*Dept. of Radiology, Vanderbilt University, 21^st and Garland, Nashville TN 37232-5316. Ph: 615-343-0595, Fax: 615-343-4890

Synonyms: Holt-Oram syndrome, cardiac-limb syndrome; cardio­melic syndrome; atriodigital dysplasia; heart-upper limb syndrome; upper limb cardiovascular syndrome.

Definition: Holt-Oram syndrome is a genetically determined disorder in which aplasia or hypoplasia of the digital rays and/or radius are associated with congenital heart disease.

Prevalence: Uncommon³. About 200 cases have been described, and 4 cases have been identified prenatally^14-15.

Etiology: Autosomal dominant disorder with 100% penetrance and variable expression. Sporadic cases are thought to represent new gene mutations.

Pathogenesis: Undetermined. Similar skeletal and cardiac abnormalities are seen as a result of thalidomide embryopathy, the critical time being the 4^th and 5^th weeks of pregnancy. It is likely that in this syndrome the abnormal gene is active at this same stage in embryogenesis.

Associated anomalies: Skeletal: digitalized or absent thumbs, clinodactyly, syndactyly, hypoplastic or aplastic radii, ulnae and/or first metacarpals, shoulder defects, articulation defects, phocomelia. Cardiovascular: atrial septal defects, ventricular septal defect, pulmonic stenosis, mitral valve prolapse, patent ductus arteriosus, hypoplastic left heart⁹, anomalous pulmonary venous return, persistent left superior vena cava⁸, and conduction defects.

Differential diagnosis: Other  radial ray defects and associated anomalies (see Table 2-3).

Prognosis: Normal intelligence. The life span and function depend on the severity of the skeletal and cardiac anomalies.

Recurrence risk: Autosomal dominant with 100% penetrance⁵ and variable expressivities of both the skeletal and cardiac defects⁶. New mutations account for 40% of the cases¹⁸.

Management: Dependent on the severity of the skeletal and cardiac anomalies.

MESH Hand-deformities, congenital, Heart-defects; Thumb abnormalities, Bone-diseases, developmental, -genetics BDE 0455 MIM 147.290 POS 3247, 3990 ICD9 755.26 CDC 759.840

Introduction

The finding of an abnormal hand associated with a cardiac defect suggests the heart-hand syndrome. We present a case in a fetus whose father was affected by the condition.

Case report

An 18-year-old G₁P₀ patient was referred to us at 20 weeks to assess whether her fetus was affected by Holt-Oram syndrome. The mother is anamnesis was unremarkable, but the father was affected by the syndrome. The 18-year-old father was born with pulmonary atresia with ventricular septal defect, absent left and right thumbs and left radius, exophoria and a sacral dimple. He had undergone a Waterson shunt at 1 week (creation of an aortopulmonary artery shunt) and at 12 years a corrective repair of both the ventricular septal defect and the Waterson shunt by patch angioplasty.  A maternal great uncle of the father was a "blue babyâ€, and a distant paternal relative was born with absent thumbs.

The ultrasound examination revealed a fetus missing thumbs bilaterally (as the father) (fig. 1-3). The radii were mildly shortened but present (fig. 4). A small atrial septal and ventricular septal defect were suspected (fig. 5-6). Two repeat examinations at 24 and 32 weeks confirmed the skeletal findings, but the ventricular septal defect was no longer identified at 32 weeks. The boy was born at 35 weeks. Physical examination confirmed the absence of thumbs bilaterally with only a skin tag present. The cardiology exam confirmed the presence of a small atrial septal defect (ASD), but the ventricular septal defect (VSD) could not be identified. At 1 month the child suffered from hypertrophic pyloric stenosis treated by pyloromyotomy. At 6 months both skin tags were removed. The child is now 2 years old and is in stable cardiac condition.

Figure 1: The four digits of the hand are seen. The radial side is well visible (arrow) and the thumb is clearly absent.

Figure 2: On the other hand, a small tag is present at the place of the thumb (arrow).

Figure 3: A coronal view of the 4 digit hand.

Figure 4: The flexed arm demonstrates that the radius and ulna end at the same level at the wrist (no radial aplasia).

Figure 5: A 1.3 mm ventricular septal defect is visible on the first examination but not at the last two examinations.

Figure 6: The apical part of the septum is missing (arrow), suggesting

a small atrial septal defect.

Discussion

History

British cardiologists Holt and Oram first described a syndrome of upper limb deformities and congenital heart disease in 1960⁷. Since that time, over 200 cases have been described in the world literature⁸.

Cardiac anomalies

The most common cardiac anomaly is a secundum type ASD, 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 malformation, replaced subclavian artery, transposition of great vessels, tricuspid atresia and, most recently, hypoplastic left heart and persistent left superior vena cava⁸ have been described (Table 1).

Table 1: Anomalies which are part of the Holt-Oram

syndrome

Skeletal anomalies

Upper extremity skeletal changes most classically involve the thumb, but the entire upper extremity may be involved. In addition to thumb manifestations which include digitalization, clinodactyly, syndactyly or absence, there may be hypoplastic or aplastic radii, ulnae and/or first metacarpals, shoulder defects, articulation defects, phocomelia, or subclinical carpal bone anomalies evident only by radiography (Table 1). The left side is more frequently affected than the right side¹⁴.

Associated anomalies

Associated anomalies occur in about 25% of cases¹⁷ and include imperforate anus, rectovaginal fistula, unilateral renal agenesis, and duodenal atresia¹⁶.

