Stevenson (1993) described a case indicating that Caffey disease can be detected in utero in familial nonlethal cases. Ultrasound examination at age 35.5 weeks showed curvature of the tibia and irregularity of the ... - Prenatal Diagnosis Stevenson (1993) described a case indicating that Caffey disease can be detected in utero in familial nonlethal cases. Ultrasound examination at age 35.5 weeks showed curvature of the tibia and irregularity of the cortex of the radius. Mild leg curvature was present at birth at 39 weeks; involvement of all long bones was documented radiographically at the age of 2.5 months. A sister, the mother, and a maternal uncle had documented Caffey disease.
Infantile cortical hyperostosis has somewhat unusual features for a hereditary disorder. It rarely if ever appears after 5 months of age and usually resolves spontaneously by 2 years of age; it is sometimes present at birth and has ... Infantile cortical hyperostosis has somewhat unusual features for a hereditary disorder. It rarely if ever appears after 5 months of age and usually resolves spontaneously by 2 years of age; it is sometimes present at birth and has been identified by x-ray in the fetus in utero. The acute manifestations are inflammatory in nature, with fever and hot, tender swelling of involved bones (e.g., mandible, ribs). Despite striking radiologic changes in the acute stages, previously affected bones are often completely normal on restudy. However, Taj-Eldin and Al-Jawad (1971) described a case followed since infancy with recurrences documented up to 19 years of age (1971). (Incontinentia pigmenti (308300) is another familial condition in which 'active' lesions at birth and early in life may leave little or no residue.) Pickering and Cuddigan (1969) suggested that vascular occlusion secondary to thrombocytosis may be involved in the pathogenesis. X-ray findings in 3 members of the family were reported by Pajewski and Vure (1967). MacLachlan et al. (1984) followed up on the French-Canadian kindred reported by Gerrard et al. (1961). To the 14 affected children identified in the original report, 20 new cases were added. MacLachlan et al. (1984) commented that the sporadic form of the disorder is disappearing with no such cases seen in the last 7 years. In sporadic cases the bones most often affected are mandible, ulna, and clavicle with fairly frequent involvement of ribs and scapulae. In their radiographic studies of 14 familial cases, no involvement of ribs or scapulae was encountered. Clavicular involvement was found in only 3 children. The tibia was most often involved in familial cases. Borochowitz et al. (1991) described 2 affected sibs in a nonconsanguineous family; a girl had involvement of the fibula at the age of 5 months and a recurrence with tibial involvement at the age of 11 years. Her brother was hospitalized at the age of 4 months because of swelling of the face, fever, and restlessness. Suphapeetiporn et al. (2007) reported a 3-generation Thai family in which 5 individuals had Caffey disease. The oldest individual, a 75-year-old man, had bowed legs since childhood, several traumatic fractures, short hands, kyphoscoliosis and compression fractures of the vertebrae. Examination of other affected family members showed angular deformities of the long bones, short stature, and dental caries, although unaffected family members also had dental caries. The authors suggested that short stature and persistent bony deformities should be included in the clinical spectrum of Caffey disease. - Prenatal Cortical Hyperostosis, Lethal Lecolier et al. (1992) described a case of prenatal Caffey disease. Ultrasound examination at 20 weeks' gestation detected major angulation of the long bones. Although no fractures were seen, irregularities of the ribs suggested multiple callus formation and the diagnosis of lethal osteogenesis imperfecta was entertained. Cordocentesis showed marked leukocytosis, mainly due to neutrophils, as well as increased serum levels of hepatic enzymes. Because of a rapid appearance of 'fetoplacental anasarca' and a probable diagnosis of osteogenesis imperfecta, pregnancy was terminated at 23 weeks' gestation. Special x-ray views showed a double contour of the diaphyseal cortex of the long bones. Histologic examination confirmed the diagnosis of Caffey disease by demonstration of thickened periosteum and infiltration of the deeper layers of the periosteum with round cells. Lecolier et al. (1992) suggested that this form should be referred to as lethal prenatal cortical hyperostosis. Perinatal death in 2 sibs with Caffey disease was described by de Jong and Muller (1995). Antenatal sonographic diagnosis was short-limb dwarfism and thoracic dysplasia of a nonspecific type, possibly osteogenesis imperfecta, in the first sib. The second sib had a similar appearance on ultrasonography. The thickened irregularly echodense diaphyses were an aid to diagnosis. De Jong and Muller (1995) agreed with LeColier et al. (1992) that fetoplacental anasarca and polyhydramnios are helpful prognostic signs. The presence of both seems to indicate a very poor prognosis. Autosomal dominant inheritance with subclinical Caffey disease in one of the parents during infancy could not be excluded since incidental discovery of the disease has been reported (Cayler and Peterson, 1956). Parental gonadal mosaicism is another possibility. In spite of the absence of parental consanguinity, the occurrence of the condition in a male and a female sib born to healthy parents suggested autosomal recessive inheritance of the lethal prenatal onset type of cortical hyperostosis. Kamoun-Goldrat et al. (2008) described a fetus that represented the first pregnancy of a young, healthy, nonconsanguineous couple. The pregnancy was medically terminated at 30 weeks' gestation after a diagnosis of severe osteogenesis imperfecta. Postmortem radiographs, autopsy, and histologic study showed typical features of a severe form of prenatal cortical hyperostosis.
