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Caffey Disease

Synonym: Infantile Cortical Hyperostosis

, MD, MEd, FRCPC, FCCMG, , MS, MSc, CGC, and , MD, MS, FACMG, FCCMG.

Author Information and Affiliations

Initial Posting: ; Last Update: May 23, 2024.

Estimated reading time: 19 minutes

Summary

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, soft-tissue swelling, and pain, with onset between birth and five months and spontaneous resolution by age two years. Recurrence of bone hyperostosis, fever, soft-tissue swelling, and pain can occur later in life. Adults with a history of Caffey disease in childhood may have 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; identification of a heterozygous COL1A1 pathogenic variant associated with Caffey disease on molecular genetic testing can confirm the diagnosis.

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; standard treatments for joint hypermobility, skin hyperextensibility, and hernias.

Surveillance: Annual evaluation of stature, fracture history, joint extensibility, and hernias throughout childhood. Consider assessment of bone mineral density in adults with a history of recurrent fractures.

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 individuals with Caffey disease 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. Once a molecular diagnosis has been established in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for Caffey disease have been published.

Suggestive Findings

Caffey disease should be suspected in probands with the following clinical, radiographic, laboratory, and family history findings. Clinical and radiographic findings typically appear between birth and age five months and resolve spontaneously by age two years, although recurrence in adolescence is possible.

Clinical findings

  • Irritability, fever, and/or pallor
  • Soft-tissue swelling and pain adjacent to involved bones (See Figure 2.)
Figure 2. . Clinical photograph and radiograph of male age two months with COL1A1 pathogenic variant p.

Figure 2.

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

Radiographic findings

  • Subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses)
  • Subperiosteal cortical hyperostosis of the ribs, scapulae, clavicles, and mandible (See Figures 1 and 2.)
Figure 1. . Skeletal survey in a female age five weeks with COL1A1 pathogenic variant p.

Figure 1.

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

Laboratory findings

  • Serum biochemical markers of inflammation (white blood cell count, erythrocyte sedimentation rate, C-reactive protein) have been elevated a few affected individuals [Gensure et al 2005].
  • Alkaline phosphatase may be elevated.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of Caffey disease is established in a proband with typical clinical and radiographic findings. Identification of a heterozygous COL1A1 pathogenic variant associated with Caffey disease (p.Arg1014Cys, p.Arg918Cys) on molecular genetic testing can confirm the diagnosis in those with atypical clinical and radiographic features (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). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Caffey disease, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of COL1A1 to detect the only reported pathogenic variants associated with Caffey disease to date, p.Arg1014Cys or p.Arg918Cys
    Note: To date, no large multiexon COL1A1 deletions or duplications have been identified in individuals with Caffey disease.
  • A multigene panel that includes COL1A1 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of Caffey disease is not considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, all COL1A1 pathogenic variants associated with Caffey disease are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Caffey Disease

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
COL1A1 Sequence analysis 3~99% 4
Gene-targeted deletion/duplication analysis 5None reported 6
Unknown 7NA
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on variants detected in this gene.

3.

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

4.

COL1A1 variants p.Arg1014Cys and p.Arg918Cys are the only variants reported to date in individuals with Caffey disease [Gensure et al 2005, Suphapeetiporn et al 2007, Cho et al 2008, Kamoun-Goldrat et al 2008, Ranganath et al 2011, Dhooge et al 2021].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

To date, no large intragenic deletions/duplications have been reported in individuals with Caffey disease.

7.

One individual with clinical and radiographic features of Caffey disease did not have an identified COL1A1 pathogenic variant [A Guerin, unpublished observation]. Also, one individual with clinical and radiographic features of Caffey disease had a homozygous AHSG pathogenic variant in the context of consanguinity [Merdler-Rabinowicz et al 2019]. To date, there are no additional reports of AHSG-related Caffey disease.

Clinical Characteristics

Clinical Description

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

Onset. The clinical findings most often appear at age two months (typically between birth and age five months). Rarely, 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 with heterozygous COL1A1 pathogenic variant p.Arg1014Cys [Kamoun-Goldrat et al 2008].

