Clinical Genetics 1977: 11: 1-7
An
Sclerosteosis autosomal recessive disorder
PETERBEIGHTON, JAMES DAVIDSON, ~LECIA DURR AND ?HERMAN HAMERSMA Department of Human Genetics, Medical School, University of Cape Town, 1 Government Health Service, Durban, and 2 Department of Otorhinolaryngology, University of Pretoria, S. Africa Sclerosteosis is a rare, potentially lethal skeletal disorder in which massive bony overgrowth leads to facial distortion, cranial nerve compression and progressive rise in intracranial pressure. Gigantism and syndactyly of the 2nd and 3rd fingers are associated features. In a nationwide investigation in South Africa, 25 affected individuals in 15 Afrikaner kindreds have been studied. The minimum prevalence of the condition in this community is 1 in 75,000. Analysis af pedigree data confirms that sclerosteosis is an autosomal recessive condition. The gene frequency in the Afrikaner people is estimated at 0.0035, with 10,000 clinically normal heterozygotes in this population. Heterozygote detection may be possible on a basis of recognition of minor changes which are apparent on skull radiographs. Received 29 March, revised 24 M a y , accepted for publication I June I976
Sclerosteosis is an unusual, potentially lethal, skeletal disorder in which massive bony overgrowth leads to facial distortion, cranial nerve compression and progressive rise in intracranial pressure. Gigantism and syndactyly of the 2nd and 2rd fingers are associated features. Sclerosteosis is rare and published reports are scanty. In an investigation in Southern Africa we have studied 25 affected individuals in 15 kindreds, all of Afrikaner stock. Analysis of pedigree data of these families confirms that sclerosteosis is an autosomal recessive condition.
Material and Methods
The Mnriifrstatioris of Sclerosteosis The clinical features which were present in the patients in the series have been fully
described and discussed elsewhere (Beighton et al. 1976a). T h e major manifestations of sclerosteosis a r e the consequence of progressive bony overgrowth and thickening. These changes are most pronounced in the skull, leading to distortion of the facies and cranial nerve entrapment, with facial palsy and conductive deafness (Fig. 1). Digital abnormalities may be the only features evident at birth, although facial palsy is seen in some patients at this time. Syndactyly of the 2nd and 3rd fingers is variable in degree, ranging from minor soft tissue webbing to complete bony union. The finger nails are dysplastic and the terminal phalanges are radially deviated. After the age of 5 years, height and weight become excessive, and the mandible enlarges. Deafness develops and, following transient attacks, facial palsy usually becomes permanent in the second decade.
2
BEIGHTON, OAVIOSON, DURR AND
HAMERSMA
is defective and their cortices are thickened. Distortion is particularly severe in the phalanges. T h e radiographic changes in the affected individuals in the series have been reported elsewhere (Beighton et al. 1976b). Survey Methodology Sclerosteosis first came to our attention when the disorder was recognised among patients with skeletal dysplasias referred to H.H. for management of facial nerve palsy or deafness. Others were subsequently located during a nationwide survey of individuals affected by conditions loosely designated “osteopetrosis.” Cases of sclerosteosis were then actively sought by scrutiny of hospital records and circularisation of general practioners and specialists throughout South Africa. Twentyone affected individuals in 15 kindreds were examined clinically by the authors, in Flg. 1. The facies in sclerosteosis
In young adults, raised intracranial pressure, due to progressive diminution of the volume of the cranial cavity, often causes intractable headache. Sudden death at or before middle age may result from the impaction of the medulla in the foramen magnum. Intelligence is normal and general health is unimpaired. However, due to the grotesque facial appearance, psycho-social problems are not uncommon. Apart from syndactyly, the skeleton is radiologically virtually normal in early childhood. Thereafter, bony widening and sclerosis are increasingly evident. Changes are most marked in the calvarium and the mandible (Fig. 3). The spine is relatively spared. In the pelvis, there is some increase in density, particularly in the ischial and pubic rami. Modelling o f the long bones
*.
radiogtaph of th8 skull of an adult with scIerosteosis.
