Alternative titles; symbols
SNOMEDCT: 34643004; ICD10CM: Q78.3; ORPHA: 1328; DO: 4997;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.2 | Camurati-Engelmann disease | 131300 | Autosomal dominant | 3 | TGFB1 | 190180 |
A number sign (#) is used with this entry because of evidence that Camurati-Engelmann disease results from domain-specific heterozygous mutations in the transforming growth factor-beta-1 gene (TGFB1; 190180) on chromosome 19q13. Also see Camurati-Engelmann disease type 2 (606631) in which no mutation in the TGFB1 gene has been found.
Camurati-Engelmann disease is a rare autosomal dominant type of bone bone dysplasia. The hallmark of the disorder is the cortical thickening of the diaphyses of the long bones. Hyperostosis is bilateral and symmetrical and usually starts at the diaphyses of the femora and tibiae, expanding to the fibulae, humeri, ulnae, and radii. As the disease progresses, the metaphyses may be affected as well, but the epiphyses are spared. Sclerotic changes at the skull base may be present. The onset of the disease is usually during childhood and almost always before the age of 30. Most patients present with limb pain, muscular weakness, a waddling gait, and easy fatigability. Systemic manifestations such as anemia, leukopenia, and hepatosplenomegaly occur occasionally (summary by Janssens et al., 2006).
Camurati (1922) of Bologna described a rare type of 'symmetrical hereditary osteitis' involving the lower limbs in a father and son and several others in a total of 4 generations. Pain in the legs and fusiform swelling of the legs below the knees were noted. Engelmann (1929) of Vienna reported an isolated case of 'osteopathica hyperostotica (sclerotisans) multiplex infantilis.' The disorder is sometimes called Camurati-Engelmann disease in recognition of the earlier description. Cockayne (1920) described a probable case before the publications of Camurati and Engelmann. The nature of the condition and the possibility that it represented syphilitic osteitis were discussed.
Lennon et al. (1961) described a case of Engelmann disease and reviewed the literature. Gross thickening of the cortex of bones, both on the periosteal surface and in the medullary canal, is characteristic. The process usually begins in the shaft of the femur or tibia but spreads to involve all bones. Onset is usually before age 30 years, often before age 10. All races and both sexes are affected. Nine examples of familial occurrence in 1 or 2 generations were mentioned. Severe bone pains, especially in the legs, and muscular hypoplasia are the distinctive features of this form of sclerotic bone disease. The bones of the base of the skull and rarely the mandible may be affected. The skeletal disorder is often associated with muscular weakness, peculiar gait, pains in the legs, fatigability, and apparent undernutrition. The muscular weakness is not necessarily progressive and typical bone changes may be found in asymptomatic persons. Because of the associated features, muscular dystrophy or poliomyelitis is sometimes diagnosed in these patients.
The condition described by Ribbing and in the past sometimes referred to as Ribbing disease (601477) has been considered by some to be Engelmann disease. Ribbing (1949) described a family in which 4 of 6 sibs were affected. The diaphyseal osteosclerosis and hyperostosis were limited to one or more (up to 4) of the long bones, the tibia being affected in all. The father, who was dead, had complained for many years of pains in the legs. Thus, the condition may be dominant; no x-ray studies of the father were available and Ribbing (1949) noted that the body had been cremated. Paul (1953) reported the same entity in 2 of 4 sibs, one of whom also had otosclerosis, which was present in several other members of the kindred. In an addendum, Paul noted that the infant son of one of his patients had difficulty walking and was found to have multiple sclerosing lesions of long bones. Again dominant inheritance was suggested. Ribbing (1949) referred to the condition described as hereditary multiple diaphyseal sclerosis (rather than dysplasia), and the same term was used by Paul (1953) and Furia and Schwartz (1990). Seeger et al. (1996) insisted that Ribbing disease is a disorder separate from Engelmann disease. Although it may appear to be identical radiographically, many clinical differences exist. Camurati-Engelmann disease presents during childhood, whereas Ribbing disease was thought by Seeger et al. (1996) to present in middle age. (They wrote: 'patients contract Ribbing disease after puberty.') The disease is confined to the diaphyses of long bones, especially the tibia and the femur. Whereas Engelmann disease is bilateral and symmetric, Ribbing disease is either unilateral or asymmetric and asynchronously bilateral. In Engelmann disease, the skull is involved as well as the long bones. The gait and neurologic abnormalities and anemia with extramedullary hematopoiesis occurs only in Engelmann disease.
Makita et al. (2000) reported a 3-generation Japanese family with Engelmann disease with a wide variation in phenotype among the affected family members. Of the 12 patients, 7 had full manifestations of Engelmann disease, while the other 5 exhibited only segmental (rhizomelic and/or mesomelic) involvement and asymmetric diaphyseal sclerosis without any clinical symptoms, resembling Ribbing disease. The authors proposed that Engelmann disease and Ribbing disease represent phenotypic variation of the same disorder.
Crisp and Brenton (1982) emphasized systemic manifestations in Engelmann disease: anemia, leukopenia, hepatosplenomegaly, and raised erythrocyte sedimentation rate. Their patient also had the Raynaud phenomenon and multiple nail-fold infarcts.
