Infantile cortical hyperostosis (ICH), also known as Caffey disease, was first reported by Roske in 1930 and described by Caffey and Silverman in 1945. ICH is a disorder affecting the skeletal system of children around 9 weeks of age. ICH most commonly affects the mandible (70% to 90% of cases) and has the appearance of periosteal reaction. Most frequent locations affected are the ascending ramus and angle of the mandible. Also known to affect the clavicle, rib, ulna, scapula and rarely the ilia, parietal bones, and metatarsals. Usually unilateral when involving the scapula. ICH can affect all bones except cuboidal bones, vertebral bodies, and phalanges. Primary bone lesions are commonly asymmetric and localized to the diaphysis with sparing of the metaphysis and epiphysis resulting in spindle-shaped bones. The disease usually spontaneously resolves within 2 years.
Gensure et al. performed a genome-wide scan followed by fine mapping of individuals known to have the autosomal dominant form of ICH. Subsequently, genes were sequenced, and PCR amplification was performed. Gel electrophoresis confirmed that the affected individuals had a missense mutation in COL1A1.
ICH rarely occurs after 5 months of age. Radiographic findings include cortical thickening (hyperostosis) and subperiosteal new bone formation. There is a prenatal form of the disease, called lethal prenatal cortical hyperostosis, that shows an autosomal recessive mode of inheritance and occurs before 35 weeks gestation. Polyhydramnios, angular deformities of the long bones, deformities of the ribs, prematurity, and lung disease are associated with this form. The infantile (classical) form that appears after 35 weeks is less severe and more common. Ultrasound in utero can show changes such as bone curvature and cortex deformities consistent with ICH.
The familial form of ICH is autosomal dominant with variable penetrance and classically is associated with a COL1A1 point gene mutation (3040C to T) on chromosome 17q21. This missense mutation results in an arginine to cysteine substitution (R836C) in the triple helix of the alpha-1 chain of type 1 collagen. Type 1 collagen is important for bone mineralization and makes up about 9% of the bone matrix. Formation of these fibers require gathering of one a2 and two a1 procollagen chains followed by cleavage of the N and C termini by proteinases. Collagens provide strength and interact with proteins to form the extracellular matrix necessary for normal cell function.
The relation between this missense mutation and the skeletal findings of ICH are unknown, but proposed mechanisms include an inability of chromosome interactions with proteins (IL-2), defective cross-linking between the bone and abnormal collagen, and decreased thermal stability of collagen. The average age of presentation of the familial form of ICH is between 6 to 8 weeks, and it commonly involves the tibias. Twenty-four percent of infants present at birth with the familial form. The sporadic form of ICH usually involves the mandible with an average age of onset between 9 and 11 weeks. Some sporadic cases result from prolonged administration of prostaglandins E1 and E2 in infants with cyanotic heart disease.
COL1A1 and COL1A2 gene mutations causes subtypes of Ehlers-Danlos syndrome and osteogenesis imperfecta. Gly substitutions in the triple helix lead to defective type I collagen resulting in fractures and findings consistent with osteogenesis imperfecta types II-IV. Some individuals with ICH have features seen in Ehlers-Danlos such as hyperextensible skin, joint hyper laxity, and inguinal hernias.
Histologic findings in the early stages of disease are limited to the periosteum. Gradually the periosteum’s fibrous layer breaks down and becomes associated with muscles, tendons, and fascia. Osteoid trabeculae enter the muscles, soft tissue, and connective tissue, forming new bone and resulting in increased diameter. Eventually, the periosteum reforms a fibrous layer over the new bone, and the extra bone is removed.
ICH commonly presents with sudden soft tissue swelling of the jaw and face, fever, and irritability. Some cases first present with swelling of the extremities followed by swelling of the face days later. These swellings become hard and fix to the bone and can also be red and painful. Other clinical findings can include conjunctivitis, decreased movement of extremities, failure to thrive due to difficulty eating, and pallor.
Laboratory findings can include increased erythrocyte sedimentation rate, C-reactive protein, alkaline phosphatase, or immunoglobulin levels and leukocytosis or thrombocytosis. There are cases of ICH where laboratory findings are all within normal limits.
Genetic testing, if available, can confirm the presence of the missense mutation but the clinical course and radiographic findings should establish a clinical diagnosis. X-rays show gradual cortical thickening, periosteal bone formation around the diaphysis, and soft tissue swelling. Magnetic resonance imaging (MRI) is consistent with periosteal thickening, low-signal intensity in soft tissues on T1 sequences, and high-signal intensity on T2 sequences. Changes take 15 to 20 days to appear on x-rays, making it difficult to diagnose ICH in the early stages. Abnormal MRI findings may sometimes present before abnormal x-ray films.
Treatment includes observation and counseling. Corticosteroids and non-steroidal anti-inflammatory medications such as naproxen, ibuprofen, and indomethacin have been reported to help with symptoms. Corticosteroids are not proven to prevent recurrences.
Time of resolution can vary between weeks to years. Throughout the disease, swelling can improve in one area and reappear in the same or a different location. ICH usually spontaneously resolves within 2 years of age. On average, resolution occurs within 6 to 9 months. Both clinical symptoms and labs usually normalize during this time. There have been rare cases of reoccurrence in adolescence and adulthood.
Complications include pleuritis, thoracic scoliosis, and exophthalmos. Rarely, bone deformities may require surgical correction at a later age.
Soft tissue swelling and irritability in a child can raise concern for non-accidental trauma. Evaluation of other traumatic injuries or sentinel injuries is important. Requesting workup by a child abuse pediatrician can help prevent misdiagnosis. ICH can mimic child abuse but can be differentiated by the age of onset, site of involvement, lack of fracture, and limitation to the diaphysis. In ICH, the areas of new bone formation are usually thick and rounded versus tapering of the bone seen in child abuse. Periosteal reaction extending into the epiphysis is more indicative of physical abuse. It is very important for clinicians to be informed about diseases that can mimic child abuse, such as ICH, to come to a correct diagnosis.