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Holt-Oram syndrome
October 1979
538
The J o u r n a l o f P E D I A T R I C S
Holt-Oram syndrome The autosomal dominant association o f upper extremity skeletal defects with congenital heart disease is known as the Holt-Oram syndrome. We reviewed our experience with 39 affected patients o f whom 15 were considered new mutations. Wide varieties of skeletal defects and congenital heart disease were observed, and the severity o f skeletal involvement did not parallel that o f cardiac disease. These patients demonstrate four previously unemphasized points: (1) There is a striking asymmetry of skeletal involvement, with the left side more severely affected. (2) Patients with skeletal defects alone can transmit both skeletal and cardiac defects to their children. (3) Hypoplastic peripheral vessels may be an associated abnormality and can result in difficulty with cardiac catheterization. (4) Electrocardiographic changes o f terminal conduction delay in the right anterior chest leads' were not uniformly present in patients with otherwise typical secundum atrial septal defects.
Ann T. Smith, M.D., George H. Sack, Jr., M.D., Ph.D.,* and G e o r g e J. T a y l o r , M . D . , B a l t i m o r e , M d .
IN 1960, Holt and Oram I described a family in which upper extremity malformations were associated with secundum atrial septal defect. The subsequent literature (about 130 patients in either case reports or family studies) has demonstrated autosomal dominant transmission of this syndrome with variable expression of skeletal and cardiac defects. The associated finding of hypoplastic peripheral vessels has not been noted again since the original report of Holt and Oram. We have reviewed the records of 39 patients with the Holt-Oram syndrome seen at the Johns Hopkins Hospital over 25 years. Fifteen patients had no family history of HOS. We observed a previously unemphasized asymmetry of skeletal involvement, with the left side more severely affected. Some patients had hypoplastic peripheral vessels, which may constitute an increased risk for cardiac catheterization. From the Department o f Medicine, Divisions o f Internal Medicine and Medical Genetics, and the Department o f Pediatrics, Johns Hopkins University School o f Medicine. Clinical studies supported by United States Public Health Service Grant 1 T32 GM07471. Dr. Sack supported in part by the Andrew Mellon Foundation and United States Public Health Service Gra~it 1 RO1 CA Z0619-O1. ~: *Reprint address: The Moore Clinic, Division of Medical Genetics, The Johns Hopkins Hospital, Baltimore, MD 21205.
METHODS The records of 22 patients with HOS followed in the Moore Genetics Clinic were reviewed, and five of these patients were re-examined. Records of an additional 17 patients were obtained from the Helen B. Taussig children's Cardiac Center. Abbreviations used HOS: Holt-Oram syndrome CHD: congenital heart disease, ASD: atrial septal defect ECG: electrocardiogram Patients with a negative family history (neither cardiac nor skeletal defects in siblings, parents, or grandparents) were included if both congenital heart disease and typical skeletal anomalies were present. Patients with a positive family history were included if they had cardiac and upper extremity anomalies or if they had typical skeletal defects alone. No family members had CHD without skeletal anomalies. Our study included 14 males and 25 females. Fifteen were black and 24 were white. Preoperative electrocardiograms on patients not receiving digitalis were evaluated in 35 patients. Anatomic cardiac defects were identified on the basis of surgical or autopsy findings in 16 patients; 11 additional patients had their cardiac diagnosis established by cardiac catheterization. In eight patients the diagnosis of CHD was made by physical examination and noninvasive laboratory studies 2
Vol. 95, No. 4, pp. 538-543
0022-3476/79/100538 + 06500.60/0 9 1979 The C. V. Mosby Co.
Volume 95 Number 4
Holt-Oram syndrome
539
Table I. Skeletal abnormalities in 39 vatients with Holt-Oram syndrome
Defect Thumb Digitalized Absent Hypoplastic Triphalangeal Syndactyly Bifid Fingers Clinodactyly Syndactyly Absent Hypoplastic Carpals Delayed formation/absent Hypoplastic Fused Irregular Extra carpal/os centralis Enlarged Miscellaneous
No. of patients 39 18 16 13 6 6 1 27 10 16 8 8 17 9 7 7 6 5 3 3
Defect
No. of patients
Defect
No. of patients
First metacarpal Absent Hypoplastic Abnormal plane Miscellaneous Second-fifthmetacarpal Radius Hypoplastic Absent Abnormal head Ulna Hypoplastic Abnormal head Miscellaneous irregularities Absent Radial-ulnar synostosis Humeral-ulnar synostosis Humerus Hypoplastic Miscellaneous irregularities Abnormal heads Absent
28 16 11 3 3 7 22 12 8 6 15 7 5 3 1 5 1 17 10 6 2 1
Clavicles Nonspecific sloping shoulders Hypoplastic "Large" Prominent acromioclavicular joint Prominent coracoclavicular joint Scapula Hypoplastic Hypoplastic glenoid fossa alone Miscellaneous Sternum Pectus excavatum Pectus carinatum Miscellaneous Ribs Hypoplastic Irregular Extra rib Vertebra Scoliosis Fusion Hemivertebrae
11 7 5 4 2 1 15 7 4 4 11 9 1 2 5 3 1 1 6 6 1 1
alone. Four other patients with murmurs and abnormal ECGs refused further evaluation. RESULTS Skeletal malformations. All patients had skeletal defects. Severity ranged from one patient with nonopposable thumbs and rounded shoulders (despite normal radiographs) to another with severe phocomelia and pectus excavatum. The most frequently involved structures were the thumbs (100%), first metacarpals (72%), and fingers (69%) (Table I). Seventeen patients had carpal abnormalities; these were more common on the radial side. Eleven of 43 radiographically identified carpal defects occurred in the navicular, 11 in the greater multangular, and the remaining 21 in the other carpals. Altered articular function was seen as a result of obvious anatomic changes and also as the only manifestation of more subtle underlying skeletal anomalies. Frequent functional limitations included impaired supination (13 patients), elbow extension (11 patients), and thumb opposition (26 patients). Limitation of pronation, elbow flexion, and range of digital or wrist motion were less frequently observed. Individual skeletal anomalies usually were associated with distal defects in the same limb. The severity of the distal lesion tended to be similar to that of the proximal lesion. For example, in all 28 patients with an abnormal
first metacarpal, the adjacent thumb also was abnormal. Furthermore, the 16 patients with a missing first metacarpal also were missing the associated thumb. Defects in the proximal aspect of a limb were never isolated but were always associated with distal deformity of the limb. Both bilateral and unilateral anomalies occurred. Severity of right- and left-sided upper extremity involvement was assessed overall and for each major skeletal structure (Fig. 1). A striking overall left-sided predominance was present in 27 of 39 patients. Cardiac abnormalities. Cardiac evaluation of 39 patients revealed 29 with well-defined abnormalities, four with undefined lesions, five with normal hearts, and one with unknown cardiac status (Table II). Electrocardiograms were available in 35 of 39 patients. The five patients without CHD had normal ECGs. Although normal in three patients with structural defects, the ECG was abnormal in the remaining 27 patients. Conduction and rhythm disturbances included firstdegree heart block in 13 patients and nodal rhythm in five. Genetic features. Eighteen patients clearly inherited the Holt-Oram syndrome; family members had CHD and skeletal defects or skeletal defects alone. A woman with phocomelia but no CHD transmitted mild skeletal defects and CHD to her daughter. No family members had CHD without skeletal anomalies. Fifteen patients had normal
540
Smith et al.