SCLEROSTEOSIS-AN AUTOSOMAL RECESSIVE DISORDER
either Pretoria or Cape Town, and in each instance radiographic studies were carried out. Medical records and family photographs facilitated confirmation of the diagnosis of sclerosteosis in deceased sibs in three of the kindreds. In the final stage of the survey, home visits were undertaken in order to construct detailed pedigrees and to examine first-degree relatives. As preliminary observations suggested that the disorder might be inherited as a n autosomal recessive trait, lateral skull radiographs were obtained from the obligatory and potential heterozygotes in an attempt to develop a method for recognition of the heterozygous carrier of the gene.
Results The affected individuals were all members of the Afrikaner community. This group are the descendents of settlers from Holland who emigrated to the Cape during the 17th century. A composite of the pedigrees of the kindreds is shown in Figure 3.
SCLEROSTEOSIS 1.
2. 3. 4.
5. b.
"00.0 0 ..000 00. O,.O&OW 0
7, 00.0 8, * M Q m 9 , *.* 15, M G O O $ G C D
13,
m0.00 '00000. 0
14.
"00000
il.
12,
15.
oooom~bo-9o0.m *?ARE:ITA.
CCNSDNC-U!IIITI.
\ DECEASEC,
Fig. 3. Composite of the pedigrees of the kindreds.
3
Table 1 Sclerosteosis segregation analysis by LenzHogben method Sibship size
Nuo;ber
Number affected Variance
sibships Observed
Expected
1.000 2.285 3.892 2.926 4.917 3.649 2.222 3.329 15
25
24.220
0.000 0.244 0.789 0.840 1.506 1.552 1.172 2.234 8.337 SD = 2.887
The foIIowing findings support the contention that sclerosteosis is transmitted as an autosomal recessive trait: i. Affected sibs were present in eight of the 15 kindreds, but none of the parents or members of other generations were affected. ii. T h e five children of the three patients who had reproduced were all normal. iii. T h e sex distribution of affected individuals was approximately equal (12 males and 13 females). iv. Parental consanguinity was present in five families. Confirmation of the autosomal recessive nature of sclerosteosis was obtained by formal statistical evaluation of the pedigree data of the affected individuals using the Lenz-Hogben or u priori method (Mc Kusick 7969). Segregation analysis by the Lenz-Hogben technique is shown in Table 1. I n this method it is assumed that all sibships with affected members have been ascertained. In view of the dramatic manifestations of sclerosteosis, and because every effort was made to ascertain all affected individuals in the country, this is a reasonable assumption.
4
BEIGHTON, DAVIDSON, DURR AND HAMERSMA
The observation of 25 affected individuals, compared with an expected total of 24.22 (s.e. 2.887) is within the 95 % confidence limits, and is therefore compatible with autosomal recessive inheritance. Fitness to Reproduce In the biological sense, the index “fitness to reproduce” refers to the extent to which an individual contributes his genes to the next generation. In sclerosteosis, the major factors which limit reproduction are the potential lethality of the disorder and the difficulty of finding a mate, due to the gross facial distortion. Assuming that the average Afrikaner family has three children and as only three of the 16 affected individuals in the series who were over the age of 20 (of whom three were under the age of 25 and two were over the age of 40) have procreated, producing five children between them, the approximate, “fitness to reproduce” of 10 % may be calculated as follows: - 16 X 3 = 48; - -- 10 % . This figure of 10 92 indicates 48 that an individual with sclerosteosis has a greatly diminished capacity for transmission of the abnormal gene. Prevalence and Gene Frequency The Afrikaner community numbers approximately 1.5 million, and the minimum prevalence of sclerosteosis in this population can be calculated as 1 in 75,000. Estimates of gene frequency, made on the basis of the “Hardy Weinberg proportions,” indicate that the gene frequency among the Afrikaner people is 0.0035. In other words, approximately 7 in every 1,000 Afrikaners (or 1 in 140) are carriers of the gene, and there must be about 10,000 clinically normal heterozygotes in this community. Heterozygote Detection In the majority of heterozygotes, definite
