Alternative titles; symbols
SNOMEDCT: 24752008; ICD10CM: M89.8; ORPHA: 1310; DO: 4257;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.33 | Caffey disease | 114000 | Autosomal dominant | 3 | COL1A1 | 120150 |
A number sign (#) is used with this entry because of evidence that Caffey disease (CAFYD) is caused by heterozygous mutation in the alpha-1 collagen type I gene (COL1A1; 120150) on chromosome 17q21.
Caffey disease (CAFYD) is an autosomal dominant disorder characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. Painful swelling and systemic fever often accompany the episode, which usually begins before the age of 5 months and resolves before age 2 years. Laboratory findings include an elevated level of alkaline phosphatase and sometimes an elevation in white blood cell count and erythrocyte sedimentation rate. Recurrent episodes are uncommon (summary by Gensure et al., 2005).
Caffey disease, also known as infantile cortical hyperostosis, has somewhat unusual features for a hereditary disorder. It rarely if ever appears after 5 months of age and usually resolves spontaneously by 2 years of age; it is sometimes present at birth and has been identified by x-ray in the fetus in utero. The acute manifestations are inflammatory in nature, with fever and hot, tender swelling of involved bones (e.g., mandible, ribs). Despite striking radiologic changes in the acute stages, previously affected bones are often completely normal on restudy. However, Taj-Eldin and Al-Jawad (1971) described a case followed since infancy with recurrences documented up to 19 years of age (1971). (Incontinentia pigmenti (308300) is another familial condition in which 'active' lesions at birth and early in life may leave little or no residue.) Pickering and Cuddigan (1969) suggested that vascular occlusion secondary to thrombocytosis may be involved in the pathogenesis. X-ray findings in 3 members of the family were reported by Pajewski and Vure (1967).
MacLachlan et al. (1984) followed up on the French-Canadian kindred reported by Gerrard et al. (1961). To the 14 affected children identified in the original report, 20 new cases were added. MacLachlan et al. (1984) commented that the sporadic form of the disorder is disappearing with no such cases seen in the last 7 years. In sporadic cases the bones most often affected are mandible, ulna, and clavicle with fairly frequent involvement of ribs and scapulae. In their radiographic studies of 14 familial cases, no involvement of ribs or scapulae was encountered. Clavicular involvement was found in only 3 children. The tibia was most often involved in familial cases. Borochowitz et al. (1991) described 2 affected sibs in a nonconsanguineous family; a girl had involvement of the fibula at the age of 5 months and a recurrence with tibial involvement at the age of 11 years. Her brother was hospitalized at the age of 4 months because of swelling of the face, fever, and restlessness.
Suphapeetiporn et al. (2007) reported a 3-generation Thai family in which 5 individuals had Caffey disease. The oldest individual, a 75-year-old man, had bowed legs since childhood, several traumatic fractures, short hands, kyphoscoliosis and compression fractures of the vertebrae. Examination of other affected family members showed angular deformities of the long bones, short stature, and dental caries, although unaffected family members also had dental caries. The authors suggested that short stature and persistent bony deformities should be included in the clinical spectrum of Caffey disease.
Clinical Variability
Lecolier et al. (1992) described a case of prenatal Caffey disease. Ultrasound examination at 20 weeks' gestation detected major angulation of the long bones. Although no fractures were seen, irregularities of the ribs suggested multiple callus formation and the diagnosis of lethal osteogenesis imperfecta was entertained. Cordocentesis showed marked leukocytosis, mainly due to neutrophils, as well as increased serum levels of hepatic enzymes. Because of a rapid appearance of 'fetoplacental anasarca' and a probable diagnosis of osteogenesis imperfecta, pregnancy was terminated at 23 weeks' gestation. Special x-ray views showed a double contour of the diaphyseal cortex of the long bones. Histologic examination confirmed the diagnosis of Caffey disease by demonstration of thickened periosteum and infiltration of the deeper layers of the periosteum with round cells. Lecolier et al. (1992) suggested that this form should be referred to as lethal prenatal cortical hyperostosis.
Perinatal death in 2 sibs with Caffey disease was described by de Jong and Muller (1995). Antenatal sonographic diagnosis was short-limb dwarfism and thoracic dysplasia of a nonspecific type, possibly osteogenesis imperfecta, in the first sib. The second sib had a similar appearance on ultrasonography. The thickened irregularly echodense diaphyses were an aid to diagnosis. De Jong and Muller (1995) agreed with LeColier et al. (1992) that fetoplacental anasarca and polyhydramnios are helpful prognostic signs. The presence of both seems to indicate a very poor prognosis. Autosomal dominant inheritance with subclinical Caffey disease in one of the parents during infancy could not be excluded since incidental discovery of the disease has been reported (Cayler and Peterson, 1956). Parental gonadal mosaicism is another possibility. In spite of the absence of parental consanguinity, the occurrence of the condition in a male and a female sib born to healthy parents suggested autosomal recessive inheritance of the lethal prenatal onset type of cortical hyperostosis.
