Holt Oram Syndrome


Article Author:
Ashley Krauser


Article Editor:
Mark Schury


Editors In Chief:
Eric Flake


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
2/28/2019 8:40:21 AM

Introduction

Holt-Oram syndrome also referred to as the heart-hand syndrome, is an autosomal dominant disorder that is distinguished by upper limb abnormalities in association with congenital heart lesions. First described in 1960 by Holt and Oram, the syndrome was identified when thumb anomalies and atrial septal defects (ASD) were observed in family members across four generations. Since then, identification of more cases and advances in technology has allowed for a greater understanding of the syndrome. However, there are still a significant proportion of individuals who are being born with the disorder in both industrialized and underdeveloped countries.[1][2][3][4]

Etiology

A heterozygous mutation in the TBX5 gene on chromosome 12q24.1 causes Holt-Oram syndrome. This gene is responsible for encoding a transcription factor, T-box5, which regulates the expression of other genes in the development of the heart and limbs. Specifically, the gene is an important factor in cardiac septation and the development of bones in the arm and hand. More than 85% percent of individuals diagnosed with Holt-Oram syndrome carry the mutated TBX5 gene.

The condition is an autosomal dominant disorder, so one copy of the mutation in each cell will lead to the development of the syndrome. For an affected parent, this means that he or she has a 50% chance of transmitting the mutation to the offspring. However, most cases of Holt-Oram syndrome are sporadic and occur via de novo mutation.

There is complete penetrance for upper-limb abnormalities and 75% penetrance for cardiac defects. The phenotypic spectrum is wide given the variable expressivity of the gene, leading to difficulty in predicting the malformation characteristics of the offspring. However, if the gene is inherited in an autosomal manner rather than de novo mutation, the offspring will often manifest greater severity in cardiac and limb deformities.[5][6][5]

Epidemiology

The incidence of Holt-Oram syndrome is estimated at 1 in 100,000 individuals, with no predilection for male or female sex. Additionally, a higher prevalence has not been identified in a specific race, ethnicity, or geographic location. The syndrome occurs in both genders with no preferences.

Pathophysiology

Holt Oram syndrome is an inherited disorder with an autosomal trait. There appears to be mutations in TBX5, which is the transcription factor for development of the upper limbs and heart,

History and Physical

There should be high suspicion for Holt-Oram syndrome in individuals who present with a family history and/or the following malformations:

  • Upper-limb malformation
  • Congenital heart malformation
  • Cardiac conduction disease
  • Family history of a relative with congenital heart defects

Upper-limb malformations can involve the carpal bones, thenar bones, and radial bones. These abnormalities may be unilateral or bilateral and symmetric or asymmetric. Most cases are unilateral and affect the left side. Fusion or anomalous development of the carpal bones may be seen. The thumb may be completely absent, grossly underdeveloped, or triphalangeal. The radius may exhibit aplasia or hypoplasia and abnormal forearm pronation and supination. Phocomelia may also be present.

Congenital heart malformations are present in 75% of individuals with Holt-Oram syndrome, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD). The septal defects may be mild or can be more severe and lead to further problems such as pulmonary hypertension, congestive heart failure, or infective endocarditis.

Individuals with Holt-Oram syndrome are also at an increased risk for cardiac conduction abnormalities. These may manifest at birth as sinus bradycardia or first-degree atrioventricular block and can progress to complete heart block without warning. Arrhythmias, such as atrial fibrillation, are also seen.

Evaluation

Both physical features and family history can help establish the diagnosis of Holt-Oram syndrome. Specifically, a family history of congenital heart malformations should warrant further investigation with an electrocardiogram and echocardiogram. In addition, upper limb x-rays can demonstrate various abnormalities. Finally, genetic testing looking for TBX5 mutations should be a consideration.

