Holt-Oram Syndrome: Hands are the Clue to the Diagnosis.
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ABSTRACT:
SUBMITTER: Kumar B
PROVIDER: S-EPMC6822328 | biostudies-literature | 2019 Oct-Dec
REPOSITORIES: biostudies-literature
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Holt-Oram Syndrome: Hands are the Clue to the Diagnosis.
Kumar Basant B Agstam Sourabh S
International journal of applied & basic medical research 20191011 4
Holt-Oram syndrome or heart-hand syndrome consists of phenotypic and genotypic abnormalities. It is characterized by abnormalities of upper limbs and congenital cardiac defects. It is an autosomal dominant disorder due to a mutation in TBX5 gene located on chromosome 12, but sporadic cases have also been reported. We describe a 26-year-old female with a history of shortness of breath for 5 years. She had bilateral hand deformities, and on evaluation, found to have ostium secundum atrial septal d ...[more]
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Project description:Holt-Oram syndrome (HOS) is a rare monogenic disorder characterized by upper limb abnormalities, congenital heart defects and/or conduction abnormalities. It is determined by mutations of TBX5 gene and is inherited in an autosomal dominant manner. Penetrance is complete, but variable expressivity is present, which gives sometimes diagnostic difficulties. Our case is a young adult with a personal history of preaxial polydactyly operated in infancy, multiple cardiac malformations (atrial septal defect, bicuspid aortic valve, left ventricular non-compaction) and radiologic findings consistent with HOS. Family history is negative for HOS. In conclusion, we present a case of HOS diagnosed in the adult period to highlight the diagnostic problems for the proband and the family and the importance of an early diagnostic.
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Project description:BACKGROUND: Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. METHODS: The study was based on data collected during 1990-2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS. RESULTS: A total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births. CONCLUSIONS: HOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes.
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Project description:BackgroundThe Holt-Oram Syndrome (HOS) or the Heart-Hand syndrome is considered as an overt autosomal hereditary disease with a complete influential effect and variable expression that emerges due to a genetic mutation. It can be vividly characterized by heart disorders and deficiencies in hand structure. Despite the existing genetic heterogeneity, the variable integration between HOS and the T-BX5 gene from the T-BOX Gene Complex has been observed during which various mutations have been reported in the affected patients. The T-BOX Gene Complex is located on chromosome 12 (12 q 24.1), and is able to encode a copying factor. That has a conservative motive with 180 amino acids. The deficiencies in only 1/3 of patients have been observed caused by the mutation of this gene.Case reportThis case was a 10-year-old child with hand disorders, incomplete growth of clavicle, moving problems in elbow joint and shoulder, disorder in ventricle and auricle walls. The disease was diagnosed as HOS, based on clinical examination and drawing the family tree diagram. It was impossible to investigate molecular mutation due to inaccessibility to the patient.ConclusionBy investigating the family members and their deficiencies and imaging disorder variables according to different reports as well as parents' state of health, the HOS can be defined as an overt heredity resulting from a new mutation in the germinating layer of sexual cells in one of the parents. There is a weak possibility that the disease results from a mosaic mutation in the male parent's testicle or the female parent's ovum. In this case, the probability for the disease to be repeated in parents' next children will be guessed between 1 and 50%.
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Project description:Holt-Oram syndrome (HOS), characterized by heart and forelimb defects, is caused by mutations in the T-box transcription factor, TBX5. While much has been done to elucidate TBX5’s transcriptional mechanisms in animal and human induced pluripotent stem cell (iPSC) models, transcriptomics from HOS patient tissue is lacking.
2024-12-16 | GSE261014 | GEO
Project description:To investigate the distinguishing morphological characteristics of children with radial longitudinal deficiency (RLD) in Holt-Oram syndrome (HOS).One hundred fourteen involved extremities in 62 patients with a diagnosis of HOS were identified at 3 institutions. Medical records and radiographs were evaluated. Radial longitudinal deficiency and thumb hypoplasia were classified according to the modified Bayne and Klug classification and Blauth classifications, respectively, when possible. Other unusual or distinguishing characteristics were catalogued.There was bilateral involvement in 84% of patients. The forearm was involved in 81% of the extremities and a shortened distal radius (Bayne and Klug type I RLD) was the most commonly identified forearm anomaly (40%). Radioulnar synostosis was present in 15% of the extremities, all in the proximal forearms with reduced radial heads. Thumb aplasia (Blauth type V hypoplastic thumb) was the most common type of classifiable thumb abnormality and occurred in 35% of involved thumbs. Twenty-seven percent of abnormal thumbs affected were not classifiable according to the Blauth classification, and 19% of involved thumbs (hypoplastic or absent) had first-web syndactyly.The upper extremity in HOS differs from the typical presentation of RLD. The forearm is more often involved and may demonstrate radioulnar synostosis. The thumb is frequently unclassifiable by the Blauth classification and has first-web syndactyly. The presence of radioulnar synostosis and syndactyly of the radial 2 digits in RLD should prompt the hand surgeon to obtain a cardiac evaluation and consider genetic testing for HOS.Diagnostic III.
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Project description:Congenital hypotrichosis may be due to a number of causes and may have multiple systemic associations. A child born of second-degree consanguineous marriage was found to have monilethrix as the cause of congenital hypotrichosis. A detailed systemic evaluation in the child revealed atrial septal defect and a hypoplastic right thumb leading to a diagnosis of coexisting Holt-Oram syndrome.
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Project description:Introduction: Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities. Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS. Case description: We present the case of a 24-year-old female with upper limb alterations (congenital dysplasia in the wrist and elbow joints) and an anomalous left main trunk arising from the right coronary sinus. The patient inherited a base T (reference C) at rs883079 from her mother and base C (reference T) at rs10850326 from her father, both of which belong to the 3'-untranslated region (UTR) of the TBX5 gene; no alterations in TBX5 expression or single-nucleotide polymorphisms (SNPs) in other exon areas were found. We explored the effects of TBX5 on cardiomyocytes using the HL-1 cell line and TBX5-knockdown cells. Discussion: Quantitative polymerase chain reaction analysis demonstrated that TEKT2, TEKT4, and SPTB expression decreased after TBX5 knockdown, while chromatin immunoprecipitation analysis further revealed that TBX5 binds to the TEKT2, TEKT4, and SPTB promoter regions to promote gene transcription. Our findings support a novel TBX5-related pathogenic mechanism in HOS.
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Project description:Mutations in TBX5, a T-box-containing transcription factor, cause cardiac and limb malformations in individuals with Holt-Oram syndrome (HOS). Mutations that result in haploinsufficiency of TBX5 are purported to cause cardiac and limb defects of similar severity, whereas missense mutations, depending on their location in the T box, are thought to cause either more severe heart or more severe limb abnormalities. These inferences are, however, based on the analysis of a relatively small number of independent cases of HOS. To better understand the relationship between mutations in TBX5 and the variable expressivity of HOS, we screened the coding and noncoding regions of TBX5 and SALL4 for mutations in 55 probands with HOS. Seventeen mutations, including six missense mutations in TBX5 and two mutations in SALL4, were found in 19 kindreds with HOS. Fewer than 50% of individuals with nonsense or frameshift mutations in TBX5 had heart and limb defects of similar severity, and only 2 of 20 individuals had heart or limb malformations of the severity predicted by the location of their mutations in the T box. These results suggest that neither the type of mutation in TBX5 nor the location of a mutation in the T box is predictive of the expressivity of malformations in individuals with HOS.
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