Number of Patients A f f e c t e d I0~ 20p
Sfrucfure Thumb
The Journal of Pediatrics October 1979
k18~///////////////~
4
Table II. Cardiac anatomy in 39 patients with HOS 30
~ 6
Fingers
~/'/////////J
Metacarpal
145////////////.t
Radius Carpal
b sP"///./51 4 I
Ulna
b8//~///.,/~ 3 I 2 [1|
Humerus Scapula
I
2 I
~
Left Predominance
[~
Right Predominance
[---'1 Symmetric or Indeterminate
Fig. 1. Distribution of skeletal involvement in patients with Holt-Oram syndrome. parents, and family history was insufficient in the six remaining patients 9 Two patients, considered sporadic mutations because of n o r m a l parents, had offspring with HOS. Karyotypes were n o r m a l in seven patients studied, including b a n d i n g studies in three, Six families accounted for 22 of our 39 patients. Autosomal d o m i n a n t inheritance was unequivocal in five families; Figs. 2 and 3 show the two largest pedigrees. Survey of each family generally revealed no grouping of specific features within a family. However, three of six patients with phocomelia and four of five patients without CHD were from the same pedigree. Cardiac and skeletal features differed little between inherited and sporadic cases. Differences between sporadic and inherited cases were sought by a review of prenatal histories. Differences in maternal and paternal ages were not statistically significant. Likewise, there were no apparent differences in gestational length, birth weight, sex, or race. Male and female patients were compared to determine if any differences occurred in syndrome~expression. There was no significant difference in the incidence or type of CHD or skeletal defects. Associated abnormalities. In addition to the skeletal abnormalities listed in Table I, six patients had higharched palates and two had cleft palates. Twelve patients were short (below the third percentile for age for children, less than 152.5 cm for adults). Miscellaneous findings included two patients with facial hemangiomas, two with anisocoria, one with an atretic right ear and facial hypoplasia, a n d one with renal agensis on the right side. Two patients had direct evidence of hyp0plastic vessels. In one 22-year-old woman, peripheral "~femoral vessel catheterization was extremely difficult, with-the subse-
Defect
Secundum atrial septal defect Ventricular septal defect Primum atrial septal defect Atrioventricular canal defect Mitral valve prolapse with regurgitation Bicuspid aortic valve with regurgitation Anomalous pulmonary venous return Persistent left superior vena cava b.c Hypoplastic pulmonary artery Dilated pulmonary artery Patent ductus arteriosus Right aortic arch Double outlet right ventricle Dextroposition Cardiomyopathy Left intraventricular mass Undefined pathology Normal Indeterminate
No. of patients
14' 9* 1 1 2 1"~ 1~ 2"~:~ 1 1 1]'}, 15 1~ 1w I 1{
4 5 1
*Three patients with ASD and three with VSD had additional anomalies. tAssociated with VSD. SAssociated with ASD. w patient has otherwise "undefined" pathology. quent development of a large retroperitoneal hematoma. Ultrasound documented a femoral artery diameter of 5 m m (normal, 11 _+ 3 mm). -~ The second patient, a 7week-old boy, had left heart catheterization via the axillary artery. The artery was described as "small, with the appearance of immature arteries seen in stillborn infants." Of 27 patients catheterized, an additional seven developed significant complications compatible with hypoplastic vessels. Four had excessive bleeding (with normal c o a g u l a t i o n tests), two had infection (one in association with a hematoma), and one developed femoral artery thrombosis. DISCUSSION The association of upper extremity skeletal defects with C H D was recognized as early as 1664 by Nicholas Stern..:' Holt and Oram 1 in 1960 described a family in which members of four generations had C H D and upper extremity skeletal deformities with autosomal d o m i n a n t transmlssxon. Extensive evaluation of four members of this famil)~ revealed ASD and skeletal defects; the ECG abnormalities in these patients were similar to those described in ours. McKusick 4 suggested that this syndrome be called atriodigital syndrome, or the HoltOram syndrome. Subsequent reports of the HOS include pedigrees .... and case reports, 1'-'-'~ which have demon-
Volume 95 Number 4
Holt-Oram syndrome
54 1
(]P Skeletal Defects 4D Congenital Heart Disease
Fig. 2. Holt-Cram syndrome pedigree showing transmission of both skeletal and cardiac defects by parents with only skeletal abnormalities. strated the wide variation in cardiac and skeletal features of HOS. As in the present series, the most frequently reported cardiac findings have been secundum ASD or ventricular septal defect. Other abnormalities not reported in our study include mitral or pulmonic stenosis, tetralogy of Fallot, coarctation of the aorta, and anomalous subclavian or coronary arteries?' a ,._,.1~. 1~. 19. 2 2 - 2 4 C H D is not a constant feature of HOS, however, as verified by catheterization or autopsy in two of our patients and in five previously described patients?' ~0. ,..,HOS family members with skeletal defects alone must be considered as having HOS, since they can have offspring affected with both CHD and skeletal defects. For example, we included a woman with phocomelia without C H D who had a daughter with a b n o r m a l thumbs and carpals and an ASD. Although HOS family members have been reported with C H D alone, ~ 12 we did not observe this in our patients. There was no correlation between the severity of skeletal deformity and the presence of cardiac disease. The ECGs in m a n y of our patients revealed arrhythmias, which some consider an important component of HOS.,. ~.._,s Some patients reportedly have arrhythmias despite normal cardiac anatomy; this may reflect cardiomyopathy due to fibrosis7 We also included a patient with unexplained left ventricular dysfunction and normal septal and valvular anatomy despite a wandering pacemaker. We included five patients with no a r r h y t h m i a s two with normal anatomy and three with CHD. Whereas Poznanski et aF ~ noted arrhythmias in all patients over age 10 with skeletal defects, we included an 18-year-old boy with a normal E C G despite hypoplastic thumbs. A notable variant in E C G findings was the frequent absence of terminal conduction delay in t h e right anterior chest leads in patients with ASDs. Only two of seven patients with secundum ASD and available ECG showed this R-S-R' pattern. Skeletal defects in patients with HOS range from subtle
,e,eta, De,ects
m
9
~ [ ) Congenital Heart Disease
