Holt-Oram syndrome is a rare genetic disorder characterized by abnormalities of the heart and upper limbs. It is an autosomal dominant disease, with mutations occurring on the long arm of chromosome 12, and patients present with congenital heart disease accompanied with deformities of the forearms and hands. A thorough workup is needed to establish the diagnosis, and treatment includes correction of cardiac abnormalities, and symptomatic therapy, as there is no cure for the disease.
The clinical presentation of patients with Holt-Oram syndrome vary from one patient to another, but predominant symptoms are related to the heart and upper limbs. This disease may be asymptomatic until adulthood, but the majority of patients present with at least some symptoms during infancy and childhood.
Cardiac manifestations include the presence of congenital heart disease, such as ASD and VSD , which may present with fatigue, tachypnea, tachycardia, but also failure to thrive. Chest pain, as well as syncope (which may be recurrent), may be present. Cyanotic heart disease can also be a clinical manifestation, which can present with generalized cyanosis as early as birth, and during the neonatal period. Disorders of cardiac conduction may also be observed in these patients, including incomplete and complete heart blocks, right bundle branch block, and other types of arrhythmias , which may depend on the accompanying cardiac malformation. Heart murmurs of at various locations on the chest wall and of various degrees may be observed during the physical examination.
Upper limb symptoms include the absence of thumbs, triphalangy (development of three phalangeal joints of the thumb), underdevelopment of radius and ulna, the fusion of thenar and carpal bones with the thumb, and abnormal position of the thumb and forearm. These abnormalities may result in an inability of the patients to fully extend or medially rotate the arms, nor can they perform pronation and supination in some cases. In more severe cases, phocomelia, the presence of hands attached to the shoulders with markedly shortened or absent humerus, radius, and ulna, may be present.
Entire Body System
- Atrial Septal Defect
The most frequent cardiac abnormalities are atrial septal defects and arrhythmias 8 and, among the former, atrial septal defects of the ostium secundum type occur in 34% of the patients 9. [scielo.br]
In the first fetus, the existence of Holt-Oram syndrome was suspected at 22 weeks of gestation; a ventricular septal defect, an atrial septal defect, and a minor skeletal defect were found. [ncbi.nlm.nih.gov]
Absent, bifid, hypoplastic, or triphalangeal thumb associated with cardiac septation defects, classically atrial septal defect (often with conduction defects) but also ventricular septal defect. [accessanesthesiology.mhmedical.com]
- Coarctation of the Aorta
Congenital heart defect (secundum type ASD, VSD, Tetralogy of Fallot, coarctation of the aorta, persistent left SVC, hypoplastic left heart syndrome, anomalous pulmonary venous return) (3,4). Intermittent cardiac arrhythmia. Bradycardia. [fetalultrasound.com]
[…] of the aorta (in 15%) Bicuspid aortic valve Trisomy 16-18 VSD PDA Double outlet right ventricle Trisomy 13-15 VSD Tetralogy of Fallot Double outlet right ventricle William syndrome (Idiopathic hypercalcemia) Supravalvular aortic stenosis (33%) ASD VSD [learningradiology.com]
- Poor Growth
In some cases, severely affected children experience poor growth, breathlessness, easy fatigability with exercise, and/or irregular heartbeats (arrhythmias). [rarediseases.org]
- Heart Disease
Holt-Oram syndrome is a rare genetic disease that is characterized by abnormalities of the upper limbs, as well as heart disease. [symptoma.com]
The criteria for diagnosing this syndrome are abnormalities in the radius in at least one upper limb and congenital heart disease with or without conduction diseases in the heart . [cureus.com]
Holt-Oram syndrome was first described in 1960 as an association of familial heart disease and musculoskeletal abnormalities. [scielo.br]
Since she had complex congenital heart disease, chronic heart failure, and severe hypoxia, the risk surrounding surgery to remove the primary tumor was predicted to be very high, and subsequently, chemotherapy was performed. [ncbi.nlm.nih.gov]
Reamon-Buettner SM, Borlak J: Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease. J Med Genet 2004;41:684-690. Reamon-Buettner SM, Borlak J: TBX5 mutations in non-Holt-Oram syndrome (HOS) malformed hearts. [karger.com]
- Thumb Hypoplasia
Beyond the wrist bones, one of the most characteristic findings in the Holt-Oram syndrome (HOS) involves a thumb anomaly; the condition of the thumbs may vary from absent [thumb aplasia] (35% - see photo 1st below), underdeveloped [thumb hypoplasia], [handresearch.com]
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. [ncbi.nlm.nih.gov]
This rare syndrome characterized by upper limb defects such as carpal bone defects, triphalangeal thumbs, hypoplasia or absence of the thumb and the radial ray are more frequent in addition to that this syndrome is associated with cardiac septal defects [ajner.com]
