Abstract
Background: Certain constitutive chromosomal abnormalities of the human X chromosome are relatively common in conspicuous neuropsychiatric findings. Although tumors or tumor-like lesions are occasionally reported in diseases of the X chromosome, they are numerically negligible, for example, in aneuploidy such as the triple X syndrome (TXS). Case Report: A 16-year-old female patient with a known TXS and premutation stage of fragile X syndrome was referred by her dentist for diagnosis and treatment of unilateral cheek swelling. The examination of the psychologically conspicuous patient revealed a unilateral mandibular tumor with dysesthesia of the mental nerve. Surgical removal of soft, crumbly spongiosa over the nerve canal resulted in sufficient pressure release of the constricted nerve and restoration of epicritic sensitivity. Imaging findings and histological and molecular genetic examination revealed monostotic craniofacial fibrous dysplasia. Conclusion: Although the data in the literature do not give reason to suppose an accumulation of neoplasms in TXS, a numb chin syndrome should be a reason for detailed diagnostics. Careful diagnosis allows for customized therapy. This is the first report on the coincidence of TXS, fragile X syndrome, and fibrous dysplasia in a single individual.
Numerical aberrations of chromosomes are relatively common in human reproduction and viable only in certain constellations (1). Viable aneuploidy of the sex chromosomes leads to variable phenotypes with different impacts on health and quality of life (2). Triple X syndrome (TXS) is a sex chromosomal abnormality (3). TXS is a relatively common occurrence in humans, with the estimated incidence being one in 1,000 females (4-6). TXS is relatively often associated with intellectual and psychological disabilities of affected individuals (5, 6). On the other hand, affected individuals can be of normal physical and mental health (3, 5). Indeed, genotype-phenotype relationships remain to be defined (3). Most reports about TXS focus on neuro-developmental disorders (5, 7). However, other features such as malformations and metabolic alterations (7-11), and immunological diseases (8) are also part of the TXS spectrum. The relationship between TXS and neoplasms has barely been studied. Given the frequency of TXS in the general population, the low number of reports of neoplasms in this syndrome is at least notable. The few publications on TXS and neoplasms so far are case reports and concede that it might be a chance or coincidence (12-16) or consider the potential influence of mosaic or constitutional TXS status on immunological therapies (17-18).
As well as numerical aberrations, the X chromosome may show other alterations with potential effects on phenotype (19). A relatively common mutation is named after a pathognomonic cytogenetic phenomenon that can be identified in the nucleus of affected individuals during preparations to determine the karyotype (20, 21). The affected X chromosome gives the erroneous impression of a localized unstable shape and thus is called fragile X syndrome (FXS) (22, 23). The phenotype was already known from clinical studies (24) and is also known under the eponym Martin–Bell syndrome (25). FXS occurs in men and women, with lower frequency in males (26). Pathfinding symptoms of diagnosis are attention-deficit/hyperactivity disorders and learning disabilities (27, 28). However, the connection between a genetic disposition and learning difficulties is often recognized late (29, 30). FXS is a neglected cause of impaired learning disorders and, according to the general view (31), probably the most common monogenic disorder associated with impaired intellectual ability after Down syndrome (32). However, FXS has a significant range of clinical findings, and emphasis is given to marked heterogeneity (28, 31). The combination of certain physical features can substantiate the suspected diagnosis (33). Molecular genetic research has shown the cause of the cytogenetic finding is a mutation of the fragile X mental retardation 1 (FMR1) gene (main location: Xq27.3), leading to massive replications of a distinct base triplet (CGG) (34-38). Thus, FXS belongs to the group of trinucleotide repeat disorders (35, 36). However, the deletion of FMR1 can also cause the FXS phenotype in rare cases (39). A lower number of replications (<59) does not appear to affect the carrier's phenotype. Individuals carrying about 59 to 200 CGG repeats define the premutation stage that is associated with diverse findings, in particular, neuropsychiatric disorders (40). Individuals with about 200 or more repetitions very likely will show the full range of findings (34). Interestingly, it has been suggested that FXS is associated with a lower risk of developing cancer (41, 42), but these relationships have been controversially discussed (43). Indeed, an increased risk of developing lip cancer in FXS was estimated (43). Furthermore, increased FMR1 mRNA levels have a negative prognostic effect in certain forms of breast cancer (44). Other reports of FXS and malignant neoplasms are likely the results of coincidences of various genetic events (45, 46). However, those individuals reported are strikingly often children and adolescents (47-52).
