Clinical characteristics.

Caffey disease is characterized by massive subperiosteal new bone formation (usually involving the diaphyses of the long bones as well as the ribs, mandible, scapulae, and clavicles) typically associated with fever, joint swelling, and pain in children, with onset between birth and five months and spontaneous resolution by age two years. Episodes of recurrence of the manifestations of Caffey disease have been reported multiple times in individuals with the classic infantile presentation. Limited follow-up information suggests that adults who had Caffey disease in childhood may manifest joint laxity, skin hyperextensibility, hernias, short stature, and an increased risk for bone fractures and/or deformities.

Diagnosis/testing.

The diagnosis of Caffey disease is established in a proband with typical clinical and radiographic findings and a c.3040C>T heterozygous pathogenic variant in COL1A1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Anti-inflammatory agents, antipyretics, and analgesics can be used in the short term to decrease swelling and fever and to relieve pain.

Surveillance: Given that Caffey disease is a collagenopathy, evaluation of stature, joint extensibility, hernias, fracture history, and dental health is recommended. Assessment of bone mineral density may be prudent in adults with a history of Caffey disease in childhood.

Genetic counseling.

Caffey disease is inherited in an autosomal dominant manner. Some individuals diagnosed with Caffey disease have a parent who had Caffey disease in childhood; others have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown. Each child of an individual who had Caffey disease in childhood has a 50% chance of inheriting the pathogenic variant. Prenatal and preimplantation genetic testing are possible if the pathogenic variant has been identified in the proband.

Suggestive Findings

Caffey disease should be suspected in probands with the following:

• Clinical findings of irritability, fever, and/or pallor accompanied by soft-tissue swelling and pain adjacent to involved bones
• Radiologic findings of subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses), as well as the ribs, scapulae, clavicles, and mandible
• Findings typically appearing between birth and age five months and resolving spontaneously by age two years, although recurrence in adolescence is possible

See Figure 1 and Figure 2.

Figure 1.

Skeletal survey in a female age five weeks with the defining COL1A1 p.Arg1014Cys pathogenic variant who presented with painful swelling over the right tibia Note widespread involvement with (a) symmetric bilateral periosteal reaction involving the mandible (more...)

Figure 2.

Clinical photograph and x-ray of male age two months with the defining COL1A1 p.Arg1014Cys pathogenic variant who presented with irritability and swelling over the right tibia Arrows denote the area of swelling on clinical examination and the subperiosteal (more...)

Establishing the Diagnosis

The diagnosis of Caffey disease is established in a proband with typical clinical and radiographic findings and a c.3040C>T heterozygous pathogenic variant in COL1A1 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Caffey disease has a limited differential diagnosis, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Caffey disease has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Caffey disease is characterized by massive subperiosteal new bone formation usually involving the diaphyses of the long bones, as well as the ribs, mandible, scapulae, and clavicles [Caffey & Silverman 1945, Caffey 1957].

Presentation. Typically the skeletal manifestations of Caffey disease first appear with fever, joint swelling, and pain between birth and age five months, and resolve before age two years [Kamoun-Goldrat & le Merrer 2008, Cerruti-Mainardi et al 2011, Ranganath et al 2011].

• The clinical findings most often appear at age two months.
• On rare occasion, the hyperostosis can be detected by ultrasound examination late in the third trimester of pregnancy [Schweiger et al 2003]. One report describes prenatal periosteal inflammation in a fetus heterozygous for the defining COL1A1 pathogenic variant [Kamoun-Goldrat et al 2008].

Recurrence. Episodes of recurrence of the manifestations of Caffey disease have been reported multiple times, in individuals with the classic infantile presentation [Navarre et al 2013]. Etiology and precipitating factors for recurrence remain unclear [Navarre et al 2013].

Other findings. In a family described by Gensure et al [2005], an individual with the defining COL1A1 pathogenic variant had a history of Caffey disease as a child and joint laxity and skin hyperextensibility with a history of hernias and multiple fractures in adulthood. Subsequent clinical examination of other individuals in that family who also had the defining COL1A1 pathogenic variant revealed varying degrees of joint laxity and hyperextensibility. Skin biopsy of affected individuals showed collagen fibrils that were larger, more variable in shape, and less densely packed than age- and sex-matched controls. Granulofilamentous material was also visible in the matrix along the collagen fibrils. Cultured fibroblasts showed a mix of normal type I collagen and abnormal disulfide crosslinking, either within or between mutated collagen fibrils. The findings reported by Gensure et al [2005] have not been found in other families with the same pathogenic variant [Cho et al 2008, Cerruti-Mainardi et al 2011, Ranganath et al 2011]

Long-term outcome. Although anecdotal evidence suggests that the manifestations of Caffey disease resolve spontaneously by age two years and do not predispose to long-term bone abnormalities, the literature on Caffey disease does not directly address long-term outcomes. The study of a single family suggested that individuals who have the defining pathogenic variant may be prone to short stature and residual bone deformities [Suphapeetiporn et al 2007]. In addition, it has been suggested that fractures (possibly related to decreased bone mineral density) may be more common in these individuals [Gensure et al 2005, Suphapeetiporn et al 2007].

Other bone-related complications may potentially occur: in one case report a child with Caffey disease developed tumoral calcinosis (thought to be due to constant remodeling) after repeated inflammatory events [Issa El Khoury et al 2012].

