Infantile Cortical Hyperostosis (Caffey Disease) 

Updated: May 09, 2018
Author: Cara Novick, MD; Chief Editor: Vinod K Panchbhavi, MD, FACS 

Overview

Background

In 1945, Caffey first described infantile cortical hyperostosis (Caffey disease), a self-limited disorder that affects infants and causes bone changes, soft-tissue swelling, and irritability.[1] Although the etiology of this condition is not completely understood, familial and sporadic forms appear to exist.[2, 3, 4, 5, 6] (Also see Caffey Disease Imaging.) Infantile cortical hyperostosis is typically self-limited; no specific treatment exists.

Pathophysiology

Infantile cortical hyperostosis is an inflammatory process of unclear etiology. In the early stages of this condition, inflammation of the periosteum and adjacent soft tissues is observed. As this resolves, the periosteum remains thickened, and subperiosteal immature lamellar bone is noted. The bone marrow spaces contain vascular fibrous tissue. Mature specimens show hyperplasia of the lamellar cortical bone without inflammation or subperiosteal changes.[4]

Etiology

Although the etiology of infantile cortical hyperostosis has not been fully elucidated, there is growing evidence of a genetic component.[7, 8]

Various studies have supported the finding that a heterozygous missense mutation (c.3040c→T [p.41014C]) in exon 41 in the type I collagen alpha1 chain gene (COL1A1) is responsible for this disease.[8, 9, 10, 11, 12, 13, 14, 15]  A link to lethal antenatal cortical hyperostosis has also been reported. Authors have noted that this places infantile cortical hyperostosis in the same family as type I collagen-related diseases such as osteogenesis imperfecta I-IV,[16] Ehlers-Danlos syndromes type I and VII,[17] idiopathic osteoporosis, and dermatofibrosarcoma protuberans.

Kitaoka et al conducted a mutation analysis of the COL1A1 and COL1A2 genes and measured bone mineral density in two patients with Caffey disease.[18]  The patients came from two different families. The index patient and two clinically healthy members of that person's family were found to carry the common heterozygous mutation; no mutations of COL1A1 or COL1A2 were identified in the affected members of the second family.

Bone mineral density (BMD) was normal in adult patients of both families who had had an episode of cortical hyperostosis, regardless of the presence or absence of the p.Arg1014Cys mutation.[18]  The investigators concluded that Caffey disease is genetically heterogeneous and that affected and unaffected adult patients with or without the common COL1A1 mutation have normal BMD.

Some have suggested that transmission may occur via an infectious agent with a long latency period. Other theories have included a primary arterial abnormality and allergic reaction.

Epidemiology

Infantile cortical hyperostosis has been reported to affect 3 of 1000 infants younger than age 6 months.[19] The disease may be present at birth or shortly thereafter. The familial form tends to have an earlier onset and is present at birth in 24% of cases, with an average age at onset of 6.8 weeks.[3, 20] The average age at onset for the sporadic form of infantile cortical hyperostosis is 9-11 weeks. No race- or sex-based predilection has been established.

Prognosis

Infantile cortical hyperostosis usually runs its course and resolves without sequelae in 6-9 months. However, the possibility of recurrence should not be ruled out.

Navarre et al reported the case of a 12-year-old female patient who presented with symptoms of pain and swelling of both forearms and legs.[21]  These symptoms were similar to symptoms present at the age of 1 month, at which time she was diagnosed as having cortical hyperostosis. Genetic analysis confirmed the COL1A1 mutation. Radiologic investigation revealed new periosteal bone formation of the right and left ulnae and the left fibula, suggesting a recurrence of cortical hyperostosis.

Navarre et al conducted a review of the literature, using the Medline database between 1948 and 2011, and found that the literature confirmed the possibility of recurrence.[21]  They concluded that the diagnosis of recurrent cortical hyperostosis should be considered for patients who experienced cortical hyperostosis in infancy and who present with similar symptoms during adolescence.

 

Presentation

History

In 1945, Caffey described a group of infants with tender swelling in the soft tissues, cortical thickening in the skeleton, and onset during the first 3 months of life. Infantile cortical hyperostosis appeared to be self-limited, and no clear etiology was noted. To date, the exact course and presentation remain variable for this disease.

Infantile cortical hyperostosis is believed to exist in two forms, familial and sporadic. These forms differ in their onset and presentation.

