Pediatric Holt-Oram Syndrome

Holt-Oram syndrome (HOS) (OMIM 142900) is a heart–upper limb malformation complex with an autosomal dominant inheritance and near-complete penetrance but variable expression. Holt and Oram first described this syndrome in 1960. Approximately 40% of cases represent new mutations.

See the image below depicting Holt-Oram syndrome in an infant.

Photograph showing hypoplastic right thumb of the right hand of a 6-month-old infant with Holt-Oram syndrome.

Defective development of the embryonic radial ray (eg, aplasia, hypoplasia, fusion, other anomalous development) results in a wide spectrum of phenotypes, including triphalangeal or absent thumbs, foreshortened arms, and phocomelia. The syndrome is associated with defective development of cardiac structures that results in atrial septal defect (ASD), most commonly the secundum type (as shown below); heart block of varying degree; or both.[1]

A 2-dimensional echocardiographic picture taken from subxiphoid window showing a large secundum atrial septal defect (arrow) in a 7-year-old boy with Holt-Oram syndrome. ASD = Atrial septal defect; RA = Right atrium; RV = Right ventricle; LA = Left atrium; LV = Left ventricle.

The responsible gene has been mapped to band 12q24.1, which encodes the human transcription factor TBX5.[2, 3, 4] A full list of the described mutations is available at the TBX5 Gene Mutation Database, an online locus-specific database that contains germline and somatic mutations of the TBX5 gene. One of the recently added loci is c.373G>A, which results in the missense mutation p.Gly125Arg; this is a novel mutation, in that it is associated with a gain-of-function mechanism and is associated with paroxysmal atrial fibrillation and no structural heart disease.[5, 6, 7]

TBX5 genotyping has high sensitivity and specificity for Holt-Oram syndrome (HOS) if stringent diagnostic criteria are used in assigning the clinical diagnosis. Mutations of this gene introduce a premature stop codon and result in truncated protein versions. Consequent abnormal expression of the cardiac and limb-specific T-box transcription factors lead to the malformations described in HOS. The T-box gene family is a group of related genes that play a critical role in human embryonic development.[8, 9]

A cardiomelic developmental field has also been postulated to relate the genetic heterogeneity of HOS (and other similar syndromes) to a cascade of molecules, including the brachyury, sonic hedgehog, bone morphogenetic protein, retinoic acid receptor, and transforming growth factor beta families.

Disturbed fetal limb muscle development has also been reported and may underlie the bony malformations.

Expression widely varies in different generations. Ogur et al reported variable clinical expression of HOS in three generations.[10] The grandfather presented with phocomelia of arms, with three digits on each hand, congenital heart defect, and narrow shoulders. His son presented with cardiac conduction disturbance with no congenital heart or skeletal defect. His granddaughter developed ventricular septal defect (VSD) and moderate radial deviations of both hands, with no obvious hypoplasia of the extremities. Cachat et al reported a father and two sons in a French family with HOS who presented with different types of ASDs: ostium primum ASD, secundum ASD, and sinus venosus ASD, respectively.[11]

Malignant hyperthermialike manifestations have been reported in a 2-month-old child with HOS undergoing cardiac surgery; however, the association or mechanism has yet to be identified.[12]

United States data

The incidence rate of Holt Oram syndrome (HOS) is unknown.

International data

In a 2014 report, 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.[13]

In Hungary, the birth prevalence is 0.95 per 100,000 total births. About 350 cases have been reported worldwide. A report identified this syndrome in 4% of patients with radial longitudinal deficiency.[14]

Race-, sex-, and age-related demographics

No valid racial data are available.

Both sexes are equally affected, although the defects tend to be more severe in females.

HOS malformations are present at birth. Age at presentation varies according to the extent of the abnormality externally visible and the type of associated heart defect, if any.

Prognosis in patients with Holt-Oram syndrome (HOS) is dictated by the severity and type of cardiac and limb malformations. Because the most common defect in HOS is atrial septal defect (ASD), the prognosis is excellent.[15]

A scoring system to assess severity has been recommended by Gall et al and modified by Gladstone and Sybert (see Presentation).

Mortality/Morbidity

No valid figures are available because the condition, in and of itself, has no specific mortality or morbidity. The mortality and morbidity relate directly to the associated congenital abnormalities, particularly those of the heart. For example, mortality and morbidity of a secundum atrial septal defect (ASD) is negligible throughout childhood, including patients who undergo procedures to close the ASD. Please see the appropriate respective articles for mortality and morbidity figures on specific cardiac defects.

Causes of death include cardiac malformation and heart block. See the respective article for each cardiac abnormality for a discussion of cause of death.

