Tatton-Brown–Rahman syndrome (TBRS) is a rare overgrowth and

intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

syndrome caused by autosomal dominant mutations in the ''

DNMT3A DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the ''DNMT3A'' gene. This enzyme is ...

'' 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

. 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 In science and engineering, the weight of an object is a quantity associated with the gravitational force exerted on the object by other objects in its environment, although there is some variation and debate as to the exact definition. Some sta ...

at least two standard deviations above the mean. Generalized

joint hypermobility Hypermobility, also known as double-jointedness, describes joints that stretch farther than normal. For example, some hypermobile people can bend their thumbs backwards to their wrists, bend their knee joints backwards, put their leg behind the ...

and

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...

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 Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...

disorder.

Febrile seizure A febrile seizure, also known as a fever fit or febrile convulsion, is a seizure associated with a high body temperature but without any serious underlying health issue. They most commonly occur in children between the ages of 6 months and 5 ye ...

s and afebrile

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s 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 fissure The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open eyelids. In simple terms, it is the opening between the eyelids. In adult humans, this measures about 10 mm vertically and 30 mm horizontally. Va ...

s; and prominent

maxillary central incisor The maxillary central incisor is a human tooth in the front upper jaw, or maxilla, and is usually the most visible of all teeth in the mouth. It is located Commonly used terms of relationship and comparison in dentistry, mesial (closer to the mid ...

s. These features often become most clinically recognizable in adolescence.

Congenital heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital h ...

s and

aortic root dilatation Aneurysm of the aortic sinus, also known as the sinus of Valsalva, is a rare abnormality of the aorta, the largest artery in the body. The aorta normally has three small pouches that sit directly above the aortic valve (the sinuses of Valsalva), ...

have been observed in ~10% of cases. Approximately 20% of males with TBRS have

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is . It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boy ...

Vesicoureteral reflux Vesicoureteral reflux (VUR), also known as vesicoureteric reflux, is a condition in which urine flows retrograde, or backward, from the urinary bladder, bladder into one or both ureters and then to the renal calyx or kidneys. Urine normally trave ...

and

hypospadias Hypospadias is a common malformation in fetal development of the penis in which the urethra does not open from its usual location on the head of the penis. It is the second-most common birth defect of the male reproductive system, affecting about ...

have been reported in some cases. Neuroimaging findings may include

corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental ...

anomalies, small

posterior cranial fossa The posterior cranial fossa is the part of the cranial cavity located between the foramen magnum, and tentorium cerebelli. It is formed by the sphenoid bones, temporal bones, and occipital bone. It lodges the cerebellum, and parts of the brai ...

, asymmetric

arcuate ''Arcuate'' (Latin for "curved") can refer to: Anatomy * Arcuate fasciculus * Arcuate line (disambiguation) * Arcuate artery (disambiguation), several arteries * Arcuate nucleus (hypothalamus) * Arcuate nucleus (medulla) * Arcuate ligaments of ...

and uncinate fasciculi, deep left

Sylvian fissure The lateral sulcus (or lateral fissure, also called Sylvian fissure, after Franciscus Sylvius) is the most prominent sulcus (neuroanatomy), sulcus of each cerebral hemisphere in the human brain. The lateral sulcus (neuroanatomy), sulcus is a deep ...

, and increased cortical thickness

Cause

TBRS is caused by

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

mutations in the ''

'' 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 A mosaic () is a pattern or image made of small regular or irregular pieces of colored stone, glass or ceramic, held in place by plaster/Mortar (masonry), mortar, and covering a surface. Mosaics are often used as floor and wall decoration, and ...

parent. ''DNMT3A'' overgrowth mutations are hypothesized to interfere with the enzyme's role in

H3K36me2 H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein. There are diverse modifications at H3K36 and have many important ...

-regulated non-CpG

DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter (genetics), promoter, DNA methylati ...

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 Early childhood intervention (ECI) is a support and educational system for very young children (aged birth to six years) who have been victims of, or who are at high risk for child abuse and/or neglect as well as children who have developmental d ...

and

special education Special education (also known as special-needs education, aided education, alternative provision, exceptional student education, special ed., SDC, and SPED) is the practice of educating students in a way that accommodates their individual di ...

(

IFSP IFSP (, ), or radial parallel interface, was a parallel interface similar to the Centronics connector (IEEE 1284) but incompatible, as it had different signal polarities and handshake protocol. It was used in printers and computers manufactured in ...

and IEP in the United States) are recommended. Because ''DNMT3A'' mutations are commonly observed in

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...

, TBRS may be associated with increased cancer risk.

References

External links

{{DEFAULTSORT:Tatton-Brown-Rahman syndrome Autosomal dominant disorders Medical conditions related to obesity Rare genetic syndromes Syndromes affecting stature Syndromic autism Syndromes with intellectual disability Syndromes with macrocephaly Syndromes with seizures

Signs and symptoms

Cause

Management and prognosis

See also

References

External links