thickening of the calvarium, with loss of the normal distinction between the tables of the skull, is apparent in lateral radiographs (Fig. 4). Twenty-two parents of affected individuals (obligatory heterozygotes) were examined radiologically, and abnormal thickness of the skull was found to be present in 18. Radiographic studies were also carried out in 26 potentially heterozygous siblings of patients with the condition. As the condition is progressive, it is unlikely that abnormalties would be detectable in the radiographs of children under the age of 5 years, and individuals in this age group were therefore excluded from this aspect of the investigation. Of the siblings studied, 15 had changes in the skull which were indicative of heterozygosity. The ratio of heterozygotes to normals is in keeping with the autosomal recessive inheritance of the disorder. Skull radiographs were also obtained in 60 other more distant relatives. These have not yet been analysed, but preliminary observations indicate that the heterozygous state is recognisable in a number of these individuals. Laboratory Studies Determinations of biochemical factors, including measurements of serum calcium, phosphorus and alkaline phosphatase levels, were undertaken in 22 parents (obligatory heterozygotes) and in 26 siblings (potential heterozygotes) of affected individuals. The concentrations were generally normal, and it can be concluded that these biochemical parameters are not of any value in heterozygote detection. Dlscusslon
Sclerosteosis is one of a number of conditions which have been grouped together as “osteopetroses” or “Albers-Schonberg
SCLEROSTEOSIS-AN AUTOSOMAL RECESSIVE DISORDER
5
Flg. 4. Lateral radiograph of the skull of an adult obligatory heterozygote
disease.” However, Truswell (1958) delineated the disorder and Hansen (1967) applied the designation “sklerosteose.” This term has gained general acceptance (Carter & Fairbank 1974, Spranger et al. 1974), and sclerosteosis is now classified with the craniotubular hyperostoses. (Gorlin et al. 1969). Detailed discussion of the differential diagnosis is outside the scope of this article, but sclerosteosis is readily recognisable by the association of severe bony manifestations and digital anomalies. Hyperostosis corticalis generalisata (van Buchem et al. 1955, 1962) is the only condition which resembles sclerosteosis, but the relative normality of the hands in van Buchem’s disease permits differentiation.
Patients with sclerosteosis are recognisable in a number of publications which have been concerned with “osteopetrosis.” (Kretzmar & Roberts 1936, Falconer & Ryrie 1937, Klintworth 1963, Hamersma 1970, 1974). T h e majority of these articles have emanated from South Africa, and several of the affected individuals have been restudied in the present investigation. The presence of consanguinity and affected siblings with normal parents in several of these kindreds led Gorlin et al. (1969) to postulate that sclerosteosis was probably inherited as an autosomal recessive. The only convincing case reports from other parts of the world concern a kindred in New York (Higinbotham & Alexander 1941) a n d a Japanese girl (Suguira & Yasu-
6
BEIGHTON, DAVIDSON, DURR AND HAMERSMA
hara 1975). The features of the Negro siblings from the USA, described by Kelly & Lawlah (1946), restudied by Witkop (1965) and widely quoted as having sclerosteosis, are not consistent with the disorder. In particular, the marked sclerosis of the vertebral bodies and the normality of the hands in these four siblings permit differentiation from sclerosteosis. As sclerosteosis is apparently rare in population groups other than the Afrikaners, it can be assumed that the mutation rate is low. There is no reason to suppose that there is any heterozygote advantage, and selection against homozygotes, by reason of their low “fitness to reproduce” would not influence the magnitude of the gene pool, as they are so few in number. For these reasons, the high gene frequency amongst the Afrikaner