You are in: eMedicine Specialties > Radiology > PEDIATRICS Caffey DiseaseArticle Last Updated: Jun 7, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Bonnie C Davis, MD, Fellow in Body Imaging, Department of Radiology, University of Maryland Medical System at Baltimore Bonnie C Davis is a member of the following medical societies: American Roentgen Ray Society, National Medical Association, and Radiological Society of North America Coauthor(s): Welansa Asrat, MD, Staff Physician, Departments of Medicine and Pediatrics, Saint Vincent's Medical Center Editors: Robert J Starshak, MD, Medical Director, Assistant Clinical Professor, Department of Radiology, Medical College of Wisconsin, Falls Medical Group; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Kieran McHugh, MBBCh, Honorary Lecturer, The Institute of Child Health; Consultant Pediatric Radiologist, Department of Radiology, Great Ormond Street Hospital for Children, London, UK; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Eugene C Lin, MD, Consulting Staff, Department of Radiology, Virginia Mason Medical Center Author and Editor Disclosure Synonyms and related keywords: infantile cortical hyperostosis, Caffey's disease, Caffey-Silverman syndrome, prenatal Caffey disease, infantile Caffey disease, prostaglandin E, sporadic Caffey disease, familial Caffey disease INTRODUCTIONSection 2 of 12
  BackgroundCaffey disease, or infantile cortical hyperostosis, is a benign, rare, proliferating bone disease affecting infants. Caffey and Silverman first reported this disease as a distinct entity in 1945. Classically, Caffey disease occurs in the early part of the first year of life (<5 mo). It is characterized by a clinical triad (fever, soft-tissue swelling, and hyperirritability) and a clinching radiographic picture of underlying cortical hyperostosis (thickening or bony expansion). In addition to the skeleton, the adjacent fascia, muscles, and connective tissues are also involved. Some have suggested that Caffey disease has a predilection for patients with immunodeficient disorders. Two forms of Caffey disease have been described: prenatal and infantile. The prenatal form is rare and has a poor prognosis. The prenatal form has been described as a more severe, congenital form of Caffey disease that is probably inherited as an autosomal recessive trait. Patients present with major angulation of the long bones, generalized symmetrical involvement of the skeleton, and polyhydramnios. Because the prenatal form is a rare presentation of Caffey disease, the remaining discussion in this article, except in the differential diagnostic section, pertains to the more common infantile form. Recently, hyperostosis has been reported in patients receiving therapeutic doses of prostaglandin E. Prostaglandins E1 and E2 maintain patency of the ductus arteriosus in infants born with ductus-dependent cyanotic congenital heart disease. This treatment helps provide adequate time for the infant to mature in preparation of surgical intervention. However, cortical hyperostosis can occur as a complication of long-term treatment (4-6 wk). The bony changes appear to be dose and duration dependent. Regression of the bony changes occurs on the discontinuation of treatment. Overall, the age of onset, clinical signs, laboratory results, and the typical radiographic features are the clues for the correct diagnosis of Caffey disease. PathophysiologyPathologic phasesThe histological analysis of areas of cortical thickening in Caffey disease reveals progressive remodeling (depletion) of the original cortical bone out of existence, with abnormal deposition of hyperplastic immature (though normal) lamellar bone. Additional findings of the surrounding tissues include thickening of the periosteum; intense proliferation of subperiosteal cells; and fibrosis of bone marrow. Collectively, the histopathological findings suggest a common pathway that leads to an inflammatory reaction without specific recognizable markers for Caffey disease.Three pathologic phases of the skeletal and soft-tissue manifestations of Caffey disease have been described: early, subacute, and late. Early phase The early phase is characterized by an acute intraperiosteal inflammatory reaction consisting of edema and cellular infiltration with subsequent thickening of the periosteum. The inflammatory process can extend into the neighboring soft tissues, and cortical resorption may be present. Subacute phase In the subacute phase, inflammation diminishes, the periosteum thickens, and ossifying periostitis subsequently develops (see Image 2). Beneath the periosteum, layers of immature lamellar bone are produced; these can be exuberant in nature. Bony deposition may occur in the neighboring soft tissues. Late phase The late phase involves the removal of peripheral bone, beginning along the