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Caffey Disease

Synonym: Infantile Cortical Hyperostosis

, BSc, MD, , MS, MSc, CGC, and , MD, MS, FACMG, FCCMG.

Author Information

Initial Posting: ; Last Revision: November 29, 2012.

Estimated reading time: 16 minutes


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 around age two months and spontaneous resolution by age two years. On rare occasion, the hyperostosis can be detected by ultrasound examination late in the third trimester of pregnancy. Limited follow-up information suggests that adults who had Caffey disease in childhood may manifest joint laxity, skin hyperextensibility, hernias, and an increased risk for bone fractures and/or deformities.


Radiologic findings of subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses), ribs, scapulae, clavicles, and mandible in a child age two months to five years suggest the diagnosis. The COL1A1 variant c.3040C>T (p.Arg1014Cys; also known as p.Arg836Cys) in exon 41 is the defining pathogenic variant currently identified in all individuals with Caffey disease undergoing molecular genetic testing. Although allelic and/or locus heterogeneity are possible, neither has been observed to date.


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: Currently, no standard surveillance protocols exist; however, yearly evaluation of linear growth, dental health, joint range of motion re extensibility, possible hernias, and fracture history is recommended.

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 testing for pregnancies at increased risk is possible if the pathogenic variant in the family has been identified.


Diagnosis of Caffey disease is based on the following [Lachman 2007]:

  • Clinical findings of irritability, fever, and/or pallor accompanied by soft tissue swelling 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. Hyperostosis typically appears between birth and age five months and resolves spontaneously by age two years.
  • Presence of the defining COL1A1 pathogenic variant c.3040C>T (p.Arg1014Cys) (also known as p.Arg836Cys)

See Figure 1, and Figure 2.

Figure 1. . Skeletal survey in a female age five weeks with the defining COL1A1 p.

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. Notice widespread involvement with (a) symmetric bilateral periosteal reaction involving the (more...)

Figure 2. . Clinical photograph and x-ray of male age two months with the defining COL1A1 p.

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. The arrows denote the area of swelling on clinical examination and the subperiosteal (more...)

Molecular Genetic Testing

Gene. COL1A1 is the only gene in which a pathogenic variant is known to cause Caffey disease. The COL1A1 c.3040C>T (p.Arg1014Cys; also known as p.Arg836Cys) variant in exon 41 is currently the defining pathogenic variant involved in Caffey disease. See Table 1.

Evidence for locus heterogeneity. All probands identified to date come to clinical attention due to episodes of cortical hyperostosis. All published cases in which molecular testing has been done involve heterozygosity for the single known c.3040C>T pathogenic variant. However, one patient who meets clinical criteria does not have this variant, suggesting allelic or genetic heterogeneity [Author, unpublished observation].

Table 1.

Summary of Molecular Genetic Testing Used in Caffey Disease

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
COL1A1Targeted analysis for pathogenic variants / sequence analysis of exon 41c.3040C>T100% for c.3040C>T targeted variant
Sequence analysis 4Sequence variants throughout the coding and splicing regions 5Unknown, none reported to date 5
Deletion/duplication analysis 6Partial- and whole-gene deletions/duplications 5Unknown, none reported to date 5

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


The clinical utility of sequencing the gene or deletion/duplication analysis is unknown. The yield is expected to be very low as no such variants have been reported as causative of Caffey disease.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in an infant or young child in whom clinical findings suggest the diagnosis of Caffey disease:

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

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]. 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].

Although episodes of recurrence of hyperostosis have been reported on occasion [Thometz & DiRaimondo 1996], the likelihood of a recurrence is unknown, as are the contributing factors.

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]

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].

Observed laboratory findings in a few affected individuals:

Genotype-Phenotype Correlations

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


Incomplete penetrance based on family history or molecular genetic testing has been noted [Newberg & Tampas 1981, Cho et al 2008]. In a family studied by Gensure et al [2005], 19 of 24 (79%) individuals with the defining COL1A1 pathogenic variant had a clinical history of an episode consistent with Caffey disease.