Skeletal manifestations. Typically the skeletal manifestations of Caffey disease first appear with soft-tissue swelling and pain over the affected bones between birth and age five months. Massive subperiosteal new bone formation usually involving the diaphyses of the long bones can be seen on imaging. Hyperostosis of the long bones is typically asymmetric, although symmetric hyperostosis has been reported [Tilva et al 2023].

Hyperostosis can also involve the ribs, mandible, scapulae, and clavicles. The hyperostosis resolves before age two years [Kamoun-Goldrat & le Merrer 2008, Cerruti-Mainardi et al 2011, Ranganath et al 2011].

Constitutional manifestations. Skeletal manifestations are accompanied by fever and elevated serum biochemical markers of inflammation (e.g., white blood cell count, erythrocyte sedimentation rate, C-reactive protein) [Gensure et al 2005].

Recurrence of hyperostosis, joint swelling, pain, and fever have been reported multiple times, until late adolescence in individuals with the typical infantile presentation [Borochowitz et al 1991; Navarre et al 2013; ALBagshi & ALZoayed 2015; A Guerin, unpublished data]. Etiology and precipitating factors for recurrence remain unclear [Navarre et al 2013].

Additional findings reported. In one reported family, an individual with COL1A1 pathogenic variant p.Arg1014Cys had a history of Caffey disease as a child and developed joint laxity, skin hyperextensibility, hernias, and multiple fractures in adulthood [Gensure et al 2005]. Additional individuals in the family with the COL1A1 pathogenic variant p.Arg1014Cys had varying degrees of joint laxity and skin 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 abnormal collagen fibrils. These findings have not been identified in other individuals/families with the same COL1A1 pathogenic variant [Cho et al 2008, Cerruti-Mainardi et al 2011, Ranganath et al 2011].

Other

Prognosis. In many individuals, the manifestations of Caffey disease resolve spontaneously by age two years and do not predispose to long-term bone abnormalities. Affected individuals from one family had short stature in adulthood and residual bone deformities [Suphapeetiporn et al 2007]. Fractures have been reported in some individuals [Gensure et al 2005, Suphapeetiporn et al 2007].

Histopathology. Bone and muscle biopsy of affected sites in a few individuals have demonstrated an inflammatory reaction [Katz et al 1981].

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations.

Penetrance

Reduced penetrance based on family history or molecular genetic testing has been reported [Cho et al 2008, Kutty et al 2010, Prior et al 2012, Kitaoka et al 2014, Dhooge et al 2021].

Nomenclature

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], Caffey disease known to be caused by a heterozygous COL1A1 pathogenic variant is referred to as COL1A1-related Caffey disease and included in the osteosclerotic disorders group.

"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.

Differential Diagnosis

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

Table 3.

Genes of Interest in the Differential Diagnosis of Caffey Disease

Gene(s)DisorderMOIFeatures of Disorder
Overlapping w/
Caffey Disease		Distinguishing from Caffey Disease
ANTXR2 Hyaline fibromatosis syndrome ARPresents w/irritability, poor feeding, fever, & soft-tissue swellingProgressive joint contractures, & often severe motor disability, thickened skin, & hyperpigmented macules/patches over bony prominences of joints
FGF23
GALNT3
KL 		Hyperphosphatemic familial tumoral calcinosis (HFTC)ARCortical hyperostosisHyperphosphatemia
GLB1
GNPTAB 		Mucolipidosis II (GNPTAB-Related Disorders) & type I (infantile) GM1 gangliosidosis (GLB1-Related Disorders)ARMucolipidosis II, type I GM1 gangliosidosis, & other storage diseases presenting in early infancy may be characterized by periosteal cloaking.The involvement of the metaphysis & generalized findings of storage disorders differentiate these disorders from Caffey disease.
TGFB1 Camurati-Engelmann disease ADBone pain, hyperostosis of diaphyses of long bonesProximal muscle weakness, limb pain, a wide-based, waddling gait, & joint contractures; facial features such as macrocephaly, frontal bossing, enlargement of mandible, proptosis, & cranial nerve impingement resulting in facial palsy

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance

Lethal prenatal Caffey disease (prenatal Caffey disease / Caffey dysplasia). This condition typically presents before 35 weeks' gestation and is characterized by cortical hyperostosis as well as bowing or angulation of the long bones and the presence of polyhydramnios and fetal lung disease [Langer & Kaufmann 1986, Lécolier et al 1992, Drinkwater et al 1997, Dahlstrom et al 2001, Savarirayan et al 2002, 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].