people is probably the result of the “founder effect” (i.e. the initial presence of the gene in a proportion of the progenitors of a small community leading to eventual dissemination of that gene throughout the population in later generations). There have been about 12 generations since the first Burgers arrived from Holland during the 17th century, and it is possible that one of these individuals was heterozygous for the abnormal gene. Conversely, if the gene arose by new mutation in one of these colonists, sufficient time has elapsed since that event for it to have been disseminated throughout the Afrikaner community. As approximately 1 in 140 normal individuals of Afrikaner stock in South Africa carries the gene for sclerosteosis, the likelihood of heterozygotes marrying within this population is 140 x 140 = 19,600. In other words, about 1 in every 20,000 Afrikaner couples are at risk of producing affected children. As the condition is inherited as an autosomal recessive, parents in this situation have a 1 in 4 chance of having a
child with sclerosteosis on each occasion that they reproduce. The parents of affected individuals are obligatory heterozygous carriers of the gene, while there is a two to one chance that any clinically normal sibling of a patient is also a heterozygote. In the same way, other family members may also have the gene. Identification of these clinically normal heterozygotes would be of considerable practical significance from the point of view of control and eradication of sclerosteosis by genetic measures. If accurate and simple methods of heterozygote detection are eventually developed they could be used for population screening, with identification of all “at risk” marriages. Similarly, new techniques of antenatal diagnosis may permit recognition of the affected foetus. These potential developments form the basis of the long-term prospects for eventual control of sclerosteosis. Acknowledgements
Our thanks are due to Professor A. S. Truswell, Dr. G. K. Klintworth and to many other colleagues for their kindness in facilitating access to affected individuals; to Mrs Greta Beighton for typing the manuscript and preparing the tables and pedigrees; and to Mr. C. Russ, Mr. R. A . deMCneaud and Mrs R. S. Henderson for their assistance with the illustrations. We are especially grateful to Professor Alan Emery for his guidance concerning the statistical aspects of this paper. Not least, we are grateful to the patients themselves for their ready co-operation in the investigations. This project was supported by grants from the University of Cape Town Staff Research Fund, the South Afrikan Medical Research Council and the Hettie de Beer Fund.
SCLEROSTEOSIS-AN AUTOSOMAL RECESSIVE DISORDER
References
Beighton, P., L. Durr & H. Hamersma (1976a). The clinical features of sclerosteosis. Ann. int. Med. 84, 393-397. Beighton, P., B. J. Cremin 19.H. Hamersma (1976b). The radiology of sclerosteosis. In press. Buchem, F. S. P. van, H. N. Hadders & R. Ubbens (1955). An uncommon familial systemic disease of the skeleton. Hyperostosis corticalis generalisata familiaris. Acta radiol. 42, 109-119. Buchem, F. S. P. van, J. F. Jansen .& M. G. Woldring (1962). Hyperostosis corticalis generalisata. Amer. J . Med. 33, 387-397. Carter, C . 0. & T. J. Fairbank (1974). The Genetics of Locotnotor Disorders. London, Oxford University Press, p. 35. Falconer, A. W. & B. J. Ryrie (1937). Report on a familial type of generalised osteosclerosis. Med. Press 195, 12-14. Gorlin, R. I., .I. Spranger & M. F. Koszalka (1969). Genetic craniotubular bone dysplasias and hyperostoses - a critical analysis. Birth Defects: Original Article Series Vol. V , No. 4. Hamersma, H. (1970). Osteopetrosis (marble bone disease) of the temporal bone. Laryngoscope 80, 1518-1539. Hamersma, H. (1974). Total decompression of the facial nerve in osteopetrosis (Marble bone disease - Morbus Albers-Schonberg). J . Oto-Rhino-Laryng. 36, 21-32. Hansen, H. G. (1967). Sklerosteose. Handbirch der Kitiderheilkirnde, Vol. 6, ed. J. Opitz & F. Schmid. Berlin, Gorringen, Heidelberg, New York, Springer, pp. 351-355.