In affected individuals and obligate carriers from 3 unrelated families with Caffey disease, Gensure et al. (2005) identified heterozygosity for an arg836-to-cys mutation in the COL1A1 gene (R836C; 120150.0063), involving the triple-helical domain of the alpha-1 chain of ... In affected individuals and obligate carriers from 3 unrelated families with Caffey disease, Gensure et al. (2005) identified heterozygosity for an arg836-to-cys mutation in the COL1A1 gene (R836C; 120150.0063), involving the triple-helical domain of the alpha-1 chain of type I collagen. None of the affected individuals or obligate carriers in any of the families had clinical signs of the major type I collagen disorder, osteogenesis imperfecta (see 166200); however, in 2 of the 3 families, individuals carrying the mutation did have joint hyperlaxity, hyperextensible skin, and inguinal hernias, features seen in Ehlers-Danlos syndrome (see 130000), some forms of which are caused by mutations in COL1A1. In affected members of a Thai family with Caffey disease, Suphapeetiporn et al. (2007) identified heterozygosity for the R836C mutation in the COL1A1 gene. Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a severe form of prenatal cortical hyperostosis from a terminated pregnancy at 30 weeks' gestation. They noted that this mutation had not been found in 2 other such cases by Gensure et al. (2005) and speculated that mutations in other genes were likely involved in the prenatal and infantile forms of cortical hyperostosis.
Diagnosis of Caffey disease is based on the following [Lachman 2007]: ...
DiagnosisDiagnosis 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, Figure 2.FigureFigure 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...)FigureFigure 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.See Table A for chromosome locus and protein name for this gene.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 pathologic 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 DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCOL1A1Targeted mutation analysis / sequence analysis of exon 41c.3040C>T100% for c.3040C>T targeted variantClinicalSequence analysisSequence variants 2 throughout the coding and splicing regions 3Unknown, none reported to date 3Deletion / duplication analysis 4Partial- and whole-gene deletions / duplications 3Unknown, none reported to date 31. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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. 3. 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.4. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).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. Genetically Related (Allelic) Disorders The following phenotypes are known to be associated with mutations in COL1A1: Osteogenesis imperfectaEhlers-Danlos syndrome, arthrochalasia type (EDS VII)Rarely, an Ehlers-Danlos syndrome phenotype that resembles the classic type. The arginine-to-cysteine amino acid substitution, Arg134Cys, in the α1(I) chain of type I collagen has been reported in individuals with classic Ehlers-Danlos syndrome [Nuytinck et al 2000]. The association of three arginine-to-cysteine changes (Arg134Cys, Arg915Cys, and Arg396Cys) reported in an Ehlers Danlos syndrome phenotype with a propensity to arterial rupture in early adulthood [Malfait et al 2007]
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. ...
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: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].
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....
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.
Other conditions may manifest as joint swelling and hyperostosis and thus need to be distinguished from Caffey disease:...
Differential DiagnosisOther 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with Caffey disease, the following evaluations are recommended:...
ManagementEvaluations 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 herniasRadiographs of long bones, ribs, scapulae, clavicles, and mandible to assess extent of disease and the stage of hyperostosisMedical genetics consultationTreatment of ManifestationsAnti-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. SurveillanceCurrently, 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 RiskSee 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 InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDCOL1A117q21.33Collagen alpha-1(I) chainCOL1A1Data 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) View in own window 114000CAFFEY DISEASE 120150COLLAGEN, TYPE I, ALPHA-1; COL1A1Molecular Genetic PathogenesisThe 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].Normal allelic variants. The transcript NM_000088.3 has 51 exons.Pathologic 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 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid Change (Alias 1)Reference Sequencesc.3040C>Tp.Arg1014Cys (Arg836Cys)NM_000088.3 NP_000079.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal 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].