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Tatton-Brown-Rahman overgrowth syndrome(TBRS)

MedGen UID:
862982
Concept ID:
C4014545
Disease or Syndrome
Synonyms: Tall stature-intellectual disability-facial dysmorphism syndrome; Tatton-Brown-rahman syndrome
SNOMED CT: Tatton Brown Rahman overgrowth syndrome (768843007); DNA methyltransferase 3 alpha overgrowth syndrome (768843007); DNMT3A-related overgrowth syndrome (768843007); Tatton Brown Rahman syndrome (768843007); Tall stature, intellectual disability, facial dysmorphism syndrome (768843007)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): DNMT3A (2p23.3)
 
Monarch Initiative: MONDO:0014382
OMIM®: 615879
Orphanet: ORPHA404443

Disease characteristics

Excerpted from the GeneReview: Tatton-Brown-Rahman Syndrome
Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference ≥2 standard deviations above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures. Individuals with TBRS have subtle dysmorphic features, including a round face with coarse features, thick horizontal low-set eyebrows, narrow (as measured vertically) palpebral fissures, and prominent upper central incisors. The facial gestalt is most easily recognizable in the teenage years. TBRS may be associated with an increased risk of developing acute myeloid leukemia. There are less clear associations with aortic root dilatation and increased risk of other hematologic and solid tumors. [from GeneReviews]
Authors:
Philip J Ostrowski  |  Katrina Tatton-Brown   view full author information

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/615879
From MedlinePlus Genetics
DNMT3A overgrowth syndrome is a disorder characterized by faster than normal growth before and after birth, subtle differences in facial features, and intellectual disability.

Individuals with DNMT3A overgrowth syndrome are often longer than normal at birth and are taller than their peers throughout life. Many affected individuals become overweight in late childhood or adolescence. They may also have an abnormally large head size (macrocephaly).

The characteristic facial appearance of individuals with DNMT3A overgrowth syndrome includes a round face; thick, horizontal eyebrows; and narrowed openings of the eyes (narrowed palpebral fissures). Additionally, the upper front teeth are often larger than normal.

Intellectual disability in DNMT3A overgrowth syndrome ranges from mild to severe. Individuals may have features of autism spectrum disorder, which are characterized by impaired communication and socialization skills.

Individuals with DNMT3A overgrowth syndrome may have other signs and symptoms, including a rounded upper back that also curves to the side (kyphoscoliosis), heart defects, flat feet (pes planus), weak muscle tone (hypotonia), or joints that are loose and very flexible (hypermobile joints). Psychological disorders such as depression, anxiety, or obsessive-compulsive disorder can also occur in this disorder.  https://medlineplus.gov/genetics/condition/dnmt3a-overgrowth-syndrome