inner surface and extending outwardly. Cortical remodeling may also be observed. Pathogenesis Various theories have been proposed regarding the inciting event responsible for the inflammatory reaction of the periosteum and adjacent connective tissues in Caffey disease. One such theory is the obliteration of small arteries in the region of bone and fascial lesions due to the proliferation of the intima of arterioles. This theory has suggested to some investigators that hypoxia may be the initial event that stimulates osteogenic activity and the remaining inflammatory manifestations of the disease. Although the end result is an abnormal mass of bone formation that blends with the bony cortex (hence, cortical hyperostosis), histologic evaluation of the affected bone during the early phase of the disease shows that the original underlying cortical tissue is progressively remodeled out of existence; this finding suggests that osteoclastic activity is present as well. Simultaneously, a fibrotic reaction of the bone marrow also occurs. Yet another theory proposes a link between Caffey disease and immaturity of the central nervous system with associated undeveloped myelinization of the peripheral nerves. It seems more than coincidental that the surrounding structures of the mandible—the most commonly involved bone in Caffey disease—are innervated by sensory branches of the trigeminal nerve, which is the last of the cranial nerves to start and subsequently become fully myelinated. Following this order of logic, the trigeminal nerve is presumably most sensitive to pathologies resulting in disorders of demyelinization. Further support for this theory is derived from the radiographic findings that demonstrate marked similarity in the posttraumatic exuberant periosteal reaction seen in sensory-deprived children with demyelinization disorders and in the periosteal changes seen in Caffey disease. EtiologyAlthough the etiology of Caffey disease remains unclear, many clinical and pathologic features are suggestive of an inflammatory process. However, other features of the disease support infectious, hereditary, and possibly allergic etiologies. Features suggesting an inflammatory etiology include the following: (1) acute inflammatory changes present in the periosteum during the initial stage; (2) in severe cases, clinical improvement, after the administration of steroids, coupled with the lack of response to antibiotics; and (3) exact replication of hyperostosis in patients receiving prostaglandins to treat ductus-dependent cyanotic congenital heart disease. (Actually, naproxen, an inhibitor of prostaglandin synthesis, has been shown to be beneficial in relieving symptoms and shortening the duration and severity of active hyperostosis.) Features suggesting an infectious etiology include the following: (1) severe and protracted fever, (2) leukocytosis, (3) elevated sedimentation rate, (4) increased levels of gamma globulins (consistent with in utero viral infection), (5) increased levels of C-reactive protein, (6) pleural exudates, and (7) cases clustered in time and location. A theory that suggests expression of a latent infectious agent (eg, virus) has been proposed. The virus, which inserts itself into the host genome, would subsequently express itself, generation after generation; certain environmental factors may promote this process. Features suggesting a hereditary etiology include the following: (1) disease present in siblings and families and (2) documentation of an autosomal dominant pattern of inheritance with incomplete penetrance and variable (clinical) expressivity. Features suggesting an allergic etiology include the following: (1) allergy to altered collagen tissue, which then promotes alterations in the surrounding osseous, muscular, soft tissues, and vascular structures; (2) documented cases of a high familial occurrence of asthma in families with Caffey disease also; and (3) reported cases with a history of allergy to milk. FrequencyInternationalCaffey disease has a worldwide distribution. Both sporadic and familial occurrences are reported, with sporadic cases more common than familial ones. The number of sporadic cases has substantially declined since 1960. Currently, the only cases reported are the occasional polyostotic familial cases. Mortality/MorbidityMortality and Morbidity are both rare occurrences associated with Caffey disease. Resnick states "Rarely, a severely affected infant will die, usually as a result of a secondary infection."1, 2 RaceAll races are affected. SexCaffey disease affects boys and girls equally. AgePatients are almost always younger than 5 months. The average age at onset is 9-10 weeks. AnatomyIn varying layers of thickness, normal bone tissue (membranous and cartilaginous) is composed of an inner spongy bone surrounded by an outside layer