Fig. 3. Holt-Cram syndrome pedigree spanning four generations with full expression in most affected members. alterations such as radiographically normal but sloping shoulders 1"~ to phocomelia. 3- 1._, A n y bone in the upper extremity or thorax may be involved. The thumb is affected most frequently. It may be absent, hypoplastic, digitalized, triphalangeal, syndactylous, or even bifid?- 3, ~. ,~. ,. 1._,.._,~ Abnormalities in other bones have been similar to those observed in our patients (Table I) 1.3-~. ,-t_~.~. ~ Skeletal defects may be subtle and, on occasion, functional rather than anatomic, such as nonopposable thumbs or inability to supinate forearms, Spina bifida occasionally has occurred in patients in whom HOS is a convincing diagnosis based on clinical features and positive family history."' We included one patient with hemivertebrae and one with fused vertebrae. Caution is needed in diagnosing patients with vertebral defects other than scoliosis as having HOS. Several reports -~9probably erroneously include patients with spina bifida who more likely represent the VATER association. a~ Poznanski et aP 1 critically evaluated the radiographs of 17 patients with HOS, stressing prominent medial epicondyles and an extra carpal bone or os centrale. These findings were present in two and five of our patients, respectively. However, Poznanski's study was based
542
Smith et al.
almost completely on the members of a single family, and others ~ have found a high intrafamilial incidence of specific skeletal features; three of our six patients with phocomelia were from one family. Thus family clustering may explain the different frequencies of various radiologic abnormalities in our study and in that of Poznanski et al. Although skeletal involvement was usually bilateral in our patients, it was more severe on the left side in 69%. This asymmetry has been noted in one previous report based on a family Study? ~ We reviewed patients described in several major articles; of 28 with sufficient documentation, 23 were more severely affected on the left side?' 8. ~.... 1_~.24 This finding has not previously been emphasized, and it may be useful in distinguishing HOS from other syndromes in which skeletal defects are usually symmetric (Fanconi anemia, thrombocytopenia with absent radius, fibrodysplasia ossificans progressiva) or are usually unilateral (VATER). TM :~-' Previous family studies have noted that skeletal defects were more severe in the females than the males. ~ ' :~' We also found that the most severe deformity occurred in females: five of six patients with phocomelia were female. On the other hand, males had a larger number of bones involved than females, and males had more clavicular involvement than females. Gall et aP suggested that, although inheritance is clearly autosomal dominant, abnorma! segregation may occur in HOS. Affected mothers in that family study produced 20 affected offspring compared to eight normal offspring. In our series, affected mothers produced nine affected and four normal children, again suggesting abnormal segregation (although not statistically significant). Although Holt and Oram 1 described hypoplastic peripheral vessels in two of their four patients, this feature of HOS has not been mentioned in subsequent reports. Abnormal peripheral vessels must be eonsidered when evaluating patients with HOS for catheterization. Precatheterization ultrasonagraphy may help identify those at risk. The pathogenesis of HOS is unknown. Cardiac, upper extremity, and peripheral blood vessel dvelopment all occur between three and seven weeks' gestation? :~ Since evidence from other species suggests that limb generation is dependent on intact peripheral nerve input? " ~ congenital abnormalities in human beings may result from a segmental defect in the embryologic nerve supply from the fifth through the eighth cervical segments, a'~ As suggested by McCredie, ~ thalidomide-induced upper extremity anomalies may be explained by sixth cervical nerve injury. The increased sensitivity of the sixth cervical nerve may reflect a longer period of vulnerability or its
The Journal of Pediatrics October 1979
association with an advanced evolutionary featurethumb opposition. 37 Our observation of the constant thumb involvement in patients with HOS is compatible with this postulated increased sensitivity of the sixth cervical nerve. The observation that patients with HOS usually are more severely affected on the left side suggests that asymmetric or unilateral neural crest changes may occur. This notion is supported by a recent report of four patients with ipsilateral upper extremity and diaphragm defects. :~8Also, nine reported patients with lung agenesis had ipsilateral upper extremity abnormalities? 9 The basis for left sided predominance in HOS is unknown. Alternately, deficient fetal blood supply due to vascular hypoplasia may produce distal maldevelopment. This theory is also attractive considering the associated feature of hypoplastic blood vessels in HOS. However, since hypoplastic vessels are not a constant feature, this remains speculative. CLINICAL
SIGNIFICANCE
Consideration of the Holt-Oram syndrome is important in the evaluation of patients with congenital heart disease. A search for associated skeletal abnormalities is justified in order to: (1) aid precise diagnosis, (2) offer appropriate genetic counseling for both patient and parents, and (3) alert the physician to the possibility of peripheral vascular hypoplasia and its attendant complications. Asymmetric skeletal changes with more left-sided involvement are seen in the majority of patients and can aid diagnostic differentiation from other syndromes. A radiograph of the left hand and forearm offers t h e best access to the majority of subtle bone changes and can be used for evaluating any suspicious clinical findings. This syndrome cannot reliably be associated with any particular cardiac lesion although secundum atrial septal defects are common (Table II). The R-S-R' pattern of terminal conduction d~fay in anterior chest leads is not found as consistently as in other patients with ASD. Moreover, more than one congenital lesion may be present, complicating both diagnosis and management. We thank Catherine A. Neill, M.D., for her help in ascertainment of patients, advice and suggestions and John P. Dorst, M.D., for his assistance in radiographic interpretation. REFERENCES*
I. Holt M, and Oram S: Familial heart disease with skeletal malformations, Br Heart J 22:236, 1960. 2. Davis RP, Neiman HL, Yao JST, and Bergan JJ: Ultra*Supplementalreferencesare availablefrom the authors.
