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Homocystinuria: A differential diagnosis of Marfan's syndrome
Homocystinuria: A differential diagnosis of Marfan’s syndrome M. 8. Leonard, P.D.S.R.C.S., M.R.C.S., L.R.C.P., Ipswich, Enghnd DENTAL
UNIT,
IPSWICH
AND
EAST
SUFFOLK
HOSPITAL
Attention is drawn to a recently discovered condition which has clinical manifestations closely similar to those of Marfan’s syndrome. The importance of recognizing the condition lies in the fact that treatment can be instituted to ameliorate the mental deterioration that frequently accompanies homocystinuria.
T
he main purpose of this article is to draw to the attention of the dental profession a relatively recently discovered disease which has oral manifestations, and is to be considered in the differential diagnosis of Marfan’s syndrome. Furthermore, its presence demands precautions if a surgical operation is to be undertaken. Homocystinuria is compatible with an autosomal recessive inheritance and is an inborn error of the metabolism of methionine, an essential sulfur-containing amino a&d. It has bee11diagnosed in patients of both sexes from 9 days” to 15 years of age,ls and 100 cases have been reported.13 CLINICAL Skeletal
FEATURES
Dolichostenomelia (“long, thin extremities”) with a low ratio of upper segment to lower segment is present in most cases (Fig. 1). Normally, the ratio of the upper segment (pubic symphysis to crown) to the lower segment (pubic symphysis to sole) is about 0.92. Because of the long lower extremities in these patients, the ratio is reduced. The patients are often taller than normal for their age; most have a pectus excavatum and a scoliosis. This latter feature is attributed to the osteoporosis and vertebral collapse which take place in this condition. Cusworth and Dent? stated that the patients are loose jointed, but this is by no means a universal finding, since Schimke and associates18 reported that some have reduced mobility of the joints. Ocular
Ectopia lentis is one of the cardinal features of the disease. The lens may not become dislocated until the age of 10 years or more, although it has been 214
Volume 36 Number 2
Fig.
Homocystinuria
2 15
1. The long thin fingers common to Marfan’s syndrome and to homocystinuria.
seen at 22 months3 The earliest sign is iridodonesis-tremulousness of the iris due to the loss of normal support that the lens provides for the iris diaphragm; this progresses to dislocation. Duke-Elder9 states that the characteristic ocular feature is the thickening of the basement membrane of the ciliary body, with atrophy of the nonpigmented epithelium leading to bilateral degeneration of the zonule and subsequent dislocation and iridodonesis of the lens. The thickened layer of hyaline material overlying the atrophic epithelium is almost pathognomonic of homocystinuria in differentiating it from other forms of ectopia lentis. The direction of dislocation may differ from that in Marfan’s syndrome; the latter is usually upward but may be in any direction. Myopia, retinal detachment, and glaucoma are additional ocular symptoms. Cardiovascular
Arterial or venous thrombosis and cutaneous flushing are the main signs. Thrombosis has been reported in the terminal aorta and in the iliac, subclavian, and renal arteries.l* Carson, and associates” reported cardiac murmurs of unknown origin, and Cusworth and Dent* observed occlusion of the pulmonary artery and car pulmonale in one of their patients. Central
Nervous
System
Very frequently, there is mental retardation. The early development is normal, but mental deterioration is progressive. Carson5 reported that sixteen of eighteen patients had I.Q.‘s ranging from 20 to 70. Schimke and associatesl’ diagnosed only twenty-two of thirty-eight of their patients as being retarded.
