879 | Autosomal dominant | 3 | DNMT3A | 602769 |
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.
Heterozygous mutation in the DNMT3A gene can also cause Heyn-Sproul-Jackson syndrome (HESJAS; 618724), a reciprocal disorder characterized by microcephalic dwarfism and impaired intellectual development.
Tatton-Brown-Rahman syndrome (TBRS) is characterized by tall stature, a distinctive facial appearance, and impaired intellectual development (Tatton-Brown et al., 2014). Some patients may have increased susceptibility to the development of acute myeloid leukemia (AML; 601626), particularly if they have DNMT3A mutations affecting the R882 residue (Hollink et al., 2017).
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.
Hollink et al. (2017) reported a 19-year-old Dutch man with TBRS confirmed by genetic analysis. He had characteristic features of the disorder, including delayed development since infancy, hypotonia, macrocephaly, obesity, scoliosis, minor cardiac septal defect, seizures, and dysmorphic facial features, including heavy eyebrows, narrow palpebral fissures, short neck, and thin upper lip. At age 15 years, he developed AML (FAB type M5), which was successfully treated with chemotherapy. Genetic analysis identified a de novo heterozygous germline R882C mutation in the DNMT3A gene (602769.0007). Analysis of leukemic cells showed an aberrant karyotype and a recurrent somatic PTPN11 mutation (T73I; 176876.0011), but no additional somatic mutations or loss of heterozygosity of the DNMT3A gene. Hollink et al. (2017) suggested that mutations at the R882 residue, which are associated with AML in the somatic state, may also predispose germline carriers of the mutation to the development of AML. The authors postulated epigenetic dysregulation as a possible molecular mechanism and suggested that patients with TBRS be followed for hematologic malignancies.
In a 6-year-old girl (patient 5), who was previously reported by DeMari et al. (2016) at age 3.5 years with global developmental delay (MRD56; 617854) and a heterozygous mutation in the CLTC gene (118955.0001), Balci et al. (2020) identified heterozygosity for the recurrent R882C mutation in the DNMT3A gene. At age 6 years, the child presented with lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphoblastic lymphoma.
Ferris et al. (2022) reported 8 patients with TBRS and a history of hematopoietic malignancy and 1 patient with TBRS and chronic multilineage cytopenias. Three of these patients, including patient 3 (patient 5 in Balci et al. (2020)), were previously reported. The diagnoses, which were made between the ages of 5 and 34 years, included 4 patients with acute myeloid leukemia, 1 patient with Hodgkin lymphoma, 1 patient with essential thrombocytosis, and 1 patient with B-cell acute lymphoblastic leukemia. One of the previously reported patients (patient 4) had a metastatic ganglioneuroblastoma diagnosed at 1.6 years of age and posttherapy T-cell lymphoblastic leukemia diagnosed at 6 years of age. Ferris et al. (2022) estimated a 4% prevalence of hematopoietic malignancies in known cases of TBRS, which suggests a greater than 250-fold increase in the risk of hematopoietic malignancy. Ferris et al. (2022) recommended annual monitoring of complete blood counts (or more frequently if abnormalities are present) to understand the risk of developing hematopoietic malignancies.
The heterozygous mutations in the DNMT3A gene that were identified by Tatton-Brown et al. (2014) in 13 unrelated patients with TBRS occurred de novo.
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 de novo 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 de novo 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.
In a 6-year-old girl (patient 5), who was previously reported by DeMari et al. (2016) at age 3.5 years with global developmental delay (MRD56; 617854) and a heterozygous mutation in the CLTC gene (118955.0001), Balci et al. (2020) identified heterozygosity for the recurrent R882C mutation in the DNMT3A gene (602769.0007). At age 6 years, the child presented with lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphoblastic lymphoma.
Balci, T. B., Strong, A., Kalish, J. M., Zackai, E., Maris, J. M., Reilly, A., Surrey, L. F., Werthei, G. B., Marcadier, J. L., Graham, G. E., Carter, M. T. Tatton-Brown-Rahman syndrome: six individuals with novel features. Am. J. Med. Genet. 182A: 673-680, 2020. [PubMed: 31961069] [Full Text: https://doi.org/10.1002/ajmg.a.61475]
DeMari, J., Mroske, C., Tang, S., Nimeh, J., Miller, R., Lebel, R. R. CLTC as a clinically novel gene associated with multiple malformations and developmental delay. Am. J. Med. Genet. 170A: 958-966, 2016. [PubMed: 26822784] [Full Text: https://doi.org/10.1002/ajmg.a.37506]
Ferris, M. A., Smith, A. M., Heath, S. E., Duncavage, E. J., Oberley, M., Freyer, D., Wynn, R., Douzgou, S., Maris, J. M., Reilly, A. F., Wu, M. D., Choo, F., Fiets, R. B., Koene, S., Spencer, D. H., Miller, C. A., Shinawi, M., Ley, T. J. DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. (Letter) Blood 139: 461-464, 2022. [PubMed: 34788385] [Full Text: https://doi.org/10.1182/blood.2021014052]
Hollink, I. H. I. M., van den Ouweland, A. M. W., Beverloo, H. B., Arentsen-Peters, S. T. C. J. M., Zwaan, C. M., Wagner, A. Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation. J. Med. Genet. 54: 805-808, 2017. [PubMed: 28432085] [Full Text: https://doi.org/10.1136/jmedgenet-2017-104574]
Kosaki, R., Terashima, H., Kubota, M., Kosaki, K. Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. Am. J. Med. Genet. 173A: 250-253, 2017. [PubMed: 27991732] [Full Text: https://doi.org/10.1002/ajmg.a.37995]
Shen, W., Heeley, J. M., Carlston, C. M., Acuna-Hidalgo, R., Nillesen, W. M., Dent, K. M., Douglas, G. V., Levine, K. L., Bayrak-Toydemir, P., Marcelis, C. L., Shinawi, M., Carey, J. C. The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies. Am. J. Med. Genet. 173A: 3022-3028, 2017. [PubMed: 28941052] [Full Text: https://doi.org/10.1002/ajmg.a.38485]
Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., del Vecchio Duarte, S., Zachariou, A., Hanks, S., O'Brien, E., Aksglaede, L., Baralle, D., Dabir, T., and 12 others. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nature Genet. 46: 385-388, 2014. Note: Erratum: Nature Genet. 46: 657 only, 2014. [PubMed: 24614070] [Full Text: https://doi.org/10.1038/ng.2917]