Educational Information - Genetics

Goals and Objectives:
- Understand the major presenting symptoms of Holt-Oram Syndrome (HOS)
- Describe the genetics and mode of transmission of HOS
- Be able to provide genetic counseling to patients and family with HOS
- Be able to clinically manage patients with HOS

Case Study:
A newborn female is referred to your pediatric cardiology clinic by her primary physician. The primary pediatrician had noted a murmur on the cardiac exam and fusion of the second and third carpal bone of the left hand on x-ray. Family history is significant for a maternal uncle who had similar features. An electrocardiogram and an echocardiogram are ordered; these tests reveal that the patient does indeed have a murmur—an ASD. What should you, as the cardiologist do next? How should you guide the family?

HOS is estimated to occur in about 1/100,000 live births. It has been reported from a number of countries worldwide, in individuals of varying racial and ethnic backgrounds. Both sexes are affected equally, although the defects tend to be more severe in females. The syndrome itself has no mortality. The morbidity and mortality relates directly to the associated congenital abnormalities, particularly cardiac. For example, mortality and morbidity of a secundum atrial septal defect (ASD) is negligible throughout childhood including those patients undergoing a procedure to close the ASD. Causes of death most often include cardiac malformation and heart block.

HOS is also known as the heart-hand syndrome. The natural history of HOS varies and is largely dependent on the severity of the congenital heart malformation. Individuals with more severe congenital heart defects may even present in the neonatal period often detected in utero by fetal ultrasound echocardiography. Malformations are first detected at birth. Upper-limb malformation most often involves the radial, thenar, or carpal bones. These malformations are variably expressed, and may be unilateral or bilateral. Upper-limb malformations can include: absent thumb(s), phocomelia (the hands are attached close to the body), unequal arm length (from aplasia), hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, and sloping shoulders and restriction of shoulder joint movement. Abnormalities are often more severe in the left upper limb than in the right upper limb. All affected individuals have, at a minimum, an abnormal carpal bone, which can be the only evidence of disease, identified by performing a PA hand X-ray.

In addition to upper-limb malformations, individuals with HOS can also have congenital heart malformations. Seventy-five percent of individuals with HOS have a congenital heart defect. The defect most commonly seen is ostium secundum ASD and muscular septal VSD. Whether or not individuals have a heart defect, patients with HOS are at risk for cardiac conduction disease. Patients may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, which can progress to complete heart block with and without atrial fibrillation. Cardiac arrhythmias also seen include paroxysmal tachycardia, prolonged PR interval, wandering atrial pacemaker, and atrial ectopies. Complications, which can be life threatening if not recognized and appropriately managed, include: congestive heart failure, pulmonary hypertension, arrhythmias, heart block, atrial fibrillation, and infective endocarditis. Some individuals with severe congenital heart malformation may require surgery early in life to repair significant septal defects.

Because HOS is a clinical diagnosis, HOS can be excluded in individuals with congenital malformations involving the following structures or organ systems: kidney, vertebra, craniofacies, auditory system (hearing loss or ear malformations), lower limb, anus, or eye.

A scoring system to assess severity on an individual with HOS has been recommended by Gall et al and modified by Gladstone and Sybert.

Table 1. Scoring System to Assess Skeletal Abnormalities in Holt-Oram Syndrome

0	No abnormality on physical or radiological examination
1	Minor abnormalities, including reduced thenar eminence, clinodactyly or hypoplasia of the thumb
2	Triphalangeal or aplastic thumbs, radial/ulnar hypoplasia
3	Arms and forearms present but with bone(s) missing
4	Phocomelia

Table 2. Scoring System to Assess Cardiac Abnormalities in Holt-Oram Syndrome

0	Asymptomatic, with no abnormal physical findings
1	Conduction defect
2	Structural heart abnormality not requiring surgery
3	Structural heart abnormality requiring surgery, but not life threatening
4	Potentially lethal malformation

S1 is split, and the S2 component may be increased in intensity, reflecting forceful right ventricular contraction and delayed closure of the tricuspid leaflets. ASDs with moderate-to-large left-to-right shunts produce a pulmonary outflow murmur that begins shortly after the S1, peaks in early-to-mid systole and ends before the S2. S2 is also widely split and fixed because of the delayed pulmonic valve closure (in almost all patients with large left-to-right shunts). Increased right ventricular stroke volume across the pulmonary outflow tract creates a crescendo-decrescendo midsystolic (ejection) murmur in the second interspace at the left sternal border. Patients with large left-to-right shunts may also have a rumbling middiastolic murmur at the lower left sternal border because of increased flow across the tricuspid valve.