Acquired conditions

  • Hypervitaminosis A 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].
  • Bone malignancies can present similarly to Caffey disease but can be distinguished on bone biopsy.
  • Osteomyelitis may be mistakenly diagnosed as joint swelling. Febrile episodes can be common to both conditions; however, the finding of hyperostosis on radiographs helps distinguish between these two entities.

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 [Lee et al 2021].

Management

No clinical practice guidelines for Caffey disease have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Caffey disease, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

Caffey Disease: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Skeletal manifestations Anti-inflammatory agents, antipyretics, & analgesics can be used in the short term to ↓ swelling & fever & relieve pain.No recommendations for the prevention of recurrence of hyperostosis currently exist.
Joint & connective tissue manifestations Standard treatments for joint hypermobility, skin hyperextensibility, & hernias

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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.
  • An individual diagnosed with Caffey disease may have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with Caffey disease caused by a de novo pathogenic variant is unknown.
  • If the proband appears to be the only family member with Caffey disease (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and a detailed medical history focusing on features of hyperostosis in infancy and current bone health.
  • If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
    • The proband has a de novo pathogenic variant.
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
  • 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 a molecular diagnosis has been established in the proband and molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in 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 a Caffey disease-related pathogenic variant, the risk to the sibs is 50%.
  • If the proband has a known Caffey disease-related pathogenic variant that 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 genetic status of the parents has not been established but neither parent is known 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 parental germline mosaicism.

Offspring of a proband. Each child of an individual who had Caffey disease in childhood has a 50% chance of inheriting a Caffey disease-related 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 in childhood, the parent's family members may be at risk.

Related Genetic Counseling Issues

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 a molecular diagnosis has been established in an affected family member, prenatal 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.

Resources

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.

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
COL1A1 17q21​.33 Collagen alpha-1(I) chain COL1A1 @ LOVD COL1A1 COL1A1

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)

114000CAFFEY DISEASE; CAFYD
120150COLLAGEN, TYPE I, ALPHA-1; COL1A1

Molecular Pathogenesis

COL1A1 encodes collagen type I, a heterotrimer consisting of two alpha-1 chains and one alpha-2 chain (encoded by COL1A2), which is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis, and tendon.

Both COL1A1 pathogenic variants associated with Caffey disease impact an Arg-to-Cys substitution in the Xaa position of the Gly-Xaa-Yaa triplet repeat of the pro-α1(I) chain and reside in regions hypothesized to interact with interleukin-2 and α1β1 integrin [Makar et al 1975, Sweeney et al 2008, Dhooge et al 2021]. Transmission electron microscopy analysis of affected probands' skin biopsies suggests that the introduction of an Arg-Cys substitution interferes with collagen fibril organization [Dhooge et al 2021].

Mechanism of disease causation. The mechanism of disease is unclear. The two COL1A1 pathogenic variants associated with Caffey disease could impact cell signaling. The location of the variants near domains hypothesized to interact with interleukin-2 and α1β1 integrin may play a role in temporary inflammation. Prostaglandin E (PGE) and transforming growth factor beta (TGF-β) may also play a role in pathogenesis, as both can promote cortical hyperostosis [Dhooge et al 2021].

Table 7.

COL1A1 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein Change
(Alias 1)		Comment [Reference]
NM_000088​.3
NP_000079​.2 		c.2752C>Tp.Arg918CysPathogenic variant assoc w/Caffey disease in ~15%-20% of reported persons [Dhooge et al 2021]
c.3040C>Tp.Arg1014Cys
(Arg836Cys)		Most common pathogenic variant assoc w/Caffey disease [Gensure et al 2005, Cho et al 2008, Cerruti-Mainardi et al 2011, Ranganath et al 2011]

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

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions.

Chapter Notes

Acknowledgments

The authors would like to acknowledge the patients and families who allowed the use of photographs in this review.

Author History

Revision History

  • 23 May 2024 (sw) Comprehensive update posted live
  • 13 June 2019 (ha) Comprehensive update posted live
  • 2 August 2012 (me) Review posted live
  • 17 February 2012 (ag) Original submission

References

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