Kamoun-Goldrat et al. (2008) described a fetus that represented the first pregnancy of a young, healthy, nonconsanguineous couple. The pregnancy was medically terminated at 30 weeks' gestation after a diagnosis of severe osteogenesis imperfecta. Postmortem radiographs, autopsy, and histologic study showed typical features of a severe form of prenatal cortical hyperostosis.
Prenatal Diagnosis
Stevenson (1993) described a case indicating that Caffey disease can be detected in utero in familial nonlethal cases. Ultrasound examination at age 35.5 weeks showed curvature of the tibia and irregularity of the cortex of the radius. Mild leg curvature was present at birth at 39 weeks; involvement of all long bones was documented radiographically at the age of 2.5 months. A sister, the mother, and a maternal uncle had documented Caffey disease.
Autosomal dominant inheritance of Caffey disease is suggested by the reports of Gerrard et al. (1961), Van Buskirk et al. (1961), Holman (1962), and others. Male-to-male transmission was observed by Van Buskirk et al. (1961). Bull and Feingold (1974) reported 2 affected sisters, one of whom had affected son and daughter and the other a normal daughter and affected son. Fried et al. (1981) observed 9 affected persons in 3 sibships of 2 generations of a family. One instance of male-to-male transmission and one of apparent nonpenetrance were reported. Newberg and Tampas (1981) gave a follow-up on a family with 11 cases reported in 1961 (Tampas et al., 1961; Van Buskirk et al., 1961). Since then, 10 new cases had occurred, confirming autosomal dominant inheritance. Emmery et al. (1983) described 8 affected persons in 3 generations.
Of the 24 affected members of a family segregating Caffey disease in which Gensure et al. (2005) identified an R836C mutation in the COL1A1 gene (120150.0063), only 19 (79%) had experienced an episode of cortical hyperostosis and 5 (21%) obligate carriers had not, consistent with reduced penetrance.
Gensure et al. (2005) performed genomewide mapping of a large family with Caffey disease, which revealed linkage to chromosome 17q21. Fine mapping reduced the linked region to a 2.3-Mb interval between markers D17S1868 and D17S1877; the maximum 2-point lod score obtained was 6.78 for marker D17S1795 (theta = 0.0).
In affected individuals and obligate carriers from 3 unrelated families with Caffey disease, Gensure et al. (2005) identified heterozygosity for an arg836-to-cys mutation in the COL1A1 gene (R836C; 120150.0063), involving the triple-helical domain of the alpha-1 chain of type I collagen. None of the affected individuals or obligate carriers in any of the families had clinical signs of the major type I collagen disorder, osteogenesis imperfecta (see 166200); however, in 2 of the 3 families, individuals carrying the mutation did have joint hyperlaxity, hyperextensible skin, and inguinal hernias, features seen in Ehlers-Danlos syndrome (see 130000), some forms of which are caused by mutations in COL1A1.
In affected members of a Thai family with Caffey disease, Suphapeetiporn et al. (2007) identified heterozygosity for the R836C mutation in the COL1A1 gene.
Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a severe form of prenatal cortical hyperostosis from a terminated pregnancy at 30 weeks' gestation. They noted that this mutation had not been found in 2 other such cases by Gensure et al. (2005) and speculated that mutations in other genes were likely involved in the prenatal and infantile forms of cortical hyperostosis.
Associations Pending Confirmation
For a discussion of a possible association between Caffey disease and variation in the AHSG gene, see 138680.0005.
See Griscom (1995) for a biographic account of John Caffey (1895-1978).
Borochowitz, Z., Gozal, D., Misselevitch, I., Aunallah, J., Boss, J. H. Familial Caffey's disease and late recurrence in a child. Clin. Genet. 40: 329-335, 1991. [PubMed: 1756606] [Full Text: https://doi.org/10.1111/j.1399-0004.1991.tb03104.x]
Bull, M. J., Feingold, M. Autosomal dominant inheritance of Caffey disease. Birth Defects Orig. Art. Ser. X: 139-146, 1974. [PubMed: 4609117]
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Kamoun-Goldrat, A., Martinovic, J., Saada, J., Sonigo-Cohen, P., Razavi, F., Munnich, A., Le Merrer, M. Prenatal cortical hyperostosis with COL1A1 gene mutation. Am. J. Med. Genet. 146A: 1820-1824, 2008. [PubMed: 18553566] [Full Text: https://doi.org/10.1002/ajmg.a.32351]
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Lecolier, B., Bercau, G., Gonzales, M., Afriat, R., Rambaud, D., Mulliez, N., de Kermadec, S. Radiographic, haematological, and biochemical findings in a fetus with Caffey disease. Prenatal Diag. 12: 637-641, 1992. [PubMed: 1359527] [Full Text: https://doi.org/10.1002/pd.1970120803]
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Suphapeetiporn, K., Tongkobpetch, S., Mahayosnond, A., Shotelersuk, V. Expanding the phenotypic spectrum of Caffey disease. Clin. Genet. 71: 280-284, 2007. [PubMed: 17309652] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00768.x]
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