of compact bone (see Image 1). In long bones, the spongy bone is removed to form a hollowed space called the medullary cavity. This cavity is lined by a thin cellular layer called endosteum and filled with a specialized type of connective tissue called marrow. The periosteum, a connective-tissue membrane, covers the surface of the bone (excluding the articular cartilage) and connects it with the surrounding soft tissues. Normal bone tissue is maintained by a balance between bone erosion (absorption) and bone deposition (formation). This equilibrium is disturbed in response to pathological changes such as inflammation, vascular obstruction or tumor proliferation, usually visualized as one process (bone formation vs erosion) predominating over the other. The cells of the endosteum and of the deeper layers of the periosteum are the osteogenic tissues of the body. It is primarily this osteogenic capability of the periosteum that produces subperiosteal new bone formation in Caffey disease. This process is not to be confused with normal (physiologic) periosteal new bone formation. In actively growing infants, the transient, frequently symmetrical, physiologic periosteal reaction of long tubular bones may be radiographically present at approximately age 2-6 months. Any other detection of periosteal new bone formation should be considered abnormal. Clinical DetailsOverall, the age of onset, clinical signs, laboratory results, and typical radiographic features are clues for the correct diagnosis of Caffey disease. Signs and symptoms The typical clinical triad includes fever of abrupt onset, hyperirritability, and soft-tissue swelling (especially over the mandible). Other clinical features may include pallor, painful pseudoparalysis of the affected area, and pleurisy. Clinical examination reveals a palpable, hard and tender soft-tissue mass over the area of cortical thickening. The soft-tissue swelling precedes the bony change. Laboratory data Laboratory studies may show an elevated erythrocyte sedimentation rate (ESR), an elevated serum alkaline phosphatase level, moderate leukocytosis, thrombocytosis, and iron-deficiency anemia. Anemia is thought to be due to widespread myelofibrosis. Clinical course The clinical course of Caffey disease is highly variable, ranging from self-limited to protracted. The self-limited course of disease is the most common pattern. The course is slow, occurring over months to years (usually before age 2 y), and the disease spontaneously resolves. The resolution of radiographic findings commences weeks to months after the initial presentation, with complete resolution in 6 months to 1 year. The protracted course of disease is marked by recurrent and persistent episodes ranging from weeks to months interspersed with remissions and relapses. As the pain and swelling overlying the bony abnormality subsides in 1 anatomic location, pain and swelling appears at another site. A marked delay in the musculoskeletal development and crippling deformities can occur in some cases depending on the location of the lesion. Examples include facial asymmetry (mandibular lesion), exophthalmos (orbital lesion), ipsilateral diaphragmatic paralysis (scapular lesion), and bowing of the limbs. Possible residual radiographic changes include diaphyseal expansion and/or longitudinal overgrowth (leading to leg-length discrepancy), cortical thinning, bowing deformities, and osseous bridging with contiguous bones (eg, ribs, radius, ulna). Compared with the sporadic type, the hereditary type is marked by an earlier age of onset (at 6-8 wk) and less mandibular involvement but greater involvement of the lower extremity. Some authorities believe that Caffey disease is not a single disease or infection, but rather a syndrome of common manifestations with heterogeneous causes. In other words, the clinical, radiographic, and laboratory findings may represent a common pathway resulting from various stimuli. Differential diagnoses and other problems to be considered Clinical differential diagnoses include osteomyelitis, parotitis and parotid gland abscess (with a monostotic mandibular presentation), and a bone tumor of the affected area. In the prenatal form, differential diagnoses include hypophosphatasia; camptomelic dysplasia, which is associated with hypoplastic fibulae and talipes equinovarus, but not periosteal new bone formation; and osteogenesis imperfecta. Regarding hypophosphatasia, poor mineralization is not present in Caffey disease. Regarding osteogenesis imperfecta, Caffey disease is less likely in cases of fractures. Differential diagnoses for the classic infantile form are shown in the Table below. Differential Diagnoses of Classic Infantile Form of Caffey Disease