Differential diagnosis of TXS before definitive karyotype results are available includes FXS, among other mutations (3). The concurrence of TXS and FXS has been reported but appears to be rare (53-55). Concerning potential bone pathologies, genetic influences on bone metabolism are of great importance in both syndromes (10, 56, 57). The coincidence of TXS or FXS with bone tumors has been registered only very rarely (12).
The following report is of a patient with known TXS and premutation stage FXS who required diagnostic and therapeutic measures due to visible and symptomatic facial tumor development.
Case Report
Medical history. The 16-year-old female patient was referred for examination and treatment an unclear swelling in the area of the right lower jaw (Figure 1A). The hardly communicative patient was accompanied by her parents for examination. The parents informed the attending surgeons that their daughter was suffering from genetically proven FXS and also TXS. The medical reports confirmed the triple X karyotype of the patient and a CGG repetition rate of the FMR1 gene slightly higher than normal (62±2 repetitions). Evaluation of the latter genetic finding explicitly emphasized that the patient's known behavioral disorders were not explained by the mutation status of the gene.
In the present case, a relatively short and flat forehead was noted in relation to the pronounced midface and chin region (Figure 1B). However, the sagittal relationships of a mandibular prognathism were not present (Figure 1C). The ears were slightly prominent. It was striking that it was practically impossible to establish any eye contact with the patient, and the medical contact had to be largely mediated through the parents.
For some time, the lower right cheek region had been swollen, and the patient had occasionally complained about pain. Visual inspection of the small patient revealed an inconspicuous external condition of the skin and facial motor functions. When palpating the face, the side of the right lower jaw was more prominent than the left lower jaw, in particular concerning the region of the right inferior border. The patient indicated a hyposensitive skin area that could be traced over the right cheek side distal to the nasolabial fold. The lips showed equally normal sensitivity to tactile stimuli, but the right chin region was less sensitive to touch than the left. The mandibular body showed no pain on pressure in the region of interest and symmetrical response on the mental foramina. Teeth were completely developed, had emerged to the oral cavity, and completed the dental arch in a symmetrical fashion. Teeth were well maintained, non-mobile, adequately responsive to cold stimuli, and the oral mucosa was rosy and intact. However, the mandibular body in the posterior region of the right side felt significantly enlarged to the lateral side without the oral vestibulum being elevated (Figure 1).
Radiology. A panoramic view radiography showed the vertical asymmetry of the mandibular corpus in favor of the right side (Figure 2A). On the right side of the mandible, the bone marrow was of gray-clouded radiopacity and had lost the trabecular structure. The contour of the deformed lower jaw was preserved, as well as the integrity and position of the teeth in the alveolar bone. An ill-defined radio-translucent region was depicted within the radiopaque lesion, immediately below the molars and approximately opposite the region from which the patient indicated feeling diminished sensitivity of the skin.
Cone-beam computed tomography of the right lower jaw showed a hyperplastic, predominantly homogeneous radiopaque cancellous bone region, which was interrupted by focal peri-radicular radiotransparent areas (Figure 2C-H). The nerve canal had a smaller diameter on the affected side than on the left side (Figure 2C-E). Both nerve channels ran horizontally at the same height (Figure 2A and C-E). Only in the area of the mental foramina, there was asymmetry of dimensions of the bone channels in which, on the lesion side, an elongation of the terminal branch of the alveolar nerve was evident in the transversal plane (Figure 2E). The increased bone volume caused by the lesion was, according to radiological findings, largely due to the expansion of the bone in the direction of the vestibular side (Figure 2F and G). The bony limitation of the nerve channel was no longer continuously detected in the area of the radiolucent region (Figure 2G and H).
Scintigraphy was performed to check whether the lesion was monostotic or polyostotic (Figure 3A-D). Scintigraphy revealed the intensified metabolism of the right side of the lower jaw as a solitary finding. The suspected diagnosis was malignant disease or osteonecrosis.
The radiological aspect of the lesion suggested fibrous dysplasia (FD), but several differential diagnoses had to be considered. Furthermore, the association of the lesion with the patient's genetic disposition was unclear.