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9. 10.
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17. 18.
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20. 21.
sound scan in diagnosis of peripheral aneurysms, Arch Surg 112:55, 1977. Pruzanski W: Familial congenital malformations of the heart and upper limbs. A syndrome of Holt-Oram, Cardiologia 45:21, 1964. McKusick VA: Medical genetics 1960, J Chronic Dis 14:1, 1961. Ashby DW, Chadha JS, and Henderson CB: Associated skeletal and cardiac abnormalities: The Holt-Oram syndrome, Q J Med 38:267, 1969. Sanchez-Cascos A: Holt-Oram syndrome, Acta Paediatr Scand 56:313, 1967. Chang CH: Holt-Oram syndrome, Radiology 88:479, 1967. Gall JC, Stern AM, Cohen MM, Adams MS, and Davidson RT: Holt-Oram syndrome i Clinical and genetic study of a large family, Am J Hum Genet 18:187, 1966. Holmes LB: Congenital heart disease and upper extremity deformities, N Engl J Med 272:437, 1965. Kaufman RL, Rimoin DL, McAlister WH, and Hartmann AF: Variable expression of the Holt-Oram syndrome, Am J Dis Child 127:21, 1974. Letts RM, Chudley AE, Cmnming G, and Shokier MH: The upper limb-cardiovascular syndrome (Holt-Oram Syndrome), Clin Orthop 116:149, 1976. Lewis KB, Bruce RS, and Motulsky AG: Upperlimb cardiovascular syndrome: An autosomal dominant genetic effect on embryogenesis, JAMA 193:98, 1965. Mark H: Familial and nonfamilial congenital abnormalities of the heart and upper extremities: A model for genetic counseling, Isr J Med Sci 5:564, 1969. Massumi RA, and Nutter DO: The syndrome of familial defects of heart and upper extremities (Holt-Oram syndrome), Circulation 34:65, 1966. Pernot C, Dupuis C, Gilgenkrantz S, and Hueber JM: Syndrome de Holt-Oram et malformations des mains assocides / t u n e cardiopathie cong6nital, Arch Mal Coeur 63:1428, 1970. Rybak M, Kozlowski K, Kleczkowska A, Lewandowska J, Sokolowski J, and Soltysik-Wilk E: Holt-Oram syndrome associated with ectromelia and chromosomal aberration, Am J Dis Child 121:490, 1971. Walter VH, Frank A, and Kambhu C: Das Holt-OramSyndrom, Z Kardiol 63:1, 1974. Zetterqvist P: The syndrome of familial atrial septal defect, heart arrhythmia, and hand malformation (Holt-Oram) in mother and son, Acta Paediatr Scand 52:115, 1963. Brans YW, and Lintermans JP: The upper limb-cardiovascular syndrome: A report of two African cases with a review of the literature. Am J Dis Child 124:779, 1972. Carroll RE, and Louis DS: Anomalies associated with radial dysplasia, J PEDIATR 84:409, 1974. Emerit I, deGrouchy J, Laval-Jeantet M, Corone P, and Vernant P: Malformations complexes des membres sup6rieurs associ6es/~ une cardiopathie congdnitale, Acta Genet Med Gamellol 14:132, 1965.
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26.
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29.
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32. 33. 34. 35. 36.
