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1993-06-18-18 Heart-hand syndrome, type 1 © Helton  www.thefetus.net/


Heart-hand syndrome, type 1

Kathleen Helton, MD*, Luis F. Gonçalves, MD, Philippe Jeanty, MD, PhD

*Dept. of Radiology, Vanderbilt University, 21st 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 prenatally14-15.

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 4th and 5th 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 baby”, 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    

Cardiac

Skeletal

Atrial septal defect (ostium secundum and primum)

Ventricular septal defect

Tricuspid atresia

Mitral stenosis

Mitral valve prolapse

Pulmonic stenosis

Hypoplastic pulmonary artery

Patent ductus arteriosus

Anomalous pulmonary venous return

Conduction defects

Tetralogy of Fallot

Aortic arch malformation

Coarctation of the aorta

Replaced subclavian artery

Persistent left superior vena cava

Transposition of great vessels

Hypoplastic left heart

Absence of the thumb

Triphalangeal thumb

Pouce flotant (thumb connected by a skin tag)

Clinodactily

Syndactily

Radial-ray aplasia

Ulnar aplasia

Aplasia of first metacarpals

Shoulder defects

Upper extremity articulation defects

Phocomelia

Carpal bone anomalies

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 (4th to 7th weeks of pregnancy) in embryogenesis11. A reduced fetal blood supply to the upper limb is thought to be associated with certain sporadic limb defects12,15. Alternatively, a segmental defect of the 5th through the 8th 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 syndrome14,15. 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)

  Differential diagnosis of radial aplasia  

Holt-Oram syndrome

Fanconi"s anemia

Thrombocytopenia with absent radii (TAR) syndrome

Aase syndrome

Trisomy 18

VACTERL association

Radial ray-choanal atresia

Baller-Gerold syndrome

Levy-Hollister syndrome

Roberts-SC phocomelia

Thalidomide embryopathy

Differential  diagnosis of triphalangeal or aplastic thumb

Aase syndrome

Holt-Oram syndrome

Baller-Gerold syndrome

Fanconi"s anemia

Levy-Hollister syndrome

Thrombycytopenia with absent radii (TAR) syndrome

Roberts-SC phocomelia

Townes syndrome

VACTERL association

Trisomy 18

Nager acrofacial dysostosis

Juberg-Hayword syndrome

Rothmund-Thomson syndrome

Duane-radial dysplasia syndrome

The IVIC syndrome

LARD syndrome (lacrimo-auriculo-radial-dental)

Radial defects with ear anomalies and cranial nerve

7 dysfunction

Radial hypoplasia, triphalangeal thumb, hypospadias,

diastema of maxillary central incisors

Thalidomide embryopathy

Table 3: The heart-hand syndromes

Type 1

Type 2

Type 3

Type 4

                                                    Skeletal manifestations

Thumb anomalies (triphlangeal thumb, hypo- or aplasia). Distal and proximal ossification of the 1st metacarpal. Abnormalities of number of carpal bones. Abnormality of the radius, ulnae, humerus, ribs, clavicles and scapulae.          Absence of the pectoralis major. Upper limb phocomelia.    Normal lower limbs.

Brachydactyly Brachytelephalangy Abnormal number of carpal bones Polydactyly           Bifid thumbs     Bowing of the radius Sloping shoulders Hypoplastic deltoid muscles                Short arms      Scoliosis            Pectus excavatum Facial dysmorphism

Brachydactyly (hypoplasia of the middle or proximal phalanx) of digit 2-5 (hands and feet)

Polydactyly         Natal teeth    Cutaneous syndactyly

Cardiac manifestations

ASD (66%)     Patent ductus arteriosus Coarctaction of the aorta         Ventricular septal defect    Transposition of the great arteries     Single coronary artery         Prolapsed mitral valve                 Atrial arrhythmias

 

Arrhythmias (atrial fibrillation)     Sino-atrial tachycardia Right displacement of the heart Cardiomegaly Coarctation Ventricular septal defect                Patent ductus arteriosus

 

Sick sinus Intraventricular conduction disorders Incomplete bundle branch blocks

Pulmonary stenosis Patent ductus arteriosus           Single atrium Ventricular septal defect

 

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.

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