Genetic studies by NGS Panels
Panel for dyskeratosis congenita (Code 10110)
Dyskeratosis congenita (DC) (OMIM #127550, #224230, #305000, #613987, #613988, #613989, #613990, #615190, #616353) is a multisystem disease with a very low incidence (<1 / 1,000,000 newborns), with defects in the maintenance of chromosomal telomeres. It is characterized mainly by mucocutaneous alterations, of which the classic triad stands out: oral leukoplakia, nail dystrophy and alteration of skin pigmentation (Zinnser, 1906). These manifestations do not necessarily occur in all individuals, neither at diagnosis nor throughout the disease. The symptoms can be very variable, both for the time of appearance of these in a same individual and for manifestations in members of the same family. Other organs mainly affected are the bone marrow (80% of marrow failure before the age of 30), the lung and the liver, in which its parenchyma is replaced by fat or fibrosis, affecting its function. Other manifestations may be: growth disorders, head and neck alterations (microcephaly, strabismus, cataracts, …), esophageal stenosis, anal mucosal leukoplakia, genitourinary alterations, osteoporosis, mental retardation, ataxia, immunodeficiency, or neoplasms (squamous carcinoma, pancreatic carcinoma, acute myeloblastic leukemia or Hodgkin’s lymphoma).
Telomeres are exanucleotides (TTAGGG) that shorten in each cell division; there is a telomerase complex that acts as protector of the telomeres, favoring its extension although incompletely, and a regulatory complex, protective of telomerase activity, called shelterin. An excessive shortening of telomeres involves apoptosis or cell death, so that the cells lose the ability to replicate earlier than expected for their age.
Patients with DC have mutations in genes that code for the telomerase complex and for the protective complex or shelterin.
The most frequent presentation of the disease is that produced by mutations in the DKC1 gene, which codes for the dyskerin protein and is X-linked inheritance. However, mutations have recently been described in other genes involved (POT1, TERC, TERD, PARN …)
The differential diagnosis should be made along with other syndromes of congenital marrow failure (Fanconi anemia, Blackfan-Diamond anemia and Swachman-Diamond syndrome), acquired medullary aplasia and idiopathic pulmonary fibrosis in young patients.
The treatment must target the affected organs; marrow failure is one of the most frequent and early complications, whose only curative treatment is hematopoietic progenitor stem cell transplantation (HSCT) with reduced intensity conditioning (myeloablative conditioning is contraindicated due to the high toxicity related to the procedure). HSCT should be performed without delay in patients with severe pancytopenia and compatible donor. Otherwise, response to androgenic derivatives (50-70% of cases) such as oxymetholone and danazol has been demonstrated. In those patients without other alternatives, transfusional support should be performed.
The main causes of death are related to bone marrow failure, cancer and lung disease, particularly fibrosis. Cancer usually develops after the third decade. The most common solid malignancies are squamous cell carcinoma of the head and neck.
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