Hospital Central Universitario “Antonio María Pineda”. Barquisimeto. Estado Lara. Venezuela

Holt-Oram Syndrome. Five Patients in the Same Family.
Héctor G Quiroga P. MD, Yormar Ottolina MD

Holt-Oram Syndrome was first described in 1960 as an association of familial heart disease and musculoskeletal abnormalities. The most important findings include atrial septal defects, atrioventricular conduction abnormalities, vascular hypoplasia and upper limb musculoskeletal deformities. We report five patients with this syndrome in the same family.

In 1960, Mary Holt and Samuel Oram¹ described this syndrome for the first time, since then about 200 cases had been reported. The presence of both, cardiac and skeletal abnormalities has inspired a series of names for this syndrome, such as "heart-hand syndromeâ€, "heart upper limb syndrome†and "upper limb cardiovascular syndromeâ€, among others. McKusick² created the name Holt-Oram syndrome when describing a case in which a mother and her daughter were affected.
Holt-Oram syndrome is an autosomal dominant disorder, caused by mutation on chromosome 12q24.¹³ that inactivated the TBX5 gene. The criteria for diagnosing this syndrome include abnormalities of the thumb (triphalangia, hypoplasia or aplasia) and congenital heart disease. The most frequent cardiac abnormalities are atrial-septal defects and arrhythmias.

Patient 1- A 6-year-old patient who was taken by her mother to the cardiologist when she was 6 month for cyanotic spell while crying. An echocardiography was performed and the findings were: situs solitus, congenital cardiopathy type ostium secundum, partial anomalous pulmonary venous connection, interventricular muscular communication and severe pulmonary arterial hypertension with poor response to oxygen. Radiology: Left Upper Limb: absent humerus and radius, absence of 5 carpal bones, absent of two metacarpals bones. Right upper limb: Absent thump and five metacarpal bones

Patient 2 - A 56 years old patient with AV Block that needed a pacemaker and mild anomalies in the upper limbs: Bilateral radius - ulnar synostosis, short clavicles and hypoplastic thenar eminence in both hands.

Patient 3 - A 30 years old patient with an unspecified cardiopathy, bilateral radio-ulnar synostosis, absence of the left hand thumb, hypoplastic right hand thumb and also short clavicles

Patient 4 - An 11 year old patient with a systolic murmur grade II/IV, short clavicles and thumb malformations in both hands.

Patient 5 - A 30 year old patient with a systolic murmur grade II/IV, bilateral radio-ulnar synostosis and malformation if the thumb of the left hand.

The Family background and genealogy demonstrate that there were members affected in three different generation: "vertical transmission pattern" , patients of both sexes show the disease with different kind of severity, so the Dominant Autosomal pattern of transmission of the disease is confirmed.

Discussion
Starke et al⁴, and Gall et al⁵ published some reports on Holt-Oram syndrome occurring in families, but the literature also provides isolated cases reports. More recently, the studies have been focusing on the genetic study of this condition, associating the morphological abnormalities with a mutation on an autosomal dominant gene (TBX5), which resides on the long arm of the chromosome 12q24.^1. Until now, the correlation between the severity of the upper limb abnormalities and the cardiac abnormalities could not be established.

The most common cardiac anomaly is an atrial septal defect, secundum type, but ostium primum ASD, VSD, and mitral and pulmonic stenosis, mitral valve prolapse, patent ductus arteriosus, anomalous pulmonary venous return, conduction defects, hypoplastic pulmonary artery, tetralogy of Fallot, coarctation of the aorta, aortic arch malformations, replaced subclavian artery, transposition of the great vessels have been described.

Skeletal defects affect the upper limb exclusively. Limb defects are always bilateral and often asymmetric, the left side more severely affected⁶.. Thumbs may be triphalangeal (finger-like) and non-opposable, hypoplastic, or even completely absent. Thenar abnormalities included distal displacement of the thenar eminence. Some patient's defects are detectable only by radiography. Therefore, clinical recognition of limb anomalies in patients with Holt-Oram syndrome with subtle defects can be difficult. Ponanski et al demonstrated the carpal abnormalities, eg extra carpal bones, are more specific than are the changes in the thumb. In some cases the thumb are normal ⁷, and limited supination of the forearm may be the only anomaly.
 In some cases, the involvement of the arm is more extensive, including narrow, sloping shoulders, hypoplastic clavicles and shortened radii. Ulnar hypoplasia occurs only in those patients with radial defects. In severe cases, phocomelia and ectromelia is observed.

Associated anomalies occur in about 25% of the cases and include lung hypoplasia and cardiomyopathy,⁸ Rokitansky-Kustner-Hauser syndrome⁹ imperforated anus, rectovaginal fistula, unilateral renal agenesis¹⁰ and duodenal atresia.
 Holt-Oram syndrome is an autosomal dominant disorder with 100 % penetrance. Sporadic cases (up to 40%) are thought to represent new gene mutations. The variable expression of this syndrome manifests an absence of correlation between the severity of the skeletal abnormalities and the severity of the congenital heart disease in the same individual.

Mutation of the TBX5 causes Holt-Oram syndrome. Molecular genetic testing is currently available on a research basis only
The criteria for diagnosis include the presence of congenital cardiac defects and radial ray skeletal abnormalities, or radial ray skeletal abnormalities with or without congenital cardiac in individual with family history of Holt-Oram Syndrome.

The differential diagnoses include Heart-Hand syndrome II (Tabatznik), Okihiro Syndrome, Autosomal Dominant triphalangeal thumb, Fancony Anemia, TAR Syndrome, Aase Syndrome, Vacterl Association, Baller Gerold syndrome and many others.

The prognosis depends on the severity of the skeletal and cardiovascular anomalies.

The management includes detailed family history, physical examination, upper limb x-rays, and surgical correction of the congenital heart defects and limb abnormalities, for the parents with an affected child, EKG, echocardiograms and a hand X-ray are recommended.

References

1. Holt M, Oram S. Familiar heart disease with skeletal malformations. Br Heart J. 1960;22:236:42
2. McKusick VA. Medical Genetics. J Chron Dis 1961:14-1.
3. Basson CT, et al. Mutations in humans cause limb and cardiac malformations in Holt-Oram syndrome. Am J Med Genet 1996; 65:128-32
4. Starke H, Schimke RN, Dunn M. Upper limb cardiovascular syndrome: a family study. Am J Cardiol 1967; 19:588.
5. Gall Jr JC, Stern AM, Cohen MN, et al. Holt-Oram Syndrome: clinical and genetic study of a large family. Am J Hum Genet 1966; 18:187
6. Smith AT, Sack GH Jr, Taylor GJ (1979) Holt-Oram syndrome. J Pediatr 95:538-43
7. Boehme DH, Shotar AO (1989) A complex deformity of appendicular skeleton and shoulder with congenital heart disease in three generation of a Jordanian Family. Clin Genet 36:442-50
8. Kullman F, Koch R, Feichtinger W, Giesen H, Schmid M, Grimm T (1993) Holt-Oram syndrome in combination with reciprocal translocation, lung hypoplasia and cardiomiopathy. Clin Pediatr 205:189-9
9. Kakih MH, Willianson HO, Seymour EQ, Pai s (1987) Concurrence of the Holt-Oram syndrome and the Rokitansky-Kustner- Hauser syndrome. A case report. J Reprod Med 32:549-50
10. Dogliani P, De Sanctis C, Balocco A (1973): Holt-Oram Syndrome with malformations of the urinary system. Minerv Pediatr 25:1002-06