216
Leonard
Fig. 8’. Prognathic shown is the crowding
Oral August,
mandible common of the dentition.
to Marfan’s
syndrome
and
to homocystinuria;
Burg. 19’73
also
Since five of their patients were college graduates, it has been suggested that these persons may have been suffering from a specific form of the disease. Epileptic seizures are frequent, and progressive clotting in the cerebral vesselsis suggested as the probable cause. Oral
and
Facial
Manifestations
Among the most striking features of this condition are sparse fine hair, malar flush, and a long face with a prognathic lower jaw (Fig. 2). Intraorally, the teeth are crowded, anti a high-arched (“gothic”) palate exists. From this review of the principal clinical features, one can easily see how closely the condition resembles Marfan’s syndrome on clinical observation. Nally,17 in a review of Marfan’s syndrome, listed dolichostenomelia, arachnodactly, pectus excavatum, scoliosis, ectopia lentis, laxity of the joints, and mental retardation as the typical features of the syndrome, although it is very doubtful that mental retardation forms part of the symptom complex of Marfan’s syndrome. The close clinical similarity of homocystinuria to Marfan’s syndrome is further shown by the fact that Carson5 reports that two of her caseswere written up as classic examples of Marfan’s syndrome by Lynas and MerretP and Loughbridge.15 Schimke and associateP describe the case of an 11-year-old girl who at first was considered to have Marfan’s syndrome, but who subsequently was proved to be suffering from homocystinuria. Talegaonkarlg believes that the condition is much more common than it is often thought to be. He discovered three cases of ectopia lentis due to homo-
Volume 36 Number 2
Homocystinuria
cystinuria in 10,395 patients seen in one year in the ophthalmology of his hospital.
2 17
department
Pathology
The chief findings so far appear to be in the cardiovascular system and consist of patchy intimal lesions made up of transverse bandlike elevations which narrow the lumen of the vessels. These thickenings appear to be fibrous tissue. The elastic fibers are thickened and disrupted.lO The frequent thromboses seen in the arteries and veins of patients with homocystinuria are due not only to changes in the vessels but also to the increased platelet adhesiveness. Although this feature is not present in all cases, thirteen patients under study by Cusworth and Dents all had abnormally sticky platelets. These authors point out that the cause of the tendency toward in vivo clotting is not revealed by the usual tests for clotting factors (in vitro techniques) and that the increased platelet adhesiveness in shown only if particular techniques are used. Hampton and Mitchellll observed that the plasma of two brothers with homocystinuria contained a factor which caused normal platelets to become abnormally sensitive to adenosine diphosphate. Cusworth and Dent* made the point that, after treatment with pyridoxine, the platelets became less sticky in the majority of their patients, but it is not known whether this will lea,1 to a diminution in thromboembolic sequelae. Biochemistry
Homocystinuria was first described by Carson and NeillG in 1962, after an examination of the urinary metabolites of mentally retarded children in Northern Ireland. Methionine is an essential amino acid; that is, it cannot be synthesized by the body in amounts necessary to fulfill normal requirements for it. Methionine has three principal functions: synthesis of protein; formation of adrenaline and creatine; and the formation of cysteine, with homocysteine as an intermediary metabolite. In homocystinuria, there is a metabolic block in the homocysteine, which is rapidly oxidized to homocystine and excreted in the urine. Cysteine cannot be formed and becomes, therefore, an essential amino acid in these patients. The diagnosis is made by finding homocystine in the urine. Treatment
The lines of treatment so far pursued have been to limit methionine in the diet and supplement it with cystine, but this produces a very monotonous diet.3 An alternative approach has been to give pyridoxine supplements, since this is the coenzyme necessary to activate cystathionine synthetase, which appears, to be the defective enzyme. So far, some patients have responded, the response being measured by reduction in urine and plasma levels of homocystine. Management
during
operation
As has been mentioned above, thrombembolic episodes may occur spontanereported that these episodes are ously as well as after operation. HarcourP common after general anesthesia.