The familial form seems to have an earlier onset; 24% of these cases are present at birth.[3] Incidence of mandibular involvement is less than that observed in the sporadic form, and the incidence of lower-extremity involvement is higher than that observed in the sporadic form. The tibia is the most frequently involved bone. The average age at onset is 6.8 weeks. The disease appears to be inherited in an autosomal dominant fashion with variable penetrance.[3]

The sporadic form is becoming less common. It has a higher incidence of mandibular involvement than does the familial form. The average age at onset is 9-11 weeks. The etiology is unclear.

Physical Examination

The classic presentation of infantile cortical hyperostosis includes a triad of irritability, swelling, and bone lesions. The swelling appears suddenly, is deep and firm, and may be tender. Fever may occur. Babies may refuse to eat, especially if they have mandibular involvement, thus creating an appearance of failure to thrive.[22, 5]  Almost all cases are evident in infants by age 5 months.

Infantile cortical hyperostosis is often multifocal and asymmetric. The disease has been described in many bones, including the mandible, tibia, ulna, clavicle, scapula, ribs, humerus, femur, fibula, skull, scapula, ilium, and metatarsals.

Complications

Long-term deformities of the involved bones, including bony fusions and limb-length inequalities, are possible[23] ; however, these sequelae are rare.

 

DDx

Diagnostic Considerations

The most significant differential diagnosis is osteomyelitis because of the need for urgent treatment. In addition, the following conditions should be included in the differential diagnosis:

  • Trauma
  • Hypervitaminosis A
  • Hyperphosphatemia
  • Prostaglandin E1 and E2 administration
  • Infection (including syphilis)
  • Metastatic neuroblastoma

Other diseases can usually be excluded on the basis of the narrow age range for presentation of infantile cortical hyperostosis; the triad of irritability, swelling, and bone lesions; and the presence of mandibular involvement.

Differential Diagnoses

 

Workup

Laboratory Studies

Although no specific laboratory tests exist to diagnose infantile cortical hyperostosis (Caffey disease), laboratory studies may be performed to help exclude other diagnoses. The erythrocyte sedimentation rate (ESR) and the alkaline phosphatase (ALP) level are often elevated. Anemia and leukocytosis may be present.

Imaging Studies

Radiography is the most valuable diagnostic study in infantile cortical hyperostosis.[24] Radiographs show layers of periosteal new bone formation, with cortical thickening in variable combinations of the long bones, mandible, and clavicle (see the image below).[25]

Radiograph from a 5-month-old infant with infantil Radiograph from a 5-month-old infant with infantile cortical hyperostosis. This image depicts cortical thickening in the pelvis secondary to the disease.

Initially, periosteal new bone is observed to engulf the diaphysis of the bone, causing an increase in bone diameter. Soft-tissue swelling is evident as well. Over time, periosteal new bone increases in density, becoming homogeneous with the underlying cortex. Eventually, the bone remodels and resumes a normal appearance.

Other diagnostic imaging studies have not proved to yield significant additional benefit. Magnetic resonance imaging (MRI) results have been described but do not add any significant information to the results obtainable with radiography.

Ultrasonography (US) may be used to diagnose prenatal cases. The appearance of infantile cortical hyperostosis on US is similar to that of cases of osteogenesis imperfecta.

The effects of infantile cortical hyperostosis can sometimes resemble those of child physical abuse. Al Kaissi reported a case of suspected child abuse involving a female infant aged 3 months with multiple inflamed swellings over the limbs.[26] Imaging studies revealed features consistent with Caffey disease, including massive sclerosis of the skull bone associated with significant cortical hyperostosis, as well as mandibular enlargement secondary to new cortical bone formation. Characteristic features of the disease were also seen in the patient's radius and tibia.

Histologic Findings

In the early stages of infantile cortical hyperostosis, inflammation of the periosteum and adjacent soft tissues is observed. As this resolves, the periosteum remains thickened, and subperiosteal immature lamellar bone is observed. The bone marrow spaces contain vascular fibrous tissue. Mature specimens show hyperplasia of lamellar cortical bone without inflammation or subperiosteal changes.

 

Treatment

Approach Considerations

No specific treatment exists for infantile cortical hyperostosis (Caffey disease). The disease is self-limited and usually resolves without sequelae.[27, 28] Some periods of exacerbation and remission may occur during the course of this condition.

Medical Care

Corticosteroids may be helpful in alleviating symptoms in severe cases, but these agents do not have any affect on the bone lesions. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used to treat symptoms.