Postgraduate Medical Journal (August 1977) 53, 488-494.

Skeletal abnormalities in homocystinuria

D. P. BRENTONM.D., M.R.C.P.

Department ofHuman Metabolism, University College Hospital Medical School, University Street, London

SummaryThe skeletal changes of thirty-four patients with thebiochemical and clinical features of cystathioninesynthase deficiency are described. It is emphasizedthat there is clinical evidence of excessive bonegrowth and the formation of bone which is structurallyweaker than normal. The similarities and differencesbetween this condition and Marfan's syndrome arestressed and the possible nature of the connectivetissue defect leading to the skeletal changes discussed.The most characteristic skeletal changes in homo-cystinuria are the skeletal disproportion (pubis-heel length greater than crown-pubis length), theabnormal vertebrae, sternal deformities, genu valgumand large metaphyses and epiphyses.

HOMOCYSTINURIA due to deficiency of the enzymecystathionine synthase is an inborn error of aminoacid metabolism affecting the pathway betweenmethionine and cysteine. The sulphur containingamino acids methionine, cysteine and cystine alloccur in dietary protein. Cysteine is a sulphydrylcompound and cystine its disulphide derivative.Du Vigneaud (1952) and others proved in mammalsthat there is a metabolic pathway from methionineto cysteine along which methionine sulphur isconverted to cysteine sulphur-the 'trans-sul-phuration pathway'-before being catabolized in aseries of steps to inorganic sulphate. Homocysteine,another sulphydryl compound, is an intermediateon the transulphuration pathway. Its correspondingdisulphide is homocystine. The accumulation ofhomocystine in plasma and urine is a consequence ofcystathionine synthase deficiency because homo-cysteine is not utilized with serine to form cysta-thionine (Fig. 1). The excretion of homocystinein the urine also occurs in some other inborn errorsaffecting the remethylation of homocysteine backto methionine which may also be impaired invitamin B12 deficiency.

Correspondence: Dr D. P. Brenton, Thorn Senior Lecturer,Department of Human Metabolism, University CollegeHospital Medical School, University Street, LondonWCIE 6JJ.

MethionineCH3

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FIG. 1. The conversion of methionine to cysteine viahomocysteine. The pathway has been simplified.

The four cardinal clinical features of cysta-thionine synthase deficiency are lens dislocation,mental retardation, skeletal abnormalities and athrombotic tendency. Not all the patients show allof these features. Lens dislocation and very similarskeletal abnormalities occur in Marfan's syndrome.Marfan (1896) originally described an unusual girlwith bizarre skeletal abnormalities and markedarachnodactyly. Lens dislocation was not re-cognized as part of the syndrome until some yearslater and neither were the aortic complications.The purpose of this paper is to concentrateon the skeletal abnormalities in cystothionine

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Skeletal abnormalities in homocystinuria

TABLE 1. Skeletal abnormali-ties in homocystinuria

Total number of patients 34High palate 25Scoliosis (usually mild) 11Pectus carinatum 9Pectus excavatum 11Genu valgum 10Pes cavus 17Pes planus 2Arachnodactyly 5Joint abnormalities 7

synthase deficiency and to review these in a series ofthirty-four patients seen at University CollegeHospital. Some of the data on the first twenty-twopatients have already been reported (Brenton et al.,1972).

The variability of the physical abnormalitiesIn patients only mildly affected, the lens dis-

location may be present possibly associated with aslightly abnormal ratio between the height of theupper and lower body segments. The patient mayotherwise appear normal. For example the Indianpatient illustrated by Brenton et al. (1972) had lensdislocation and mild pes cavus but normal intel-ligence and no other abnormality. He remains welland illustrates that cystathionine synthase de-ficiency occurs in other races. Another very normallooking patient is illustrated in Fig. 2. He has anormal IQ, only minimal bone changes and lens dis-location. Family screening of urine samples revealedan affected sister sixteen years old without lens dis-location and of normal IQ.

In severely affected patients lens dislocationoccurs with mental retardation of varying severity.Such patients have marked skeletal changes of thekind discussed below. Fair hair and a rather cyanoticmalar flush may be present but these are not constantand the cause of the flush is uncertain. Majorthrombotic episodes may occur both in arteries andveins. A severely affected patient is illustrated inFig. 3. In general, the severity of the disease tends tobe similar in affected siblings, either both mild orboth severe, but this is not entirely true, as illustratedin the two sisters in Fig. 4. The very severely affectedsister has a gross scoliosis and loss of extension atthe elbows and finger joints. Her IQ is extremely lowand she knows only two or three words. The lessseverely affected sister has an IQ of about 60 and isable to earn her living in a simple job as a packer.Her skeletal abnormalities are much milder. Thereason for this difference between siblings is notclear.