7
Higinbotham, N. L. & S . F. Alexander (1941). Osteopetrosis, four cases in one family. Amer. J . Surg. 53, 444-454. Kelley, C. H. ik J. W. Lawlah (1946). AlbersSchonberg - a family study. Radiology 47, 507-510. Klintworth, G. K. (1963). The neurologic manifestations of osteopetrosis (Albers-Schonberg's disease). Neurology (Minneap.) 13, 5 12-519. Kretzmar, J. H. & R. A. Roberts (1936). Case of Albers-Schonberg disease. Brit. med. J . 1, 837-839. McKusick, V. A. (1969). Human Genetics, 2nd Ed. New York, Prentice-Hall, p. 138. Spranger, J. W., L. 0. Langer .& H. S. Weidemann (1974). Bone dysplasias. Stuttgart, Gustav Fischer Verlag, p. 302. Suguira, Y. 8r T. Yasuhara (1975). Sclerosteosis. J . Bone J t Surg. SIA, 273-276. Truswell, A. S . (1958). Osteopetrosis with syndactyly. A morphological variant of AlbersSchonberg Disease. J . Bone J t Surg. 40B, 208-218. Witkop, C. J. (1965). Genetic disease of the oral cavity. Oral Pathology, ed. Tiecke, R. W. New York, McGraw-Hill.
Address: Peter Beighton, M . D . , Ph.D., F.R.C.P., D.C.H. Dept. of H u m a n Genetics Medical School University of Cape Town Cape Town S. Africa
An
Sclerosteosis autosomal recessive disorder
PETERBEIGHTON, JAMES DAVIDSON, ~LECIA DURR AND ?HERMAN HAMERSMA Department of Human Genetics, Medical School, University of Cape Town, 1 Government Health Service, Durban, and 2 Department of Otorhinolaryngology, University of Pretoria, S. Africa Sclerosteosis is a rare, potentially lethal skeletal disorder in which massive bony overgrowth leads to facial distortion, cranial nerve compression and progressive rise in intracranial pressure. Gigantism and syndactyly of the 2nd and 3rd fingers are associated features. In a nationwide investigation in South Africa, 25 affected individuals in 15 Afrikaner kindreds have been studied. The minimum prevalence of the condition in this community is 1 in 75,000. Analysis af pedigree data confirms that sclerosteosis is an autosomal recessive condition. The gene frequency in the Afrikaner people is estimated at 0.0035, with 10,000 clinically normal heterozygotes in this population. Heterozygote detection may be possible on a basis of recognition of minor changes which are apparent on skull radiographs. Received 29 March, revised 24 M a y , accepted for publication I June I976
Sclerosteosis is an unusual, potentially lethal, skeletal disorder in which massive bony overgrowth leads to facial distortion, cranial nerve compression and progressive rise in intracranial pressure. Gigantism and syndactyly of the 2nd and 2rd fingers are associated features. Sclerosteosis is rare and published reports are scanty. In an investigation in Southern Africa we have studied 25 affected individuals in 15 kindreds, all of Afrikaner stock. Analysis of pedigree data of these families confirms that sclerosteosis is an autosomal recessive condition.
Material and Methods
The Mnriifrstatioris of Sclerosteosis The clinical features which were present in the patients in the series have been fully
described and discussed elsewhere (Beighton et al. 1976a). T h e major manifestations of sclerosteosis a r e the consequence of progressive bony overgrowth and thickening. These changes are most pronounced in the skull, leading to distortion of the facies and cranial nerve entrapment, with facial palsy and conductive deafness (Fig. 1). Digital abnormalities may be the only features evident at birth, although facial palsy is seen in some patients at this time. Syndactyly of the 2nd and 3rd fingers is variable in degree, ranging from minor soft tissue webbing to complete bony union. The finger nails are dysplastic and the terminal phalanges are radially deviated. After the age of 5 years, height and weight become excessive, and the mandible enlarges. Deafness develops and, following transient attacks, facial palsy usually becomes permanent in the second decade.