I–II syndactyly, elbow mobility defect; b Right thumb hypoplasia; c Left thumb hypoplasia; d Left triphalangeal thumb; e Left thumb agenesis in a foetus: f Left digitalised thumb, I–II syndactyly, radial hypoplasia; g Radial and ulnar hypoplasia, I–II [nature.com]
- Short Forearm
In complete syndrome there is congenital cardiovascular malformations – commonly an atrial septal defect – secundum atrial septal defect with bony abnormalities of the upper extremity, including polydactyly and syndactyly, resulting in short forearms [whonamedit.com]
She had short forearms with difficulty in forearm supination and pronation, and a prominence on both of her elbows representing subluxation of the radial heads. She had no facial dysmorphism and no other upper or lower limb defects. [nature.com]
- Hip Dislocation
The types of anomalies (one bilateral hip dislocation, one lower limb shortening, one club foot) would suggest random association rather than the clinical spectrum of HOS. [ojrd.biomedcentral.com]
The first step in the diagnosis of Holt-Oram syndrome is obtaining a thorough patient history, followed by a complete physical examination. A family history of identical signs and symptoms may point towards a familial disorder, which may be supported by the facts observed during the physical examination. Once the examination is conducted, workup involves primarily radiographic imaging to assess the severity of cardiac and skeletal malformations.
- X-ray of upper limbs - X-rays of both arms are sufficient to assess the severity of abnormalities related to the deformities in the upper limbs.
- Electrocardiography (ECG) studies - Patients with suspected arrhythmias should be examined using ECG studies, to determine which type of arrhythmia is present, and if arrhythmias are intermittent, a 24 hour Holter monitoring may be useful to assess cardiac conduction.
- Echocardiography - Ultrasound of the heart is the diagnostic method of choice, and provides a clear view of the cardiac structures, as well as functional capacity. Previously mentioned congenital heart diseases, as well as distended pulmonary arteries and accompanying syndromes may be observed . In addition to obtaining a diagnosis, echocardiography may provide useful information regarding treatment strategies.
- Molecular testing - The definite diagnosis of Holt-Oram syndrome may be established through gene testing, and TBX5 gene mutation testing if available. However, molecular testing is usually performed only if patients meet the diagnostic criteria, as the testing is not commonly performed.
- Right Axis Deviation
[…] ventricular hypertrophy with right axis deviation. [annalspc.com]
Electrocardiogram showed sinus rhythm, right axis deviation, tall and peaked P waves in leads II and V2 to V6, and right ventricular hypertrophy. [jpma.org.pk]
Electrocardiogram showed normal sinus rhythm with right ventricular hypertrophy with right axis deviation. [hindawi.com]
After a thorough clinical examination and workup, treatment principles include correction of cardiac manifestations of Holt-Oram syndrome, as well as providing optimal supportive and symptomatic care for the patient.
There is no specific cure for this condition, although several therapeutic agents have been proposed for patients with this genetic disorder, including antibiotic prophylaxis to prevent possible endocarditis , as well as anticoagulant therapy, to reduce the risk of embolism.
Surgical therapy is indicated for patients with ASD or VSD, as these structural malformations are fully correctable, while patients with advanced heart blocks and arrhythmias that cannot be corrected with medications, insertion of permanent pacemakers may be indicated. Surgical treatment of upper limb abnormalities may be considered, such as pollicization of the fifth digit, which implies replacement of deficient thumb for one of the fingers. It can be performed in the case of hypoplasia of the thumb, to improve upper limb function. Reconstructive surgery and placement of prostheses may also be an option.
Physical therapy is an important aspect of managing Holt-Oram syndrome, as improving limb functions, and overall fitness is important in ensuring life quality, and prevention of potential complications that may arise.
Prognosis depends on the severity of the heart disease, since the majority of patients present with cardiac manifestations such as arrhythmia, and require correction of cardiac abnormalities. But the prognosis is usually good. However, cyanotic heart disease, heart failure, as well as the development of infective endocarditis and Eisenmenger syndrome (development of portal hypertension as a result of cyanotic heart disease) may occur, which can be life-threatening, and require mandatory treatment.
Skeletal abnormalities are usually present at birth, but may not be apparent until later in life. However, severe cases may cause significant limitations, and pose a great burden to the patient.