Growth and statureIn normal white children the crown-pubis length

is longer that the pubis-heel length in infancy butthe legs grow relatively quicker than the trunk so thatthe crown-pubis and pubis-heel lengths becomeequal at about the age of 7 years and then remain sothroughout life. This equality may be disturbed bysome physiological events such as an unusually latepuberty when the legs become relatively long or bydiseases which affect growth of legs or trunk. Skele-tal disproportion is a cardinal feature of olderpatients with homocystinuria (Fig. 5), the pubis-heellength being invariably longer than the crown-pubis.length. The extent of this disproportion is under-estimated in Fig. 5 because the data of McKusickwere obtained by measuring the standing height,the pubis-heel length in the standing position andthe crown-pubis length calculated by difference.Standing tends to shorten the trunk length and solowers the ratio in normal subjects appreciablybelow unity. The measurements of the patients withhomocystinuria were made in the lying position.Skeletal disproportion is also a cardinal feature ofMarfan's syndrome. In both conditions there seemsto be an excessive growth of long bones probablymore marked in Marfan's syndrome since arach-nodactyly does not seem very common in homo-cystinuria. An excessive growth of long bones inhomocystinuria is indicated by the height measure-ments (Fig. 6). Only five of the thirty-four patientshave heights on the 50th centile or below includingthe patient in Fig. 4 whose height is really meaning-less because of the scoliosis. Almost 50¶V0 of thepatients are on the 95th centile or over. In homo-cystinuria (unlike Marfan's syndrome) vertebralabnormalities actually shorten the crown-pubislength (see below) and contribute to the skeletaldisproportion. The growth curves illustrated in Fig. 7show the development of the disproportion in achild who did not respond biochemically to pyri-doxine and so has remained biochemically abnormalthroughout her growth.

Physical deformities and radiological changesThe incidence of the commonest physical ab-

normalities is listed in Table 1. They are consideredhere with the radiological changes. No abnor-malities are noted in the head and skull except forsome large sinuses in one or two patients and a highpalate which seems to be a common feature but isa different physical sign and may have been over-diagnosed. Severe scoliosis is not usual but milderdegrees of scoliosis are quite common. Radiologicallyvertebral changes are usually present. The vertebraeare thin indicating that osteoporosis is present. Onlyin one patient however have crush fractures occurred(see Brenton et al., 1972 for illustration and Fig. 8).The vertebrae commonly appear flatter than usualand elongated anteroposteriorly with a rather

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FIG. 2. Patient D.W. Age 23 years.FIG. 3. Patient J.Cr. Age 11 years. Note the short trunk and long legs.FIG. 4. Affected sisters H.D. (right) and S.D. (left). Note the much more severe.skeletal abnormalities in S.D. compared to her sister.

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Skeletal abnormalities in homocystinuria 491

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FIG. 5. The ratio of crown-pubis length to pubis-heellength measured in the lying position in patients withhomocystinuria. The lines for normal subjects areredrawn from the data of McKusick (1966) and re-present the normal mean, -I and -2 s.d. *, malepatients; 0, female patients.

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FIG. 6. Distribution of centile heights in the patientswith homocystinuria. Since most of the patients aregrowing children the distribution of their final centileheights is not yet known. The centile height of patientS.D. (Fig. 4) is omitted (see text for explanation).

posteriorly placed biconcave deformity. These arenot normal vertebrae which have become osteoporoticand then crushed but vertebrae which do not growand develop normally in the childhood years. Therelative flatness and biconcavity presumably in-dicate failure to attain normal structural strength and

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FIG. 7. Growth curve in the patient Ca.G: Note therelatively fast growth of the legs and the poor growth ofthe trunk. A-A, standing height; 0, crown-pubislength (lying); 0 pubis-heel length (lying).

the long anteroposterior diameter an abnormaldegree of growth. Clinically there are no detectableabnormalities in the hips and pelvis but radiologi-cally there are changes which are variable frompatient to patient. The femoral heads may appearvery large and the femoral necks wide. Sometimesthe femoral necks are unduly long (Fig. 9). Wideningof the metaphyses of the long bones is a markedfeature of cystathionine synthase deficiency (Fig. 10,and also Brenton et al., 1972). This is most easilyseen at the knees and parents of affected childrensometimes comment that they had noticed the largeknees. Genu valgum is common. Surgical correctionby osteotomy with subsequent immobilization maylead to serious venous thombosis as happened intwo of the patients in this series. These changes atthe hips and knees are also those of abnormalgrowth. Although in some of the children the longbones show thinness of cortical bone there has beenno particular predisposition to long bone fracturesso that the degree of osteoporosis has not beensevere. Perhaps the sternal changes also reflectexcessive growth in the ribs. Excessive growth of themetacarpals and phalanges causes the arach-nodactyly which is not a feature of most patientsbut occurs in some. Other changes in connective

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FIG. 8. Lateral lumbar spine in patient J.Cr. Note thewedged LI vertebra which is a true crush fracture.

tissues presumably cause the joint abnormalitieswhich have been noted, namely limited extension atthe elbows, limited supination of the forearms andfixed flexion of the fingers usually slight but some-times severe (Fig. 4).