2
BEIGHTON, OAVIOSON, DURR AND
HAMERSMA
is defective and their cortices are thickened. Distortion is particularly severe in the phalanges. T h e radiographic changes in the affected individuals in the series have been reported elsewhere (Beighton et al. 1976b). Survey Methodology Sclerosteosis first came to our attention when the disorder was recognised among patients with skeletal dysplasias referred to H.H. for management of facial nerve palsy or deafness. Others were subsequently located during a nationwide survey of individuals affected by conditions loosely designated “osteopetrosis.” Cases of sclerosteosis were then actively sought by scrutiny of hospital records and circularisation of general practioners and specialists throughout South Africa. Twentyone affected individuals in 15 kindreds were examined clinically by the authors, in Flg. 1. The facies in sclerosteosis
In young adults, raised intracranial pressure, due to progressive diminution of the volume of the cranial cavity, often causes intractable headache. Sudden death at or before middle age may result from the impaction of the medulla in the foramen magnum. Intelligence is normal and general health is unimpaired. However, due to the grotesque facial appearance, psycho-social problems are not uncommon. Apart from syndactyly, the skeleton is radiologically virtually normal in early childhood. Thereafter, bony widening and sclerosis are increasingly evident. Changes are most marked in the calvarium and the mandible (Fig. 3). The spine is relatively spared. In the pelvis, there is some increase in density, particularly in the ischial and pubic rami. Modelling o f the long bones
*.
radiogtaph of th8 skull of an adult with scIerosteosis.
SCLEROSTEOSIS-AN AUTOSOMAL RECESSIVE DISORDER
either Pretoria or Cape Town, and in each instance radiographic studies were carried out. Medical records and family photographs facilitated confirmation of the diagnosis of sclerosteosis in deceased sibs in three of the kindreds. In the final stage of the survey, home visits were undertaken in order to construct detailed pedigrees and to examine first-degree relatives. As preliminary observations suggested that the disorder might be inherited as a n autosomal recessive trait, lateral skull radiographs were obtained from the obligatory and potential heterozygotes in an attempt to develop a method for recognition of the heterozygous carrier of the gene.
Results The affected individuals were all members of the Afrikaner community. This group are the descendents of settlers from Holland who emigrated to the Cape during the 17th century. A composite of the pedigrees of the kindreds is shown in Figure 3.
SCLEROSTEOSIS 1.
2. 3. 4.
5. b.
"00.0 0 ..000 00. O,.O&OW 0
7, 00.0 8, * M Q m 9 , *.* 15, M G O O $ G C D
13,
m0.00 '00000. 0
14.
"00000
il.
12,
15.
oooom~bo-9o0.m *?ARE:ITA.
CCNSDNC-U!IIITI.
\ DECEASEC,
Fig. 3. Composite of the pedigrees of the kindreds.
3
Table 1 Sclerosteosis segregation analysis by LenzHogben method Sibship size
Nuo;ber
Number affected Variance
sibships Observed
Expected
1.000 2.285 3.892 2.926 4.917 3.649 2.222 3.329 15
25
24.220
0.000 0.244 0.789 0.840 1.506 1.552 1.172 2.234 8.337 SD = 2.887
The foIIowing findings support the contention that sclerosteosis is transmitted as an autosomal recessive trait: i. Affected sibs were present in eight of the 15 kindreds, but none of the parents or members of other generations were affected. ii. T h e five children of the three patients who had reproduced were all normal. iii. T h e sex distribution of affected individuals was approximately equal (12 males and 13 females). iv. Parental consanguinity was present in five families. Confirmation of the autosomal recessive nature of sclerosteosis was obtained by formal statistical evaluation of the pedigree data of the affected individuals using the Lenz-Hogben or u priori method (Mc Kusick 7969). Segregation analysis by the Lenz-Hogben technique is shown in Table 1. I n this method it is assumed that all sibships with affected members have been ascertained. In view of the dramatic manifestations of sclerosteosis, and because every effort was made to ascertain all affected individuals in the country, this is a reasonable assumption.
