Caffey Disease

Author: Professor Christine Hall Creation date: September 2001 Updated: February 2005

Scientific Editor: Professor Raoul Hennekam

Department of , Hospital for Children, Great Ormond Street , WC1N 3JH London, UK [email protected]

Abstract Key-words Synonyms Brief description and clinical findings Radiological findings Laboratory findings Histopathology findings Management Aetiology Unresolved issues Prenatal perinatally lethal Caffey disease References

Abstract Caffey disease is a rare condition which presents most commonly in . It is characterized by irritability, pain, tenderness, hyperaesthesia, soft tissue swelling and redness involving one or several areas of the body. Systemic changes with are usually present in the early stages. The pain may be severe enough to result in pseudoparalysis and individual nerve involvement may result in true localized palsies. Other reported clinical findings include dysphagia and nasal obstruction. Inheritance is thought to be autosomal dominant in some cases. However the incidence of the disease appears to fluctuate and other environmental effects may exert an influence. An underlying viral aetiology has been implicated. The clinical course is variable and unpredictable but the symptoms usually resolve over the course of a few months and the outcome is good with spontaneous resolution. Relapses may sometimes occur several years later. Radiographic examination reveals periosteal new formation that can be quite florid and subsequently becomes compact causing pronounced cortical thickening. Management is essentially palliative, aimed at pain relief. However, some authors claim a good response to high-dose immunoglobulin. Corticosteroids have been used to hasten .

Key-words Infantile Cortical , fever, pain, tenderness, hyperaesthesia, soft tissue swelling, redness, periosteal new bone formation

Synonyms tissue swelling and redness involving one or Infantile Cortical Hyperostosis, several areas of the body. Systemic changes Caffey-Silverman syndrome, with fever are usually present in the early stages. de Toni-Caffey disease. Presentation with proptosis has been reported (Faure et al., 1977). The pain may be severe Brief description and clinical findings enough to result in pseudoparalysis and In 1945, Caffey and Silverman reported a new individual nerve involvement may result in true, syndrome which they called infantile cortical localised palsies. Other reported clinical findings hyperostosis, following an earlier report by include dysphagia (Sheppard et al., 1988) and Roske, 1930. nasal obstruction. This rare condition presents most commonly in The clinical course is variable and unpredictable infants, usually under the age of six months, with but usually the acute symptoms resolve over the irritability, pain, tenderness, hyperaesthesia, soft

Hall C. Caffey disease. Orphanet encyclopedia. February 2005. http://www.orpha.net/data/patho/GB/uk-caffey05.pdf 1 course of a few months and the outcome is good remodelling and indomethacin has been used to with spontaneous resolution. Sometimes control flare-ups (Couper et al., 2001). relapses may occur several years later (Blank, Differential diagnosis 1975; Borochowitz et al., 1991; Taj-Eldin and Al- In the early stages of the disease, when only one Jawal, 1971). The bony changes usually resolve area of the body is affected, the clinical completely but sometimes, when paired presentation may be confused with a fracture; such as the and or and , or malignant or invasive soft tissue have been affected, a long-term tumour and occasionally have been may be that of cross-fusion. Similar fusions may undertaken. The multifocal manifestations occur when adjacent ribs have been involved require differentiation from multifocal and may result in a progressive thoracic osteomyelitis and congenital syphilis but the with respiratory compromise. Facial periosteal new bone in Caffey disease spares and mandibular asymmetry may be a long-term the metaphyses and epiphyses and is not consequence. associated with lytic areas of bone destruction. Radiological findings Leukaemia may present with systemic changes Radiographic examination reveals periosteal and multiple diaphyseal periosteal reactions but new bone formation that can be quite florid and this is generally after the age of six months. subsequently becomes compact causing Differentiation from Caffey disease is also pronounced cortical thickening. The periosteal required with the shearing traumatic periosteal new bone is seen in bones underlying areas of reactions seen in non-accidental , from soft tissue swelling. The distribution is patchy vitamin A toxicity and following long-term and asymmetric but is multifocal, although cases treatment with prostaglandin E for ductus- of monostotic involvement have been reported dependent cyanotic congenital heart disease. (Kaufmann et al., 1977). The is almost Periosteal 'cloaking' is a feature of some storage invariably involved and other commonly affected disorders in infancy, I-cell disease or areas include the clavicles, ribs and long bones mucolipidosis type II and GM gangliosidosis type of the limbs. Typically the periosteal new bone or I, but the generalised nature of the skeletal periosteal 'cloaking' is confined to the diaphyses changes and metaphyseal irregularities will of the long bones, sparing the metaphyses and differentiate these conditions. Hypertrophic epiphyses. There are a few reports of lytic areas osteoarthropathy (primary and secondary) both affecting the skull vault and facial bones but this present later (Ved and Haller, 2002). is uncommon (Boyd et al., 1972; Faure et al., Aetiology 1977; Lachaux et al., 1992). The spine, Inheritance is thought to be autosomal dominant phalanges and are hardly ever involved. in some cases (Bull and Feingold, 1974; Clemett Increased uptake of radioisotope from a and Williams, 1963; Fried et al., 1981; radioisotope bone scan shows areas of Langewisch, 1975; MacLachlan et al., 1984; involvement before radiographic changes are Saul et al., 1982). However the incidence of the present (Taillefer et al., 1983). disease appears to fluctuate and other Laboratory findings environmental effects may exert an influence. An Laboratory results demonstrate a high underlying viral aetiology has been implicated. erythrocyte sedimentation rate, Unresolved issues thrombocythaemia, high white cell count, high There are several reports of the prenatal onset levels, high of Caffey disease. Most of these cases have immunoglobulin levels and high C-reactive been severe, presenting before 35 weeks protein levels (Pickering and Cuddigan 1969; gestation and resulting in perinatal death. It is Tabardel et al., 1988; Temperley et al., 1972). unclear if there is any relationship to the more Histopathology findings common postnatal form of Caffey disease. A few of affected areas shows fibrinoid (usually those presenting after 35 weeks degeneration in hyperostotic bone and gestation) follow the expected course of the hyperplastic fibres. Acute inflammatory postnatal form and may simply represent early changes may be present and also numerous presentation but many are perinatally lethal with mitotic figures within mature lamellar bone. different radiological features. Management Prenatal perinatally lethal Caffey disease Management is essentially palliative, aimed at Characteristically the prenatal onset, perinatally pain relief, but some authors claim a good lethal cases present before 35 weeks gestation, response to high dose immunoglobulin. have severe organised cortical thickening Corticosteroids have been used to hasten bone affecting ribs and long bones uniformly and the mandible is likely to be spared. The tibia is

