British Heart Journal, I970, 32, 241.

Familial skeletal cardiovascular syndrome(Holt-Oram) in a polygamous African family

Asuquo U. AntiaFrom the Department of Paediatrics, University College Hospital, Ibadan, Nigeria

A polygamous Nigerian family with inherited skeletal cardiovascular anomalies (Holt-Oramsyndrome) is described. Common to the affected individuals in this family were pectus excavatumand abnormalities of the thumbs. Atrial septal defect was proven by angiocardiography in one andclinically diagnosed in another member of the family. The mode of inheritance of the abnormalitiesin this family as in other reported cases is thought to be an autosomal dominant type which isunaffected by the polygamous situation.

Association of congenital skeletal anomaliesand cardiovaseular malformations occurringin a number of Caucasian families has beenpreviously described (Holt and Oram, I960;McKusick, 196I; Zetterqvist, I963; Pruz-anski, I964; Holmes, I965; Lewis et al.,Received x August i969.

I965; Gellis and Feingold, I966; Chang,I967). Studies of pedigrees in the reportedcases suggest an autosomal dominant type ofinheritance. To our knowledge the presentstudies of this syndrome in a polygamousNigerian family represent the first to bereported in the African. The studies further

FIG . I Pedigree offamily with skeletal-cardiovascular syndrome.

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1 2 3 4 5 6 7 8 9 _

III ,,V* SD&D~* @' SKELETAL AND CARDIOVASCULAR ANOMALIES

0 0' SKELETAL ANOMALIES

O C' NORMAL

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.IV

DEAD

PROPOSITUS

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F I G. 2 Hands of the propositus (Case i)showing the abnormalities of the thumbs andlittle fingers.

confirm the suggested mode of inheritance,i.e. an autosomal dominant, which as expec-ted is unaffected by the polygamous situa-tion. Though the skeletal anomalies arecommon in the upper extremities and areemphasized in previous communications,the present report draws attention to theequally common anomaly of the sternum.

The familyThe pedigree of the family studied is shown inFig. i. The grandfather (I.2) of the propositusIII.i and all the living members in generationsII and III were examined by the author. Thehistories were obtained from the grandfather, thetwo living daughters II.2 and ii, and the onlyliving son II.io. The examination included physi-cal evaluation, x-rays of the chest and upperextremities, and electrocardiogram. Angiocardi-ography was carried out in the propositus. Noinformation was available regarding the cardio-vascular status of the dead members of thefamily II.6 and 8, and I1.12, who are said tohave had conspicuous deformities of the hands.Death occurred in these children at birth, and atthe age of 6 months, respectively in II.6 and 8,and at the age of i week in III.2. No necropsywas carried out on any of these infants. The casereports which follow concern the propositus(III.i), his mother (II.2), an aunt (II.ii), andthe grandfather (I.2).

Case reportsCase I. (III.i). This propositus, a 4+-year-oldboy, was referred to University College Hospital(UCH No. 207337) on account of recurrentepistaxis for two years. The recent episode waspreceded by fever which lasted for a week. Onphysical examination he weighed only I4-6 kg.The epistaxis was caused by vessels in the nasal

FIG. 3 X-ray of the hands (Case I). Noterudimentary intermediate phalanx left thumb.The phalanges in the right thumb are largerthan normal.

septum; these were cauterized. Examination ofthe musculo-skeletal system showed moderatepectus excavatum. There was some wasting ofthe thenar and hypothenar muscles of bothhands. The right thumb was slightly bigger thanthe left. Both thumbs were finger-like in shapeand in the same plane as the fingers. There wasincurving of both little fingers and the leftthumb (Fig. 2). In the cardiovascular system,the peripheral pulses were regular, equal, andof good volume. Blood pressure measuredIIo/70 mm. Hg in both arms. There was a rightventricular thrust. Apex beat was in the 5thleft intercostal space, 9 cm. from the midline.There were no thrills. Pulmonary valve closuresound was accentuated and widely split, thesplitting being unaffected by respiration. Therewas a grade 2-3/6 mid-systolic murmur maximumin the pulmonary area, but widely transmittedto the back and both axillae. Diastole was clear.Radiograph of the hands showed a rudimentaryintermediate phalanx in the left thumb and largerthan normal phalanges in the right thumb (Fig.3). The rest of the skeletal system was normal.Chest x-ray with barium swallow revealedmoderate cardiac enlargement, prominence ofthe pulmonary artery segment, and increasedlung vascularity.

Electrocardiogram showed sinus rhythm, QRSfrontal axis + I200, and right ventricular hyper-trophy. Angiocardiography showed atrial septaldefect. Other investigations included Hb Ii-o g./IoO ml. (75 %), PCV 34 per cent, and Hb genotypeAS.

Case 2 (II.2). This was the mother of the pro-positus. She had no cardiovascular symptoms.Physical examination showed a moderate degreeof pectus excavatum. No other abnormality wasfound either in the skeletal or cardiovascularsystem. Hb genotype was AS.

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Holt-Oram syndrome 243

FIG. 4 Case 3. Note the elongated finger-like thumbs lying in the same plane as thefingers.

Case 3 (II.II). Her father was the grandfatherof the propositus. She had no cardiovascularsymptoms. Physical examination revealed con-spicuous pectus excavatum. Both thumbs wereelongated and fingerlike (Fig. 4). The right thumband the little fingers showed incurving. The thenarand hypothenar eminences were flattened. Shecould not fully extend the left elbow, and leftsupination and pronation were considerablylimited. X-rays of the skeletal system showedthree phalanges in both thumbs (Fig. 5), theintermediate phalanx in the left being smallerthan the right. The right thumb was longer thanthe right little finger. There was partial fusion ofthe proximal parts of the left radius and ulna,and also deformity of the distal end of the lefthumerus; the olecranon fossae on both sideswere shallow. Examination of the cardiovascularsystem revealed normal regular pulses. Bloodpressure measured I20/90 mm. Hg. The heartwas enlarged clinically. No thrills were present.There was a grade 2 systolic murmur in the pul-monary area. Pulmonary valve closure sound wasloud and widely split. The findings were sug-gestive of an atrial septal defect. The patientrefused cardiac catheterization and angiocardio-graphy.