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Harris LC, and Osborne WP: Congenital absence or hypoplasia of the radius with ventricular septal defect: Ventriculoradial dysplasia, J PEDIATR 68:265, 1962. Miller AB, Salcedo EE, and Bahler RC: Prolapsed mitral valve associated with the Holt-Oram syndrome, Chest 67:230, 1975. Mitsuoka H, Chughtai S, Cutarelli R, Beg RA, Naraghipour J, and Kay EB: Holt-Oram syndrome associated with combined ostium primum and secundum atrial septal defects: successful surgical closure, Am J Cardiol 36:967, 1975. Moguilevsky HC, O'Reilly MV, Dizadji H, and Shaffer AB: Atrial septal defect associated with skeletal anomalies (Holt-Oram Syndrome), Chest 57:230, 1970. Nik-Akhtar B, Khakpour M, Rashed MA, and Hakami F: Association of Holt-Oram syndrome and lymphosarcoma, Chest 66:729; 1974. Ockey CH, Feldman GV, Macaulay ME, and Delaney MJ: A large deletion of the long arm of chromosome No. 4 in a child with limb abnormalities, Arch Dis Child 42:428, 1967. Poznanski AK, Stern AM, and Gall JC Jr: Skeletal anomalies in genetically determined congenital heart disease, Radiol Clin North Am 9:435, 1971. Silver W, Steier M, Schwartz O, and Zeichner MB: The Holt-Oram syndrome with previously undescribed associated anomalies, Am J Child 124:911, 1972. Temtamy SA, and Miller JD: Extending the scope of the VATER association: Definition of the VATER syndrome, J PEDIATR 85:345, 1974. Poznanski AK, Gall JC Jr, and Stern AM: Skeletal manifestations of the Holt-Oram syndrome, Radiology 94:45, 1970. Johnson CF: Abnormal thumbs and physical diagnosis, Clin Pediatr 9:131, 1970. Langman J: Medical embryology, Baltimore, 1969, The Williams & Wilkins Company. Singer M: The influence of the nerve in regeneration of the amphibian extremity, Q Rev Biol 27:169, 1952. Zalewski AA: Trophic function of neurons in transplanted neonatal ganglia, Exp Neurol 45:189, 1974. McCredie J: Neural crest defects: A neuroanatomic basis for classification of multiple malformations related to phocomelia, J Neurol Sci 28:373, 1976. McCredie J: Embryonic neuropathy: A hypothesis of neural crest injury as the pathogenesis of congenital malformations, Med J Aust 1:159, 1974. McCredie J, and Reid IS: Congenital diaphragmatic hernia associated with homolateral upperlimb malformation: A study of possible pathogenesis in four cases, J PEDIATR 92:762, 1978. Maltz DL, and Nadas AS: Agenesis of the Lung: Presentation of 8 new cases and review of the literature, Pediatrics 42:175, 1968.
538
The J o u r n a l o f P E D I A T R I C S
Holt-Oram syndrome The autosomal dominant association o f upper extremity skeletal defects with congenital heart disease is known as the Holt-Oram syndrome. We reviewed our experience with 39 affected patients o f whom 15 were considered new mutations. Wide varieties of skeletal defects and congenital heart disease were observed, and the severity o f skeletal involvement did not parallel that o f cardiac disease. These patients demonstrate four previously unemphasized points: (1) There is a striking asymmetry of skeletal involvement, with the left side more severely affected. (2) Patients with skeletal defects alone can transmit both skeletal and cardiac defects to their children. (3) Hypoplastic peripheral vessels may be an associated abnormality and can result in difficulty with cardiac catheterization. (4) Electrocardiographic changes o f terminal conduction delay in the right anterior chest leads' were not uniformly present in patients with otherwise typical secundum atrial septal defects.
Ann T. Smith, M.D., George H. Sack, Jr., M.D., Ph.D.,* and G e o r g e J. T a y l o r , M . D . , B a l t i m o r e , M d .
IN 1960, Holt and Oram I described a family in which upper extremity malformations were associated with secundum atrial septal defect. The subsequent literature (about 130 patients in either case reports or family studies) has demonstrated autosomal dominant transmission of this syndrome with variable expression of skeletal and cardiac defects. The associated finding of hypoplastic peripheral vessels has not been noted again since the original report of Holt and Oram. We have reviewed the records of 39 patients with the Holt-Oram syndrome seen at the Johns Hopkins Hospital over 25 years. Fifteen patients had no family history of HOS. We observed a previously unemphasized asymmetry of skeletal involvement, with the left side more severely affected. Some patients had hypoplastic peripheral vessels, which may constitute an increased risk for cardiac catheterization. From the Department o f Medicine, Divisions o f Internal Medicine and Medical Genetics, and the Department o f Pediatrics, Johns Hopkins University School o f Medicine. Clinical studies supported by United States Public Health Service Grant 1 T32 GM07471. Dr. Sack supported in part by the Andrew Mellon Foundation and United States Public Health Service Gra~it 1 RO1 CA Z0619-O1. ~: *Reprint address: The Moore Clinic, Division of Medical Genetics, The Johns Hopkins Hospital, Baltimore, MD 21205.
METHODS The records of 22 patients with HOS followed in the Moore Genetics Clinic were reviewed, and five of these patients were re-examined. Records of an additional 17 patients were obtained from the Helen B. Taussig children's Cardiac Center. Abbreviations used HOS: Holt-Oram syndrome CHD: congenital heart disease, ASD: atrial septal defect ECG: electrocardiogram Patients with a negative family history (neither cardiac nor skeletal defects in siblings, parents, or grandparents) were included if both congenital heart disease and typical skeletal anomalies were present. Patients with a positive family history were included if they had cardiac and upper extremity anomalies or if they had typical skeletal defects alone. No family members had CHD without skeletal anomalies. Our study included 14 males and 25 females. Fifteen were black and 24 were white. Preoperative electrocardiograms on patients not receiving digitalis were evaluated in 35 patients. Anatomic cardiac defects were identified on the basis of surgical or autopsy findings in 16 patients; 11 additional patients had their cardiac diagnosis established by cardiac catheterization. In eight patients the diagnosis of CHD was made by physical examination and noninvasive laboratory studies 2
Vol. 95, No. 4, pp. 538-543
0022-3476/79/100538 + 06500.60/0 9 1979 The C. V. Mosby Co.