 In addition to using physical features to aid in the diagnosis, a lack of certain features are involved, the diagnosis is unlikely: head and face region, eyes, ear malformations or hearing loss, kidneys, vertebrae, lower limbs, or anus.[7][8][9]

Treatment / Management

The treatment of Holt-Oram syndrome is individualized and based on specific symptoms. In some cases, many providers are involved, including pediatricians, cardiologists, surgeons, and orthopedists.

Medications to consider depend on the specific cardiac defects. For example, if congestive heart failure is present, diuretics, angiotensin-converting enzyme inhibitors, beta-adrenergic antagonists, and cardiac glycosides may be warranted. 

Surveillance is critical and should include an annual electrocardiogram. If a patient has a conduction abnormality, an annual Holter monitor should be considered. Finally, those patients with septal defects should have an echocardiogram every one to 5 years.

Upper limb abnormalities may require corrective or reconstructive surgery in addition to physical and occupational therapy. Those with cardiac malformations may require medications, an artificial pacemaker, or surgical correction. Finally, psychosocial aspects should be addressed to allow the individual to reach his or her full potential and enjoy a satisfying quality of life.

During surgical procedures, prophylaxis must be considered to avoid complications of bacterial infective endocarditis and pericarditis. This includes simple procedures, such as tooth extractions, or more complex procedures, such as surgical repair of septal defects. Finally, individuals with Holt-Oram syndrome are more susceptible to respiratory infections and therefore should be monitored closely; there should be a low threshold for the initiation of antibiotics.

Differential Diagnosis

The following diseases or conditions can be mistaken for Holt-Oram syndrome and should be ruled out:

  • Heart-hand syndrome type II
  • Heart-hand syndrome type III
  • Duane-radial ray syndrome
  • Ulnar-mammary syndrome
  • Long thumb brachydactyly
  • Thrombocytopenia-absent radius syndrome
  • Teratogen exposure (thalidomide, valproate)

Prognosis

Life expectancy for Holt-Oram syndrome varies among affected individuals and predominantly depends on the severity of the congenital heart defect. However, patients who have intracardiac shunts need treatment otherwise they may develop the Eisenmenger syndrome later in life. 

Consultations

A cardiologist should be consulted to determine the need for anticoagulation, antiarrhythmics, surgery as well as antibiotic prophylaxis for bacterial endocarditis. Other possible consultations to consider include the family physician, orthopedic specialist, occupational therapist, physiotherapist, psychiatrist, psychologist, radiologist, pharmacist, and dietician.

Deterrence and Patient Education

All patients and family members should receive genetic counseling from a qualified clinician. It is imperative that the patient and his/her family is aware that Holt-Oram syndrome is an autosomal dominant disorder and that an affected individual has a 50% chance of having an offspring with the disorder. It should also be made known that the severity of the condition in a parent is not necessarily an indication of the potential severity in the patient's children.

Pearls and Other Issues

Holt-Oram syndrome also referred to as the heart-hand syndrome, is an autosomal dominant disorder that is distinguished by upper limb abnormalities in association with congenital heart lesions.

All patients and family members should receive genetic counseling from a qualified clinician.

Individuals with Holt-Oram syndrome are also at an increased risk for cardiac conduction abnormalities. These may manifest at birth as sinus bradycardia or first-degree atrioventricular block and can progress to complete heart block without warning. Arrhythmias, such as atrial fibrillation, are also seen.

Life expectancy for Holt-Oram syndrome varies among affected individuals and predominantly depends on the severity of the congenital heart defect. 

 

Enhancing Healthcare Team Outcomes

The treatment of Holt-Oram syndrome is individualized and based on specific symptoms. In some cases, many providers are involved, including pediatricians, cardiologists, nurse practitioners, surgeons, and orthopedists.

Medications to consider depend on the specific cardiac defects. For example, if congestive heart failure is present, diuretics, angiotensin-converting enzyme inhibitors, beta-adrenergic antagonists, and cardiac glycosides may be warranted. 