Oral August,
Leonard
218
Surg. 1973
I. Comparison of principal features of Marfan’s syndrome and Homocystinuria Table
Homcystinwia
Feature Inheritance Skeletal abnormality Eye
signs
Skin Mental Vascular Oral
retardation anomalies
and facial
signs
Autosomal recessive Osteoporosis; occasionally arachnodactyly and loose-jointedness pectus excavatum Ectopia lentis Malar flush Frequent Arterial and venous High-arched crowding
Marfan’s
;
palate, prognathic of teeth
Autosomal dominant Arachnodactyly, loose-jointeclness more frequent ; pectus excavatum Ectopia sclera
thrombosis jaw,
syndrome
lentis,
occasionally
Not common Dilation of ascending aorta; dissecting aneurysm High-arched palate, crowding teeth
blue
of
Crooke, Towers and Taylor’ reported a patient with homocystinuria who was given a general anesthetic for the removal of six carious teeth and conservation of three teeth. The period of anesthesia lasted for 1 hour and 55 minutes. In order to prevent possible postoperative thrombosis, measures were taken to reduce blood viscosity and platelet adhesiveness and to accelerate postoperative recovery. The procedure was to infuse dextran 70, which has been shown by Bennett and co-workers1 to reduce platelet adhesiveness,and to reverse the muscle relaxation with atropine and neostigmine at the completion of the operation. After the operation, the platelet adhesiveness was decreased and remained so for several days, and it was thought that the regimen adopted had brought this about. The two patients operated on in this unit were mentally retarded (ages X and 13 years). All of the first permanent molars were removed in both children, and becauseof the mental state of the patients, general anesthesia was necessary. The period of anesthesia lasted less than 20 minutes and no muscle relaxants were used. The patients were ambulant within 2 hours after the operation. Brenton2 advised no special precautions since the periods of anesthesia were to be very short. DISCUSSION
Casesof Marfan’s syndrome are not common, and yet the features are often so typical that the diagnosis springs to mind. The asymptomatic patient may well be readily noticed by the dental surgeon because of the oral manifestations. It has now become apparent that when such suspicions are aroused, one must bear in mind the possibility of homocystinuria, for it is very closely akin to Marfan’s syndrome on clinical examination, particularly the oral and facial signs. The principal features of both conditions are compared in Table I. The importance of considering a diagnosis of homocystinuria is due to the fact that confirmation may allow treatment and thus arrest the mental and visual deterioration.14 Furthermore, if oral surgery is to be undertaken, local anesthesia is preferable; but if general anesthesia is necessary, then particular attention to the duration of the operation is important, since measures to reduce
Volume Number
Homocystinuria
36 2
platelet sary.
adhesiveness and the tendency to thromboembolic
2 19
episodes may be neces-
SUMMARY
A review of the clinical manifestations of homocystinuria is presented, with emphasis on its close similarity to Marfan’s syndrome. Attention is drawn to the differences and the need to plan surgical procedures while one bears in mind the tendency of homocystinuria to lead to thromboembolic episodes. I wish to thank Mr. V. E. Ireland and Mr. patients, and for encouragement and advice.