Holt-Oram syndrome belongs to the group of Heart-hand syndromes and is an autosomal dominant genetic disease. The most commonly described mutations in this syndrome occur on the long arm of chromosome 12 (12q24.1)  , where inactivation of the transcription factor TBX5 occurs , through unknown mechanisms. Up to 75% of patients with this genetic disorder have confirmed mutations of the TBX5 transcription factor, whose role is yet to be fully defined, but presumably, is involved in the formation of cardiac and upper limb structures . However, sporadic disease, and development of de novo mutations are also observed. Moreover, it is estimated that about 85% of patients who develop Holt-Oram syndrome are due to new mutations in the TBX5 gene.
Nevertheless, the autosomal dominant nature of this genetic disease implies family history as one of the most important factors in the transmission of this disease from generation to generation.
It is estimated that the prevalence of Holt-Oram syndrome is 1 per 100,000 births . It seems that this disorder has no sexual or racial predilections, and occurs in children of both genders and of any ethnic origin. Approximately 75% of patients with Holt-Oram syndrome develop some cardiac abnormalities, most common being atrial septal defects (ASDs) or ventricular septal defects (VSDs) , while the majority of cases have some form of limb involvement, which may not be apparent at birth, and may be observed later in life.
Holt-Oram syndrome occurs as a result of mutations in the transcription factor TBX5 on the long arm of chromosome 12, which is presumably involved in the development of the heart and upper limbs , through yet undefined mechanisms. Although de novo mutations have been observed, the majority of patients have confirmed mutations. So far, environmental factors have not been established in the pathogenesis of this genetic disorder .
Specific measures of prevention are not established, although genetic counseling may be useful for families with confirmed Holt-Oram syndrome. But since the majority of cases still occur due to de novo mutations, prevention of this disorder is highly unlikely. Screening of family members of patients with confirmed Holt-Oram syndrome should be performed. Patient follow-up, however, should be performed on a regular basis, to prevent further complications of the disease.
Initially described in patients with atrial septal defects and deformities of the thumbs by Holt and Oram , Holt-Oram syndrome is a rare disorder which features congenital heart disease such as development of atrial and ventricular septal defects, as well as cyanotic heart disease, together with abnormalities in growth of the upper limbs, most notably the forearms, hands, and the thumbs. This syndrome is autosomal dominant in nature, meaning that family history plays an important factor in the diagnosis of new cases, but a substantial number of cases occur as a result of de novo mutations. The principal mutation involves the TBX5 gene on the long arm of chromosome 12, whose role is still undefined completely. Features of clinical presentation include dysplasia of upper limbs, including hypoplasia of the thumb, clinodactyly, radial aplasia, and phocomelia , together with cardiac abnormalities such as heart blocks, and other forms of arrhythmia. The diagnosis of this rare genetic disorder can be made after an extensive diagnostic workup, including electrocardiogram studies, echocardiography, as well as radiographic studies such as X-ray, while genetic testing provides a definite diagnosis. There is no cure for this syndrome, and treatment is directed at correcting cardiac abnormalities, either through medication or surgery, as well as rehabilitation and symptomatic therapy.
Holt-Oram syndrome is a rare genetic disease that is characterized by abnormalities of the upper limbs, as well as heart disease. It occurs in 1 of 100,000 births and is as a result of autosomal dominant transmission, which means that a single copy of the affected individual may be sufficient to cause disease. Given the fact that one copy is provided by the affected person, and another copy from the non-affected person, there is a 50% chance that the child will develop this genetic disease. Symptoms may not be present at birth, but usually, manifestations occur in early infancy, and include the presence of certain congenital heart diseases which manifest with fatigue, tachycardia, increased breathing rates, as well as arrhythmias, which may be sometimes life-threatening. Development of upper limbs may be altered, and patients often present with a deficient growth of thumbs and bones of the forearm. The diagnosis is obtained through evaluation of signs and symptoms, as well as performing X-rays of the bones of the upper limbs, and echocardiography, to establish the presence of accompanying heart anomalies, while a definite diagnosis can be made through genetic testing. There is no cure for Holt-Oram syndrome, and treatment is directed at correcting heart anomalies and associated symptoms with either surgery or medication, while some drugs such as antibiotics and anticoagulants are recommended to prevent possible complications such as infection or thrombosis and development of emboli. It is important to screen family members of patients who already have Holt-Oram syndrome, in order to provide timely genetic counseling and to diagnose this syndrome in its early stages.
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