Similar telomere attrition rates in androgen-treated and untreated patients with dyskeratosis congenita

Abstract

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome and the prototypic telomere biology disorder (TBD). Leukocyte telomere length (TL) less than the first percentile for age, measured by flow cytometry with in situ hybridization (flow FISH), is diagnostic of DC. Androgens are a therapeutic option for DC/TBD-associated bone marrow failure (BMF). One report has shown an apparent increase in TL in patients while on treatment with the attenuated androgen danazol. The aim of this study was to compare TL over time in 10 androgen-treated and 16 untreated patients with DC. All subjects were enrolled in institutional review board-approved longitudinal cohort studies of inherited BMF. TL in 6-panel leukocyte subsets was measured by flow FISH. Generalized estimating equations (GEE) methodology was used to compare TL changes over time between groups. Unadjusted analyses showed annual median total lymphocyte TL attrition of -62 base pairs/year (bp/y) in androgen-treated patients with DC compared with -76 bp/y in untreated DC patients ( = .71). Longitudinal analysis using a GEE model, adjusted for age at sample collection, showed no statistically significant difference in TL change over time between treated and untreated patients ( = .24). The results were similar for each individual leukocyte subset evaluated. In summary, our data show the expected age-associated longitudinal telomere shortening in patients with DC, irrespective of androgen therapy. Caution is warranted when recommending androgen therapy for non-BMF manifestations of DC or TBDs until the biological mechanisms are better understood.

Aspectos clínicos, etiológicos y terapéuticos de la disqueratosis congénita

“…La evidencia de múltiples dientes permanentes con disminución de la relación raíz/corona pueden sugerir el diagnóstico de DC (4). Entre otros hallazgos clínicos se encuentran fibrosis pulmonar, e insuficiencia o fibrosis hepática (1)(2)(3)5,7,10). Presentan además un riesgo de 50 veces mayor de la población general de desarrollar tumores hematológicos y sólidos, incluidos el síndrome mielodisplásico, la leucemia mieloide aguda, el linfoma no Hodgkin, el carcinoma de células escamosas de cabeza y cuello, el cáncer de esófago, anogenital, y el carcinoma de células basales, como complicaciones graves (1,2,4,5,8,10).…”

“…Los telómeros, están constituidos por repeticiones de 6 nucleótidos en los extremos de los cromosomas (5). Es un complejo de nucleoproteínas esencial para la estabilidad cromosómica, y se acortan con cada división celular (5,7).…”

“…Los trastornos en la biología de los telómeros o telomeropatías, representan un grupo de entidades genéticas, en que la disqueratosis congénita (DC), fue la primera en describirse (1), cuya forma clásica se caracteriza clínicamente por presentar la tríada mucocu-tánea diagnóstica, de pigmentación reticulada de encaje en piel (1,2), que afecta principalmente el área del cuello y el tórax anterosuperior (2), distrofia ungueal y leucoplasia oral (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) (Fig. 1).…”

Aplastic anemia: Etiology, molecular pathogenesis, and emerging concepts

“…54 However, a recent retrospective study found no difference in the telomere attrition rates of androgen-treated or untreated patients with dyskeratosis congenita irrespective of the type of androgen therapy used or leukocyte subset evaluated; such data imply a mechanism of clinical response other than androgen-related effects on telomere homeostasis. 55 It remains to be seen whether or not abrogation of telomere length shortening seen in AA (and the foreseeable chromosomal instability) with androgen therapy averts the molecular pathogenesis of clonal evolution.…”

Pulmonary fibrosis: Genetic analysis of telomere‐related genes, telomere length measurement‐or both?

“…found an increase in TL using qPCR in patients treated with danazol, whereas Khincha et al . did not observe increased TL in danazol‐treated patients when assessed by Flow‐FISH, raising the question of the most appropriate TL measurement technique . Conversely, qPCR provided reproducible data in an idiopathic pulmonary fibrosis (IPF) study, suggesting that qPCR may offer reliable results in experienced hands and under well‐defined conditions, although this will require further investigation.…”