Clinical Genetics 1975: 8: 107-111
Autosomal recessive inheritance of osteogenesis imperfecta FRANK HORAN* AND PETERBEIGHTON** Department of Human Genetics, Medical School, University of Cape Town, South Africa Six individuals in two closely related families in Southern Africa had osteogenesis imperfecta (01).Although 0 1 is usually inherited as an autosomal dominant, the pattern of transmission in this kindred was consistent with autosomal recessive inheritance. Received 15 January, uccepted for publication 17 March 1975
Osteogenesis imperfecta (01) is a well known disorder characterised by bony fragility in association with other manifestations of collagen abnormality, including blueness of the sclerae, laxity of the digital joints, widening of the bitemporal diameter of the skull, Wormian bones in the occipital sutures and otosclerotic deafness. The condition is usually inherited as an autosomal dominant with varying clinical expression. However, it has been suggested that 01 might be heterogeneous (McKusick 1972), and there has been considerable discussion as to whether an autosomal recessive variety of the disorder exists. We have recently studied a large kindred in Southern Africa in whom the pattern of inheritance is consistent with autosoma1 recessive transmission. The pertinent data are presented in this paper. Material and Methods
The families were visited in their homes and all available affected and unaffected indi-
*
**
viduals were examined. In view of the great variation which can occur in the clinical stigmata of 01, care was taken to exclude the presence of minor abnormalities in the ostensibly normal individuals. The two living parents were subjected to special scrutiny, including radiographic studies of their skulls. In some instances, medical reports or photographs were available for diagnostic confirmation in deceased individuals. Family studies The affected individuals were members of two closely related families, the majority of whom lived in Natal, South Africa. They were of African Negro stock, with some Scots and Indian admixture. The fathers of the affected sibs were an uncle and nephew (11-1 and 111-3) who had married two sisters (111-1 and 111-4). Thus, although there was no consanguinity, each pair of parents had a significant proportion of their genes in common (Fig. l., pedigree). These parents and their progenitors had been normal. In one family, four out of 13
Senior Orthopaedic Registrar, St. Mary’s Hospital, London, W.2. and Northwick Park Hospital, Harrow, Middlesex, England. Professor of Human Genetics.
108
HORAN AND BEIGHTON
offspring had 01, while in the other, two out of 14 sibs had been affected. None of the individuals with 01 had reproduced, but all offspring of their unaffected siblings were normal. Case 1 G.R. (IV-23), a 32-year-old male, was asymptomatic until 2 years of age. He subsequently suffered multiple fractures of the upper and lower limbs and has been unable to walk since early childhood. When examined in 1974 he was grossly dwarfed, with a marked kyphoscoliosis. Both femora and both tibiae were very bowed and he sat in a chair with his lower limbs curled around each other. He was unable to walk and moved by crawling about the floor. His hip joints were stiff but a normal range of movement was present in the shoulders and elbows. The wrist and finger joints were lax. His head was normal in shape and the sclerae were not blue. Mild deafness was apparent in the right ear. The teeth were in good condition. Cask 2 E.R. (IV-28), a 21-year-old female, was the sister of patient IV-23. She had sustained the first of many fractures when aged 2 and had been admitted in early childhood to a home for crippled children,
Fig. 1. The pedigree of the kindred.
where she had remained until the age of 14. On examination she was found to be only 105 cm in height. She had a severe kyphoscoliosis and there was marked bowing of the humeri and femora (Fig. 2). She was able to walk with the aid of long leg calipers and crutches. She had minimal blueing of the sclerae, excellent teeth and normal hearing. Case 3 C.R. (IV-29), a brother of patients IV-23 and IV-28, had died at the age of 19 from diphtheria. H e had sustained multiple fractures in his lifetime and had never been able to walk. His relatives confirmed that he had been very short in stature, with severe limb deformities. Case 4 T.R. (IV-301, a female, was the youngest of the affected children in the family and had died at the age of 19 from pulmonary tuberculosis. She had been of even shorter stature than her affected sister, and had marked limb bowing. She had sustained approximately 10 major long bone fractures and had been able to walk only with considerable difficulty. Case 5 L.R. (IV-8), a male, had been a cousin of the above-mentioned patients. He
A U T O S 0M A L R E C E S S I VE I N H E R I T A N C E
109
Flg. 2. Patient IV-28, aged 21; shows severe dwarfing with marked bony deformities.
