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Variable expressivity familial cherubism: woman transmitting cherubism without suffering the disease
© Pérez-Sayáns et al.; licensee BioMed Central Ltd. 2013
Received: 21 August 2013
Accepted: 31 October 2013
Published: 5 November 2013
Cherubism is classified within the group of benign osteo-fibrous lesions. Aside from facial deformities, it may account for major complications. It has been observed that the disease is caused by a mutation in the gene SH3BP2 (SH3-domain binding protein 2), which is located at chromosome 4pl6.3. Here we present two cases of familial cherubism, uncle and nephew, with variable clinical involvement (“Expressivity”), and one case of a woman (sister and mother, respectively), who transmitted cherubism without suffering the disease. In this article we have shown that, in familial cherubism cases, the mutation is inherited through an autosomal dominant transmission. Mutations affecting gene SH3BP2 cause variable clinical involvement (variable expressivity), involvement can be moderate, severe or may result merely in asymptomatic carriers. Since the possibility of transmission reaches 50% of chances, we believe that it is important to develop genetic counseling for both patients and carriers, in order to prevent or minimize new affected offspring.
Cherubism, listed by OMIM (Online Mendelian Inheritance in Man) as OMIM 118400, is a rare genetic disease of dominant autosomal inheritance with variable penetrance and expressivity, characterized by an abnormal growth of the bones of the face, mainly the jaw . Prevalence is unknown, but is probably less than 1 in 10,000 . In general, it appears around age 4 with painless bilateral swelling of the jaws (which create a cherubim-like look) and stops progression in the late teens, with residual manifestations persisting in adult life . The term cherubism was suggested to describe the appearance of the patients due to their resemblance to a Renaissance cherub .
Cherubism is classified within the group of benign osteo-fibrous lesions, differentiating from osteo-cementum lesions and fibrous dysplasia because of its unique clinical and radiological features . Besides facial deformities, there may be complications, including vision loss due to optic neuropathy, obstruction of upper airways, sleep apnea, language disorders and difficulty chewing due to alterations in the appearance and development of teeth . Teething is also abnormal and dental agenesis, lack of eruption, displacement, root resorption and malocclusions are common problems. X-ray imaging contributes to the diagnosis showing multiocular radiolucencies that are well defined and, with age, thick sclerotic lines, usually symmetrical . The definitive diagnosis is made histologically, with the appearance of randomly distributed multinucleated giant cells and vascular spaces within the stroma of the fibrous connective tissue. These multinucleated giant cells are positive for osteoclast-specific markers .
It has been observed that the disease is due to a mutation in gene SH3BP2, which is located at chromosome 4pl6.3, which encodes a protein formed by 561 amino acids . In patients with cherubism, mutations have only been described in exon 9 of gene SH3PB2. To date, mutations in the other exons of this gen have not been described. It has also been related to a range of other diseases such as Noonan and Noonan-like syndromes (caused by mutations in gene PTPN11), and Ramon’s syndrome, which is related to gingival fibromatosis and type I neurofibromatosis .
Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. The present study was approved by the CHUS research ethics committee.
In these two clinical cases, we decided to conduct a confirmatory molecular study of the uncle (Patient 1), mother, and her firstborn son (Patient 2) and develop a predictive study of Patient 2′s younger brother, who is now 5 years old and clinically asymptomatic. EDTA blood samples were collected for sequencing analysis in all patients. The analysis consisted of the capillary sequencing of the amplified exon 9 of gene SH3BP2.
For Patient 1, with extreme phenotype, we observed a genotype: SH3BP2 R415Q/normal (in HGVS nomenclature: c. [1244G > A], [=]), showing that the mutation of R415Q causes a change in the Arg amino acid by Gln at position 415 of the protein and is described as pathologic with reduced penetration and variable expression. This result confirms the diagnosis of cherubism in which the chances of transmitting the mutation amount to 50%. Meanwhile, in the mother, with healthy phenotype, we also observed a SH3BP2 R415Q/normal genotype with the same likelihood of transmission. The eldest son, the sibling affected by an extreme phenotype, showed the same genotype SH3BP2 R415Q/normal. However, the youngest son, who is phenotypically asymptomatic, presented a SH3BP2 normal/normal genotype and does not carry the mutation. Therefore he is not at risk of developing the disease or transmitting it.
Cherubism is an autosomal dominant disease, with variable expressivity (different from the classical concept of “penetrance”) . By sex, expressivity amounts to nearly 100% in men, and shows reduced expression in women ranging from 50 to 75%, although sporadic cases of cherubism have been reported [12, 13]. This can be seen in the family that we describe, both men have clearly established cherubism, while the woman is completely asymptomatic.