W. Gray
for
permission
to use records
of their
REFERENCES
1. Bennett, P. N., Dhall, D. P., McKenzie, F. N., and Matheson, N. A.: Effects of Dextran Infusions on the Adhesiveness of Human Blood Platelets, Lancet 2: 1001-1003, 1966. 2. Brenton, D. P. : Personal communication, 1970. 3. Carson, N. A. J.: Homocystinuria, Proo. R. 800. Med. 63: 41-43, 1970. 4. Carson, N. A. J., Dent, C. E., Field, C. M. B., and Gaull, G. E. : Homocystinuria: Clinical and Pathological Review of 10 Cases, J. Pediatr. 66: 565-583, 1965. 5. Carson, N. A. J.: Homocystinuria, Br. J. Hosp. Med. 2: 439-443, 1969. 6. Carson, N. A. J., and Neill, D. W.: Metabolic Abnormalities Detected in a Survey of Mentally Backward Individuals in Northern Ireland, Arch. Dis. Child. 37: 505-513, 1962. W. H.: Management of Patients With 7. Crooke, J. W., Towers, J. F., and Taylor, Homocystinuria Requiring Surgery Under General Anaesthesia, Br. 5. Anaesth. 43: 96-99, 1971. 8. Gusworth, D. C., and Dent, C, E.: Homocystinuria, Br. Med. Bull. 25: 42-47, 1969. 9. Duke-Elder, S. and Perluns, E. S.: System of Ophthalmology, vol. IX, London, 1966, Henry Kimpton, p. 646. 10. Gibson, J. B., Carson, N. A. J., and Neil& D. W.: Pathological Findings in Homocystinuria, J. Clin. Pathol. 17: 427-437, 1964. 11. Hampton, J. R., and Mitchell, J. R. A.: A Transferable Factor Causing Abnormal Platelet Behaviour in Vascular Disease, Lancet 2: 764-768, 1966. 12. Harcourt, R. B.: Ocular Manifestations of Inborn Errors of Metabolism, Br. J. Hosp. Med. 2: 831839, 1969. 13. Harrison, T. H.: Principles of Internal Medicine, ed. 6, New York, 1971, McGraw-Hill Book Company, Inc.., p. 584. 14. Genetic Heterogeneity in Connective Tissue Disorders, Lancet 1: 960, 1971. (Annotation.) 15. Lo;g;i5qdge, L. W.: Renal Abnormalities in Marfan Syndrome, Quart. J. Med. 28: 53116. LyAas, M. A., and Merrett, J. D.: Data on Linkage in Man; Mar-fan’s Syndrome Northern Ireland, Ann. Hum. Genet. 22: 310, 1958. 17. Nally, F. F. : The Marfan Syndrome, ORAL SURG. 22: 715-723, 1966. 18. Schimke, R. N., McKusick, V. A., Huang, T., and Pollack, A. D.: Homocystinuria, J. A. M. A. 193: 711-719, 1965. 19. Talegaonkar, S. K. : Letter to the Editor, Lancet 1: 1433, 1968. Reprint
requests
to:
Dr. M. Leonard Department of Oral Surgery Royal Dental Hospital Leicester Square London, WCBH 7LJ, England
in
UNIT,
IPSWICH
AND
EAST
SUFFOLK
HOSPITAL
Attention is drawn to a recently discovered condition which has clinical manifestations closely similar to those of Marfan’s syndrome. The importance of recognizing the condition lies in the fact that treatment can be instituted to ameliorate the mental deterioration that frequently accompanies homocystinuria.
T
he main purpose of this article is to draw to the attention of the dental profession a relatively recently discovered disease which has oral manifestations, and is to be considered in the differential diagnosis of Marfan’s syndrome. Furthermore, its presence demands precautions if a surgical operation is to be undertaken. Homocystinuria is compatible with an autosomal recessive inheritance and is an inborn error of the metabolism of methionine, an essential sulfur-containing amino a&d. It has bee11diagnosed in patients of both sexes from 9 days” to 15 years of age,ls and 100 cases have been reported.13 CLINICAL Skeletal
FEATURES
Dolichostenomelia (“long, thin extremities”) with a low ratio of upper segment to lower segment is present in most cases (Fig. 1). Normally, the ratio of the upper segment (pubic symphysis to crown) to the lower segment (pubic symphysis to sole) is about 0.92. Because of the long lower extremities in these patients, the ratio is reduced. The patients are often taller than normal for their age; most have a pectus excavatum and a scoliosis. This latter feature is attributed to the osteoporosis and vertebral collapse which take place in this condition. Cusworth and Dent? stated that the patients are loose jointed, but this is by no means a universal finding, since Schimke and associates18 reported that some have reduced mobility of the joints. Ocular
Ectopia lentis is one of the cardinal features of the disease. The lens may not become dislocated until the age of 10 years or more, although it has been 214
Volume 36 Number 2
Fig.
