Holt Oram Syndrome

What is Holt Oram Syndrome?

Holt Oram syndrome is an hereditary disorder described as heart-hand syndrome. The syndrome is related to the deformity of the upper limb and heart. The upper limb or hand related deformity is due to abnormal bone formation. In some cases, the deformity is not noticeable and detect only In X-Ray plate, whereas some individuals have distinct abnormalities, including an absent thumb, an extended thumb that is similar as a finger, incomplete development of the forearm due to complete or partial missing of bones,  a stunted bone of the upper arm, and defective shoulder blades or clavicle (collar bone). The mentioned skeletal system related problems may limit in one hand or both the hands affect.

Including with these abnormalities, additional problems are related to the heart. This increases the life risk. In Holt Oram syndrome, the separating partition between right and left side chambers i.e septum has a hole. Bradycardia, arterial fibrillation, coordination problem between arterial and ventricular chambers are common heart related problems arise in Holt Oram syndrome. ^(1,2,4)

Prevalence

The incidence rate is quite rare. Only one child had diagnosed with Holt oram syndrome among 10,0000 live birth.  ⁽³⁾

Signs & Symptoms

Some typical cardiac sign and symptoms related to Holt Oram syndrome are as follows:

• Congenital heart malfunctioning due to septal defect.
• The defective septal at upper portion causes an atrial septal defect (ASD)
• The defective septal at lower portion causes ventricular septal defect (VSD).
• Cardiac arrhythmia or irregular heart beat is common in ASD due to excessive workload in the right atria. The included symptoms are slow physical development, shortness of breath, tremendous fatigability after little physical exercise, and/or irregular heartbeats.
• VSD is more life threatening, as ventricles are responsible for pumping out blood and maintain the circulatory system. The size of the hole is very important for VSD. Large size Hole can cause congestive heart failure. The included symptoms are chest pain, heart failure, rapid heartbeat (tachycardia), breathlessness, fast and laborious breathing, excessive sweating and other related symptoms. VSD can cause lung damage.
• Abnormal ECG findings are common in Holt Oram syndrome with or without congenital heart malformation.
• Skeletal system related abnormality is quite common with Holt Oram syndrome. The abnormality is majorly found in thumb and wrist bones. The positional alteration of thumb, and deform shoulder and upper arm are also included symptoms.

• The abnormality in hand bones may develop in one hand or both the hands and cause hand extension difficulty, abnormal forearm rotation, palm positioning alteration; short arm size and abnormal wrist are common symptoms. ^(2,4)

Causes

Holt Oram syndrome is caused by an abnormal genetic mutation, developed in the TBX5 gene present in the chromosome 12 (12q24.1). The T-box5 is a gene encodes of TBX5. De novo types of genetic mutations occur in Holt Oram syndrome.

The TBX5  is responsible for genetic development of the heart and upper limbs. The abnormal mutation leads to  atypical transcription factor regulation of the gene expression present in cardiac and upper limbs.  The abnormal TBX5 genetic mutation finding is common in almost 85% HOS diagnosed individuals. ⁽³⁾

Diagnosis

• The initial findings is depends upon physical examination and clinical presentation of the patient.
• Expert team also considers the family history during detail diagnosis.
• X-ray is performed to diagnose the exact bone deformity in the upper limb

• Electrocardiogram, Eco-cardiogram, MRI and CT scan are ordered to get different images to conclude the heart related problems.
• Molecular genetic analysis confirmed the abnormal genetic findings.
• Prenatal diagnosis of heart abnormality is diagnosed after conducting the ultrasound of the fetal heart in affected parent. ^(3,4)

Management

A Management plan is estimated depending upon the severity of the symptoms. Usually a multidisciplinary expert team has needed to take care of this type of cases. The included expert team members are cardiologists, pediatric orthopedics, orthopedic surgeons, geneticists, and social support networks. The severe cardiac arrhythmia, which leads to heart block can be corrected by insertion of an artificial permanent pacemaker. Yearly electrocardiograms gram recording is required to estimate the patient’s heart condition. An echocardiogram is recommended depending upon the cardiac findings.

The complete cure is not possible; but supportive treatment depending upon the severity of the abnormality can provide better outcomes. The available  supportive treatment for Holt Oram syndrome are an artificial replacement of forearm, thumb, prosthetic limb attachment, etc.  Physiotherapy can improve the immovability or hand extension problem.

In most of the cases Genetic counseling is recommended to the parents and detail knowledge a TBX5 mutation abnormality is discussed and also inform them that 50% chance of genetic transmitting is possible on their next generations. ^(3,4)

Prognosis

Treatment prognosis is not same in every cases.  A variable result obtained depending upon the severity of the symptoms  varies. The daily activity related difficulties depend upon the type and extend of hand related abnormality. ⁽³⁾

Life Expectancy

Variable life expectancy occurs in Individuals affected with the Holt Oram syndrome. One of the major causes of variability of life expectancy is due to the severity of heart related abnormalities are not same in every case.⁽³⁾

References

1. Craig T Basson (2016); Holt-Oram Syndrome; Retrieve from: http://emedicine.medscape.com/article/159911-overview
2. Holt-Oram syndrome; Genetic Home References; https://ghr.nlm.nih.gov/condition/holt-oram-syndrome#diagnosis
3.  Holt Oram Syndrome; National Organization for Rare Disorders; Retrieve from: http://rarediseases.org/rare-diseases/holt-oram-syndrome/
4. Dr Craig BASSON (2013); Holt-Oram syndrome; Orphanet; Retrieve from: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=392
5. www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=392
6. circ.ahajournals.org/content/99/10/1395
7. https://www.dovemed.com/diseases-conditions/holt-oram-syndrome/
8. https://en.wiktionary.org/wiki/Holt-Oram_syndrome
9. https://www.fulgentgenetics.com/Holt-Oram-Syndrome
10. https://www.genedx.com/test-catalog/disorders/holt-oram-syndrome/