Clinical features

From HPO
Vesicoureteral reflux
MedGen UID:
21852
Concept ID:
C0042580
Disease or Syndrome
Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).
Talipes valgus
MedGen UID:
57757
Concept ID:
C0152236
Congenital Abnormality
Outward turning of the heel, resulting in clubfoot with the person walking on the inner part of the foot.
Patellar subluxation
MedGen UID:
163635
Concept ID:
C0857276
Pathologic Function
The kneecap normally is located within the groove termed trochlea on the distal femur and can slide up and down in it. Patellar subluxation refers to an unstable kneecap that does not slide centrally within its groove, i.e., a partial dislocation of the patella.
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Mitral regurgitation
MedGen UID:
7670
Concept ID:
C0026266
Disease or Syndrome
An abnormality of the mitral valve characterized by insufficiency or incompetence of the mitral valve resulting in retrograde leaking of blood through the mitral valve upon ventricular contraction.
Tricuspid regurgitation
MedGen UID:
11911
Concept ID:
C0040961
Disease or Syndrome
Failure of the tricuspid valve to close sufficiently upon contraction of the right ventricle, causing blood to regurgitate (flow backward) into the right atrium.
Tall stature
MedGen UID:
69137
Concept ID:
C0241240
Finding
A height above that which is expected according to age and gender norms.
Hemihypertrophy
MedGen UID:
90701
Concept ID:
C0332890
Congenital Abnormality
Overgrowth of only one side of the body.
Overgrowth
MedGen UID:
376550
Concept ID:
C1849265
Finding
Excessive postnatal growth which may comprise increased weight, increased length, and/or increased head circumference.
Febrile seizure (within the age range of 3 months to 6 years)
MedGen UID:
3232
Concept ID:
C0009952
Disease or Syndrome
A febrile seizure is any type of seizure (most often a generalized tonic-clonic seizure) occurring with fever (at least 38 degrees Celsius) but in the absence of central nervous system infection, severe metabolic disturbance or other alternative precipitant in children between the ages of 3 months and 6 years.
Encephalomalacia
MedGen UID:
4936
Concept ID:
C0014068
Disease or Syndrome
Encephalomalacia is the softening or loss of brain tissue after cerebral infarction, cerebral ischemia, infection, craniocerebral trauma, or other injury.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Chiari type I malformation
MedGen UID:
196689
Concept ID:
C0750929
Congenital Abnormality
Arnold-Chiari type I malformation refers to a relatively mild degree of herniation of the posteroinferior region of the cerebellum (the cerebellar tonsils) into the cervical canal with little or no displacement of the fourth ventricle. It is characterized by one or both pointed (not rounded) cerebellar tonsils that project 5 mm below the foramen magnum, measured by a line drawn from the basion to the opisthion (McRae Line)
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Sagittal craniosynostosis
MedGen UID:
140921
Concept ID:
C0432123
Congenital Abnormality
A kind of craniosynostosis affecting the sagittal suture.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Blepharophimosis
MedGen UID:
2670
Concept ID:
C0005744
Anatomical Abnormality
A fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures.
Round face
MedGen UID:
116087
Concept ID:
C0239479
Finding
The facial appearance is more circular than usual as viewed from the front.
Thin vermilion border
MedGen UID:
108294
Concept ID:
C0578038
Finding
Height of the vermilion of the medial part of the lip more than 2 SD below the mean, or apparently reduced height of the vermilion of the lip in the frontal view. The vermilion is the red part of the lips (and confusingly, the vermilion itself is also often referred to as being equivalent the lips).
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Deep philtrum
MedGen UID:
374311
Concept ID:
C1839797
Finding
Accentuated, prominent philtral ridges giving rise to an exaggerated groove in the midline between the nasal base and upper vermillion border.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Exaggerated cupid bow
MedGen UID:
376842
Concept ID:
C1850629
Finding
More pronounced paramedian peaks and median notch of the Cupid's bow.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Short columella
MedGen UID:
341783
Concept ID:
C1857479
Finding
Reduced distance from the anterior border of the naris to the subnasale.
Narrow palpebral fissure
MedGen UID:
382506
Concept ID:
C2675021
Finding
Reduction in the vertical distance between the upper and lower eyelids.
Horizontal eyebrow
MedGen UID:
478649
Concept ID:
C3277019
Finding
An eyebrow that extends straight across the brow, without curve.
Everted upper lip vermilion
MedGen UID:
869272
Concept ID:
C4023698
Finding
Inner aspect of the upper lip vermilion (normally apposing the teeth) visible in a frontal view, i.e., the presence of an everted upper lip.
Fetal distress
MedGen UID:
5164
Concept ID:
C0015930
Pathologic Function
An intrauterine state characterized by suboptimal values in the fetal heart rate, oxygenation of fetal blood, or other parameters indicative of compromise of the fetus. Signs of fetal distress include repetitive variable decelerations, fetal tachycardia or bradycardia, late decelerations, or low biophysical profile.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Optic nerve hypoplasia
MedGen UID:
137901
Concept ID:
C0338502
Disease or Syndrome
Underdevelopment of the optic nerve.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVTatton-Brown-Rahman overgrowth syndrome

Recent clinical studies

Etiology

Lui JC, Baron J
J Clin Endocrinol Metab 2024 Jan 18;109(2):312-320. doi: 10.1210/clinem/dgad420. PMID: 37450557Free PMC Article
Tenorio J, Alarcón P, Arias P, Dapía I, García-Miñaur S, Palomares Bralo M, Campistol J, Climent S, Valenzuela I, Ramos S, Monseny AM, Grondona FL, Botet J, Serrano M, Solís M, Santos-Simarro F, Álvarez S, Teixidó-Tura G, Fernández Jaén A, Gordo G, Bardón Rivera MB, Nevado J, Hernández A, Cigudosa JC, Ruiz-Pérez VL, Tizzano EF; SOGRI Consortium, Lapunzina P
Eur J Hum Genet 2020 Apr;28(4):469-479. Epub 2019 Nov 4 doi: 10.1038/s41431-019-0485-3. PMID: 31685998Free PMC Article
Polonis K, Blackburn PR, Urrutia RA, Lomberk GA, Kruisselbrink T, Cousin MA, Boczek NJ, Hoppman NL, Babovic-Vuksanovic D, Klee EW, Pichurin PN
Cold Spring Harb Mol Case Stud 2018 Aug;4(4) Epub 2018 Aug 1 doi: 10.1101/mcs.a002899. PMID: 29802153Free PMC Article
Hollink IHIM, van den Ouweland AMW, Beverloo HB, Arentsen-Peters STCJM, Zwaan CM, Wagner A
J Med Genet 2017 Dec;54(12):805-808. Epub 2017 Apr 21 doi: 10.1136/jmedgenet-2017-104574. PMID: 28432085
Kosaki R, Terashima H, Kubota M, Kosaki K
Am J Med Genet A 2017 Jan;173(1):250-253. Epub 2016 Nov 7 doi: 10.1002/ajmg.a.37995. PMID: 27991732