had died at the age of 29 following a massive haematemesis. He had been dwarfed, and had sustained numerous fractures. He was able to walk with a wheeled frame which incorporated crutches. A family photograph of him in this device showed the shortness of stature and lower limb deformities very clearly. Cuse 6 S.R. (IV-l2), the sister of patient
IV-8, is 26 years old. She is the least severely affected of the surviving members of the
kindred. She is able to walk well with the aid of bilateral long leg calipers, which she wears more for safety than support. She walked normally until the age of 4 when she sustained the first of many fractures, mostly in the lower limbs, but also in the right arm. On examination in 1974, she was found to be 145 cm in height. She had a marked thoracic kyphus but minimal scoliosis. Both tibiae were markedly bowed anteriorly while the femora were moderately bowed. The
110
HORAN AND BEIGHTON
joints were generally lax and her sclerae were blue. Her hearing was unimpaired and her teeth were in good condition. Parents. From the pedigree it is evident that the mothers of the two branches of the kindred were sisters and that the fathers were nephew and uncle. The mother of one set of siblings (patient 111-4) died following a coronary thrombosis while the father of the other group (patient 11-1) died from the complications of peripheral vascular disease. The offspring of the deceased individuals were unanimous in their opinion that the parents had been of normal stature, and that no stigmata of 01 had been present. Similarly, none of the other deceased progenitors in generations I and 11 were thought to have had any stigmata of 01. The two surviving parents were examined (patients 111-1 and 111-3). The father was aged 60 and was 173 cm in height. He had no clinical stigmata of 01 and a lateral radiograph of his skull showed no evidence of Wormian bones. The mother was 70 years old and 166 cm in height. She had neither clinical nor radiographic evidence of the condition. Discussion
Autosomal dominant inheritance is well established in 0 1 and it is widely accepted that the disorder is transmitted by this mechanism in the majority of affected kindreds. It is also well known that clinical expression of the abnormal gene can be very variable (Rosenbaum 1944) and that on occasion it may be non-penetrant. The occurrence of “sporadic” patients has usually been ascribed to new mutation or to non-penetrance of the gene in the parent (Seedorff 1949). However, there have been a few instances of parental consanguinity (Awwaad & Reda 1960, Remigio & Grin-
walsky 1970) or multiple affected siblings with normal parents (Chawla 1964, Goldfarb & Ford 1954), and the possibility has arisen that there may be an autosomal recessive form of 01. McKusick (1972) reviewed the relevent evidence and concluded that an uncommon autosomal recessive form of 0 1 probably exists. The three living patients in the kindreds whom we investigated had unequivocal 01, and there is little doubt that the three deceased individuals also had the disorder. The ratios of affected and unaffected siblings in each of these families (two out of 14 and four out of 13) are in accordance with Mendelian ratios for autosomal recessive inheritance. Furthermore, there was no evidence whatsoever of the condition in the two living parents, while the two deceased parents and their immediate progenitors were reliably described as having been normal. As the two sets of parents were closely related, it is not unreasonable to suppose that they could have all been heterozygous for a recessive gene, while the six affected offspring were homozygotes. Clinically, 01 has been sub-divided into “congenita” and “tarda” forms, based upon the age of onset. There is considerable overlap in the manifestations, but in general the former type tends to be severe, while the latter may be comparatively mild. McKusick (1972) suggested that a small proportion of sporadic individuals with 0 1 congenita may have autosomal recessive disease. However, although our patients were severely affected, their bony fragility was not evident until after infancy. They would therefore fall into the “tarda” rather than the “congenita” group. This apparent anomaly may represent further evidence of heterogeneity within the syndrome. Each of our patients had gross dwarfing and marked deformity, while the other characteristic minor stigmata of 01 were present in varying degrees. There are no
AUTOSOMAL RECESSIVE INHERITANCE
specific clinical manifestations which permit accurate recognition of this presumed autosomal recessive type of 0 1 and further delineation will await identification of the basic biochemical defect. As 01 is a relatively common disorder, affected individuals are encountered in most genetic clinics. T h e existence of an autosomal recessive form of the condition, which, although severe, is compatible with survival into adulthood, has considerable practical implications from the point of view of genetic counselling.