Surgery. It was decided that a bone sample would be obtained to determine the nature of the bone lesion. The osteolytic area beneath the molars was also to be examined, and the canal relieved of compression by the lesion. Under general anesthesia, the muco-periosteum of the right lower jaw's vestibulum was lifted off. Below was an inconspicuous cortex. By means of piezo-surgery, a block of bone was removed from below the roots of the right molars (Figure 3E), and the mandibular canal was exposed. During this preparation, crumbly cancellous bone appeared below the cortex and was removed from the edge of the nerve canal. This area corresponded to the radiological transparency at the apices of the molars. The exposed alveolar nerve was intact, of normal size and, after removal of the altered bone in the remaining canal, without any adhesions to be removed. The bone barely bled during the procedure. Wound healing was unremarkable (Figure 2B). Eight weeks later, the patient described that the discomfort of the right cheek had disappeared. Likewise, the epicritic sensitivity of the lip and chin skin was intact.
Histology. The examination of the bone showed the typical features of FD (Figure 4A). In addition, the tissue was prepared for DNA extraction and amplification of the gene coding for guanine nucleotide-binding protein, alpha-stimulating activity polypeptide 1 (GNAS1) for mutation on codon 201 (exon 8). The lesion showed the c.602G>A (p.R201H) mutation (Figure 4B). This mutation provides evidence in the tissue sample for the phenotype called FD. Murine double minute 2 (MDM2) gene amplification in the bone sample was excluded (58).
Discussion
This report shows the coincidence of a somatic mutation resulting in tumor-like bone growth in an adolescent female with X-chromosomal aberrations. This coincidence of findings has not been described so far. Unusual in this case was the course of the diagnosis, because due to the knowledge of the genetic disease of the patient, it was essential to assess the clinical findings accurately as well as to take into account that the findings might have been independent of the underlying disease.
It is well-known that aneuploidy is a regular feature of the malignant phenotype arising from cells that were subjected to somatic mutation (59). In contrast to somatic aneuploidy, viable constitutional aneuploidy is rare (60). When examining the relationship of constitutive aneuploidy and the emergence of neoplasms, a careful distinction is made between autosomal and sex chromosomes. Neoplasms in constitutive aneuploidy arising in autosomes are, for example, transient myeloproliferative disorder or full-blown acute myeloid leukemia in patients with trisomy 21. In patients with sex chromosomal abnormality, the tendency to develop neoplasms is mainly due to increased tumor formation in Turner syndrome (45,X) and Klinefelter syndrome (47,XXY) (60). However, in both these X-chromosome-linked syndromes, the study also showed a lower incidence of certain neoplasms in patients with gonosomal aneuploidy compared to the respective control group (60). TXS patients are not listed in the discussion of cancer and other tumors and sex chromosomal constitutive aneuploidy (60).
Fibrous Dysplasia
Genetics. FD is a non-tumorous bone disorder that is characterized by the overproduction and deposition of a poorly organized fibro-osseous matrix, slowly replacing the normal cancellous bone (61, 62). The disorder is caused by a mutation of the GNAS1 gene on chromosome 20 (63-65). It is believed that the disease is viable in humans only as a somatic mutation. It follows that in a patient with this mutation, the more cells the mutation captures, and thus potentially the more organs, the earlier the defining genetic change has occurred in ontogenesis (66, 67). The phenotype is correspondingly variable (68). McCune–Albright syndrome is based on GNAS1 mutation happening early during embryogenesis and resulting in a phenotype characterized by significant endocrine dysregulation in addition to metabolic bone and pigmentation disorders (69). For skeletal manifestations of the GNAS1 mutation, an influence of the bone metabolism by gene product Gs alpha on the parathyroid receptor is assumed (64). In osteoclasts, adenylyl cyclase is activated, and consequent increased production of cyclic adenosine monophosphate stimulates the proliferation, differentiation, and overproduction of poorly organized fibro-osseous tissues (70-72).
