Oral Leukoplakia in Dyskeratosis Congenita: Associations between genotype and phenotype

Objective:   Dyskeratosis Congenita (DC), a cancer-prone inherited bone marrow failure syndrome (IBMFS), is associated with defects in telomere biology. DC is diagnosed by the presence of very short, age-adjusted telomeres in white blood cell subsets. The classical diagnostic criteria include at least two features of the triad of lacy reticular skin pigmentation (SP), nail dystrophy (ND), and oral leukoplakia (OL). DC patients have an 11-fold increased risk of cancer including ~1000-fold increase of tongue cancer. DC patients may have high rates of bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), anogenital cancers, pulmonary fibrosis, and other medical problems. Very little is known about the clinical or histopathological features of OL in DC or in the more severe Hoyeraal Hreidarsson (HH) or Revesz Syndrome (RS) variants. This cross sectional study correlates OL with causative genes and severity of BMF to analyze the clinical expression of DC in the oral cavity.

Methods: Detailed oral examination (radiographs, clinical images) were performed in 44 individuals with DC, participants in the NCI cohort study of IBMFS (02-C-0052). The presence/absence of OL was associated with laboratory studies and mutation analyses (Fisher’s exact test and Cochran-Armitage trend test).

Results:   The prevalence of OL was 64%: 75% in children and 50% in adults. 93% of OL localized to the dorsal tongue (plaque-like lichenoid white lesions with papillary atrophy). Subjects with DKC1 were significantly more likely to have OL than with TERT. A significant association was found between OL and severity of BMF (Table 1).

Conclusion: OL in DC develops at an unusually young age, is characteristic in appearance and location, and is associated with genetic mutations and severity of BMF. Phenotypically similar to oral lichen planus, the role of the inflammatory environment may be important in the initiation and promotion of malignant transformation in DC.

 

TABLE 1. Oral Lesions in Patients with Dyskeratosis Congenita

	n	Oral Lesions	No Oral Lesions	p value
TOTAL	44	28 (64%)	16 (36%)
Gender (% males)	35	22 (63%)	13 (37%)
Age (years)		13 (3-53)	21 (1-69)	0.120
n<18 years old	24	18 (75%)	6 (25%)
n>18 years old	20	10 (50%)	10 (50%)
LESION SITE
Dorsal Tongue	28	26 (93%)
Bilateral Buccal Mucosa	28	2 (7%)
DIAGNOSTIC TRIAD
Minimum 2/3 features	44	24 (55%)	5 (11%)	0.0002*
DISEASE VARIANT				0.290
Dyskeratosis Congenita	30	18 (60%)	12 (40%)
Hoyeraal Hreidaarsson	13	10 (77%)	3 (23%)
Revesz Syndrome	1	0	1 (100%)
CAUSATIVE GENE				0.024*
WRAP53	2	2 (100%)	0
DKC1	10	9 (90%)	1 (10%)
TERC	3	2 (67%)	1 (33%)
TINF2	11	6 (55%)	5 (45%0
TERT	6	1 (17%)	5 (83%)
Unknown	12	8 (67%)	4 (33%)
BONE MARROW FAILURE SEVERITY				0.017*
None	6	2 (33%)	4 (67%)
Mild	9	4 (44%)	5 (56%)
Moderate	3	2 (67%)	1 (33%)
Severe	26	20 (77%)	6 (23%)