Homocystinuria
2 15
1. The long thin fingers common to Marfan’s syndrome and to homocystinuria.
seen at 22 months3 The earliest sign is iridodonesis-tremulousness of the iris due to the loss of normal support that the lens provides for the iris diaphragm; this progresses to dislocation. Duke-Elder9 states that the characteristic ocular feature is the thickening of the basement membrane of the ciliary body, with atrophy of the nonpigmented epithelium leading to bilateral degeneration of the zonule and subsequent dislocation and iridodonesis of the lens. The thickened layer of hyaline material overlying the atrophic epithelium is almost pathognomonic of homocystinuria in differentiating it from other forms of ectopia lentis. The direction of dislocation may differ from that in Marfan’s syndrome; the latter is usually upward but may be in any direction. Myopia, retinal detachment, and glaucoma are additional ocular symptoms. Cardiovascular
Arterial or venous thrombosis and cutaneous flushing are the main signs. Thrombosis has been reported in the terminal aorta and in the iliac, subclavian, and renal arteries.l* Carson, and associates” reported cardiac murmurs of unknown origin, and Cusworth and Dent* observed occlusion of the pulmonary artery and car pulmonale in one of their patients. Central
Nervous
System
Very frequently, there is mental retardation. The early development is normal, but mental deterioration is progressive. Carson5 reported that sixteen of eighteen patients had I.Q.‘s ranging from 20 to 70. Schimke and associatesl’ diagnosed only twenty-two of thirty-eight of their patients as being retarded.
216
Leonard
Fig. 8’. Prognathic shown is the crowding
Oral August,
mandible common of the dentition.
to Marfan’s
syndrome
and
to homocystinuria;
Burg. 19’73
also
Since five of their patients were college graduates, it has been suggested that these persons may have been suffering from a specific form of the disease. Epileptic seizures are frequent, and progressive clotting in the cerebral vesselsis suggested as the probable cause. Oral
and
Facial
Manifestations
Among the most striking features of this condition are sparse fine hair, malar flush, and a long face with a prognathic lower jaw (Fig. 2). Intraorally, the teeth are crowded, anti a high-arched (“gothic”) palate exists. From this review of the principal clinical features, one can easily see how closely the condition resembles Marfan’s syndrome on clinical observation. Nally,17 in a review of Marfan’s syndrome, listed dolichostenomelia, arachnodactly, pectus excavatum, scoliosis, ectopia lentis, laxity of the joints, and mental retardation as the typical features of the syndrome, although it is very doubtful that mental retardation forms part of the symptom complex of Marfan’s syndrome. The close clinical similarity of homocystinuria to Marfan’s syndrome is further shown by the fact that Carson5 reports that two of her caseswere written up as classic examples of Marfan’s syndrome by Lynas and MerretP and Loughbridge.15 Schimke and associateP describe the case of an 11-year-old girl who at first was considered to have Marfan’s syndrome, but who subsequently was proved to be suffering from homocystinuria. Talegaonkarlg believes that the condition is much more common than it is often thought to be. He discovered three cases of ectopia lentis due to homo-
Volume 36 Number 2
Homocystinuria
cystinuria in 10,395 patients seen in one year in the ophthalmology of his hospital.