Volume 95 Number 4
Holt-Oram syndrome
539
Table I. Skeletal abnormalities in 39 vatients with Holt-Oram syndrome
Defect Thumb Digitalized Absent Hypoplastic Triphalangeal Syndactyly Bifid Fingers Clinodactyly Syndactyly Absent Hypoplastic Carpals Delayed formation/absent Hypoplastic Fused Irregular Extra carpal/os centralis Enlarged Miscellaneous
No. of patients 39 18 16 13 6 6 1 27 10 16 8 8 17 9 7 7 6 5 3 3
Defect
No. of patients
Defect
No. of patients
First metacarpal Absent Hypoplastic Abnormal plane Miscellaneous Second-fifthmetacarpal Radius Hypoplastic Absent Abnormal head Ulna Hypoplastic Abnormal head Miscellaneous irregularities Absent Radial-ulnar synostosis Humeral-ulnar synostosis Humerus Hypoplastic Miscellaneous irregularities Abnormal heads Absent
28 16 11 3 3 7 22 12 8 6 15 7 5 3 1 5 1 17 10 6 2 1
Clavicles Nonspecific sloping shoulders Hypoplastic "Large" Prominent acromioclavicular joint Prominent coracoclavicular joint Scapula Hypoplastic Hypoplastic glenoid fossa alone Miscellaneous Sternum Pectus excavatum Pectus carinatum Miscellaneous Ribs Hypoplastic Irregular Extra rib Vertebra Scoliosis Fusion Hemivertebrae
11 7 5 4 2 1 15 7 4 4 11 9 1 2 5 3 1 1 6 6 1 1
alone. Four other patients with murmurs and abnormal ECGs refused further evaluation. RESULTS Skeletal malformations. All patients had skeletal defects. Severity ranged from one patient with nonopposable thumbs and rounded shoulders (despite normal radiographs) to another with severe phocomelia and pectus excavatum. The most frequently involved structures were the thumbs (100%), first metacarpals (72%), and fingers (69%) (Table I). Seventeen patients had carpal abnormalities; these were more common on the radial side. Eleven of 43 radiographically identified carpal defects occurred in the navicular, 11 in the greater multangular, and the remaining 21 in the other carpals. Altered articular function was seen as a result of obvious anatomic changes and also as the only manifestation of more subtle underlying skeletal anomalies. Frequent functional limitations included impaired supination (13 patients), elbow extension (11 patients), and thumb opposition (26 patients). Limitation of pronation, elbow flexion, and range of digital or wrist motion were less frequently observed. Individual skeletal anomalies usually were associated with distal defects in the same limb. The severity of the distal lesion tended to be similar to that of the proximal lesion. For example, in all 28 patients with an abnormal
first metacarpal, the adjacent thumb also was abnormal. Furthermore, the 16 patients with a missing first metacarpal also were missing the associated thumb. Defects in the proximal aspect of a limb were never isolated but were always associated with distal deformity of the limb. Both bilateral and unilateral anomalies occurred. Severity of right- and left-sided upper extremity involvement was assessed overall and for each major skeletal structure (Fig. 1). A striking overall left-sided predominance was present in 27 of 39 patients. Cardiac abnormalities. Cardiac evaluation of 39 patients revealed 29 with well-defined abnormalities, four with undefined lesions, five with normal hearts, and one with unknown cardiac status (Table II). Electrocardiograms were available in 35 of 39 patients. The five patients without CHD had normal ECGs. Although normal in three patients with structural defects, the ECG was abnormal in the remaining 27 patients. Conduction and rhythm disturbances included firstdegree heart block in 13 patients and nodal rhythm in five. Genetic features. Eighteen patients clearly inherited the Holt-Oram syndrome; family members had CHD and skeletal defects or skeletal defects alone. A woman with phocomelia but no CHD transmitted mild skeletal defects and CHD to her daughter. No family members had CHD without skeletal anomalies. Fifteen patients had normal
540
Smith et al.
Number of Patients A f f e c t e d I0~ 20p
Sfrucfure Thumb
The Journal of Pediatrics October 1979
k18~///////////////~
4
Table II. Cardiac anatomy in 39 patients with HOS 30
~ 6
Fingers
~/'/////////J
Metacarpal
145////////////.t
Radius Carpal
b sP"///./51 4 I
Ulna
b8//~///.,/~ 3 I 2 [1|
Humerus Scapula
I
2 I
~
Left Predominance
[~
Right Predominance
[---'1 Symmetric or Indeterminate
Fig. 1. Distribution of skeletal involvement in patients with Holt-Oram syndrome. parents, and family history was insufficient in the six remaining patients 9 Two patients, considered sporadic mutations because of n o r m a l parents, had offspring with HOS. Karyotypes were n o r m a l in seven patients studied, including b a n d i n g studies in three, Six families accounted for 22 of our 39 patients. Autosomal d o m i n a n t inheritance was unequivocal in five families; Figs. 2 and 3 show the two largest pedigrees. Survey of each family generally revealed no grouping of specific features within a family. However, three of six patients with phocomelia and four of five patients without CHD were from the same pedigree. Cardiac and skeletal features differed little between inherited and sporadic cases. Differences between sporadic and inherited cases were sought by a review of prenatal histories. Differences in maternal and paternal ages were not statistically significant. Likewise, there were no apparent differences in gestational length, birth weight, sex, or race. Male and female patients were compared to determine if any differences occurred in syndrome~expression. There was no significant difference in the incidence or type of CHD or skeletal defects. Associated abnormalities. In addition to the skeletal abnormalities listed in Table I, six patients had higharched palates and two had cleft palates. Twelve patients were short (below the third percentile for age for children, less than 152.5 cm for adults). Miscellaneous findings included two patients with facial hemangiomas, two with anisocoria, one with an atretic right ear and facial hypoplasia, a n d one with renal agensis on the right side. Two patients had direct evidence of hyp0plastic vessels. In one 22-year-old woman, peripheral "~femoral vessel catheterization was extremely difficult, with-the subse-