HOS is transmitted in an autosomal dominant manner. The gene involved in this syndrome is TBX5 on chromosome 12q24.1.

TBX5 functions as a transcription factor in the T-box gene family, that has an important role in both cardiogenesis and limb development. Over 30 mutations have been described, ranging from missense, nonsense mutations to large deletions. It is hypothesized that most nonsense and frameshift mutations lead to mutant TBX5 mRNAs that are degraded with resulting haploinsufficiency or that some missense mutations result in transcripts that have diminished DNA binding activity. Both result in a reduced TBX5 gene dose, which leads to HOS. Consequent abnormal expression of the cardiac and limb-specific T-box transcription factors lead to the malformations described in HOS.

Genetic testing can be useful in identification of at-risk family members for appropriate cardiac management, and genetic counseling which may be useful for predicting recurrence risks for future offspring of affected individuals. Some individuals diagnosed with HOS have an affected parent. In a patient found to have HOS, even if it appears to be de novo, evaluation of the parents should be undertaken to prevent complications in both the parents, and for future progeny. Evaluation should include echocardiography, ECG, and hand x-rays to determine their affected status. Additionally, molecular genetic testing can be performed on the parents if the TBX5 mutation in the child has been identified.

Siblings of patients affected with HOS depends upon the genetic status of the parents. If a parent is affected, the risk to the siblings is 50%. If the parents are clinically unaffected and do not have a disease-causing mutation, the risk to the siblings is low (similar to the general population risk). Offspring of affected patients are at 50% risk of being affected. Because of the effects of modifying genes and the significant variable expressivity observed in individuals with HOS, the phenotype of affected offspring cannot be accurately predicted. The risk to other family members depends upon the status of the patient’s parents. If a parent is found to be affected, his or her family members are at risk.

The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. DNA banking can be utilized for future use to study genes of affected family members. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA. In pregnancies at 50% risk, detailed high-resolution prenatal ultrasound examination may detect upper-limb malformations and/or congenital heart malformations. However, a normal ultrasound examination does not eliminate the possibility of HOS in the fetus. Prenatal testing for HOS may be most useful in families with a known mutation to confirm ultrasound findings.

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted by amniocentesis performed at about 15-18 weeks' gestation. Because of the significant variable expressivity observed in individuals with HOS, both within and among families with the same mutation, the severity of upper-limb defects and congenital heart malformations cannot be accurately predicted by molecular genetic testing alone.

The management of individuals with HOS should involve a multidisciplinary team approach, including specialists in medical genetics, cardiology, and orthopedics, including a specialist in hand surgery. A cardiologist can assist in determining the need for antiarrhythmic medications and surgery. Individuals with severe heart block may require pacemaker implantation. Pharmacologic treatment for affected individuals with pulmonary hypertension may be appropriate. Individuals with pulmonary hypertension and/or structural heart malformation may require tertiary care center cardiology follow-up. The orthopedic team may help decide options for surgery for improved upper limb and hand function, as well as physical and occupational therapy options. Those individuals born with severe upper-limb malformations may be candidates for surgery such as pollicization (creation of a thumb-like digit by moving another digit into the thenar position). Children with severe limb shortening may benefit from prostheses.
For preventative measures anticoagulants and antibiotic prophylaxis for bacterial endocarditis (SBE) can be administered in patients with congenital heart malformations.

Resources for patients:
National Library of Medicine Genetics Home Reference
Holt-Oram syndrome
American Heart Association
National Center
7272 Greenville Avenue
Dallas TX 75231
Phone: 800-AHA-USA-1 (800-242-8721)
www.americanheart.org
Congenital Heart Information Network (CHIN)
1561 Clark Drive
Yardley PA 19067
Phone: 215-493-3068
Email: mb@tchin.org
http://www.tchin.org/
Reach: The Association for children with Hand or Arm Deficiency
PO Box 54
Helston
Cornwall TR13 8WD
United Kingdom
Phone: (+44) 0845 1306 225
Fax: (+44) 0845 1300 262
Email: reach@reach.org.uk
www.reach.org.uk

Hunt, SA, Abraham, WT, Chin, MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005; 112:e154.

Gall J.C, Stern A.M, Cohen M.M, Adams M.S, Davidson R.T. Holt-Oram syndrome: clinical and genetic study of a large family. Am. J. Hum. Genet. 18: 187-200, 1966.

Gladstone I, Sybert V.P. Holt-Oram syndrome: penetrance of the gene and lack of maternal effect. Clin. Genet. 21: 98-103, 1982.

Venugopalan P (2006). Holt-Oram Syndrome. Retrieved August 23, 2006 from http://www.emedicine.com/ped/topic1021.htm#section~author_information.