Laboratory findings observed in a few affected individuals:

• Serum biochemical markers of inflammation (white blood cell count, erythrocyte sedimentation rate, C-reactive protein) have been elevated [Gensure et al 2005].
• Anemia and thrombocytosis have been described in single case reports [Restrepo et al 2004, Krishnamurthy & Srinivasan 2012].
• Bone and muscle biopsy of affected sites in a few individuals have demonstrated an inflammatory reaction [Katz et al 1981].

Genotype-Phenotype Correlations

Within the range of COL1A1 pathogenic variants responsible for different phenotypes, c.3040C>T is the defining variant responsible for the Caffey disease phenotype. See Molecular Pathogenesis.

Penetrance

Incomplete penetrance based on family history or molecular genetic testing has been noted [Cho et al 2008, Kutty et al 2010, Prior et al 2012, Kitaoka et al 2014]. In a family studied by Gensure et al [2005], 19 of 24 individuals with the defining COL1A1 pathogenic variant had a clinical history of an episode consistent with Caffey disease.

Nomenclature

"Prenatal lethal forms of hyperostosis," also referred to as "prenatal Caffey disease" or "Caffey dysplasia" [Nemec et al 2012], are distinct from Caffey disease (also known as infantile cortical hyperostosis) (see Differential Diagnosis).

Prevalence

The number of clinical reports of Caffey disease described to date is no more than a few hundred; however, given the spontaneous resolution of this condition in early childhood, it is likely underdiagnosed.

The defining COL1A1 c.3040C>T pathogenic variant does not appear to be more prevalent in one particular population; it has been described in individuals of northern European [Gensure et al 2005, Cerruti-Mainardi et al 2011], Indian [Ranganath et al 2011], Thai [Suphapeetiporn et al 2007], Korean [Cho et al 2008], and Japanese [Hasegawa et al 2004] ancestry.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Caffey disease, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Evaluation for joint range of motion, tissue hyperlaxity, and hernias
• Radiographs of long bones, ribs, scapulae, clavicles, and mandible to assess the extent of disease and stage of hyperostosis
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Anti-inflammatory agents, antipyretics, and analgesics can be used in the short term to decrease swelling and fever and to relieve pain [Thometz & DiRaimondo 1996, Parnell & Parisi 2010].

No recommendations for the prevention of recurrence of hyperostosis currently exist.

Surveillance

Currently, no standard surveillance protocols exist. However, given that Caffey disease is a collagenopathy, yearly evaluation of stature, joint extensibility, hernias, fracture history, and dental health is recommended.

Although no systematic reviews of bone mineral density in adults with the defining pathogenic variant have been performed, reports of fractures and short stature in adults with other COL1A1 pathogenic variants suggest that assessment of bone mineral density may be prudent in adults with a history of Caffey disease in childhood.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Caffey disease is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with Caffey disease have a parent who had Caffey disease in childhood.
• A proband with Caffey disease may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown.
• Recommendations for the evaluation of the parents of a proband with an apparent de novo pathogenic variant include molecular testing for COL1A1 c.3040C>T and a detailed medical history focusing on symptoms of hyperostosis in infancy and current bone health.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with Caffey disease may appear to be negative because of failure to recognize or remember the occurrence of the disorder in family members or because of reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband had Caffey disease in childhood and/or is known to have the COL1A1 c.3040C>T pathogenic variant, the risk to the sibs is 50%.
• If the COL1A1 c.3040C>T pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the COL1A1 c.3040C>T pathogenic variant but are known not to have had Caffey disease in childhood, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Caffey disease because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual who had Caffey disease in childhood has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent had Caffey disease, the parent's family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who were affected as children.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the COL1A1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Ultrasound evaluation. A diagnosis of the typical infantile form of Caffey disease presenting with hyperostosis was made on the basis of ultrasound examination after 35 weeks' gestation [Schweiger et al 2003].

Molecular Pathogenesis

COL1A1 encodes collagen type I, a heterotrimer consisting of two α1 chains and one α2 chain (encoded by COL1A2), which is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis, and tendon.

Mechanism of disease causation. The mechanism of p.Arg1014Cys (formerly known as p.Arg836Cys) pathogenesis is unknown. Possibilities as to why p.Arg1014Cys causes the Caffey disease phenotype include the following:

• Disruption of protein-protein interaction since p.Arg1014 is located in the carboxy-terminal cyanogen bromide terminus 6 (CB6) of the α1(I) chain, which has been shown to interact with both IL-2 and the amyloid protein precursor (APP) [Somasundaram et al 2000, Di Lullo et al 2002].
• Reduced thermal stability of the collagen triple helix [Gensure et al 2005].

Author Notes

Dr Guerin, Ms Dupuis, and Dr Mendoza are currently conducting a research study for individuals with a clinical or molecular diagnosis of Caffey disease. The goals of the study are to better describe the natural history, pathogenesis, and complications in order to enhance the management and counseling of Caffey disease.

Revision History

• 13 June 2019 (ha) Comprehensive update posted live
• 29 November 2012 (cd) Revision: prenatal testing available
• 2 August 2012 (me) Review posted live
• 17 February 2012 (ag) Original submission

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