Hall C. Caffey disease. Orphanet encyclopedia. February 2005. http://www.orpha.net/data/patho/GB/uk-caffey05.pdf 2 almost invariably affected. In addition the long Boyd RDH, Shaw DG, Thomas BM. Infantile bones may be short and bowed or angulated. cortical hyperostosis with lytic lesions in the There is disease, prematurity and maternal skull. Arch Dis Child 1972;47:471-472. polyhydramnios. Presentation after 35 weeks Bull MJ, Feingold M. Autosomal dominant gestation is usually of the milder type. inheritance of Caffey disease. BDOAS 1974;10:139-146. Prenatal diagnosis Caffey J, Silverman WA. Infantile cortical Prenatal diagnosis on ultrasound is usually as a hyperostosis: preliminary report of a new result of short, angulated long bones. The syndrome. Am J Roentgenol 1945;54:1-16. diaphyses are irregular with increased Clemett AR, Williams JH. The familial echogenicity and no evidence of fractures occurrence of infantile cortical hyperostosis. (Dahlstrom et al., 2001). Radiology 1963;80:409-416. Postmortem finding Couper RT, McPhee A, Morris L. Indomethecin Postmortem findings show lung hypoplasia and treatment of infantile cortical periostosis in twins. hepatomegaly and dysmorphic features have J Paediatr Child Health 2001;37:305-308. been described (Dahlstrom et al., 2001; Dahlstrom JE, Arbuckle SM, Kozlowski K, Peek Turnpenny et al., 1993). MJ, Thomson M, Reynolds GJ, Sillence DO. Letha prenatal onset infantile cortical Genetic advice hyperostosis (Caffey disease). Pathology Several sets of siblings have been described 2001;33:521-525. with this severe lethal form of Caffey disease De Jong G, Muller LMM. Perinatal death in two and in these the inheritance may be autosomal sibs with infantile cortical hyperostosis (Caffey recessive, although germ line mosaicism is also disease). Am J Med Genet 1995;59:134-138. possible. Dominant inheritance also occurs Drinkwater BM, Crino JP, Garcia J, Ogburn J, within the severe prenatal form (De Jong and Hecht JT. Recurrent severe infantile cortical Muller, 1995; Drinkwater et al., 1997; Schweiger hyperostosis (Caffey disease) in siblings. et al., 2003; Turnpenny et al., 1993). Prenatal Diagn 1997;17:773-776. Differential diagnosis Faure C, Beyssac JM, Montagne JP. Other perinatally lethal conditions with Predominant or exclusive orbital and facial diaphyseal periosteal new bone that require involvement in infantile cortical hyperostosis (de differentiation from intrauterine Caffey disease Toni-Caffey disease). Pediatr Radiol 1977;6:103- include mucolipidosis type II and GM 106. gangliosidosis type I, both of which have other Fried K, Manor A, Pajewski M, et al. Autosomal radiological changes with coarse trabeculae and dominant inheritance with incomplete metaphyseal irregularity. has penetrance of Caffey disease (infantile cortical characteristic facies, microcephaly and cleft hyperostosis). Clin Genet 1981;19:271-274. palate and is a lethal dysplasia with Kaufmann HJ, et al. Monosteal infantile cortical (Raine et al., 1989). The case hyperostosis. Skeletal Radiol 1977;2:109. reported by Kozlowski and Tsuruta (1989) Kozlowski K, Tsuruta T. Dysplastic cortical represents a further different condition with hyperostosis: a new form of lethal neonatal hydrops, lung hypoplasia, renal duplication and . Br J Radiol 1989;62:376-378. coronal cleft vertebrae. Lachaux A, Le Gall C, Duclaux IL, Hermier M. When bowed or angulated long bones are Familial infantile cortical hyperostosis with identified prenatally on ultrasound, differentiation lacunar lesions in the skull. Arch Fr Pediatr is required from severe forms of osteogenesis 1992;49:525-528. imperfecta (Berceau et al., 1991), campomelic Langewisch WH. Infantile cortical hyperostosis - dysplasia and . familial occurrence in a mother and daughter. J Pediatr 1975;87:323-324. References MacLachlan AK, Gerrard JW, et al. Familial Berceau G, Gonzalez M, Afriat R et al. The infantile cortical hyperostosis in a large difficulty of diagnosing Caffey's disease in utero. Canadian family. Can Med Assoc J A propos of a case simulating lethal 1984;130:1172-1174. . Ann Pediatr (Paris) Pajewski M, Vure E. Late manifestations of 1991;38:15-18. infantile cortical hyperostosis (Caffey's disease) Blank E. Recurrent Caffey's cortical Br J Radiol 1967;40:90-95. hyperostosis and persistent deformity. Pickering D, Cuddigan B. Infantile cortical 1975;55:856-860. hyperostosis associated with thrombocythaemia. Borochowitz Z, Gozal D, Misselevitch I, et al. Lancet 1969;2:464-465. Familial Caffey's disease and late recurrence in Raine J, Winter RM, Davey A, Tucker SM. a child. Clin Genet 1991;40:329-335. Unknown syndrome: microcephaly, hypoplastic