Acknowledgements
W e are grateful to Mrs Greta Beighton for drawing the pedigree and typing the manuscript, to M r R . A . Du MCnaud for preparing the clinical photographs and to Sister Lecia Durr f o r arranging the home visits. This investigation was supported by grants from the University of Cape Town Staff Research Fund and the South African Medical Research Council.
111
References
Awwaad, S. & M. Reda (1960). Osteogenesis imperfecta; a review of literature and report on three cases. Arch. Pediat. 77, 280-290. Chawla, S. (1964). Intrauterine osteogenesis irnperfecta in four siblings. Brit. med. J . 1, 99-101.
Goldfarb, A. A. & D. Ford (1954). Osteogenesis imperfecta in consecutive siblings. J . Pediat. 44, 264-268.
McKusick, V. A. (1972). Heritable Disorders o f Connecfive Tissue, 4th Ed. St. Louis, C. V. Mosby Co. Remigio, P. A. & H. T. Grinwalsky (1970). Osteogenesis imperfecta; association with conspicuous extraskeletal connective tissue dysplasia. Amer. J . Dis. Child. 119, 524-528. Rosenbaum, S. (1944). Osteogenesis imperfecta and osteopsathyrosis; a contribution to the study of their identity and their pathogenesis. J . Pediat. 25, 161-167. Seedorff, K. S. (1949). Osteogenesis Imperfecta; A Study of Clinical Features and Heredity Based on 55 Danish Families Comprising 180 Affected Persons. Copenhagen, Munks-
gaard. Address: Professor Peter Beighfon Department of Human Genetics Medical School University of Cape Town Cape Town, South Africa
Autosomal recessive inheritance of osteogenesis imperfecta FRANK HORAN* AND PETERBEIGHTON** Department of Human Genetics, Medical School, University of Cape Town, South Africa Six individuals in two closely related families in Southern Africa had osteogenesis imperfecta (01).Although 0 1 is usually inherited as an autosomal dominant, the pattern of transmission in this kindred was consistent with autosomal recessive inheritance. Received 15 January, uccepted for publication 17 March 1975
Osteogenesis imperfecta (01) is a well known disorder characterised by bony fragility in association with other manifestations of collagen abnormality, including blueness of the sclerae, laxity of the digital joints, widening of the bitemporal diameter of the skull, Wormian bones in the occipital sutures and otosclerotic deafness. The condition is usually inherited as an autosomal dominant with varying clinical expression. However, it has been suggested that 01 might be heterogeneous (McKusick 1972), and there has been considerable discussion as to whether an autosomal recessive variety of the disorder exists. We have recently studied a large kindred in Southern Africa in whom the pattern of inheritance is consistent with autosoma1 recessive transmission. The pertinent data are presented in this paper. Material and Methods
The families were visited in their homes and all available affected and unaffected indi-
*
**
viduals were examined. In view of the great variation which can occur in the clinical stigmata of 01, care was taken to exclude the presence of minor abnormalities in the ostensibly normal individuals. The two living parents were subjected to special scrutiny, including radiographic studies of their skulls. In some instances, medical reports or photographs were available for diagnostic confirmation in deceased individuals. Family studies The affected individuals were members of two closely related families, the majority of whom lived in Natal, South Africa. They were of African Negro stock, with some Scots and Indian admixture. The fathers of the affected sibs were an uncle and nephew (11-1 and 111-3) who had married two sisters (111-1 and 111-4). Thus, although there was no consanguinity, each pair of parents had a significant proportion of their genes in common (Fig. l., pedigree). These parents and their progenitors had been normal. In one family, four out of 13
Senior Orthopaedic Registrar, St. Mary’s Hospital, London, W.2. and Northwick Park Hospital, Harrow, Middlesex, England. Professor of Human Genetics.