Complications

Complications secondary to heart disease and heart failure include tachyarrhythmia, especially atrial fibrillation[5, 16]  and conduction abnormalities place patients at special risk during anesthetic procedures.

Complications secondary to limb malformation include the following:

• Those secondary to interventions that may be required

• Contractures and deformity

Psychological problems may arise secondary to disability.

Parents and patients

Parents and patients should understand the various manifestations and should undergo genetic counseling. Note the following:

• In any child with atrial septal defect (ASD), the patient and parents should be carefully examined for limb malformations, and a family history should be studied in detail.

• Detection of subtle limb defect alters the recurrence risk in offspring from the empirical risk of an isolated ASD (3%) to that for an autosomal dominant trait (50%).

Patient should avoid any activity beyond tolerance as well as avoid postures that might lead to deformities.

Prenatal counseling

Note the following:

• Prospective parents should be alerted to the fact that a child born with Holt-Oram syndrome to an affected parent has a 1 in 3 chance of having a severe reduction abnormality of the upper limb, with a 1 in 22 risk of phocomelia.

• If an ASD is present, the risk of serious limb abnormality is greater than if a VSD or conduction defect occurs alone.

• Severity is likely to be greater if the transmitting parent is female.

• The detection of a severe reduction defect before or after birth indicates a high probability of an associated structural cardiac lesion.

Clinical features of Holt-Oram syndrome (HOS) vary depending on the severity of the cardiac and limb malformation.[17, 18] Note the following:

• Individuals with more severe congenital heart defects may present in the neonatal period. Abnormalities may also be detected in utero using fetal ultrasonography and fetal echocardiography.

• Cardiac symptoms depend on the type of congenital heart defect. Atrial septal defect (ASD), the most common heart defect in HOS, causes no symptoms in the vast majority of affected individuals.

• Severity of cardiac and limb malformations appears to be positively correlated in some studies; however, this has not been replicated in other studies.

• In any sporadic case of ASD, the patient and parents should be examined for limb malformations, and the family history should be studied in detail.

Physical findings may include musculoskeletal and/or cardiac defects. Intelligence in patients with Holt-Oram syndrome (HOS) is normal.

Musculoskeletal defects

Note the following:

• Upper limbs are usually affected, although the importance of isolated lower limb involvement associated with specific mutations has been reported.[1]

• Although bilateral, the left side is often more significantly affected.

• The most severe form is phocomelia with rudimentary limbs.

• Mildest forms include clinodactyly, limited supination, and sloping shoulders.

• The most common defects include radial thumb anomalies ranging from absent thumbs to displaced (distally placed), duplicated, or triphalangeal thumbs. Carpal and metacarpal anomalies (especially the fourth) may also be present. Refer to the following images.

  Photograph of the left hand of a 6-month-old infant with Holt-Oram syndrome showing total aplasia of the left thumb.

  Photograph showing hypoplastic right thumb of the right hand of a 6-month-old infant with Holt-Oram syndrome.

• Hypoplasia of the radius manifests as short deformed forearm, although it may be so mild that it is detectable only on radiography of the forearm (see image below)

  Plain radiograph of the right forearm and hand of a 5-month-old infant with Holt-Oram syndrome showing hypoplastic radius and ulna and only 4 metacarpals.

• Sprengel deformity (upward displacement of the scapula) and hypoplasia of the shoulders, clavicles, and humerus have also been reported.

• The number and location of hypoplastic muscles correlate with the severity of skeletal involvement. Accordingly, patients with hypoplasia of large and proximal muscles have phocomelia, and those with intrinsic hand muscle hypoplasia have only a triphalangeal thumb or no skeletal malformation.

• Associated muscular hypoplasia that involves the hypothenar, wrist extensor, supinator, biceps brachii, triceps brachii, deltoid, pectoral, and trapezium muscles has also been reported.

• Isolated (sporadic) patients have more severe involvement, which can include the ulnar ray.

Heart defects

Note the following:

• The reported incidence ranges from 50-95%.

• The most common lesion is a secundum astrial septal defect (ASD). Others include ventricular septal defect (VSD), atrioventricular (AV) block, pulmonic stenosis (including peripheral arterial), and mitral valve prolapse.

• Approximately 17% of patients have more complex cardiac malformations, such as tetralogy of Fallot, hypoplastic left heart syndrome, endocardial cushion defects, and truncus arteriosus. Cardiac arrhythmias include paroxysmal atrial tachycardia, prolonged PR interval, wandering atrial pacemaker, atrial ectopics, AV block, and sinus bradycardia. Syncope and sinus arrest have been reported. Multiple VSDs have also been reported.