Chest x-ray showed moderate cardiac enlarge-ment, and increased vascularity in the lung fields.Electrocardiogram revealed sinus rhythm, normalfrontal QRS axis, and normal QRS voltages.Hb genotype was AS.

Case 4 (I.2). This old man was the grandfatherof the propositus. He married two wives eachof whom had a daughter (Cases 2 and 3, respec-tively). He had no cardiovascular symptoms. Onphysical examination he had conspicuous pectusexcavatum. The right thumb (Fig. 6) was finger-like and curved inwards; the left thumb wasdiminutive. There was flattening of the thenarand hypothenar eminences in both hands. He

FIG. 5 Case 3. X-ray of hands showingthree phalanges in each thumb.

could not fully supinate or pronate the left arm,and extension at the left elbow was conspicuouslylimited. The left upper arm was smaller than theright. X-rays of the hands showed three phalangesin both thumbs, and fusion of the left scaphoidand lunate (Fig. 7). The left humerus was smallerthan the right, and the left olecranon fossa wasshallow. Examination of the heart revealed anirregular pulse, rate 6o a minute. Blood pressurewas I20/80 mm. Hg (RA), I30/80 mm. Hg (LA).There was no cardiac enlargement or murmur.The heart sounds were normal. Chest x-rayshowed normal heart shadow and normal vas-cularity. Electrocardiogram revealed prolongedPR interval (0o28 sec.) and the rate 56 a minute.Hb genotype was AS.

DiscussionIn I960 Holt and Oram first reported afamily in which 9 members in 4 generationshad peculiar skeletal deformities affectingmainly the upper limbs, and congenitalcardiac defects. The authors considered thisan example of an inherited abnormality.Since the original report of the syndrome,other well-documented cases have been des-cribed in Caucasian families. The termsHolt-Oram (Zetterqvist, I963; Pruzanski,I964; Gellis and Feingold, I966; Chang,I967) and upper limb cardiovascular syn-dromes (Lewis et al., I965) have been sug-gested for these skeletal cardiovascularanomalies. The latter term seems inappro-priate since the skeletal anomalies, though

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FIG. 6 Case 4. The right thumb is finger-like and is larger than the left. Note alsothe abnormality' of the palms.

affecting mainly the upper extremities, in-volve other bones as well - the sternum inparticular, the palate, the clavicle, and thevertebrae (Holt and Oram, I960; Holmes,I965; Lewis et al., I965). However, thesyndrome consists essentially of inheritedanomalies of the musculo-skeletal system anda spectrum of congenital heart defects, themost common being secundum type atrialseptal defect. The Nigerian family whichforms the basis of the present report exhibitsmost of the anomalies already described. Theanomalies in the thumbs were identical inthe father and daughter; pectus excavatumwas present in all four cases. Clinically twoofthe four members ofthe family had evidenceof atrial septal defect though this was provenby angiocardiography in one. The threemembers of the family who had anomaliesof the fingers and died in infancy presumablyhad serious cardiac defects. Holmes (I965)found that the affected women tended to befar more seriously handicapped than the men.In the present study of the three affectedfemale patients, one infant who died at theage of 6 months presumably had a seriouscardiac defect; the remaining two were notseriously affected. The mother of the pro-positus had only pectus excavatum.The mode of inheritance in the present

family as well as in the previously reportedcases appears to be an autosomal dominanttype. The skeletal and cardiovascular ab-normalities are presumably caused by asingle gene or gene complex. In the presentfamily the fact that the grandfather of thepropositus is a polygamist does not affectthis mode of inheritance, because he himselfcarries the gene, and, therefore, with everychild that he fathers there would be one

FIG. 7 Case 4. X-ray of the hands showingthree phalanges in each thumb.

chance in two on the average that he willpass on the gene to the offspnrng regardlessof whether or not the child is borne by thesame woman.

I wish to thank Professor P. E. Polani and Dr. J.Fraser Roberts, Paediatrics Research Unit, Guy'sHospital Medical School, London, and ProfessorL. Luzzatto, Department of Haematology,University College Hospital, Ibadan, Nigeria,for their help in the genetic aspect of the study.

ReferencesChang, C. H. (I967). Holt-Oram syndrome. Radiology,

88, 479.Gemlis, S. S., and Feingold, M. (I966). Holt-Oram

syndrome. AmericanJournal of Diseases of Children,112, 465.

Holmes, L. B. (I965). Congenital heart disease andupper-extremity deformities. New EnglandJournalof Medicine, 272, 437.

Holt, M., and Oram, S. (I96o). Familial heart diseasewith skeletal malformations. British Heart journal,22, 236.

Lewis, K. B., Bruce, R. A., Baum, D., and Motulsky,A. G. (I965). The upper limb-cardiovascularsyndrome.Journal of the American Medical Associa-tion, 193, I080.

McKusick, V. A. (I96I). Medical genetics, I960.J7ournal of Chronic Diseases, 14, I.

Pruzanski, W. (I964). Familial congenital malforma-tions of the heart and upper limbs: a syndrome ofHolt-Oram. Cardiologia (Basel), 45, 2I.

Zetterqvist, P. (I963). The syndrome of familialatrial septal defect, heart arrhythmia and handmalformation (Holt-Oram) in mother and son.Acta Paediatrica (Uppsala), 52, 115.

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