108
HORAN AND BEIGHTON
offspring had 01, while in the other, two out of 14 sibs had been affected. None of the individuals with 01 had reproduced, but all offspring of their unaffected siblings were normal. Case 1 G.R. (IV-23), a 32-year-old male, was asymptomatic until 2 years of age. He subsequently suffered multiple fractures of the upper and lower limbs and has been unable to walk since early childhood. When examined in 1974 he was grossly dwarfed, with a marked kyphoscoliosis. Both femora and both tibiae were very bowed and he sat in a chair with his lower limbs curled around each other. He was unable to walk and moved by crawling about the floor. His hip joints were stiff but a normal range of movement was present in the shoulders and elbows. The wrist and finger joints were lax. His head was normal in shape and the sclerae were not blue. Mild deafness was apparent in the right ear. The teeth were in good condition. Cask 2 E.R. (IV-28), a 21-year-old female, was the sister of patient IV-23. She had sustained the first of many fractures when aged 2 and had been admitted in early childhood to a home for crippled children,
Fig. 1. The pedigree of the kindred.
where she had remained until the age of 14. On examination she was found to be only 105 cm in height. She had a severe kyphoscoliosis and there was marked bowing of the humeri and femora (Fig. 2). She was able to walk with the aid of long leg calipers and crutches. She had minimal blueing of the sclerae, excellent teeth and normal hearing. Case 3 C.R. (IV-29), a brother of patients IV-23 and IV-28, had died at the age of 19 from diphtheria. H e had sustained multiple fractures in his lifetime and had never been able to walk. His relatives confirmed that he had been very short in stature, with severe limb deformities. Case 4 T.R. (IV-301, a female, was the youngest of the affected children in the family and had died at the age of 19 from pulmonary tuberculosis. She had been of even shorter stature than her affected sister, and had marked limb bowing. She had sustained approximately 10 major long bone fractures and had been able to walk only with considerable difficulty. Case 5 L.R. (IV-8), a male, had been a cousin of the above-mentioned patients. He
A U T O S 0M A L R E C E S S I VE I N H E R I T A N C E
109
Flg. 2. Patient IV-28, aged 21; shows severe dwarfing with marked bony deformities.
had died at the age of 29 following a massive haematemesis. He had been dwarfed, and had sustained numerous fractures. He was able to walk with a wheeled frame which incorporated crutches. A family photograph of him in this device showed the shortness of stature and lower limb deformities very clearly. Cuse 6 S.R. (IV-l2), the sister of patient
IV-8, is 26 years old. She is the least severely affected of the surviving members of the
kindred. She is able to walk well with the aid of bilateral long leg calipers, which she wears more for safety than support. She walked normally until the age of 4 when she sustained the first of many fractures, mostly in the lower limbs, but also in the right arm. On examination in 1974, she was found to be 145 cm in height. She had a marked thoracic kyphus but minimal scoliosis. Both tibiae were markedly bowed anteriorly while the femora were moderately bowed. The
110
HORAN AND BEIGHTON
joints were generally lax and her sclerae were blue. Her hearing was unimpaired and her teeth were in good condition. Parents. From the pedigree it is evident that the mothers of the two branches of the kindred were sisters and that the fathers were nephew and uncle. The mother of one set of siblings (patient 111-4) died following a coronary thrombosis while the father of the other group (patient 11-1) died from the complications of peripheral vascular disease. The offspring of the deceased individuals were unanimous in their opinion that the parents had been of normal stature, and that no stigmata of 01 had been present. Similarly, none of the other deceased progenitors in generations I and 11 were thought to have had any stigmata of 01. The two surviving parents were examined (patients 111-1 and 111-3). The father was aged 60 and was 173 cm in height. He had no clinical stigmata of 01 and a lateral radiograph of his skull showed no evidence of Wormian bones. The mother was 70 years old and 166 cm in height. She had neither clinical nor radiographic evidence of the condition. Discussion