4
BEIGHTON, DAVIDSON, DURR AND HAMERSMA
The observation of 25 affected individuals, compared with an expected total of 24.22 (s.e. 2.887) is within the 95 % confidence limits, and is therefore compatible with autosomal recessive inheritance. Fitness to Reproduce In the biological sense, the index “fitness to reproduce” refers to the extent to which an individual contributes his genes to the next generation. In sclerosteosis, the major factors which limit reproduction are the potential lethality of the disorder and the difficulty of finding a mate, due to the gross facial distortion. Assuming that the average Afrikaner family has three children and as only three of the 16 affected individuals in the series who were over the age of 20 (of whom three were under the age of 25 and two were over the age of 40) have procreated, producing five children between them, the approximate, “fitness to reproduce” of 10 % may be calculated as follows: - 16 X 3 = 48; - -- 10 % . This figure of 10 92 indicates 48 that an individual with sclerosteosis has a greatly diminished capacity for transmission of the abnormal gene. Prevalence and Gene Frequency The Afrikaner community numbers approximately 1.5 million, and the minimum prevalence of sclerosteosis in this population can be calculated as 1 in 75,000. Estimates of gene frequency, made on the basis of the “Hardy Weinberg proportions,” indicate that the gene frequency among the Afrikaner people is 0.0035. In other words, approximately 7 in every 1,000 Afrikaners (or 1 in 140) are carriers of the gene, and there must be about 10,000 clinically normal heterozygotes in this community. Heterozygote Detection In the majority of heterozygotes, definite
thickening of the calvarium, with loss of the normal distinction between the tables of the skull, is apparent in lateral radiographs (Fig. 4). Twenty-two parents of affected individuals (obligatory heterozygotes) were examined radiologically, and abnormal thickness of the skull was found to be present in 18. Radiographic studies were also carried out in 26 potentially heterozygous siblings of patients with the condition. As the condition is progressive, it is unlikely that abnormalties would be detectable in the radiographs of children under the age of 5 years, and individuals in this age group were therefore excluded from this aspect of the investigation. Of the siblings studied, 15 had changes in the skull which were indicative of heterozygosity. The ratio of heterozygotes to normals is in keeping with the autosomal recessive inheritance of the disorder. Skull radiographs were also obtained in 60 other more distant relatives. These have not yet been analysed, but preliminary observations indicate that the heterozygous state is recognisable in a number of these individuals. Laboratory Studies Determinations of biochemical factors, including measurements of serum calcium, phosphorus and alkaline phosphatase levels, were undertaken in 22 parents (obligatory heterozygotes) and in 26 siblings (potential heterozygotes) of affected individuals. The concentrations were generally normal, and it can be concluded that these biochemical parameters are not of any value in heterozygote detection. Dlscusslon
Sclerosteosis is one of a number of conditions which have been grouped together as “osteopetroses” or “Albers-Schonberg
SCLEROSTEOSIS-AN AUTOSOMAL RECESSIVE DISORDER
5
Flg. 4. Lateral radiograph of the skull of an adult obligatory heterozygote
disease.” However, Truswell (1958) delineated the disorder and Hansen (1967) applied the designation “sklerosteose.” This term has gained general acceptance (Carter & Fairbank 1974, Spranger et al. 1974), and sclerosteosis is now classified with the craniotubular hyperostoses. (Gorlin et al. 1969). Detailed discussion of the differential diagnosis is outside the scope of this article, but sclerosteosis is readily recognisable by the association of severe bony manifestations and digital anomalies. Hyperostosis corticalis generalisata (van Buchem et al. 1955, 1962) is the only condition which resembles sclerosteosis, but the relative normality of the hands in van Buchem’s disease permits differentiation.
