Controlled studies of the associated oral and dental findings in DC have not been reported previously. Although the prevalence of oral leukoplakia has been reported in larger cohorts, other previously reported dental findings were identified from case reports of one or two patients. In this study of 17 individuals with DC, the most commonly found oral changes were oral leukoplakia (65% of the entire population), decreased root/crown ratio (75% of patients with sufficient tooth development to permit evaluation) and mild taurodontism (57% with radiographs and sufficient tooth development to permit evaluation). Other previously reported oral features of this disease, increased dental caries, hypodontia, thin enamel and aggressive periodontitis, were not detected in this DC population.
The most common change of the oral mucosal tissues in DC was leukoplakia, one of the three features originally described in this disease. It was not present in every patient, and the prevalence in our cohort (65%) is similar to the 78% prevalence reported from a registry of 118 male patients with presumed XLR DC14
. The clinical presentation of oral leukoplakia in these patients was very heterogeneous, which is consistent with the clinical variability reported for the skin changes associated with DC14
. Other authors have proposed that the heterogeneity of the clinical DC presentation suggests modification of the phenotype by other genetic factors and/or the environment.
Very little is known about the histopathological features of oral leukoplakia in DC. A longitudinal study of one patient characterized histological features associated with progression from hyperkeratosis to dysplasia of a lesion on the tongue15
. The dysplastic tissue from the ventral tongue exhibited abnormal keratin expression, consisting of co-expression of keratins K16, K10 and K13 15
. p53 expression was not found in the first biopsy, but was present in all subsequent specimens. Unfortunately, no biopsies of leukoplakic tissues were available to permit similar studies from our patients.
In addition to leukoplakia, the tongues in some patients demonstrated atrophy of the papilla. The mechanism underlying this atrophy may be provided by studies with a mouse model (mTR+/− mice on the CAST/EiJ) of autosomal dominant DC16
. Interbreeding of these mice that are heterozygous for deficiency of the RNA subunit of telomerase creates progressive telomere shortening. Histopathological examination of the intestines of later generation mice found crypt depletion and villi atrophy, suggesting normal telomere length is needed for maintenance of these tissues16
. It is possible there is a similar requirement to maintain adequate telomere length to sustain healthy tongue epithelium, which is in constant need of replenishment from basal cells17
Intraoral brown pigmentation, found in two patients with TERC
mutations, may reflect an imbalance in telomerase activity. Recent work has demonstrated chromosomal imbalances involving TERC
in various types of malignant melanoma18
The finding of shortened roots in a high percentage of DC patients suggests normal telomere length or adequate telomerase activity is needed for complete root development. Two other reports further support this hypothesis. A recent study found cementoblast progenitor cells, believed to be responsible for root development, were immortalized by expression of human telomerase reverse transcriptase (TERT
) and the gene for polycomb group protein, Bmi-119
. Transduced single cell clones subsequently expressed mRNA for bone sialoprotein, osteocalcin, osteopontin, and type I collagen when implanted in immunodeficient mice. In another report, stem cells, which require functional telomerase, were identified in the apical root during certain stages of root formation of the rat tooth20
. Alternatively, it is possible that the proteins encoded by the mutated genes in DC have functions in root and oral epithelial development by mechanisms not yet defined.
Root development of teeth may also provide information about the time of disease progression in patients with DC. Root development begins after the crown of the tooth is formed. The earliest root development of the permanent teeth occurs at about age 3 years, beginning with the central incisors21–23
. The second permanent molar roots begin to form between age 7 and 8 years. Insults to the developing teeth, such as radiation, chemotherapy and/or hematopoietic stem cell transplant during that time can disturb root development22
. Children surviving cancer may present later in life with clinically normal crowns and abnormally short roots of certain teeth22
, marking the time of their cancer therapy. It is likely that a portion of dental follicular cells responsible for root development in DC cease functioning as telomeres shorten through repeated divisions. If all of the roots of the permanent teeth in a DC patient are short, telomerase activity or telomere length may have been inadequate since early childhood. If the only teeth with short roots are the second permanent molars, then telomerase activity may have been adequate until the early teenage years.
Taurodont teeth have enlarged pulp chambers and short roots13
. Since root length is reduced in the DC patients, it was not surprising that taurodontism was found in four of seven evaluated patients. In addition, pulp chambers normally decrease in size with age because of secondary dentin deposition24
. This process is believed to be mediated by stem cells in dental pulps that express dentin sialoprotein (DSP)25
. It is possible that pulp stem cells that produce secondary dentin also are dysfunctional in DC. However, this presumed dysfunction did not appear to be profound, as the taurodontism in our patients was of the mildest form using the classification system of Shifman13
Previously reported oral findings (aggressive periodontal disease, increased dental caries, thin enamel and hypodontia) associated with DC were not part of the oral phenotype found in this cohort. We were surprised that none of our patients had evidence of past or current aggressive periodontitis, and feel this may reflect the better dental hygiene of these DC patients or their absence of profound neutropenia. Most had absolute neutrophil counts (ANC) >1000 cells/μL (). One of the patients with an ANC <1000 cells/μL had radiographic suggestions of alveolar bone loss in the posterior teeth, but she was also undergoing full orthodontic therapy. Therefore, alveolar bone height assessments using radiographs were considered unreliable. Dental radiographs were not obtainable on the 3 year old with decreased ANC. Other previously reported findings of increased caries, hypodontia and thin enamel7, 9, 26
were not confirmed in this study. Given the heterogeneous nature of this patient group, these findings might be found in a larger study of patients and appropriate controls. In particular, studies of dental caries must be of significant size to control for the multiple other factors associated with caries in children 27, 28
to determine whether the frequency of caries is increased in DC.
In summary, the oral phenotype of DC is characterized by leukoplakia, decreased root/crown ratios and mild taurodontism. From the clinical perspective, a diagnosis of DC or another inherited bone marrow failure syndrome should be considered in any young person with oral leukoplakia, particularly those with no history of tobacco use. Continued studies with this cohort should define the oral phenotype more completely and determine what factors are most associated with the development of oral squamous cell carcinomas in these patients.