Tatton-Brown–Rahman syndrome

Overgrowth syndrome caused by DNMT3A gene mutation Medical condition

Tatton-Brown–Rahman syndrome
Other names	DNMT3A overgrowth syndrome
Specialty	Medical genetics
Symptoms	Intellectual disability, overgrowth, facial dysmorphisms
Usual onset	Present at birth
Causes	DNMT3A mutation
Diagnostic method	Molecular genetic testing
Differential diagnosis	Cohen–Gibson syndrome, Fragile X syndrome, Malan syndrome, Simpson–Golabi–Behmel syndrome, Sotos syndrome, Weaver syndrome
Treatment	Based on symptoms
Frequency	90 reported cases
Named after	Nazneen Rahman

Tatton-Brown–Rahman syndrome (TBRS) is a rare overgrowth and intellectual disability syndrome caused by autosomal dominant mutations in the DNMT3A gene. The syndrome was first recognized in 2014 by Katrina Tatton-Brown, Nazneen Rahman, and collaborators.

Signs and symptoms

TBRS is defined by overgrowth and mild-to-severe intellectual disability. All individuals with TBRS experience some degree of developmental delay and/or intellectual disability, with 86% of well-documented cases falling in the mild to moderate range. Most individuals with TBRS exhibit increased stature, head circumference, and weight at least two standard deviations above the mean.

Generalized joint hypermobility and hypotonia are observed in ~75% and ~55% of cases, respectively, and are often associated with musculoskeletal pain and joint instability. Approximately half of individuals exhibit behavioral or psychiatric issues; the most common diagnosis is autism spectrum disorder. Febrile seizures and afebrile seizures have been reported in ~20% of individuals with TBRS.

The facial gestalt of TBRS includes a round face; thick, horizontal, low-set eyebrows; vertically narrow palpebral fissures; and prominent maxillary central incisors. These features often become most clinically recognizable in adolescence.

Congenital heart defects and aortic root dilatation have been observed in ~10% of cases. Approximately 20% of males with TBRS have cryptorchidism. Vesicoureteral reflux and hypospadias have been reported in some cases.

Neuroimaging findings may include corpus callosum anomalies, small posterior cranial fossa, asymmetric arcuate and uncinate fasciculi, deep left Sylvian fissure, and increased cortical thickness

Cause

TBRS is caused by autosomal dominant mutations in the DNMT3A gene. Nearly all cases are caused by de novo mutations; rarely, a pathogenic variant can be inherited from an affected parent or an unaffected mosaic parent. DNMT3A overgrowth mutations are hypothesized to interfere with the enzyme's role in H3K36me2-regulated non-CpG DNA methylation.

Management and prognosis

The majority of individuals with TBRS are in good health. An individual's specific features are treated and managed as indicated. Early childhood intervention and special education (IFSP and IEP in the United States) are recommended.

Because DNMT3A mutations are commonly observed in acute myeloid leukemia, TBRS may be associated with increased cancer risk.

References

^ Ostrowski PJ, Tatton-Brown K (2022-06-30). Adam MP, Feldman J, Mirzaa GM, et al. (eds.). "Tatton-Brown-Rahman Syndrome". GeneReviews. University of Washington, Seattle. PMID 35771960. Retrieved 2024-01-09.
^ Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, et al. (2014). "Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability". Nat Genet. 46 (4): 385–8. doi:10.1038/ng.2917. PMC 3981653. PMID 24614070.
^ Tatton-Brown K, Zachariou A, Loveday C, Renwick A, Mahamdallie S, et al. (2018). "The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants". Wellcome Open Research. 3: 46. doi:10.12688/wellcomeopenres.14430.1. PMC 5964628. PMID 29900417.
Jiménez de la Peña M, Rincón-Pérez I, López-Martín S, Albert J, Martín Fernández-Mayoralas D, Fernández-Perrone AL, et al. (2023). "Tatton-Brown-Rahman syndrome: Novel pathogenic variants and new neuroimaging findings". Am J Med Genet A. 194 (2): 211–217. doi:10.1002/ajmg.a.63434. PMID 37795572.
Hamagami N, Wu DY, Clemens AW, Nettles SA, Li A, Gabel HW (2023). "NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons". Mol Cell. 83 (9): 1412–1428.e7. doi:10.1016/j.molcel.2023.04.001. PMC 10230755. PMID 37098340.

External links

Classification	D ICD-11: LD2C ICD-10: Q87.3 OMIM: 615879
External resources	Orphanet: 404443

v t e Congenital abnormality syndromes
Craniofacial	Acrocephalosyndactyly Apert syndrome Carpenter syndrome Pfeiffer syndrome Saethre–Chotzen syndrome Sakati–Nyhan–Tisdale syndrome Bonnet–Dechaume–Blanc syndrome Other Baller–Gerold syndrome Cyclopia Goldenhar syndrome Moebius syndrome Pierre Robin sequence
Short stature	1q21.1 deletion syndrome Aarskog–Scott syndrome Cockayne syndrome Cornelia de Lange syndrome Dubowitz syndrome Noonan syndrome Robinow syndrome Silver–Russell syndrome Seckel syndrome Smith–Lemli–Opitz syndrome Snyder–Robinson syndrome Turner syndrome
Limbs	Adducted thumb syndrome Holt–Oram syndrome Klippel–Trénaunay syndrome Nail–patella syndrome Rubinstein–Taybi syndrome Gastrulation/mesoderm: Caudal regression syndrome Ectromelia Sirenomelia VACTERL association
Overgrowth syndromes	Bannayan–Riley–Ruvalcaba syndrome Beckwith–Wiedemann syndrome Benign symmetric lipomatosis Klippel–Trénaunay syndrome Neurofibromatosis type I Perlman syndrome Proteus syndrome Sotos syndrome Tatton-Brown–Rahman syndrome Weaver syndrome
Laurence–Moon–Bardet–Biedl	Bardet–Biedl syndrome Laurence–Moon syndrome
Combined/other, known locus	2 (Feingold syndrome) 3 (Zimmermann–Laband syndrome) 4/13 (Fraser syndrome) 8 (Branchio-oto-renal syndrome, CHARGE syndrome) 12 (Keutel syndrome, Timothy syndrome) 15 (Marfan syndrome) 19 (Donohue syndrome) Multiple Fryns syndrome

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