Radiology. Radiographic imaging of craniofacial FD is considered typical, showing a radiopaque lesion described with different metaphors such as sclerotic, ground-glass, or peu d'orange appearing. The lesion's margins are ill-defined. Cortex is usually absent in FD. In mandibular cases, FD affects predominantly the post-mental region (73). Cyst-like lesions within a bone are well-known in FD (66). Nuclear-medical diagnosis of FD is not unique (74-76). Scintigraphy was an effective diagnostic measure in the presented case for classifying FD as monostotic. Indeed, scintigraphy is a strategy for locating polyostotic FD (73). However, no decision was made based on scintigraphy in assessing whether the lesion was benign. The differential diagnosis of inflammatory or neoplastic bone changes may be difficult in cases of FD (76-81). Malignant degeneration of FD is rare (82-91). However, reports of malignancy arising from FD suggest the affected body region should be under long-term monitoring (90, 91). Patients with FD have an increased risk of developing breast cancer (92).
Dentition. Although craniofacial FD may cause malocclusion of the teeth, and some teeth may be displaced by the growth of FD (93), changes in dental arch curvature are not a regular sign of this entity (94).
Disorders of the cranial nerves. The most important complication of craniofacial FD in terms of functional impairment of cranial nerves is the compression of altered and growing bone on the optic canal with consequent obstruction (95). However, it has been pointed out that compression of the nerve canal does not necessarily lead to a reduction in vision. Rather, many cases with craniofacial FD and orbital involvement show that the vision can remain unaffected over a long period of time (96). From this experience, it has been concluded that decompression of the optic canal must be considered very carefully because the risk of iatrogenic nerve damage is inherent to the surgical procedure (96). For the mandibular nerve, isolated hyperesthesia has been described in mandibular FD (97). However, reports of pain in patients with FD are much more common in axial skeletal locations. Pain in craniofacial FD occurs in about 30% of cases (92). The reduced sensitivity in the terminal branches of the mandibular nerve is unusual in connection with an FD in the bone surrounding the nerve. Rather, this finding should be regarded as a sign of malignant neoplasm if no local findings can adequately explain other causes of this symptom (98-102).
Treatment is overwhelmingly surgical, with modeling osteotomies being preferred over extensive resections (103-108). Alternative drug therapies aim to stop rapidly progressive FD (109) but still need long-term evaluation of risks and benefits of anti-resorptive therapy.
Histology. The histological evaluation of the FD is unambiguous in the majority of cases and allows the diagnosis of the disease based on characteristic features under conventional light microscopy (70). However, borderline cases of osteo-pathological assessment have been reviewed in the literature, including manifestations of the jaws (110). The molecular genetic identification of typical mutations of the GNAS1 gene ensures histological diagnosis (64, 111).
TXS
Risk of cancer. Some case reports on the diagnosis and treatment of malignant neoplasm in TXS have been published (12). Therapy and prognosis do not seem to differ from that of a normal population. Bone tumors are extremely rare in TXS patients developing cancer (12). It can be concluded from the few publications on the subject that the diagnosis of TXS was known in a few cases of cancer.
Craniofacial morphology. Targeted analyzes of TXS patients have detected a number of malformations in this group (7, 10). Facial malformations of TXS include cleft lip and palate. However, it was explicitly pointed out that the majority of TXS patients are not diagnosed at all, and the frequencies of the findings in the presented study were considerably influenced by the recruitment method, which necessarily led to a collection of difficult cases (7). Some cephalometric parameters differ in TXS patients and controls. From this, it was deduced that TXS may develop midfacial hypoplasia, becoming evident in the analysis of the sagittal dimension. Likewise, sagittal underdevelopment (‘length’) of the mandible was found to be more common in TXS than in controls (11). It is possible that TXS patients have a shorter skull base than controls (112). However, anthropometric signs are not so pronounced that a typical phenotype can be derived from these findings.
Dentition. Few studies include oral findings in TXS. The focus of clinical investigations is on the assessment of dental status. Dental disorders were observed in almost half of all TXS patients (7). Here, the need for treatment of many patients is stressed, mainly the rehabilitation of carious dentition. The disorder of facial development with numerical aberration of the dentition is apparently extremely rare in TXS (113), as well as changes in tooth form (114).
FXS
Risk of cancer. Some reports on the diagnosis and treatment of malignant neoplasm in FXS have been published. A recent survey presented 40 cases (115). Another study describes an increased risk for the development of lip cancer in FXS (43). Therapy and prognosis of FXS patients do not seem to differ from that of a normal population. Bone tumors are extremely rare in FXS patients developing cancer (115). The individual reports of an increased risk of breast cancer in patients with FXS (44) [or FD (92)] suggest that the patient should be advised to undergo regular gynecological examinations at an early age.