Defect
Secundum atrial septal defect Ventricular septal defect Primum atrial septal defect Atrioventricular canal defect Mitral valve prolapse with regurgitation Bicuspid aortic valve with regurgitation Anomalous pulmonary venous return Persistent left superior vena cava b.c Hypoplastic pulmonary artery Dilated pulmonary artery Patent ductus arteriosus Right aortic arch Double outlet right ventricle Dextroposition Cardiomyopathy Left intraventricular mass Undefined pathology Normal Indeterminate
No. of patients
14' 9* 1 1 2 1"~ 1~ 2"~:~ 1 1 1]'}, 15 1~ 1w I 1{
4 5 1
*Three patients with ASD and three with VSD had additional anomalies. tAssociated with VSD. SAssociated with ASD. w patient has otherwise "undefined" pathology. quent development of a large retroperitoneal hematoma. Ultrasound documented a femoral artery diameter of 5 m m (normal, 11 _+ 3 mm). -~ The second patient, a 7week-old boy, had left heart catheterization via the axillary artery. The artery was described as "small, with the appearance of immature arteries seen in stillborn infants." Of 27 patients catheterized, an additional seven developed significant complications compatible with hypoplastic vessels. Four had excessive bleeding (with normal c o a g u l a t i o n tests), two had infection (one in association with a hematoma), and one developed femoral artery thrombosis. DISCUSSION The association of upper extremity skeletal defects with C H D was recognized as early as 1664 by Nicholas Stern..:' Holt and Oram 1 in 1960 described a family in which members of four generations had C H D and upper extremity skeletal deformities with autosomal d o m i n a n t transmlssxon. Extensive evaluation of four members of this famil)~ revealed ASD and skeletal defects; the ECG abnormalities in these patients were similar to those described in ours. McKusick 4 suggested that this syndrome be called atriodigital syndrome, or the HoltOram syndrome. Subsequent reports of the HOS include pedigrees .... and case reports, 1'-'-'~ which have demon-
Volume 95 Number 4
Holt-Oram syndrome
54 1
(]P Skeletal Defects 4D Congenital Heart Disease
Fig. 2. Holt-Cram syndrome pedigree showing transmission of both skeletal and cardiac defects by parents with only skeletal abnormalities. strated the wide variation in cardiac and skeletal features of HOS. As in the present series, the most frequently reported cardiac findings have been secundum ASD or ventricular septal defect. Other abnormalities not reported in our study include mitral or pulmonic stenosis, tetralogy of Fallot, coarctation of the aorta, and anomalous subclavian or coronary arteries?' a ,._,.1~. 1~. 19. 2 2 - 2 4 C H D is not a constant feature of HOS, however, as verified by catheterization or autopsy in two of our patients and in five previously described patients?' ~0. ,..,HOS family members with skeletal defects alone must be considered as having HOS, since they can have offspring affected with both CHD and skeletal defects. For example, we included a woman with phocomelia without C H D who had a daughter with a b n o r m a l thumbs and carpals and an ASD. Although HOS family members have been reported with C H D alone, ~ 12 we did not observe this in our patients. There was no correlation between the severity of skeletal deformity and the presence of cardiac disease. The ECGs in m a n y of our patients revealed arrhythmias, which some consider an important component of HOS.,. ~.._,s Some patients reportedly have arrhythmias despite normal cardiac anatomy; this may reflect cardiomyopathy due to fibrosis7 We also included a patient with unexplained left ventricular dysfunction and normal septal and valvular anatomy despite a wandering pacemaker. We included five patients with no a r r h y t h m i a s two with normal anatomy and three with CHD. Whereas Poznanski et aF ~ noted arrhythmias in all patients over age 10 with skeletal defects, we included an 18-year-old boy with a normal E C G despite hypoplastic thumbs. A notable variant in E C G findings was the frequent absence of terminal conduction delay in t h e right anterior chest leads in patients with ASDs. Only two of seven patients with secundum ASD and available ECG showed this R-S-R' pattern. Skeletal defects in patients with HOS range from subtle
,e,eta, De,ects
m
9
~ [ ) Congenital Heart Disease
Fig. 3. Holt-Cram syndrome pedigree spanning four generations with full expression in most affected members. alterations such as radiographically normal but sloping shoulders 1"~ to phocomelia. 3- 1._, A n y bone in the upper extremity or thorax may be involved. The thumb is affected most frequently. It may be absent, hypoplastic, digitalized, triphalangeal, syndactylous, or even bifid?- 3, ~. ,~. ,. 1._,.._,~ Abnormalities in other bones have been similar to those observed in our patients (Table I) 1.3-~. ,-t_~.~. ~ Skeletal defects may be subtle and, on occasion, functional rather than anatomic, such as nonopposable thumbs or inability to supinate forearms, Spina bifida occasionally has occurred in patients in whom HOS is a convincing diagnosis based on clinical features and positive family history."' We included one patient with hemivertebrae and one with fused vertebrae. Caution is needed in diagnosing patients with vertebral defects other than scoliosis as having HOS. Several reports -~9probably erroneously include patients with spina bifida who more likely represent the VATER association. a~ Poznanski et aP 1 critically evaluated the radiographs of 17 patients with HOS, stressing prominent medial epicondyles and an extra carpal bone or os centrale. These findings were present in two and five of our patients, respectively. However, Poznanski's study was based
542
Smith et al.