2 17
department
Pathology
The chief findings so far appear to be in the cardiovascular system and consist of patchy intimal lesions made up of transverse bandlike elevations which narrow the lumen of the vessels. These thickenings appear to be fibrous tissue. The elastic fibers are thickened and disrupted.lO The frequent thromboses seen in the arteries and veins of patients with homocystinuria are due not only to changes in the vessels but also to the increased platelet adhesiveness. Although this feature is not present in all cases, thirteen patients under study by Cusworth and Dents all had abnormally sticky platelets. These authors point out that the cause of the tendency toward in vivo clotting is not revealed by the usual tests for clotting factors (in vitro techniques) and that the increased platelet adhesiveness in shown only if particular techniques are used. Hampton and Mitchellll observed that the plasma of two brothers with homocystinuria contained a factor which caused normal platelets to become abnormally sensitive to adenosine diphosphate. Cusworth and Dent* made the point that, after treatment with pyridoxine, the platelets became less sticky in the majority of their patients, but it is not known whether this will lea,1 to a diminution in thromboembolic sequelae. Biochemistry
Homocystinuria was first described by Carson and NeillG in 1962, after an examination of the urinary metabolites of mentally retarded children in Northern Ireland. Methionine is an essential amino acid; that is, it cannot be synthesized by the body in amounts necessary to fulfill normal requirements for it. Methionine has three principal functions: synthesis of protein; formation of adrenaline and creatine; and the formation of cysteine, with homocysteine as an intermediary metabolite. In homocystinuria, there is a metabolic block in the homocysteine, which is rapidly oxidized to homocystine and excreted in the urine. Cysteine cannot be formed and becomes, therefore, an essential amino acid in these patients. The diagnosis is made by finding homocystine in the urine. Treatment
The lines of treatment so far pursued have been to limit methionine in the diet and supplement it with cystine, but this produces a very monotonous diet.3 An alternative approach has been to give pyridoxine supplements, since this is the coenzyme necessary to activate cystathionine synthetase, which appears, to be the defective enzyme. So far, some patients have responded, the response being measured by reduction in urine and plasma levels of homocystine. Management
during
operation
As has been mentioned above, thrombembolic episodes may occur spontanereported that these episodes are ously as well as after operation. HarcourP common after general anesthesia.
Oral August,
Leonard
218
Surg. 1973
I. Comparison of principal features of Marfan’s syndrome and Homocystinuria Table
Homcystinwia
Feature Inheritance Skeletal abnormality Eye
signs
Skin Mental Vascular Oral
retardation anomalies
and facial
signs
Autosomal recessive Osteoporosis; occasionally arachnodactyly and loose-jointedness pectus excavatum Ectopia lentis Malar flush Frequent Arterial and venous High-arched crowding
Marfan’s
;
palate, prognathic of teeth
Autosomal dominant Arachnodactyly, loose-jointeclness more frequent ; pectus excavatum Ectopia sclera
thrombosis jaw,
syndrome
lentis,
occasionally
Not common Dilation of ascending aorta; dissecting aneurysm High-arched palate, crowding teeth
blue
of
Crooke, Towers and Taylor’ reported a patient with homocystinuria who was given a general anesthetic for the removal of six carious teeth and conservation of three teeth. The period of anesthesia lasted for 1 hour and 55 minutes. In order to prevent possible postoperative thrombosis, measures were taken to reduce blood viscosity and platelet adhesiveness and to accelerate postoperative recovery. The procedure was to infuse dextran 70, which has been shown by Bennett and co-workers1 to reduce platelet adhesiveness,and to reverse the muscle relaxation with atropine and neostigmine at the completion of the operation. After the operation, the platelet adhesiveness was decreased and remained so for several days, and it was thought that the regimen adopted had brought this about. The two patients operated on in this unit were mentally retarded (ages X and 13 years). All of the first permanent molars were removed in both children, and becauseof the mental state of the patients, general anesthesia was necessary. The period of anesthesia lasted less than 20 minutes and no muscle relaxants were used. The patients were ambulant within 2 hours after the operation. Brenton2 advised no special precautions since the periods of anesthesia were to be very short. DISCUSSION
Casesof Marfan’s syndrome are not common, and yet the features are often so typical that the diagnosis springs to mind. The asymptomatic patient may well be readily noticed by the dental surgeon because of the oral manifestations. It has now become apparent that when such suspicions are aroused, one must bear in mind the possibility of homocystinuria, for it is very closely akin to Marfan’s syndrome on clinical examination, particularly the oral and facial signs. The principal features of both conditions are compared in Table I. The importance of considering a diagnosis of homocystinuria is due to the fact that confirmation may allow treatment and thus arrest the mental and visual deterioration.14 Furthermore, if oral surgery is to be undertaken, local anesthesia is preferable; but if general anesthesia is necessary, then particular attention to the duration of the operation is important, since measures to reduce
Volume Number
Homocystinuria
36 2
platelet sary.