Clybouw et al. (1994) reported a 10-year-old girl with characteristic clinical and roentgenologic manifestations of Camurati-Engelmann disease. Scintigraphy with 99mTc showed increased osteoblastic activity in the diaphyseal portions of almost all long bones. Clinical and roentgenologic investigations of her parents produced normal results, but a clear focus of osteoblastic hyperactivity was demonstrated scintigraphically at the base of the skull of the proband's mother. Some persons with Camurati-Engelmann disease may have subclinical manifestations. According to Clybouw et al. (1994), a detailed study including x-ray examination and scintigraphy is necessary for genetic counseling in apparently sporadic cases.
Grey et al. (1996) provided a 45-year follow-up on a patient with Engelmann disease initially described by Stronge and McDowell (1950) when he was 28 years of age. The disease had shown progression over the subsequent 45 years, characterized by the unique involvement of the femoral capital epiphyses. The patient had changed little in physical appearance, apart from aging. He was thin and tall with generalized underdevelopment and weakness of the muscles, particularly around the pelvic girdle and thighs. The legs were bowed and the lumbar lordosis had increased. Serum alkaline phosphatase levels had remained normal. In 1950 the disease involved only the diaphyses of the affected limbs. By 45 years later it had affected the metaphyses of all limbs, the epiphyses, and the articular surfaces of the femoral heads and acetabula, as well as the right tibial epiphysis. The spine and hands, unaffected in 1950, showed changes and there was some progression of the disease in the skull.
Saraiva (2000) described anticipation as judged by age of onset of symptoms in successive generations of a large family with 15 affected members in 3 generations.
Wallace et al. (2004) reported a 4-generation pedigree with 7 individuals affected by CED. The pedigree demonstrated autosomal dominant inheritance but with remarkable variation in expressivity and reduced penetrance. The most severely affected individual had progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over 30 years. His carrier father, on the other hand, remained asymptomatic into his ninth decade and had no radiographic hyperostosis or sclerosis of the bones. Symptomatic relatives presented with lower limb pain and weakness. They were initially diagnosed with a variety of other conditions. Two of the symptomatic individuals were treated successfully with prednisone. Linkage to 19q13.1-q13.3 was confirmed. The arg218-to-his mutation in the TGFB1 gene (R218H; 190180.0003) was identified in the affected individuals, the asymptomatic obligate carrier, and in another unaffected relative.
Janssens et al. (2006) reported 41 individuals with CED confirmed by genetic analysis from 14 families and provided a detailed review of the disorder.
Girdany (1959) described a family with 6 affected persons in 3 generations (no male-to-male transmission). A case reported by Singleton et al. (1956) had strikingly similar clinical features. Restudy indicated that 3 generations were affected in that family also (Singleton, 1967). Father and 2 children (son and daughter) were affected in a family reported by Ramon and Buchner (1966). The father was much more severely affected than the offspring. Allen et al. (1970) presented a family in which 11 persons in 3 generations were known to have been affected. Sparkes and Graham (1972) reported a remarkable family with many affected persons in several successive generations. A particularly remarkable feature was lack of penetrance in persons who must have had the gene but, as adults at any rate, showed no abnormality by x-ray.
The beneficial effects of corticosteroids were apparently first described by Royer et al. (1967), followed shortly by Allen et al. (1970) and by Lindstrom (1974). Minford et al. (1981) noted not only relief from pain but also return of radiologic findings toward normal during treatment with corticosteroids.
Campos-Xavier et al. (2001) stated that 5 mutations in the TGFB1 gene had been identified in 21 families with CED. In 1 Australian family and 6 European families with CED, they found 3 of these mutations, R218H (190180.0002) in 1 family, R218C (190180.0003) in 3 families, and C225R (190180.0001) in 3 families, which had previously been observed in families of Japanese and Israeli origin. The R218C mutation appeared to be the most prevalent worldwide, having been found in 17 of 28 reported families.
Campos-Xavier et al. (2001) found no obvious correlation between the nature of TGFB1 mutations and the severity of the clinical manifestations of CED, but observed a marked intrafamilial clinical variability, supporting incomplete penetrance of CED.
Xavier et al. (2000) suggested that DPD1 is genetically homogeneous; however, Hecht et al. (2001) excluded the TGFB1 gene as the site of mutation in a DPD1 family, thus indicating the existence of at least one other form.
Also see Camurati-Engelmann disease type II (606631) in which no mutation in the TGFB1 gene has been found.
Ghadami et al. (2000) performed a genomewide linkage analysis of 2 unrelated Japanese families with CED, in which a total of 27 members were available for study; 16 of them were affected with CED. Two-point linkage analysis showed a maximum lod score of 7.41 (recombination fraction 0.00; penetrance = 1.00) for the D19S918 microsatellite marker locus. Haplotype analysis revealed that all the affected individuals shared a common haplotype observed, in each family, between D19S881 and D19S606, at 19q13.1-q13.3 (within a genetic interval of 15.1 cM). This linkage was confirmed by Janssens et al. (2000) and Vaughn et al. (2000).
Because the transforming growth factor-beta-1 gene (TGFB1; 190180) maps to the same region of chromosome 19, Kinoshita et al. (2000) screened it for mutations in Camurati-Engelmann disease in 7 unrelated Japanese families and 2 families of European descent. They detected 3 different heterozygous missense mutations in exon 4, near the carboxy terminus of the latency-associated peptide (LAP), in all 9 families examined.
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