• According to Mglinets, "a specific feature of the syndrome is a change in the main palmar lines and their termination on the radial border of the hand not only in the absence of the thumb but also in the case of formation of the abortive xT-line, its radiants, and the axial triradius."[19]

• Pulmonary hypoplasia has occasionally been reported and can present with neonatal respiratory distress.[20, 21] No other associated visceral anomaly has been reported.

• Occasionally left ventricular non-compaction may be associated with Holt-Oram syndrome. ^[22]

A scoring system to assess severity of Holt-Oram syndrome (HOS) anomalies has been recommended by Gall et al and modified by Gladstone and Sybert. These are outlined below.

Skeletal defects

A scoring system to assess skeletal abnormalities in HOS is as follows:

• 0 - No abnormality on physical or radiological examination

• 1 - Minor abnormalities, including reduced thenar eminence, clinodactyly, or hypoplasia of the thumb

• 3 - Present arms and forearms, with one or more bones missing

• 4 – Phocomelia

Cardiac defects

A scoring system to assess cardiac abnormalities in HOS is as follows:

• 0 - Asymptomatic, with no abnormal physical findings

• 1 - Conduction defect

• 2 - Structural heart abnormality that does not require surgery

• 3 - Structural heart abnormality that requires surgery but is not life threatening

• 4 - Potentially lethal malformation

Blood tests are required for molecular genetics in patients with Holt-Oram syndrome (HOS) and for management, because the cardiac anomaly present may be a major one that causes and cause symptoms or requires intervention.

Imaging studies of upper limbs

Note the following:

• The scapula may be raised and small, with abnormalities at the acromial region, a prominent coracoclavicular joint, and a small glenoid fossa.

• The humerus may be hypoplastic or absent in patients with phocomelia. In other patients, the medial epicondyles are large and the humeral head may be deformed with epiphyseal irregularities. Radioulnar and humeroulnar synostosis, radial hypoplasia or absence, and ulnar absence are all reported.

• Scaphoid anomalies are particularly common and include hypoplasia and bipartite ossification. In the normal fetus, a scaphoid bone called the os central (representing a third row of carpal centres) usually fuses with the scaphoid, but this may not occur in patients with Holt-Oram syndrome (HOS).

• Additional carpal bones may be present. Other carpal anomalies include absence, hypoplasia, enlargement, irregularity, and fusion.

• The first through fifth metacarpals may have both proximal and distal epiphyses. Structural changes such as hypoplasia may be present.

Chest radiography

Chest radiography findings are either normal or reflect the type of cardiac abnormality.

Doppler-echocardiography evaluation

Doppler echocardiography (ECHO) is used to reveal the primary heart defect, its severity, and associated cardiac malformations. It also allows estimation of certain hemodynamic values, such as blood flows and chamber size and pressure. Doppler ECHO studies are extremely useful in identifying the cardiac defects (eg, atrial, septal defect, ventricular septal defect) and quantitating the severity of the defects.

Doppler ECHO is an integral part of echo-Doppler study and is indicated in patients at any age with a skeletal abnormality suggestive of HOS, as depicted below.

Color Doppler echocardiographic picture taken from subxiphoid window showing the large left-to-right flow of blood (arrow) across the atrial septal defect. The red color pattern depicts flow direction from left atrium (LA) to right atrium (RA). ASD = Atrial septal defect; RA = Right atrium; RV = Right ventricle; LA = Left atrium; LV = Left ventricle.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is helpful for delineating cardiac and skeletal involvement, but it may not be necessary in all cases. MRI may also be used to confirm muscular hypoplasia and to help distinguish the muscle involvement from those of any coexisting progressive neuromuscular disorders.

Electrocardiography

Electrocardiography (ECG) reveals the features of the underlying heart defect. The most common defect, secundum atrial septal defect  (ASD), usually demonstrates right atrial enlargement and right ventricular enlargement.

Cardiac rhythm disturbances include both tachyarrhythmia and bradyarrhythmia. Prominent among these are heart blocks (first-, second-, or third-degree), wandering atrial pacemaker, and sinus bradycardia.

Twenty-four–hour Holter ECG

Twenty-four hour Holter ECG reveals paroxysmal tachycardia, especially atrial tachycardia. Occasional sinus pauses or sinus arrest is found.

This test is especially important in patients with a history of syncope.

Karyotyping and molecular studies

Detailed cytogenetic analysis may help to map the breakpoints within the critical area of 12q.

This study requires a combination of chromosome painting and fluorescent in situ hybridization (FISH) with yeast artificial chromosomes (YAC) and cosmids.

Prenatal diagnosis

Note the following:

• Amniocentesis and chorionic villus biopsy may be indicated based on the family history.