Hall C. Caffey disease. Orphanet encyclopedia. February 2005. http://www.orpha.net/data/patho/GB/uk-caffey05.pdf 3 nose, exophthalmos, gum , cleft immunoglobulin levels. Arch Fr Pediatr palate, low set ears and osteosclerosis. J Med 1988;45:263-265. Genet 1989;26:786-788. Taillefer R, Danais S, Marton D. Aspect Roske G. Eine eigenartige scintigraphique de l'hyperostose corticale Knochenerkrankrankung im Sauglingsalter. infantile (maladie de Caffey). J Can Assoc Monats Kinderheilkd 1930;47:385-400. Radiol 1983;34:12-15. Saul RA, Lee WH, Stevenson RE. Caffey's Taj-Eldin S, Al-Jawad J. Cortical hyperostosis. disease revisited: further evidence for autosomal Infantile and juvenile manifestations in a boy. dominant inheritance with incomplete Arch Dis Child 1971;46:565-566. penetrance. Am J Dis Child 1982;136:56-60. Temperley IJ, Douglas SJ, Rees JPR. Raised Schweiger S, Chaoui R, Tennstedt C, et al. immunoglobulin levels and thrombocytopenia in Antenatal onset of cortical hyperostosis (Caffey infantile cortical hyperostosis. Arch Dis Child disease): case report and review. Am J Med 1972;47:982-983. Genet A 2003;120:547-552. Turnpenny PD, Davidson R, Stockdale EJN, et Sheppard JJ, et al. Dysphagia in infantile al. Severe prenatal infantile cortical hyperostosis cortical hyperostosis (Caffey's disease): a case (Caffey's disease). Clin Dysmorphol 1993;2:81- study. Dev Med Child Neurol 1988;30:108. 86. Tabardel Y, Seghaye MC, Senterre J. Neonatal Ved N, Haller JT. with Caffey-Silverman disease with thrombocythemia normal-appearing underlying bone: and increased C-reactive protein and mimicker. Emerg Radiol 2002;9:278-282.

Hall C. Caffey disease. Orphanet encyclopedia. February 2005. http://www.orpha.net/data/patho/GB/uk-caffey05.pdf 4