Transmission

Holt-Oram syndrome is an autosomal-dominant disorder with 100% penetrance. Sporadic cases (up to 40% of the cases) are thought to represent new gene mutations⁵. Recently, Braulke¹⁰ reported Holt-Oram syndrome in four half-siblings with unaffected parents (three different mothers, one father) and proposed a paternal mutation resulting in mosaicism which was probably restricted to the germline.  The variable expression of Holt-Oram syndrome manifests as an absence of correlation between the severity of the skeletal abnormalities and the severity of the congenital heart disease in the same individual. There may also be absence of correlation between the severity of the affected parent and their offspring⁵.

Pathogenesis

The pathogenesis of Holt-Oram syndrome is undetermined, but several explanations have been proposed. Since similar skeletal and cardiac anomalies are seen as a result of thalidomide embryopathy, it is likely that the abnormal gene is active at the same stage (4^th to 7^th weeks of pregnancy) in embryogenesis¹¹. A reduced fetal blood supply to the upper limb is thought to be associated with certain sporadic limb defects^12,15. Alternatively, a segmental defect of the 5^th through the 8^th cervical nerve segments was suggested by Smith⁶ as contributing to Holt-Oram syndrome pathogenesis. No consistent cytogenetic abnormality has been determined and may be reflected in the heterogeneity of Holt-Oram syndrome⁶.

Diagnosis

Prenatal ultrasonographic diagnosis of Holt-Oram syndrome has been described in four fetuses at risk for Holt-Oram syndrome^14,15. Brons concluded that the best time for evaluation of the ulnar-radius complex is between 13 and 16 weeks of gestation secondary to a relatively large amount of amniotic fluid and the ease of movement of the extremities. Forearm and hand structures should be identified, as well as hand posture, since most cases of radial hypoplasia are associated with a clubhand deformity¹⁴. Fetal echocardiography is best obtained at 18-22 weeks.

Differential diagnosis

The differential diagnoses of radial aplasia and triphalangeal thumb are listed in Table 2. Cultured peripheral blood lymphocytes and dermal fibroblasts may show a significant increase in chromosome breakages in patients with Fanconi anemia. This may be useful in differentiating between Fanconi anemia and thrombocytopenia with absent radius. The differential diagnoses of the heart-hand syndrome are listed in Table 3.

Table 2: Diferential diagnosis (adapted from 4,6)

Table 3: The heart-hand syndromes

Prognosis

Depends on the severity of the skeletal and cardiac anomalies. The intelligence is normal.

Prenatal management

No alteration of the prenatal care.

Postnatal management

The postnatal management of these children is a combination of conservative and surgical treatments. The conservative treatments aim at correcting position and muscle strength, and consist of casting, exercising specific muscle groups, and developing adaptive skills. Surgical treatments include soft-tissue releases, osteotomies and bone grafts to elongate the segment or  stabilize the wrist as well as pollicization of the index finger. Pollicization should only be performed unilaterally in bilaterally affected infants and should be done  before 2 years of age.

References

1. Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias, Chicago, Year Book Medical Publishers, Inc., 1990.

2. McKusic VA: Mendelian Inheritance in Man, Catalogs of Autosomal Dominant, Autosomal Recessive and X-linked phenotypes, 9th Edition. The Johns Hopkins University Press, Baltimore, 1990.

3. Buyse ML: Birth Defects Encyclopedia. Blackwell Scientific Publications. Cambridge, Mass, 1990.

4. Fleischer A, Romero R, Manning F, Jeanty P, et al. The Principles and Practice of Ultrasonography in Obstetrics and Gynecology, 4th Edition. Appleton & Lange. Norwalk, CT, 1991. p 302.

5. Glasdstone I, Sybert VP: Holt-Oram syndrome: penetrance of the gene and lack of maternal effect. Clin Genet 21;98:103, 1982.

6.  Smith AT, Sack GH, Taylor GJ: The Holt-Oram syndrome. J Pediatr 95:538-543, 1979.

7. Holt M, Oram S: Familial heart disease with skeletal malformations. Br Heart J 22:236-242, 1960.

8. Cheng TO: Holt-Oram syndrome in a Puerto Rican Family-Case Reports. Angiology 896-902,1987.

9. Glauser TA, Zackai E, Weinberg P, Clancy R: Holt-Oram syndrome associated with the hypoplastic left heart syndrome. Clin Genet 36:69-72, 1989.

10. Braulke I, Herzog S, Thies U, Zoll B: Holt-Oram syndrome in four half-siblings with unaffected parents: brief clinical report. Clin Genet 39:241-244, 1991.

11. Lewis KB, Bruce RA, Baum D, Motulksy AG: The upper limb-cardiovascular syndrome. JAMA 193:1080-1086, 1965.

12. Hoyme HE, Van Allen MI, Jones KL: The vascular pathogenesis of some sporadically occurring limb defects. Semin Perinatol 7:299-306, 1983.

13.  Kristoffersson U,  Mineur A, Heim S, et al: Normal high-resolution karyotypes in three patients with the Holt-Oram syndrome. Am J Med Genet 28:229-231, 1987.

14. Brons JT, Van Giejn HP, Wladimiroff JW, et al: Prenatal ultrasound diagnosis of the Holt‑Oram syndrome. Prenat Diag 8:175-181, 1988.

15. Muller LM, De Jong G, Van Heerden KM: The antenatal ultrasonographic detection of the Holt‑Oram syndrome. SAMJ 68:313-315, 1985.

16. Bartolomei B, Eng GD: The Holt-Oram syndrome: a case presentation and review of management parameters. Arch Phys Med Rehabil 68:41‑45, 1987.

17. Brans YW, Lingermans JP: Upper limb-cardiovascular syndrome: report of two African cases with review of the literature. J Dis Child 124: 779‑83, 1972.

18. Cox H, Viljoen D, Versfeld G, et al: Radial ray defects and associated anomalies. Clin Genet 35:322-30, 1989.