• Fetal ultrasonography may reveal a skeletal abnormality suggestive of HOS.

• Prenatal diagnosis is feasible in families with HOS linked to band 12q2.

• DNA-based diagnosis must be coupled with noninvasive fetal imaging techniques to define phenotypic manifestations.

Cardiac catheterization and angiography

Cardiac catheterization and angiography are performed in selected patients in whom echocardiographic findings are either inconclusive or more accurate hemodynamic assessment is considered necessary. Findings reflect the specific cardiac abnormality. Cardiac catheterization is an integral part of transcatheter occlusion of atrial septal defects if there are adequate septal rims.

Complications during the procedure may include blood vessel rupture, tachyarrhythmias, bradyarrhythmias, and vascular occlusion, but these are uncommon. Postcatheterization problems are rare but include hemorrhage, vascular disruption after balloon dilation, pain, nausea and vomiting, and arterial or venous obstruction due to thrombosis or spasm.

Acute-stage management in patients with Holt-Oram syndrome

Treatment is directed at the cardiac manifestations. Care may be necessary with exacerbations of heart failure, for interventional procedures, or for surgical correction of heart disease. Administer medications as dictated by the heart disease.

Establish a complete diagnosis, and counsel the patient and family.

Consultations

Consult with the following:

• Pediatric cardiologist

• Orthopedic specialist

• Radiologist

• Nuclear medicine specialist

• Family physician

• Occupational therapist

• Physiotherapist

• Psychologist

• School teacher

• Specialist nurse

• Pharmacist

• Dietitian

Transfer

Transfer may be necessary for further evaluation and surgical or transcatheter intervention.

Diet and activity

Patients with Holt-Oram syndrome may require dietary modification because of their specific cardiac abnormality.

No activity restrictions are required unless a specific cardiac abnormality indicates otherwise.

Outpatient monitoring

Regular follow-up is essential for both cardiac and skeletal conditions. The patient should be seen by orthopedic and occupational therapists, as well as by physiotherapists.

At each visit, the importance of prevention of deformity must be emphasized.

Cardiac defect

Treatment for the heart defect includes the following:

• Appropriate surgical or nonsurgical correction of the heart defect is indicated and possible. A vast majority of atrial septal defects may be closed by transcatheter methods.

• Palliative surgery, as indicated, if complete correction is not possible

Musculoskeletal defects

Treatment for musculoskeletal defects may include the following:

• Take adequate measures to prevent acquired deformities and to treat existing deformities.

• Surgical management of hand anomalies depends on the age, pattern, and degree of accompanying malformations of the upper limb.

• Pollicization to improve function of index finger is recommended for patients with aplasia of the thumb. This is also recommended following amputation of a rudimental thumb.

The specific cardiac defect and its effects dictate appropriate therapy. For example, treatment of congestive heart failure may include diuretics, an ACE inhibitor, and digoxin. Iron supplements are appropriate in patients with cyanotic heart disease.

Bacterial endocarditis prophylaxis is administered to patients with Holt-Oram syndrome (HOS) based on the specific cardiac condition. An isolated secundum atrial septal defect (ASD) does not require this treatment. For more information, see Antibiotic Prophylactic Regimens for Endocarditis.

Class Summary

These agents eliminate retained fluid and lower preload.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. DOC in acute heart failure and in exacerbations of CHF. Used for the long-term management of CHF.

Spironolactone (Aldactone)

A potassium-sparing diuretic. For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Amiloride (Midamor)

Potassium-sparing diuretic that acts directly on the distal renal tubule. Usually used along with a potassium-losing diuretic.

Class Summary

These agents reduce afterload and decrease myocardial remodeling that worsen chronic heart failure.

Captopril (Capoten)

Widely accepted as an essential part of CHF treatment. Improves symptoms and prolongs survival. Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Class Summary

These agents improve symptoms, exert a positive inotropic effect on both the normal and failing heart, and are mediated through inhibition of transmembranous active transport of sodium and potassium. Clinically important actions are on the sinoatrial (SA) and AV nodes. Cardiac glycosides increase efferent vagal impulses, reflexly reduce sympathetic tone, and decrease the sinus rate. They decrease conduction velocity through the AV node.

Digoxin (Lanoxin)

Improves myocardial contractility, reduces heart rate, and lowers sympathetic stimulation in chronic heart failure.

Class Summary

These agents relieve infundibular spasm in hypercyanotic spells.

Propranolol (Inderal)

Inhibits both beta1- and beta2-adrenergic receptors. The exact mechanism of benefit is uncertain, although it is believed to relieve infundibular spasm that precipitates hypercyanotic spells.