Caffey Disease

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Retrieved

2021-01-18

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Gene_reviews

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Genes

COL1A1, A4GALT, AHSG, COL1A2, SLC37A2

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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, 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.

Diagnosis

Suggestive Findings

Caffey disease should be suspected in individuals 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).

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 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. All published cases in which molecular testing has been done involve heterozygosity for the single known c.3040C>T pathogenic variant.
Perform sequence analysis first. If the single known pathogenic variant is not found, gene-targeted deletion/duplication analysis can be performed to detect intragenic deletions or duplications. However, no large multiexon gene deletions or duplications have been identified to date in individuals with Caffey disease
A multigene panel that includes COL1A1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost 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 (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of Caffey disease.

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 ¹	Method	Proportion of Probands with a Pathogenic Variant ² Detectable by Method
COL1A1	Sequence analysis ³	100% ⁴
COL1A1	Gene-targeted deletion/duplication analysis ⁵	Unknown ⁶
Unknown ⁷	NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic 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 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.
4.: All individuals with Caffey disease have had the c.3040C>T pathogenic variant [Gensure et al 2005, Suphapeetiporn et al 2007, Cho et al 2008, Kamoun-Goldrat et al 2008, Ranganath et al 2011].
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
7.: All published cases of Caffey disease in which molecular testing has been done have identified heterozygosity for the single known c.3040C>T pathogenic variant. However, one individual who met clinical criteria did not have this variant, suggesting allelic or genetic heterogeneity [Author, unpublished observation].

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].

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 patients 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 ethnic group. 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.

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 polyhydramnios 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 autosomal recessive disorder caused by pathogenic variants in FGF23, GALNT3, 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 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].

Management

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.