Continuing Education Activity

Infantile cortical hyperostosis (ICH), or Caffey disease, is a rare disorder that primarily affects infants and is characterized by inflammation of the periosteum and new bone formation, most commonly involving the mandible. This condition typically presents within the first few months of life and can resemble child abuse due to visible bone changes. However, ICH can be distinguished from abuse by factors such as age of onset, affected bone locations, and lack of fractures. The periosteal reaction in ICH is also more uniform, whereas fractures from abuse often display irregular or tapering bone growth.

Participants in this course gain insights into the clinical presentation, workup, and management of ICH, learning to differentiate it from conditions like child abuse. The course highlights the importance of collaborating with an interprofessional team—including radiologists, pediatricians, and social workers—to ensure accurate diagnosis and avoid unnecessary interventions. By improving diagnostic accuracy and fostering teamwork, clinicians are better equipped to provide appropriate care, which leads to improved patient outcomes and reduced misdiagnosis.

Objectives:

• Differentiate infantile cortical hyperostosis from other conditions such as child abuse and bone malignancies.

• Identify the clinical features and radiographic findings associated with infantile cortical hyperostosis.

• Screen infants for common presentations of infantile cortical hyperostosis, including mandible involvement and periosteal reactions.

• Communicate modalities to improve care coordination among interprofessional team members in managing infantile cortical hyperostosis to improve patients' outcomes.

Introduction

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 infants.[1] ICH most commonly affects the mandible (70% to 90% of cases) and has the appearance of a periosteal reaction. ICH is also known to affect the clavicle, rib, ulna, scapula, and rarely the ilia, parietal bones, and metatarsals. Usually unilateral when involving the scapula. Primary bone lesions are commonly asymmetric and localized to the diaphysis with sparing of the metaphysis and epiphysis. This pattern of involvement usually results in spindle-shaped bones and usually spontaneously resolves within 2 years.[2]

Etiology

Gensure et al performed a genome-wide scan followed by fine mapping of individuals with the ICH's autosomal dominant form. Subsequently, genes were sequenced, and polymerase chain reaction amplification was performed. Gel electrophoresis confirmed that the affected individuals had a missense mutation in the COL1A1 gene.[3]

Epidemiology

ICH rarely occurs after the first year of life.[4] Radiographic findings include cortical thickening (hyperostosis) and subperiosteal new bone formation. There is a prenatal form of the disease called lethal prenatal cortical hyperostosis, which 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 of gestation is less severe and more common.[2] Ultrasound in utero can show changes such as bone curvature and cortex deformities consistent with ICH.[4]

Pathophysiology

ICH's familial form is autosomal dominant with variable penetrance and classically associated with a COL1A1 point gene mutation (3040C to T) on chromosome 17q21.[5] 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 essential for bone mineralization and makes up about 9% of the bone matrix. These fibers comprise one a2 and 2 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 cell function.[6]

The relation between this missense mutation and the skeletal findings of ICH is unknown. Still, proposed mechanisms include an inability of chromosome interactions with proteins (interleukin-2), defective cross-linking between the bone and abnormal collagen, and decreased thermal stability of collagen.[6] The average age of presentation of ICH's familial form is between 6 to 8 weeks, commonly involving the tibias. Twenty-four percent of infants present at birth with the familial form. ICH's sporadic form 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.[4]

COL1A1 and COL1A2 gene mutations cause 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 hyperlaxity, and inguinal hernias.[6]

Histopathology

Histologic findings in the early stages of the disease are limited to the periosteum. The periosteum’s fibrous layer gradually 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.[4]

History and Physical

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, fixed to the bone, and red and painful.[1] Other clinical findings can include conjunctivitis, decreased movement of extremities, failure to thrive due to difficulty eating, and pallor.[1]

Evaluation

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.[5] 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 diagnosing ICH in the early stages difficult. Abnormal MRI findings may sometimes present before abnormal x-ray films.[2][4]

Treatment / Management

Treatment includes observation and counseling. Acetaminophen and nonsteroidal anti-inflammatory medications such as naproxen, ibuprofen, and indomethacin have been reported to help with symptoms. Corticosteroids can be used in severe cases; however, they have not been proven to prevent recurrences.[5]

Differential Diagnosis

Differential diagnoses include child abuse, malignancy, hypervitaminosis A, hypoparathyroidism, parotitis, osteomyelitis, prostaglandin administration, scurvy, or other collagen synthesis defects.[7][2][8]

Prognosis

The time of resolution can vary between weeks to years. Throughout the disease, swelling can improve in one area and reappear in the same or different locations. ICH usually spontaneously resolves within 2 years of age; on average, resolution occurs within 6 to 9 months. Both clinical symptoms and labs generally normalize during this time. There have been rare cases of reoccurrence in adolescence and adulthood.[4]

Complications

ICH usually resolves with no major clinical sequelae. A few cases have complications, including pleuritis, thoracic scoliosis, and exophthalmos. Rarely, bone deformities may require surgical correction at a later age.[4]

Enhancing Healthcare Team Outcomes

Soft tissue swelling and irritability in a child can raise concern for non-accidental trauma. Evaluation of other traumatic injuries or sentinel injuries is essential. Requesting a 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, new bone formation areas 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. Clinicians need to have a high index of suspicion of the conditions that can mimic child abuse, such as ICH, to correct diagnosis.[9]