Surveillance is critical and should include an annual electrocardiogram. If a patient has a conduction abnormality, an annual Holter monitor should be considered. Finally, those patients with septal defects should have an echocardiogram every one to 5 years. The outlook of these patients depend on the severity of the defects and number of defects. If the cardiac defect is left untreated, it can lead to eisenmenger syndrome.[10]


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Holt Oram Syndrome - Questions

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Which congenital heart disorder is associated with Holt-Oram syndrome?



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Which of the following congenital heart diseases is most likely to be associated with absent radius syndrome?



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An infant is born with agenesis of the forearm resulting in the left hand originating at the elbow, low sloping shoulders, cardiac anomalies, a bifid thumb, and chest wall deformities. What is the most likely diagnosis?



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A mother brings her son to the emergency department with hand pain after he fell while riding his tricycle. Because the child was adopted, she is not able to provide much of a medical history. However, she does state that he had a murmur at birth and was being regularly followed by a pediatrician. An x-ray is ordered to rule out a fracture (see image below). Auscultation reveals a fixed split second heart sound. What type of congenital heart defect is he most likely to have?

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  • Image 6295 Not availableImage 6295 Not available
    Image courtesy S Bhimji MD
Attributed To: Image courtesy S Bhimji MD



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A 7-year-old presents as a new patient for care. Upon first glance, the young boy’s left upper extremity is abnormally pronated, and phocomelia is present. During the physical exam, there is a widely split and fixed S2 heart sound. An echocardiogram and upper extremity radiographs are ordered. The radiographs are done in the office and demonstrate a triphalangeal thumb and hypoplastic radius. What gene mutation is most likely to have caused this condition?



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Holt Oram Syndrome - References

References

Vanlerberghe C,Jourdain AS,Ghoumid J,Frenois F,Mezel A,Vaksmann G,Lenne B,Delobel B,Porchet N,Cormier-Daire V,Smol T,Escande F,Manouvrier-Hanu S,Petit F, Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. European journal of human genetics : EJHG. 2019 Mar;     [PubMed]
Ríos-Serna LJ,Díaz-Ordoñez L,Candelo E,Pachajoa H, A novel de novo {i}TBX5{/i} mutation in a patient with Holt-Oram syndrome. The application of clinical genetics. 2018;     [PubMed]
Arkoumanis PT,Gklavas A,Karageorgou M,Gourzi P,Mantzaris G,Pantou M,Papaconstantinou I, Holt-Oram Syndrome in a Patient with Crohn's Disease: a Rare Case Report and Literature Review. Medical archives (Sarajevo, Bosnia and Herzegovina). 2018 Oct;     [PubMed]
Spiridon MR,Petris AO,Gorduza EV,Petras AS,Popescu R,Caba L, Holt-Oram Syndrome With Multiple Cardiac Abnormalities. Cardiology research. 2018 Oct;     [PubMed]
Ross SB,Bagnall RD,Yeates L,Sy RW,Semsarian C, Holt-Oram syndrome in two families diagnosed with left ventricular noncompaction and conduction disease. HeartRhythm case reports. 2018 Apr;     [PubMed]
Shankar B,Bhutia E,Kumar D,Kishore S,Das SP, Holt-Oram Syndrome: A Rare Variant. Iranian journal of medical sciences. 2017 Jul;     [PubMed]
Aoki H,Horie M, Electrical disorders in atrial septal defect: genetics and heritability. Journal of thoracic disease. 2018 Sep;     [PubMed]
Vargesson N,Hootnick DR, Arterial dysgenesis and limb defects: Clinical and experimental examples. Reproductive toxicology (Elmsford, N.Y.). 2017 Jun;     [PubMed]
Virdis G,Dessole M,Dessole S,Ambrosini G,Cosmi E,Cherchil PL,Capobianco G, Holt Oram syndrome: a case report and review of the literature. Clinical and experimental obstetrics     [PubMed]
McDermott DA,He J,Song YS,Kligman I,Basson CT, Update: PGD and Holt-Oram syndrome. American journal of medical genetics. Part A. 2005 Jul 15;     [PubMed]

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