DiscussionIt is interesting to speculate about the cause of

these skeletal changes because Marfan's syndromeand cystathionine synthase deficiency have a numberof skeletal features and lens dislocation in common,it is possible that they have some connective tissuedefect in common. Such a defect would presumablybe the result of quite different primary biochemicalabnormalities. The similarities of the skeletal defectsshould not hide the fact that there are differencesparticularly in the vertebrae. Moreover life ex-pectation in Marfan's syndrome is less than normalmostly because of serious aortic and cardiac defects(McKusick, 1972). Aortic dissection apparentlydoes not occur in cystathionine synthase deficiencyand this might also indicate that the connectivetissue defect in the two conditions is dissimilar. Thispiece of evidence however is difficult to evaluatebecause of the surprisingly few patients over 30years of age with cystathionine synthase deficiencyreported in the literature. Most patients with Mar-fan's syndrome do not develop aortic dissectionuntil after this age. It could be that aortic dissectionmight occur in older patients who are cystathioninesynthase-deficient. The lack of such patients both inthe literature and in the series discussed here can onlymean that either older patients with lens dislocation

FIG. 9. Pelvis of patient L.Th. The femoral necks are elongated.

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Skeletal abnormalities in homocystinuria 493

FIG 10. Knees of patient G.C. Note the wide metaphyses.

are not being tested for the presence of homocystinein the urine or the prognosis of the untreatedcondition is so poor that relatively few survive tothe fourth decade and beyond. Thrombosis isundoubtedly the main threat to survival.There is appreciable experimental evidence that

sulphur amino acids with a sulphydryl group mayaffect collagen structure. Most of the experimentalwork has been done with penicillamine which is3,f3'-dimethylcysteine and therefore has structural

similarities to cysteine and homocysteine. Penicil-lamine cysteamine and other aminothiols reduce thetensile strength of skin and tendon experimentallyand probably do so by reacting with the aldehydegroups formed from hydroxylysine residues in thecollagen peptide chain (Pinnel and Martin, 1968).It is possible that homocysteine may act in a similarway. Kang and Trelstad (1973) investigated solutionsof collagen which were heated to 37°C to form a gel.The gel forms as cross links are made between thealdehyde groups originally formed from the hydroxy-lysine residues. The gel is normally stable on cooling.In the presence of homocysteine a stable gel is notformed indicating some interference with the cross-linkage mechanism. The significance of the experi-ments to the pathology of cystathionine synthasedeficiency is uncertain because the concentration ofhomocysteine used is about 100 times that found inthe plasma of affected patients. One disease which

quite definitely interferes with the cross linkageprocess has been described in which the collagen ishydroxylysine-deficient (Pinnell et al., 1972). Thesepatients have recurrent joint dislocation which is nota feature of cystathionine synthase deficiency and donot have lens dislocation which is usual in cysta-thionine synthase deficiency. It is therefore reason-able to question whether the skeletal changes ofcystathionine deficiency are due to a direct effect ofhomocysteine on collagen and to remember that astimulant effect of homocystine on the formation ofsulphated proteoglycans has also been described(Dehnel and Francis, 1972).

ReferencesBRENTON, D.P., Dow, C.J., JAMES, J.I.P., HAY, R.L. &WYNNE-DAVIEs, R. (1972) Homocystinuria and Marfan'ssyndrome. Journal of Bone and Joint Surgery, 54B, 277.

DEHNEL, J.M. & FRANCIS, M.J.O. (1972) Somatomedin(sulphation factor)-like activity of homocystine. ClinicalScience, 43, 903.

Du VIGNEAUD, V. (1952) A Trail of Research in SulphurChemistry and Metabolism and Related Fields. CornellUniversity Press, Ithaca, New York.

KANG, A.H. & TRELSTAD, R.L. (1973) A collagen defectin homocystinuria. Journal of Clinical Investigation, 52,2571.

McKusIcK, V.A. (1966) Heritable Disorders of ConnectiveTissue, 3rd edn. C. V. Mosby Co. Ltd, St Louis.

McKusIcK, V.A. (1972) Heritable Disorders of ConnectiveTissue, 4th edn. C. V. Mosby Co. Ltd, St Louis.

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MARFAN, A.B. (1896) Un cas de deformation cong6nitaledes quatre membres plus prononcee aux extr6mit6scharacterisee par I'allongement des os avec un certaindegre d'amincissement. Bulletin mensuel de la SociftMedicale des HOpitaux de Paris, 13, 220.

PINNELL, S.R., KRANE, S.M., KENZORA, J.E. & GLIMCHER,M.J. (1972) A heritable disorder of connective tissue:

hydroxylysine-deficient collagen disease. New EnglandJournal of Medicine, 286, 1013.

PINNELL, S.R., & MARTIN, G.R. (1968) The cross linking ofcollagen and elastin: enzymatic conversion of lysine inpeptide linkage to a-amino adipic-delta-semialdehyde.Proceedings of the National Academy of Sciences of theUnited States of America, 61, 708.

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