Patients with sclerosteosis are recognisable in a number of publications which have been concerned with “osteopetrosis.” (Kretzmar & Roberts 1936, Falconer & Ryrie 1937, Klintworth 1963, Hamersma 1970, 1974). T h e majority of these articles have emanated from South Africa, and several of the affected individuals have been restudied in the present investigation. The presence of consanguinity and affected siblings with normal parents in several of these kindreds led Gorlin et al. (1969) to postulate that sclerosteosis was probably inherited as an autosomal recessive. The only convincing case reports from other parts of the world concern a kindred in New York (Higinbotham & Alexander 1941) a n d a Japanese girl (Suguira & Yasu-
6
BEIGHTON, DAVIDSON, DURR AND HAMERSMA
hara 1975). The features of the Negro siblings from the USA, described by Kelly & Lawlah (1946), restudied by Witkop (1965) and widely quoted as having sclerosteosis, are not consistent with the disorder. In particular, the marked sclerosis of the vertebral bodies and the normality of the hands in these four siblings permit differentiation from sclerosteosis. As sclerosteosis is apparently rare in population groups other than the Afrikaners, it can be assumed that the mutation rate is low. There is no reason to suppose that there is any heterozygote advantage, and selection against homozygotes, by reason of their low “fitness to reproduce” would not influence the magnitude of the gene pool, as they are so few in number. For these reasons, the high gene frequency amongst the Afrikaner people is probably the result of the “founder effect” (i.e. the initial presence of the gene in a proportion of the progenitors of a small community leading to eventual dissemination of that gene throughout the population in later generations). There have been about 12 generations since the first Burgers arrived from Holland during the 17th century, and it is possible that one of these individuals was heterozygous for the abnormal gene. Conversely, if the gene arose by new mutation in one of these colonists, sufficient time has elapsed since that event for it to have been disseminated throughout the Afrikaner community. As approximately 1 in 140 normal individuals of Afrikaner stock in South Africa carries the gene for sclerosteosis, the likelihood of heterozygotes marrying within this population is 140 x 140 = 19,600. In other words, about 1 in every 20,000 Afrikaner couples are at risk of producing affected children. As the condition is inherited as an autosomal recessive, parents in this situation have a 1 in 4 chance of having a
child with sclerosteosis on each occasion that they reproduce. The parents of affected individuals are obligatory heterozygous carriers of the gene, while there is a two to one chance that any clinically normal sibling of a patient is also a heterozygote. In the same way, other family members may also have the gene. Identification of these clinically normal heterozygotes would be of considerable practical significance from the point of view of control and eradication of sclerosteosis by genetic measures. If accurate and simple methods of heterozygote detection are eventually developed they could be used for population screening, with identification of all “at risk” marriages. Similarly, new techniques of antenatal diagnosis may permit recognition of the affected foetus. These potential developments form the basis of the long-term prospects for eventual control of sclerosteosis. Acknowledgements
Our thanks are due to Professor A. S. Truswell, Dr. G. K. Klintworth and to many other colleagues for their kindness in facilitating access to affected individuals; to Mrs Greta Beighton for typing the manuscript and preparing the tables and pedigrees; and to Mr. C. Russ, Mr. R. A . deMCneaud and Mrs R. S. Henderson for their assistance with the illustrations. We are especially grateful to Professor Alan Emery for his guidance concerning the statistical aspects of this paper. Not least, we are grateful to the patients themselves for their ready co-operation in the investigations. This project was supported by grants from the University of Cape Town Staff Research Fund, the South Afrikan Medical Research Council and the Hettie de Beer Fund.
SCLEROSTEOSIS-AN AUTOSOMAL RECESSIVE DISORDER
References
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Address: Peter Beighton, M . D . , Ph.D., F.R.C.P., D.C.H. Dept. of H u m a n Genetics Medical School University of Cape Town Cape Town S. Africa