Preferred ExaminationThe general radiographic findings of Caffey disease reflect the features described below. The bones most commonly affected are flat bones: mandible (75% involvement), clavicle, rib (especially the lateral arches), scapula, skull, and ilium. The tubular bones most commonly affected are the ulna bones, which usually show asymmetric involvement. Bones rarely affected are the vertebrae, carpus, tarsus, and phalanges. Symmetrical or asymmetrical distributions may be observed, and involvement can be monostotic and polyostotic. Tubular-bone involvement affects the diaphysis and spares the metaphysis and epiphysis. The scapula is altered in 10% of cases, and any associated with exuberant hyperostosis may resemble neoplasm. Scapular involvement is also associated with neurologic deficit and diaphragmatic elevation. When the ribs are affected, costal hyperostosis can be associated with an ipsilateral exudative pleural effusion. Bony rib fusion may occur and lead to scoliosis. In the forearm, when both the radius and ulna are affected, bony fusion is a particular risk and the resulting synostosis may persist after the disease resolves. DIFFERENTIALSSection 3 of 12
Other Problems to Be ConsideredClinical differential diagnoses
Hypophosphatasia Camptomelic dysplasia Osteogenesis imperfecta Classic infantile form Hypervitaminosis A Healing scurvy Healing rickets Trauma, especially battered child syndrome Osteomyelitis Leukemia Neuroblastoma Osteogenesis imperfecta Syphilis Camurati-Engelmann disease Hyperphosphatemia Hypertrophic osteoarthropathy Bone tumor Complications of long-term prostaglandin therapy (ie, prostaglandin periostitis) RADIOGRAPHSection 4 of 12
FindingsPlain radiographs may show soft-tissue swelling and/or cortical hyperostosis (with doubling or tripling of the normal width of the bone). The periosteal reaction progresses to subperiosteal new bone formation. Radiographic findings can range from a subtle indistinctness of the cortical margin (mild periosteal reaction) associated with soft-tissue swelling to a thick bony cloaking of the diaphysis of long bones. Although Caffey disease is an abnormality of bone formation, destructive lesions of the skull or tubular bones have been identified. See also Preferred Examination. CT SCANSection 5 of 12
FindingsCT findings in Caffey disease include the following: soft-tissue swelling; periosteal reaction (ossifying periostitis), which can progress to abundant subperiosteal new bone formation; and cortical thickening (cortical sclerosis due to the deposition of new bone). CT is seldom necessary and is generally avoided because of its high radiation burden. MRISection 6 of 12
FindingsT1- and T2-weighted MRIs reveal the periosteal reaction, which appears prior to the characteristic radiographic findings of hyperostosis. MRI provides excellent differentiation between bone and soft tissues. MRI also allows an evaluation of the extent of soft-tissue involvement, which includes edema. Soft-tissue edema has decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images. Marrow edema has increased signal intensity on T2-weighted MRI. Degree of ConfidenceCompared with plain radiography overall, MRI adds little important additional information for the clinical evaluation of Caffey disease, but is useful when infection or neoplasia are considered more likely diagnoses. MRI may be used to exclude subperiosteal hemorrhage; however, it is rarely used in this way. MRIs depict hemorrhage with subsequent new bone formation, as seen with differential diagnoses (eg, trauma, scurvy). ULTRASOUNDSection 7 of 12
FindingsSoft tissue may be easily identified with ultrasonography, which is easy to perform on infants. Early periosteal new bone formation is also easily visualized with high frequency (10-14 MHz) transducers. Degree of ConfidenceA soft tissue mass would have nonspecific appearances and could not reliably exclude infection or neoplasia. NUCLEAR MEDICINESection 8 of 12
FindingsThe distribution of radiotracer accumulation is similar with bone and gallium scans. Accumulation of the radiopharmaceutical in the involved bones is markedly increased during the active phase of the disease. The characteristic "bearded-child" appearance is due to the intense and diffuse abnormal accumulation of radiotracer in the mandible. Degree of ConfidenceNuclear medicine scans are positive before radiographic signs develop. In addition, nuclear medicine studies may be useful for documenting the extent of skeletal involvement. INTERVENTIONSection 9 of 12
Medical/Legal Pitfalls
ACKNOWLEDGMENTSSection 10 of 12
The authors wish to thank Middleton Funches and Shauna Fields for their tremendous technical assistance. We are greatly indebted to Dr Clifton Leftridge, Jr, for providing invaluable images. Special thanks to Alice Davis for her unwavering support. MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
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