Proposed clinical classification for cherubism, modified from Raposo-Amaral classification
Existence of the mutation without expression of the disease.
Lesion of the mandible without signs of root resorption
Lesions involving the mandible and maxilla without signs of root resorption
Aggressive lesion of the mandible with signs of root resorption
Lesions involving the mandible and maxilla with signs of Root resorption
The rare, massively growing, aggressive, and extensively deforming juvenile lesions involving the maxilla and mandible
The rare, massively growing, aggressive, and extensively deforming juvenile lesions involving the maxilla, mandible, and orbits
The differential diagnosis must be made with fibrous dysplasia, odontogenic cyst, juvenile ossifying fibroma, giant cell granuloma, fibrous osteoma, osteosarcomae hyperparathyroidism. The histopathology is characterized by a large number of multinucleated giant cells, scattered throughout the fibro-osseous connective tissue, with the presence of spindle cells and osteoid trabeculae .
We must clarify a persistent error in many of the papers dealing with cherubism, which affirm that the lesions that appear in the jaws are cysts. This is absolutely false, since a cyst is a pathological cavity (often filled with liquid) that is surrounded by epithelium . In cherubism, the lesions that insufflate the jaws are essentially tissue masses similar to giant cell granulomas. We believe that this error derives from the first description of the disease, which was coined by Jones: “Familial multilocular cystic disease of the jaws” .
Ueki et al.  identified mutations in gene SH3BP2, which caused cherubism and established the genetic basis for classifying the disease as a separate entity of fibrous dysplasia of the jaws. Gene SH3BP2 is located at 4p16.3 and transcribes a protein of 561 amino acids that binds to the SH3 domains of certain transducer proteins, having proven its expression in multi-nucleated cells and the stromal cells of fibrous tissue of cystic lesions of affected patients . Although this mutation persists throughout the life of the patient, the expression of the related genes changes with age (unknown mechanism) and the existing lesions tend to auto-resolve in adulthood [2, 6].
There have been reports of cherubism cases associated with Noonan syndrome without showing mutations at gene SH3BP2, which is considered as an expression of the disease rather than two related entities . The association between Ramon’s syndrome  and the Jaffe-Campanacci  and the fragile X syndrome  has also been described. The most common genetic abnormality is the R415Q mutation that causes a change in amino acid Arg by Gln at position 415 of the protein . Other mutations have been described for the same gene, with varying degrees of clinical involvement. Li et al.  describe the change of the base of A1517G that causes a substitution of the D419G amino acid. Carvalho et al. , describe a mutation corresponding to the deletion of cytosine (408 of C), located in the PH domain in SH3BP2. Lietman et al.  describe a missense mutation (aspartic acid to asparagine, p.D419N (g.1371G > A, c.1255G > A) in exon 9 of SH3BP2. Other mutations described are: p.D420E (c.1259G > A) , and p.P418R (c.1253C > G) .
Other hypotheses have been described in the pathogenesis of cherubism. Thus, Hyckel et al. consider that cherubism is a disorder induced by altered signals in the transduction of the parathyroid hormone due to the influence of protein SH3BP2 in the regulation of the union of the receptor of the parathyroid-hormone and Parathyroid hormone-related protein (PTHrP) .
The main complications described in the disease are optic neuropathy caused by orbital involvement, sleep, speech and chewing disorders and airway obstruction [5, 7]. In the cases presented, one of the patients had orbital and ophthalmic involvement with no signs of optic neuritis, while the other patient has not presented any other problem aside from the dentoskeletal deformity of the jaws and the resulting difficulty chewing.
To treat cherubism, in Patient 1′s case, we have resorted to surgical decompression of the orbit and a reconstructive surgery of the jaws , but sometimes one can opt for watchfully waiting for the involution of the lesions that is expected by the end of adolescence. In the family that we studied, we were able to confirm the presence of the same mutation in the heterozygous genotype, resulting in a dominant inheritance and not a denovo mutation.
In this article we have shown that, in familial cherubism cases, the mutation is inherited through an autosomal dominant transmission. Mutations affecting gene SH3BP2 cause variable clinical involvement (variable expressivity), involvement can be moderate, severe or may result merely in asymptomatic carriers. Since the possibility of transmission reaches 50% of chances, we believe that it is important to develop genetic counseling for both patients and carriers, in order to prevent or minimize new affected offspring.
We would like to thank Professor JR Antúnez his invaluable assistance in the diagnosis of clinical cases.
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