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Defining Features of the Upper Extremity in Holt-Oram Syndrome.

ABSTRACT: 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.

SUBMITTER: Wall LB

PROVIDER: S-EPMC4757499 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Defining Features of the Upper Extremity in Holt-Oram Syndrome.

Wall Lindley B LB Piper Samantha L SL Habenicht Rolf R Oishi Scott N SN Ezaki Marybeth M Goldfarb Charles A CA

The Journal of hand surgery 20150801 9

<h4>Purpose</h4>To investigate the distinguishing morphological characteristics of children with radial longitudinal deficiency (RLD) in Holt-Oram syndrome (HOS).<h4>Methods</h4>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, respec ...[more]

PMID: 26243320

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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.

Project description:MicroRNAs (miRNAs) are small non-coding RNAs that play an important role in the post-transcriptional regulation of gene expression. miRNAs are involved in the regulation of many biological processes such as differentiation, apoptosis, and cell proliferation. miRNAs are expressed in embryonic, postnatal, and adult hearts, and they have a key role in the regulation of gene expression during cardiovascular development and disease. Aberrant expression of miRNAs is associated with abnormal cardiac cell differentiation and dysfunction. Tbx5 is a member of the T-box gene family, which acts as transcription factor involved in the vertebrate heart development. Alteration of Tbx5 level affects the expression of hundreds of genes. Haploinsufficiency and gene duplication of Tbx5 are at the basis of the cardiac abnormalities associated with Holt-Oram syndrome (HOS). Recent data indicate that miRNAs might be an important part of the regulatory circuit through which Tbx5 controls heart development. Using high-throughput technologies, we characterized genome-widely the miRNA and mRNA expression profiles in WT- and Tbx5-depleted zebrafish embryos at two crucial developmental time points, 24 and 48 h post fertilization (hpf). We found that several miRNAs, which are potential effectors of Tbx5, are differentially expressed; some of them are already known to be involved in cardiac development and functions, such as miR-30, miR-34, miR-190, and miR-21. We performed an integrated analysis of miRNA expression data with gene expression profiles to refine computational target prediction approaches by means of the inversely correlation of miRNA-mRNA expressions, and we highlighted targets, which have roles in cardiac contractility, cardiomyocyte proliferation/apoptosis, and morphogenesis, crucial functions regulated by Tbx5. This approach allowed to discover complex regulatory circuits involving novel miRNAs and protein coding genes not considered before in the HOS such as miR-34a and miR-30 and their targets.

Dataset Information

Defining Features of the Upper Extremity in Holt-Oram Syndrome.

Publications

Defining Features of the Upper Extremity in Holt-Oram Syndrome.

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