Dyskeratosis Congenita


This inherited disorder is characterized by cutaneous and mucous membrane abnormalities, progressive marrow insufficiency, and a predisposition to malignant transformation. It is much more common in males than in females, and occurs in about 1 per 1 million population.221,238

Pathogenesis  & cause

Dyskeratosis usually is inherited as a recessive X-chromosome–linked disorder although rare cases can have autosomal dominant or autosomal recessive inheritance (Table 34–9). The disease is a reflection of telomere complex dysfunction,239,240 and it results from defective telomerase activity resulting from mutations in the telomerase-related genes (Fig. 34–5).240 The telomerase complex maintains the length of telomeres, which are nucleotide tandem repeat structures residing at the termini of eukaryotic chromosomes (e.g., 5′-TTAGGG-3′). Telomerase restores the G-rich telomere repeats that are lost as a result of end-processing during normal cell division. Combined with protein, located at the ends of chromosomes, they maintain chromosome integrity by preventing end-to-end chromosome fusion, preventing chromosome degradation, and preventing chromosome instability.

Table 34–9. Gene Mutations in Dyskeratosis Congenita
Gene Chromosome Location % of Patients Inheritance Protein Function
DKC1 Xq28 30 XLR Essential part of snoRNPs and telomerase
TERC 3q26 <5 AD RNA 3′ end processing and stability
TERT 5p15.33 <6 AD, AR Reverse transcriptase component of telomerase
NOP10 (NOLA3) 15q14-q15 <1 AR RNA binding
TINF2 14q11.2 11 AD ? Binds to TRF1 to regulate telomere length
To be identified ~50%
AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.

NOTE: Table prepared from data in references 221, 223, and 273. Percent of patients is approximate because of continuing identification of mutations.

In dyskeratosis congenita, the telomeres are markedly shortened resulting in genomic instability and cell (including marrow cell) apoptosis. Rapidly proliferating cells are at highest risk for dysfunction. Mutations of the DKC1 gene are responsible for the X-linked recessive form. DKC1 encodes dyskerin, which is a conserved multifunctional protein component of the telomerase complex. Mutations of the TERT, TERC, and TINF2 genes are the principal abnormalities in the autosomal dominant form. TERC is the RNA component of the telomerase reverse transcriptase that TERT, the reverse transcriptase, uses to synthesize the 6-bp repeats on the 3′ end of telomeric DNA. TINF2 is a component of the shelterin complex. The latter permits the distinction of telomeres from sites of DNA damage, preventing their otherwise inappropriate processing. Recessive mutations in NOP10, which encodes small ribonucleoproteins associated with the telomerase complex, have been described in a consanguineous family.241 Homozygous recessive mutations in the telomerase reverse transcriptase (TERT) produce a severe variant, referred to as the Høyeraal-Hreidarsson syndrome.275

Clinical Findings

The cutaneous findings usually appear after 5 years of age and include reticulated, tan to gray, hyperpigmented and hypopigmented cutaneous macules; alopecia of scalp, eyelashes, and eyebrows; adermatoglyphia (loss of dermal ridges on fingers and toes); hyperkeratosis of palms and soles; mucosal leukoplakia in 75 percent of patients; and dystrophic nails in more than 85 percent of patients.221,238,239 Other mucosal sites, such as conjunctiva, lacrimal duct, esophagus, urethra, vagina, and anus, can be involved, sometimes with stenosis and, for example, dysphagia or dysuria. Pulmonary vascular involvement occurs in a significant minority of affected children. Aplastic anemia usually develops in late childhood or early adulthood and is evident in the classical blood and marrow findings described under acquired aplastic anemia, above. Female carriers of X-linked dyskeratosis congenital may have slight abnormalities such as a dystrophic nail, a single area of hypopigmentation, or slight leukoplakia.238


The diagnosis results from the combination of phenotypic findings and blood cell deficiencies. Genetic analysis for telomerase complex gene mutations should be used to confirm the clinical conclusion. Shortened telomere length in leukocytes also can be assessed by flow cytometric fluorescence in situ hybridization studies.242

Treatment & Management

Stem cell hematopoietic transplantation in Dyskeratosis Congenita

Has had inconsistent results because of frequent and severe posttransplantation complications.243 Nonmyeloablative transplantation might improve results.244,245 Transplantation might improve the cytopenias but not the abnormalities of other organs or the frequency of secondary nonhematopoietic cancer.

Course and Prognosis

The incidence of squamous cell carcinoma of mucosal sites is increased and they often originate in sites of leukoplakia in the skin, gastrointestinal, or genitourinary tracts. These usually develop between the ages of 20 and 30 years. Mortality from neutropenic infection or thrombocytopenic hemorrhage occurs in about two-thirds of patients with aplastic anemia. Median survival is about 30 years.

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