adhesiveness and the tendency to thromboembolic
2 19
episodes may be neces-
SUMMARY
A review of the clinical manifestations of homocystinuria is presented, with emphasis on its close similarity to Marfan’s syndrome. Attention is drawn to the differences and the need to plan surgical procedures while one bears in mind the tendency of homocystinuria to lead to thromboembolic episodes. I wish to thank Mr. V. E. Ireland and Mr. patients, and for encouragement and advice.
W. Gray
for
permission
to use records
of their
REFERENCES
1. Bennett, P. N., Dhall, D. P., McKenzie, F. N., and Matheson, N. A.: Effects of Dextran Infusions on the Adhesiveness of Human Blood Platelets, Lancet 2: 1001-1003, 1966. 2. Brenton, D. P. : Personal communication, 1970. 3. Carson, N. A. J.: Homocystinuria, Proo. R. 800. Med. 63: 41-43, 1970. 4. Carson, N. A. J., Dent, C. E., Field, C. M. B., and Gaull, G. E. : Homocystinuria: Clinical and Pathological Review of 10 Cases, J. Pediatr. 66: 565-583, 1965. 5. Carson, N. A. J.: Homocystinuria, Br. J. Hosp. Med. 2: 439-443, 1969. 6. Carson, N. A. J., and Neill, D. W.: Metabolic Abnormalities Detected in a Survey of Mentally Backward Individuals in Northern Ireland, Arch. Dis. Child. 37: 505-513, 1962. W. H.: Management of Patients With 7. Crooke, J. W., Towers, J. F., and Taylor, Homocystinuria Requiring Surgery Under General Anaesthesia, Br. 5. Anaesth. 43: 96-99, 1971. 8. Gusworth, D. C., and Dent, C, E.: Homocystinuria, Br. Med. Bull. 25: 42-47, 1969. 9. Duke-Elder, S. and Perluns, E. S.: System of Ophthalmology, vol. IX, London, 1966, Henry Kimpton, p. 646. 10. Gibson, J. B., Carson, N. A. J., and Neil& D. W.: Pathological Findings in Homocystinuria, J. Clin. Pathol. 17: 427-437, 1964. 11. Hampton, J. R., and Mitchell, J. R. A.: A Transferable Factor Causing Abnormal Platelet Behaviour in Vascular Disease, Lancet 2: 764-768, 1966. 12. Harcourt, R. B.: Ocular Manifestations of Inborn Errors of Metabolism, Br. J. Hosp. Med. 2: 831839, 1969. 13. Harrison, T. H.: Principles of Internal Medicine, ed. 6, New York, 1971, McGraw-Hill Book Company, Inc.., p. 584. 14. Genetic Heterogeneity in Connective Tissue Disorders, Lancet 1: 960, 1971. (Annotation.) 15. Lo;g;i5qdge, L. W.: Renal Abnormalities in Marfan Syndrome, Quart. J. Med. 28: 53116. LyAas, M. A., and Merrett, J. D.: Data on Linkage in Man; Mar-fan’s Syndrome Northern Ireland, Ann. Hum. Genet. 22: 310, 1958. 17. Nally, F. F. : The Marfan Syndrome, ORAL SURG. 22: 715-723, 1966. 18. Schimke, R. N., McKusick, V. A., Huang, T., and Pollack, A. D.: Homocystinuria, J. A. M. A. 193: 711-719, 1965. 19. Talegaonkar, S. K. : Letter to the Editor, Lancet 1: 1433, 1968. Reprint
requests
to:
Dr. M. Leonard Department of Oral Surgery Royal Dental Hospital Leicester Square London, WCBH 7LJ, England
in