Acromegaly in the setting of Tatton-Brown-Rahman Syndrome.
Hage C,Sabini E,Alsharhan H,Fahrner J A,Beckers A,Daly A,Salvatori R
PURPOSE:Tatton-Brown-Rahman syndrome (TBRS) is a newly defined genetic entity characterized by overgrowth and intellectual disability, resulting from germline mutations in the gene encoding DNA methyltransferase 3 alpha (DNMT3A). Affected individuals with benign and malignant tumors have been reported; to our knowledge pituitary adenomas (and other tumors identified in our patient) have not yet been described in this syndrome. CASE:We report the case of a 34-year-old woman with TBRS who developed a GH-secreting pituitary macroadenoma and other benign tumors and cystic lesions involving diverse organ systems. Whole-exome sequencing revealed a heterozygous, likely pathogenic variant (c.700_709 del10, p. Gly234ArgfsX79) in exon7 of DNMT3A, and a heterozygous variant of uncertain significance (c.25 C>T, p.Arg9Trp) in exon 1 of the gene encoding aryl hydrocarbon receptor-interacting protein (AIP). The patient failed somatostatin analog treatment, and underwent surgery. The tumor retained AIP expression, and analysis of tumor DNA indicated the presence of both AIP alleles, consistent with no loss of heterozygosity. These findings suggest that the AIP variant was not the primary driver of pituitary adenoma development. CONCLUSION:Our case suggests that TBRS might be associated with pituitary adenoma and a broader spectrum of tumors than previously thought, making long-term follow up of these patients crucial to identify tumors early, and to elucidate the clinical spectrum of the disorder for optimization of management.
[Tatton-Brown-Rahman syndrome associated with the DNMT3A gene: a case report and literature review].
Chen Min,Li Si-Tao,Cai Yao,Xiao Xin,Shi Cong-Cong,Hao Hu
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics
This article reports the clinical and genetic features of a case of Tatton-Brown-Rahman syndrome (TBRS) caused by DNMT3A gene mutation. A girl, aged 8 months and 14 days, had the clinical manifestations of psychomotor retardation, hypotonia, ventricular enlargement, and tonsillar hernia malformation. Gene analysis identified a novel heterozygous mutation, c.134C>T(p.A45V), in the DNMT3A gene, and the wild type was observed at this locus in her parents. This mutation was determined as a possible pathogenic mutation according to the guidelines of American College of Medical Genetics and Genomics, which had not been reported in previous studies and conformed to autosomal dominant inheritance. This child was diagnosed with TBRS. TBRS often has a good prognosis, with overgrowth and mental retardation as the most common clinical manifestations, and behavioral and psychiatric problems, scoliosis, and afebrile seizures are possible complications of TBRS. The possibility of TBRS should be considered for children with overgrowth and mental retardation, and genetic diagnosis should be conducted when necessary.
Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients.
Tenorio Jair,Alarcón Pablo,Arias Pedro,Dapía Irene,García-Miñaur Sixto,Palomares Bralo María,Campistol Jaume,Climent Salvador,Valenzuela Irene,Ramos Sergio,Monseny Antonio Martínez,Grondona Fermina López,Botet Javier,Serrano Mercedes,Solís Mario,Santos-Simarro Fernando,Álvarez Sara,Teixidó-Tura Gisela,Fernández Jaén Alberto,Gordo Gema,Bardón Rivera María Belén,Nevado Julián,Hernández Alicia,Cigudosa Juan C,Ruiz-Pérez Víctor L,Tizzano Eduardo F, ,Lapunzina Pablo
European journal of human genetics : EJHG
Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers. Germline gain-of-function variants in this gene have been recently implicated in microcephalic dwarfism. Common clinical features of patients with TBRS include tall stature, macrocephaly, intellectual disability (ID), and a distinctive facial appearance. Differential diagnosis of TBRS comprises Sotos, Weaver, and Malan Syndromes. The majority of these disorders present other clinical features with a high clinical overlap, making necessary a molecular confirmation of the clinical diagnosis. We here describe seven new patients with variants in DNMT3A, four of them with neuropsychiatric disorders, including schizophrenia and psychotic behavior. In addition, one of the patients has developed a brain tumor in adulthood. This patient has also cerebral atrophy, aggressive behavior, ID, and abnormal facial features. Clinical evaluation of this group of patients should include a complete neuropsychiatric assessment together with psychological support in order to detect and manage abnormal behaviors such as aggressiveness, impulsivity, and attention deficit-hyperactivity disorder. TBRS should be suspected in patients with overgrowth, ID, tall stature, and macrocephaly, who also have some neuropsychiatric disorders without any genetic defects in the commonest overgrowth disorders. Molecular confirmation in these patients is mandatory.
Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation.
Kosaki Rika,Terashima Hiroshi,Kubota Masaya,Kosaki Kenjiro
American journal of medical genetics. Part A
DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown-Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML. © 2016 Wiley Periodicals, Inc.
Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome.