"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).


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 p.Arg1014Cys (also known as p.Arg836Cys) pathogenic variant does not appear to be more prevalent in one particular ethnic group. It has been described in white [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 individuals [Hasegawa et al 2004].

Differential Diagnosis

Other conditions may manifest as joint swelling and hyperostosis and thus need to be distinguished from Caffey disease:

  • Lethal prenatal Caffey disease (prenatal Caffey disease/Caffey dysplasia). This condition typically presents before 35 weeks’ gestation and is characterized by corticial hyperostosis as well as bowing or angulation of the long bones and the presence of polyhydramnious and fetal lung disease [Langer & Kaufmann 1986, Lécolier et al 1992, Drinkwater et al 1997, Dahlstrom et al 2001, Savarirayan et al 2002, Hall 2005, Hochwald & Osiovich 2011, Nemec et al 2012]. Autosomal recessive inheritance involving genes other than COL1A1 has been proposed [de Jong & Muller 1995, Drinkwater et al 1997, Schweiger et al 2003, Gensure et al 2005].
  • Non-accidental childhood injury (child physical abuse/non-accidental trauma). The prevalence of physical abuse is much greater than the prevalence of Caffey disease. Often the clinical history and presence of fractures, which are not usually a presenting feature of Caffey disease, aid in distinguishing the two conditions [Al Kaissi et al 2009, Lo et al 2010].
  • Hypervitaminosis A, which can result in bone pain and swelling, similar to that seen in Caffey disease. In addition, hyperostosis has been documented in adults with hypervitaminosis A [Wendling et al 2009].
  • Prostaglandin E1 (PGE1) exposure. Reversible hyperostosis and long bone swelling has been noted in neonates on PGE1 therapy for several weeks for maintenance of ductus arteriosus patency in the context of congenital heart disease [de Almeida et al 2007].
  • Hyperphosphatemic familial tumoral calcinosis (HFTC). A rare disorder caused by pathogenic variants in GALNT3, FGF23, or KL. HFTC is characterized by hyperphosphatemia, normal or elevated 1,25-dihydroxyvitamin D3 concentrations, and cortical hyperostosis [Olauson et al 2008].
  • Storage diseases presenting in early infancy (including I-cell disease (mucolipidosis type II) and GM1 gangliosidosis type I), which may be characterized by periosteal cloaking; however, the involvement of the metaphysis and generalized findings of these conditions differentiate them from Caffey disease [Hall 2005].
  • Bone malignancies, which may also be suspected initially; biopsies have been performed in the past to rule out this diagnosis [Katz et al 1981].
  • Osteomyelitis, which may be mistakenly diagnosed as joint swelling. Febrile episodes can be common to both conditions; however, the finding of hyperostosis on x-ray helps distinguish between these two entities [Behbehani et al 1997].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Caffey disease, the following evaluations are recommended:

  • Evaluation for joint range of motion, tissue hyperlaxity, and hernias
  • Radiographs of long bones, ribs, scapulae, clavicles, and mandible to assess extent of disease and the 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].

Although immunoglobulins have also been tried [Berthier et al 1988], no definitive treatment guidelines exist.

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


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.

Pregnancy Management

No special recommendations for management of either a fetus known to be heterozygous for the disease-defining pathogenic variant or a mother known to have had Caffey disease in childhood.

Therapies Under Investigation

Search in the US and 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 [Tampas et al 1961, Bull & Feingold 1974, Fried et al 1981, Newberg & Tampas 1981].
  • 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.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of the parents of a proband with an apparent de novo pathogenic variant include molecular testing for the known variant and detailed medical history focusing on symptoms of hyperostosis in infancy and current bone health. Therefore, an apparently negative family history cannot be confirmed until molecular testing for the known pathogenic variant has been performed.
    Note: Although some individuals diagnosed with Caffey disease have a parent who had Caffey disease in childhood, the family history 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 [Fried et al 1981].