Craniofacial morphology. Examinations of the skull in FXS are focused on findings that characterize the phenotype (33). Similarly to TXS, studies on FXS emphasize the reduced facial depth, as well as hypoplasia of the nasal bone cartilage interface, narrow mid-facial width, and exaggerated ear prominence (33). However, even these mild findings are often very discreet, not adequately consistent enough to prove all findings in the same patient, and the coincidence of medical findings is also often not very conspicuous. In fact, it was acknowledged that the facial characteristics of FXS are often very subtle (33). In contrast, previous studies on craniofacial anthropology in FXS highlighted the shortened upper face height and increased jaw length compared to sex and age-matched controls (116-118). Further studies provide evidence for cleft lip and palate arising somewhat more frequently in FXS than in the normal population (119).
Sella turcica malformation was reported in two fetuses with FXS (120). The authors detailed a deep sella turcica, notching in the anterior wall, very short dorsum sellae, and irregularly arranged remnants of the notochord in the dorsum. A further study on this subject was performed on lateral cephalograms of FXS patients, revealing normal bone in all five cases of study. However, sella turcica was of normal shape in only one case. Two of the individuals showed deformities of the anterior wall or reduced dorsum height (121). In the case we presented, the anterior wall of the sella turcica was also clearly oblique.
Dentition. In one study, numerical and structural changes in teeth were demonstrated in FXS (122). The dental findings are abnormalities of root morphology, the comparatively early emergence of molars, and a larger jaw angle. However, the correlations of the findings were generally low (122). Earlier studies had shown significantly more frequent malocclusions but no differences in jaw relations and palatal dimensions in FXS (123). Taurodentism was demonstrated in a study in both FXS and TXS (114).
FXS and cherubism. In a case with FXS, a cherubism phenotype was detected (125). This case is interesting because there are overlaps of the phenotype in FD of jaws and cherubism. Cherubism is caused by a mutation of a gene coding for the sarcoma homology 3 domain-binding protein 2 (SH3BP2). SH3BP2 is a protein encoded by a gene located on chromosome 4 (126). FD is a unilocular or multilocular disease with origin in a somatic mutation that potentially affects every bone. On the other hand, cherubism is a hereditary disease with different penetrance but skeletal findings being preferentially located in the jaws. The patient's phenotype with cherubism is characterized by bilateral, spongious hyperplasia of jaws (127). However, unilateral cases of cherubism are also known (126). Therefore, the clinicoradiological findings of unilateral mandibular hyperplasia of the presented case do not exclude cherubism in principle. The histological findings in cherubism and FD are sometimes difficult to distinguish from each other (110). Indeed, cherubism has been called the familial form of FD (127) before the genetic delineation to FD was known. Another monogenetic disease, neurofibromatosis type 1 (NF1), can lead to a cherubism phenotype (128).
TXS, FXS, and FD and other syndromic diseases. Coincidences of NF1 with FXS (129), TXS (130) or FD (131) have been published as case reports. In cases with gonosomal disease and NF1, metabolic and developmental disorders were predominant findings but not the characteristic of NF1 as a tumor-suppressor gene or phakomatosis. The presented patient had no clinical findings pointing to a coincidence with NF1 according to established diagnostic criteria. In patients with FD and NF1, the skin hyperpigmentation pattern differed markedly from the aspect expected in McCune–Albright syndrome. The coincidence of FXS and other syndromes has been reported, e.g. for trisomy 21 (132, 133), and Robin sequence (134).
Conclusion
FD of the jaw is a rare condition in which the focus is on differentiation from other lesions and tumors. The coincidence of FD with other syndromic diseases is known from individual reports. Therapy is symptomatic and carried out after careful examination of the patient.
Acknowledgements
The Authors would like to thank the patient and her parents for permission to publish the case report.
Footnotes
Author's Contributions
REF treated the patient, researched the literature, and wrote the article. FKK checked the scientific literature and wrote the article. AML provided morphological and molecular genetic findings and checked the article. All Authors gave final approval for publication.
This article is freely accessible online.
Conflicts of Interest
The Authors declare that there are no conflicts of interest regarding publication.
- Received November 1, 2019.
- Revision received November 13, 2019.
- Accepted November 14, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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