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Caffey Disease

Synonym: Infantile Cortical Hyperostosis

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

Author Information
, BSc, MD
Division of Clinical and Metabolic Genetics
Department of Paediatrics
The Hospital for Sick Children and University of Toronto
Toronto, Canada
, MS, MSc, CGC
Division of Clinical and Metabolic Genetics
Department of Paediatrics
The Hospital for Sick Children and University of Toronto
Toronto, Canada
, MD, MS, FACMG, FCCMG
Division of Clinical and Metabolic Genetics
Department of Paediatrics
The Hospital for Sick Children and University of Toronto
Toronto, Canada

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

Summary

Disease 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.

Diagnosis/testing. 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 mutation c.3040C>T (p.Arg1014Cys; also known as p.Arg836Cys) in exon 41 is the defining mutation 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.

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: 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 new mutation. The proportion of cases caused by a de novo mutation is unknown. Each child of an individual who had Caffey disease in childhood has a 50% chance of inheriting the disease-causing mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family has been identified.

Diagnosis

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 mutation c.3040C>T (p.Arg1014Cys) (also known as p.Arg836Cys)

See Figure 1, and Figure 2.

Figure 1

Figure

Figure 1. Skeletal survey in a five-week-old female with the defining COL1A1 p.Arg1014Cys mutation who presented with painful swelling over the right tibia. Notice widespread involvement with (a) symmetric bilateral periosteal reaction involving the mandible (more...)

Figure 2

Figure

Figure 2. Clinical photograph and x-ray of two-month-old male with the defining COL1A1 p.Arg1014Cys mutation 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 mutation is known to cause Caffey disease. The COL1A1 c.3040C>T (p.Arg1014Cys; also known as p.Arg836Cys) mutation in exon 41 is currently the defining mutation 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 mutation. However, one patient who meets clinical criteria does not have this mutation, suggesting allelic or genetic heterogeneity [Author, unpublished observation].

Table 1. Summary of Molecular Genetic Testing Used in Caffey Disease

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
COL1A1Targeted mutation analysis / 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

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

2. See Molecular Genetics for information on allelic variants.

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

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

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

6. 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:

  • Perform a skeletal survey for evidence of cortical hyperostosis in the long bones, clavicles, ribs mandible, and any other areas that clinically appear to be swollen.
  • If hyperostosis is found, perform molecular genetic testing for the defining COL1A1 c.3040C>T (p.Arg1014Cys; also known as p.Arg836Cys) mutation.
    Note: At this time, there is no role for either sequence analysis of the COL1A1 coding region or duplication/deletion analysis.

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

Clinical Description

Natural History

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 mutation [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 mutation 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 mutation 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 mutant collagen fibrils. The findings reported by Gensure et al [2005] have not been found in other families with the same mutation [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 mutation 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 mutations responsible for different phenotypes, the COL1A1 c.3040C>T mutation is the defining mutation responsible for the Caffey disease phenotype. See Molecular Genetic Pathogenesis.

Penetrance

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 mutation 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 p.Arg1014Cys (also known as p.Arg836Cys) mutation 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].
  • Hyperphosphatemia-hyperostosis syndrome (HHS). A rare disorder caused by mutations in GALNT3, HHS is characterized by hyperphosphatemia, normal or elevated 1,25-dihydroxyvitamin D(3) 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].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • Medical genetics consultation

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.

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 mutation have been performed, reports of fractures and short stature in adults with other COL1A1 mutations 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 mutation or a mother known to have had Caffey disease in childhood.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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 new mutation. The proportion of cases caused by a de novo mutation is unknown.
  • If the disease-causing mutation 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 mutation 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 mutation include molecular testing for the known pathologic mutation 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 pathologic mutation 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 disease-causing mutation 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 disease-causing mutation.

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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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

Molecular genetic testing. If the disease-causing mutation of an affected family member has been identified, prenatal diagnosis for pregnancies at increased risk may be available through laboratories offering testing for this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like Caffey disease) do not affect intellect and have some treatment available are not common. 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. Although decisions about prenatal testing are 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].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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.

  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Caffey Disease (View All in OMIM)

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

Molecular Genetic Pathogenesis

The recurrence of the defining mutation in unrelated individuals suggests that this CpG dinucleotide is a mutational hot spot in COL1A1 [Tomso & Bell 2003]. The mutation 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 mutation causes the Caffey disease phenotype include the following:

  • The mutation 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 Symbol.

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

Table 2. Selected COL1A1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.3040C>Tp.Arg1014Cys
(Arg836Cys)
NM_000088​.3
NP_000079​.2

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. 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, on the other hand, is normally present in the amino and carboxyl propeptides of type I procollagen chains, but is removed during collagen processing [Persikov et al 2000].

References

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Suggested Reading

  1. Glorieux FH. Caffey disease: an unlikely collagenopathy. J Clin Invest. 2005;115:1142–4. [PMC free article: PMC1087190] [PubMed: 15864344]
  2. Van Buskirk FW, Tampas JP, Peterson OS. 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) Initial submission
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