Diagnosis

Thomas H, Alix T, Renard É, Renaud M, Wourms J, Zuily S, Leheup B, Geneviève D, Dreumont N, Schmitt E, Bronner M, Muller M, Divoux M, Wandzel M, Ravel JM, Dexheimer M, Becker A, Roth V, Willems M, Coubes C, Vieville G, Devillard F, Schaefer É, Baer S, Piton A, Gérard B, Vincent M, Nizon M, Cogné B, Ruaud L, Couque N, Putoux A, Edery P, Lesca G, Chatron N, Till M, Faivre L, Tran-Mau-Them F, Alessandri JL, Lebrun M, Quélin C, Odent S, Dubourg C, David V, Faoucher M, Mignot C, Keren B, Pisan É, Afenjar A, Julia S, Bieth É, Banneau G, Goldenberg A, Husson T, Campion D, Lecoquierre F, Nicolas G, Charbonnier C, De Saint Martin A, Naudion S, Degoutin M, Rondeau S, Michot C, Cormier-Daire V, Oussalah A, Pourié C, Lambert L, Bonnet C
J Med Genet 2024 Aug 29;61(9):878-885. doi: 10.1136/jmg-2024-110031. PMID: 38937076
Kalil GH, Christopher WO, Brister KA, Orr WS
Am Surg 2023 Jul;89(7):3203-3204. Epub 2023 Feb 14 doi: 10.1177/00031348231157840. PMID: 36788738
Cecchi AC, Haidar A, Marin I, Kwartler CS, Prakash SK, Milewicz DM
Am J Med Genet A 2022 Feb;188(2):628-634. Epub 2021 Oct 13 doi: 10.1002/ajmg.a.62541. PMID: 34644003Free PMC Article
Balci TB, Strong A, Kalish JM, Zackai E, Maris JM, Reilly A, Surrey LF, Wertheim GB, Marcadier JL, Graham GE, Carter MT
Am J Med Genet A 2020 Apr;182(4):673-680. Epub 2020 Jan 21 doi: 10.1002/ajmg.a.61475. PMID: 31961069
Hollink IHIM, van den Ouweland AMW, Beverloo HB, Arentsen-Peters STCJM, Zwaan CM, Wagner A
J Med Genet 2017 Dec;54(12):805-808. Epub 2017 Apr 21 doi: 10.1136/jmedgenet-2017-104574. PMID: 28432085

Prognosis

Lennartsson O, Lodefalk M, Wehtje H, Stattin EL, Sävendahl L, Nilsson O
Front Endocrinol (Lausanne) 2021;12:752756. Epub 2021 Oct 13 doi: 10.3389/fendo.2021.752756. PMID: 34721301Free PMC Article

Clinical prediction guides

Thomas H, Alix T, Renard É, Renaud M, Wourms J, Zuily S, Leheup B, Geneviève D, Dreumont N, Schmitt E, Bronner M, Muller M, Divoux M, Wandzel M, Ravel JM, Dexheimer M, Becker A, Roth V, Willems M, Coubes C, Vieville G, Devillard F, Schaefer É, Baer S, Piton A, Gérard B, Vincent M, Nizon M, Cogné B, Ruaud L, Couque N, Putoux A, Edery P, Lesca G, Chatron N, Till M, Faivre L, Tran-Mau-Them F, Alessandri JL, Lebrun M, Quélin C, Odent S, Dubourg C, David V, Faoucher M, Mignot C, Keren B, Pisan É, Afenjar A, Julia S, Bieth É, Banneau G, Goldenberg A, Husson T, Campion D, Lecoquierre F, Nicolas G, Charbonnier C, De Saint Martin A, Naudion S, Degoutin M, Rondeau S, Michot C, Cormier-Daire V, Oussalah A, Pourié C, Lambert L, Bonnet C
J Med Genet 2024 Aug 29;61(9):878-885. doi: 10.1136/jmg-2024-110031. PMID: 38937076
Bell-Hensley A, Beard DC, Feeney K, Zheng H, Jiang Y, Zhang X, Liu J, Gabel H, McAlinden A
Bone 2024 Jun;183:117085. Epub 2024 Mar 23 doi: 10.1016/j.bone.2024.117085. PMID: 38522809Free PMC Article
Cecchi AC, Haidar A, Marin I, Kwartler CS, Prakash SK, Milewicz DM
Am J Med Genet A 2022 Feb;188(2):628-634. Epub 2021 Oct 13 doi: 10.1002/ajmg.a.62541. PMID: 34644003Free PMC Article
Shen W, Heeley JM, Carlston CM, Acuna-Hidalgo R, Nillesen WM, Dent KM, Douglas GV, Levine KL, Bayrak-Toydemir P, Marcelis CL, Shinawi M, Carey JC
Am J Med Genet A 2017 Nov;173(11):3022-3028. Epub 2017 Sep 21 doi: 10.1002/ajmg.a.38485. PMID: 28941052
Kosaki R, Terashima H, Kubota M, Kosaki K
Am J Med Genet A 2017 Jan;173(1):250-253. Epub 2016 Nov 7 doi: 10.1002/ajmg.a.37995. PMID: 27991732

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