Caffey Disease

Caffey disease is an osteosclerotic dysplasia characterized by acute inflammation with massive subperiosteal new bone formation usually involving the diaphyses of the long bones, as well as the ribs, mandible, scapulae, and clavicles. The disease is associated with fever, irritability pain and soft tissue swelling, with onset around the age of 2 months and resolving spontaneously by the age of 2 years. However, prenatal disease onset has also been described.

Epidemiology

To date <100 cases have been described in the literature.

Clinical description

Caffey disease is characterized by periosteal new bone formation which leads to cortical thickening (hyperostosis) of the affected bone. The bone lesions are often asymmetric with a characteristic involvement of the mandible (70-90% of cases), clavicle, ribs and scapula (20-30%), skull, ilium, long bones. Typically the disease presents with fever and/or pallor, joint swelling (adjacent to involved bones), pain and irritability between birth and age 5 months (average age of onset is 9 weeks). When the mandible is affected, infants may refuse to eat, leading to failure to thrive. The pain may be severe enough to result in pseudo paralysis and individual nerve involvement may result in true localized palsies. The swelling becomes wood hard and fixes to underlying tender bone, but edematous soft tissue remains freely mobile and is never discolored. A prenatal form exists that presents before 35 weeks gestation and is potentially lethal. It is characterized by corticial hyperostosis, bowing or angulation of the long bones and presence of polyhydramnios and fetal lung disease.

Etiology

Autosomal dominant Caffey disease is caused by a mutation in the COL1A1 gene (17q21.33). Additional genetic or environmental conditions may be required for the manifestation of the disease. In addition to the autosomal dominant form, several Caffey cases have been described, in which no COL1A1 mutation could be identified.

Diagnostic methods

Diagnosis is based on clinical features and radiologic findings of subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses), ribs, scapulae, clavicles, and mandible in a child age 2 months to 5 years. Magnetic resonance imaging of bone can also detect inflammatory signals in adjacent muscle, connective tissue, and in the bone marrow. Laboratory findings include elevated erythrocyte sedimentation and alkaline phosphatase levels along with increased C-reactive protein and immunoglobulin levels. Diagnosis is confirmed by genetic screening.

Differential diagnosis

Differential diagnosis includes osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, mucopolysaccharidosis type 2 and Hurler syndrome (see these terms), non-accidental childhood injury, hypervitaminosis A, prostaglandin E1 exposure, bone malignancies, osteomyelitis and parotitis.

Antenatal diagnosis

Prenatal and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family. On rare occasions, hyperostosis can be detected by ultrasound late in the 3rd trimester of pregnancy, even for the autosomal dominant form.

Genetic counseling

Caffey disease either occurs sporadically or is inherited in an autosomal dominant manner with incomplete penetrance. The prenatal form is thought to be inherited in an autosomal recessive manner.

Management and treatment

Management is mainly supportive and includes use of non-steroidal anti-inflammatory drugs or corticosteroids to improve inflammation and pain, antipyretics, and analgesics in the short term to decrease fever and to relieve pain. Yearly evaluation of linear growth, dental health, joint range of motion re-extensibility, possible hernias and fracture history is recommended.

Prognosis

Caffey disease usually has a favorable prognosis as it spontaneously resolves by the age of 2 years. However, the disease sometimes recurs in childhood or adolescence. Moreover, adults who had Caffey disease in childhood may manifest joint laxity, skin hyperextensibility, hernias, and an increased risk for bone fractures and/or deformities.