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A genetic syndrome with limb reduction defects characterized by skeletal abnormalities of the upper limbs and mild-to-severe congenital cardiac defects.
ORPHA:392Classification level: Disorder
Holt-Oram syndrome (HOS) prevalence is estimated at 1/ 100,000 live births (in Hungary), but various cases have been published worldwide.
The clinical picture of HOS covers a wide spectrum of upper extremity defects, always including the radial ray, and cardiac defects. Radial ray upper limb anomalies include carpal bone malformation(s) as well as triphalangeal or absent thumb(s), phocomelia, hypoplasia or aplasia involving the radius often resulting in unequal arm lengths, transverse upper limb defects including abnormal forearm pronation and supination. Patients may have more severe left than right upper-limb abnormalities. Most frequent congenital cardiac malformations observed are atrial septal defect, ostium secundum type (ASD) and ventricular septal defect (VSD). Conduction abnormalities like paroxysmal atrial fibrillation, sometimes associated with various degrees of atrioventricular block, have been reported. Other variable anomalies reported include craniofacial, axillary, tracheal, vertebral and lower-limb anomalies, as well as deafness, abdominal situs inversus and renal abnormalities, but in many cases these findings reflect phenocopy syndromes rather than HOS itself.
HOS is caused by a mutation in the TBX5 gene located on the long arm of chromosome 12 (12q24.1). The TBX5 gene encodes T-box5, a transcription factor regulating the expression of other genes in developing heart and limbs. More than 85% of the clinically diagnosed HOS individuals carry a TBX5 mutation.
Diagnosis of HOS is based on clinical findings and family history. It can be confirmed by molecular genetic analyses.
Differential diagnosis includes heart-hand syndrome type 2, heart-hand syndrome type 3, brachydactyly-long thumb, SAL4-related disorders (Okihiro and acro-renal-ocular syndrome), ulnar-mammary syndrome, Slovenian type heart-hand syndrome, Fanconi anemia, distal 22q11.2 microdeletion syndrome, VACTERL association, thalidomide embryopathy, fetal valproate syndrome.
Prenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known HOS mutation. In women with HOS, cardiac defects should be evaluated by a cardiologist to determine what monitoring and care may be needed during pregnancy.
The majority of the HOS mutations occur de novo. HOS is inherited in an autosomal dominant manner with complete penetrance for upper-limb malformations, and 75% penetrance for congenital heart malformations and with variable expressivity leading to a wide spectrum of phenotypes. Genetic counseling should be offered to parents with a TBX5 mutation informing them of their 50% risk of transmitting it on to their children. Molecular genetic testing is not sufficient to precisely predict the severity of upper-limb and congenital heart anomalies.
Management and treatment
Management is multidisciplinary and includes geneticists, cardiologists, orthopedic surgeons and pediatric orthopedics as well as social support networks. Patients with advanced heart block may require a permanent pacemaker. An echocardiogram is recommended every one to five years if cardiac defects are present. Electrocardiograms (EKGs) are recommended annually for adults.
Prognosis is variable. Functional impact in everyday life is based on the type and severity of upper-limb anomalies. Life expectancy depends on the severity of cardiac anomalies.
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