Autosomal dominant inheritance is well established in 0 1 and it is widely accepted that the disorder is transmitted by this mechanism in the majority of affected kindreds. It is also well known that clinical expression of the abnormal gene can be very variable (Rosenbaum 1944) and that on occasion it may be non-penetrant. The occurrence of “sporadic” patients has usually been ascribed to new mutation or to non-penetrance of the gene in the parent (Seedorff 1949). However, there have been a few instances of parental consanguinity (Awwaad & Reda 1960, Remigio & Grin-
walsky 1970) or multiple affected siblings with normal parents (Chawla 1964, Goldfarb & Ford 1954), and the possibility has arisen that there may be an autosomal recessive form of 01. McKusick (1972) reviewed the relevent evidence and concluded that an uncommon autosomal recessive form of 0 1 probably exists. The three living patients in the kindreds whom we investigated had unequivocal 01, and there is little doubt that the three deceased individuals also had the disorder. The ratios of affected and unaffected siblings in each of these families (two out of 14 and four out of 13) are in accordance with Mendelian ratios for autosomal recessive inheritance. Furthermore, there was no evidence whatsoever of the condition in the two living parents, while the two deceased parents and their immediate progenitors were reliably described as having been normal. As the two sets of parents were closely related, it is not unreasonable to suppose that they could have all been heterozygous for a recessive gene, while the six affected offspring were homozygotes. Clinically, 01 has been sub-divided into “congenita” and “tarda” forms, based upon the age of onset. There is considerable overlap in the manifestations, but in general the former type tends to be severe, while the latter may be comparatively mild. McKusick (1972) suggested that a small proportion of sporadic individuals with 0 1 congenita may have autosomal recessive disease. However, although our patients were severely affected, their bony fragility was not evident until after infancy. They would therefore fall into the “tarda” rather than the “congenita” group. This apparent anomaly may represent further evidence of heterogeneity within the syndrome. Each of our patients had gross dwarfing and marked deformity, while the other characteristic minor stigmata of 01 were present in varying degrees. There are no
AUTOSOMAL RECESSIVE INHERITANCE
specific clinical manifestations which permit accurate recognition of this presumed autosomal recessive type of 0 1 and further delineation will await identification of the basic biochemical defect. As 01 is a relatively common disorder, affected individuals are encountered in most genetic clinics. T h e existence of an autosomal recessive form of the condition, which, although severe, is compatible with survival into adulthood, has considerable practical implications from the point of view of genetic counselling.
Acknowledgements
W e are grateful to Mrs Greta Beighton for drawing the pedigree and typing the manuscript, to M r R . A . Du MCnaud for preparing the clinical photographs and to Sister Lecia Durr f o r arranging the home visits. This investigation was supported by grants from the University of Cape Town Staff Research Fund and the South African Medical Research Council.
111
References
Awwaad, S. & M. Reda (1960). Osteogenesis imperfecta; a review of literature and report on three cases. Arch. Pediat. 77, 280-290. Chawla, S. (1964). Intrauterine osteogenesis irnperfecta in four siblings. Brit. med. J . 1, 99-101.
Goldfarb, A. A. & D. Ford (1954). Osteogenesis imperfecta in consecutive siblings. J . Pediat. 44, 264-268.
McKusick, V. A. (1972). Heritable Disorders o f Connecfive Tissue, 4th Ed. St. Louis, C. V. Mosby Co. Remigio, P. A. & H. T. Grinwalsky (1970). Osteogenesis imperfecta; association with conspicuous extraskeletal connective tissue dysplasia. Amer. J . Dis. Child. 119, 524-528. Rosenbaum, S. (1944). Osteogenesis imperfecta and osteopsathyrosis; a contribution to the study of their identity and their pathogenesis. J . Pediat. 25, 161-167. Seedorff, K. S. (1949). Osteogenesis Imperfecta; A Study of Clinical Features and Heredity Based on 55 Danish Families Comprising 180 Affected Persons. Copenhagen, Munks-
gaard. Address: Professor Peter Beighfon Department of Human Genetics Medical School University of Cape Town Cape Town, South Africa