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, the risk to the sibs is 50%.
  • When the parents did not have Caffey disease, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for Caffey disease because of the possibility of reduced penetrance in a parent.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of 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, his or her 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 or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the COL1A1 pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for Caffey disease are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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].


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Skeletal Dysplasia Registry
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Caffey Disease: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Caffey Disease (View All in OMIM)


Molecular Genetic Pathogenesis

The recurrence of the defining pathogenic variant in unrelated individuals suggests that this CpG dinucleotide is a mutational hot spot in COL1A1 [Tomso & Bell 2003]. The pathogenic variant is predicted to introduce an arginine-to-cysteine substitution into the triple-helical domain of α1(I) chains of type I collagen [Dalgleish 1997].

Although the exact mechanism of pathogenesis is unknown, possibilities as to why this variant causes the Caffey disease phenotype include the following:

  • The variant may disrupt a site important for protein interaction since it 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].
  • The p.Arg1014Cys substitution (also known as p.Arg836Cys) within the α1(I) chain reduces the thermal stability of the collagen triple helix [Gensure et al 2005].

Gene structure. The transcript NM_000088.3 has 51 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. COL1A1 c.3040C>T is the defining pathogenic variant responsible for the Caffey disease phenotype. No other allelic variants are known to be responsible for this disease. The COL1A1 database of allelic variants (initiated by Dalgleish [1997]) describes this variant.

Table 2.

Selected COL1A1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. Type I collagen has 1464 amino acid residues.

Abnormal gene product. The p.Arg1014Cys amino acid substitution (also known as p.Arg836Cys) changes the X position of Gly-X-Y repeating amino acid triplets of the α1(I) chain of type I collagen. In most collagenopathies, the pathogenesis of the disease is thought to be related to alterations in the glycine residues. Cysteine, in contrast, is normally present in the amino and carboxyl propeptides of type I procollagen chains, but is removed during collagen processing [Persikov et al 2000].


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  • Somasundaram R, Ruehl M, Tiling N, Ackermann R, Schmid M, Riecken EO, Schuppan D. Collagens serve as an extracellular store of bioactive interleukin 2. J Biol Chem. 2000;275:38170–5. [PubMed: 10982811]
  • Suphapeetiporn K, Tongkobpetch S, Mahayosnond A, Shotelersuk V. Expanding the phenotypic spectrum of Caffey disease. Clin Genet. 2007;71:280–4. [PubMed: 17309652]
  • Tampas JP, Van Buskirk FW, Peterson OS Jr, Soule AB. Infantile cortical hyperostosis. JAMA. 1961;175:491–3. [PubMed: 13775121]
  • Thometz JG, DiRaimondo CA. A case of recurrent Caffey’s disease treated with naproxen. Clin Orthop Relat Res. 1996;(323):304. [PubMed: 8625597]
  • Tomso DJ, Bell DA. Sequence context at human single nucleotide polymorphisms: overrepresentation of CpG dinucleotide at polymorphic sites and suppression of variation in CpG islands. J Mol Biol. 2003;327:303–8. [PubMed: 12628237]
  • Wendling D, Hafsaoui C, Laurain JM, Runge M, Magy-Bertrand N, Prati C. Dysphagia and hypervitaminosis A: cervical hyperostosis. Joint Bone Spine. 2009;76:409–11. [PubMed: 19289294]

Suggested Reading

  • Glorieux FH. Caffey disease: an unlikely collagenopathy. J Clin Invest. 2005;115:1142–4. [PMC free article: PMC1087190] [PubMed: 15864344]
  • Van Buskirk FW, Tampas JP, Peterson OS Jr. Infantile cortical hyperostosis; an inquiry into its familial aspects. Am J Roentgenol Radium Ther Nucl Med. 1961;85:613–32. [PubMed: 13779881]

Chapter Notes

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

  • 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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