almost completely on the members of a single family, and others ~ have found a high intrafamilial incidence of specific skeletal features; three of our six patients with phocomelia were from one family. Thus family clustering may explain the different frequencies of various radiologic abnormalities in our study and in that of Poznanski et al. Although skeletal involvement was usually bilateral in our patients, it was more severe on the left side in 69%. This asymmetry has been noted in one previous report based on a family Study? ~ We reviewed patients described in several major articles; of 28 with sufficient documentation, 23 were more severely affected on the left side?' 8. ~.... 1_~.24 This finding has not previously been emphasized, and it may be useful in distinguishing HOS from other syndromes in which skeletal defects are usually symmetric (Fanconi anemia, thrombocytopenia with absent radius, fibrodysplasia ossificans progressiva) or are usually unilateral (VATER). TM :~-' Previous family studies have noted that skeletal defects were more severe in the females than the males. ~ ' :~' We also found that the most severe deformity occurred in females: five of six patients with phocomelia were female. On the other hand, males had a larger number of bones involved than females, and males had more clavicular involvement than females. Gall et aP suggested that, although inheritance is clearly autosomal dominant, abnorma! segregation may occur in HOS. Affected mothers in that family study produced 20 affected offspring compared to eight normal offspring. In our series, affected mothers produced nine affected and four normal children, again suggesting abnormal segregation (although not statistically significant). Although Holt and Oram 1 described hypoplastic peripheral vessels in two of their four patients, this feature of HOS has not been mentioned in subsequent reports. Abnormal peripheral vessels must be eonsidered when evaluating patients with HOS for catheterization. Precatheterization ultrasonagraphy may help identify those at risk. The pathogenesis of HOS is unknown. Cardiac, upper extremity, and peripheral blood vessel dvelopment all occur between three and seven weeks' gestation? :~ Since evidence from other species suggests that limb generation is dependent on intact peripheral nerve input? " ~ congenital abnormalities in human beings may result from a segmental defect in the embryologic nerve supply from the fifth through the eighth cervical segments, a'~ As suggested by McCredie, ~ thalidomide-induced upper extremity anomalies may be explained by sixth cervical nerve injury. The increased sensitivity of the sixth cervical nerve may reflect a longer period of vulnerability or its
The Journal of Pediatrics October 1979
association with an advanced evolutionary featurethumb opposition. 37 Our observation of the constant thumb involvement in patients with HOS is compatible with this postulated increased sensitivity of the sixth cervical nerve. The observation that patients with HOS usually are more severely affected on the left side suggests that asymmetric or unilateral neural crest changes may occur. This notion is supported by a recent report of four patients with ipsilateral upper extremity and diaphragm defects. :~8Also, nine reported patients with lung agenesis had ipsilateral upper extremity abnormalities? 9 The basis for left sided predominance in HOS is unknown. Alternately, deficient fetal blood supply due to vascular hypoplasia may produce distal maldevelopment. This theory is also attractive considering the associated feature of hypoplastic blood vessels in HOS. However, since hypoplastic vessels are not a constant feature, this remains speculative. CLINICAL
SIGNIFICANCE
Consideration of the Holt-Oram syndrome is important in the evaluation of patients with congenital heart disease. A search for associated skeletal abnormalities is justified in order to: (1) aid precise diagnosis, (2) offer appropriate genetic counseling for both patient and parents, and (3) alert the physician to the possibility of peripheral vascular hypoplasia and its attendant complications. Asymmetric skeletal changes with more left-sided involvement are seen in the majority of patients and can aid diagnostic differentiation from other syndromes. A radiograph of the left hand and forearm offers t h e best access to the majority of subtle bone changes and can be used for evaluating any suspicious clinical findings. This syndrome cannot reliably be associated with any particular cardiac lesion although secundum atrial septal defects are common (Table II). The R-S-R' pattern of terminal conduction d~fay in anterior chest leads is not found as consistently as in other patients with ASD. Moreover, more than one congenital lesion may be present, complicating both diagnosis and management. We thank Catherine A. Neill, M.D., for her help in ascertainment of patients, advice and suggestions and John P. Dorst, M.D., for his assistance in radiographic interpretation. REFERENCES*
I. Holt M, and Oram S: Familial heart disease with skeletal malformations, Br Heart J 22:236, 1960. 2. Davis RP, Neiman HL, Yao JST, and Bergan JJ: Ultra*Supplementalreferencesare availablefrom the authors.
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Harris LC, and Osborne WP: Congenital absence or hypoplasia of the radius with ventricular septal defect: Ventriculoradial dysplasia, J PEDIATR 68:265, 1962. Miller AB, Salcedo EE, and Bahler RC: Prolapsed mitral valve associated with the Holt-Oram syndrome, Chest 67:230, 1975. Mitsuoka H, Chughtai S, Cutarelli R, Beg RA, Naraghipour J, and Kay EB: Holt-Oram syndrome associated with combined ostium primum and secundum atrial septal defects: successful surgical closure, Am J Cardiol 36:967, 1975. Moguilevsky HC, O'Reilly MV, Dizadji H, and Shaffer AB: Atrial septal defect associated with skeletal anomalies (Holt-Oram Syndrome), Chest 57:230, 1970. Nik-Akhtar B, Khakpour M, Rashed MA, and Hakami F: Association of Holt-Oram syndrome and lymphosarcoma, Chest 66:729; 1974. Ockey CH, Feldman GV, Macaulay ME, and Delaney MJ: A large deletion of the long arm of chromosome No. 4 in a child with limb abnormalities, Arch Dis Child 42:428, 1967. Poznanski AK, Stern AM, and Gall JC Jr: Skeletal anomalies in genetically determined congenital heart disease, Radiol Clin North Am 9:435, 1971. Silver W, Steier M, Schwartz O, and Zeichner MB: The Holt-Oram syndrome with previously undescribed associated anomalies, Am J Child 124:911, 1972. Temtamy SA, and Miller JD: Extending the scope of the VATER association: Definition of the VATER syndrome, J PEDIATR 85:345, 1974. Poznanski AK, Gall JC Jr, and Stern AM: Skeletal manifestations of the Holt-Oram syndrome, Radiology 94:45, 1970. Johnson CF: Abnormal thumbs and physical diagnosis, Clin Pediatr 9:131, 1970. Langman J: Medical embryology, Baltimore, 1969, The Williams & Wilkins Company. Singer M: The influence of the nerve in regeneration of the amphibian extremity, Q Rev Biol 27:169, 1952. Zalewski AA: Trophic function of neurons in transplanted neonatal ganglia, Exp Neurol 45:189, 1974. McCredie J: Neural crest defects: A neuroanatomic basis for classification of multiple malformations related to phocomelia, J Neurol Sci 28:373, 1976. McCredie J: Embryonic neuropathy: A hypothesis of neural crest injury as the pathogenesis of congenital malformations, Med J Aust 1:159, 1974. McCredie J, and Reid IS: Congenital diaphragmatic hernia associated with homolateral upperlimb malformation: A study of possible pathogenesis in four cases, J PEDIATR 92:762, 1978. Maltz DL, and Nadas AS: Agenesis of the Lung: Presentation of 8 new cases and review of the literature, Pediatrics 42:175, 1968.