Xin B,Cruz Marino T,Szekely J,Leblanc J,Cechner K,Sency V,Wensel C,Barabas M,Therriault V,Wang H
Tatton-Brown-Rahman syndrome (TBRS) was recently described in 13 isolated cases with de novo mutations in the DNMT3A gene. This autosomal dominant condition is characterized by tall stature, intellectual disability and a distinctive facial appearance. Here, we report six cases of inherited TBRS caused by novel DNMT3A germline mutations. The affected individuals belong to two sib-ships: four from an Old Order Amish family in America and two from a French Canadian family in Canada. All of them presented with characteristic features of TBRS, including dysmorphic facial features, increased height, intellectual disability, and variable additional features. We performed clinical exome sequencing and identified two mutations in the DNMT3A gene, a c.2312G>A (p.Arg771Gln) missense mutation in the Amish family and a c.2296_2297delAA (p.Lys766Glufs*15) small deletion in the French Canadian family. Parental DNA analysis by Sanger sequencing revealed that the Amish mutation was inherited from the healthy mosaic father. This study reflects the first cases with inherited TBRS and expands the phenotypic spectrum of TBRS.
The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with constitutive variants.
Tatton-Brown Katrina,Zachariou Anna,Loveday Chey,Renwick Anthony,Mahamdallie Shazia,Aksglaede Lise,Baralle Diana,Barge-Schaapveld Daniela,Blyth Moira,Bouma Mieke,Breckpot Jeroen,Crabb Beau,Dabir Tabib,Cormier-Daire Valerie,Fauth Christine,Fisher Richard,Gener Blanca,Goudie David,Homfray Tessa,Hunter Matthew,Jorgensen Agnete,Kant Sarina G,Kirally-Borri Cathy,Koolen David,Kumar Ajith,Labilloy Anatalia,Lees Melissa,Marcelis Carlo,Mercer Catherine,Mignot Cyril,Miller Kathryn,Neas Katherine,Newbury-Ecob Ruth,Pilz Daniela T,Posmyk Renata,Prada Carlos,Ramsey Keri,Randolph Linda M,Selicorni Angelo,Shears Deborah,Suri Mohnish,Temple I Karen,Turnpenny Peter,Val Maldergem Lionel,Varghese Vinod,Veenstra-Knol Hermine E,Yachelevich Naomi,Yates Laura, , ,Rahman Nazneen
Wellcome open research
Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous variants. Here we have undertaken a detailed clinical study of 55 individuals with variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS.
Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar R882 mutation.
Hollink Iris H I M,van den Ouweland Ans M W,Beverloo H Berna,Arentsen-Peters Susan T C J M,Zwaan C Michel,Wagner Anja
Journal of medical genetics
BACKGROUND:Recently a novel syndromic form of overgrowth with intellectual disability and distinct facial features was identified caused by constitutional mutations in the epigenetic regulator DNA-methyltransferase 3A (), referred to as Tatton-Brown-Rahman syndrome (TBRS). Somatically acquired mutations in occur in haematological malignancies and are frequently present in acute myeloid leukaemia (AML) affecting in more than 50% the arginine residue at position 882 (R882). To date, additional cases with TBRS have been published but so far none of the reported cases with TBRS developed AML. METHODS AND RESULTS:Here we present the first case of TBRS who developed AML at the age of 15 years. Whole-exome sequencing identified a constitutional heterozygous R882C mutation. Our case exhibits macrocephaly, intellectual disability, distinct facial dysmorphism and other recurrent features fitting with the TBRS phenotype. The AML of the myelomonocytic subtype harboured only few additional somatically acquired mutations, that is, an aberrant karyotype and a recurrent mutation. DISCUSSION:The peculiarity of the specific R882 mutation in contrast to other mutations is discussed, including the hypothesis of the more aggressive nature of this variant.Our case represents the first evidence of the possible increased risk of the development of haematological malignancies in particular AML in cases with TBRS.
First identified Korean family with Tatton-Brown-Rahman Syndrome caused by the novel DNMT3A variant c.118G>C p.(Glu40Gln).
Lee Cha Gon,Jang Ja-Hyun,Seo Ji-Young
Annals of pediatric endocrinology & metabolism
Tatton-Brown-Rahman Syndrome (TBRS), an overgrowth syndrome caused by heterozygous mutation of DNMT3A, first was described in 2014. Approximately 60 DNMT3A variants, including 32 missense variants, have been reported, with most missense mutations located on the DNMT3A functional domains. Autosomal dominant inheritance by germ-line mutation of DNMT3A has been reported, but vertical transmission within a family is extremely rare. Herein, we report the first Korean family with maternally inherited TBRS due to the novel heterozygous DNMT3A variant c.118G>C p.(Glu40Gln), located outside the main functional domain and identified by multigene panel sequencing. The patient and her mother had typical clinical features, including tall stature during childhood, macrocephaly, intellectual disability, and characteristic facial appearance. TBRS shows milder dysmorphic features than other overgrowth syndromes, potentially leading to underdiagnosis and underestimated prevalence; thus, targeted multigene panel sequencing including DNMT3A will be a useful tool in cases of overgrowth and unexplained mild intellectual disability for early diagnosis and genetic counseling.
The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.
Shen Wei,Heeley Jennifer M,Carlston Colleen M,Acuna-Hidalgo Rocio,Nillesen Willy M,Dent Karin M,Douglas Ganka V,Levine Kara L,Bayrak-Toydemir Pinar,Marcelis Carlo L,Shinawi Marwan,Carey John C
American journal of medical genetics. Part A
De novo, germline variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder. Furthermore, based on the investigation of previously reported variants in patients with TBRS, we found overlap in the spectrum of DNMT3A variants observed in this disorder and somatic variants in hematological malignancies.