Are You Confident of the Diagnosis?

What you should be alert for in the history

Dyskeratosis congenita (DC) is a bone marrow failure (BMF) syndrome characterized by genetic mutations in the telomere complex. In its classic presentation, DC is a diagnosis based on clinical findings, although the onset of clinical findings may be highly variable. Because it is possible that bone marrow failure or a history of cancer may precede other clinical findings, it is important to consider DC a diagnosis, especially in a patient with a history of bone marrow failure. A family history of DC should also alert the clinician to the possibility of DC, even if it presents differently in other family members.

DC can involve many organ systems, most commonly skin, nails and oral mucosa, although any mucosal surface may be involved. Abnormalities have been reported in the ophthalmic, dental, pulmonary, gastrointestinal, genitourinary, hematologic, immunologic, neurologic, musculoskeletal, and endocrinologic systems. Psychiatric and developmental abnormalities are also known to occur. Clinical features of DC often appear in childhood, with skin pigmentary and nail changes occurring first, usually before the age of 10 years. There appears to be a male:female ratio of 3:1.

Characteristic findings on physical examination

The classic triad of DC includes lacy reticular pigmentation of the upper chest and/or neck, dysplastic nails, and oral leukoplakia. The pigmentary changes are characterized by hypo- and hyperpigmented macules, tan to brown, located most commonly on the upper chest, neck, and face (Figure 1, Figure 2). Poikilodermatous changes of atrophy and telangiectasia may also be seen. Other cutaneous findings include alopecia of the scalp, eyebrows, or eyelashes, premature graying of the hair, adermatoglyphia and hyperhidrosis. Other eyelash abnormalities may include sparse eyelashes, trichiasis, ectropion or entropion.

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Figure 1.

Dyskeratosis congenita. Photo courtesy of Dr Maurice van Steensel.

Figure 2.

Dyskeratosis congenita. Photo courtesy of Dr Maurice van Steensel.

Nail findings include ridging and longitudinal splitting. The nails may become thinned and atrophic leading to pterygium formation or absent nails. The changes in the fingernails and toenails may worsen over time (Figure 3, Figure 4).

Figure 3.

Dyskeratosis congenita. Photo courtesy of Dr Maurice van Steensel.

Figure 4.

Dyskeratosis congenita. Photo courtesy of Dr Eli Sprecher.

Oral leukoplakia, which can develop in childhood, may involve the bucal mucosa, tongue, palate, and oropharynx. The leukoplakia may become verrucous and lead to ulceration. Patients with DC have a high risk of developing squamous cell carcinomas, and all patients with oral leukoplakia should be followed very closely. Dental caries and periodontal disease are also seen.

Other mucosal sites of involvement include the urethra, glans penis, vagina, anorectal area, and gastrointestinal tract with changes including leukoplakia that can lead to stenosis and strictures in any of the noted mucosal surfaces.

Expected results of diagnostic studies

DC is a congenital disorder that is caused by mutation in genes that are associated with telomere maintenance. All patients with suspected DC should be tested for shortened telomeres in their lymphocytes and lymphocyte subsets. Given the marked clinical heterogeneity in this disorder, family members should be tested as well. Those patients who are suspected of having the disease can then be tested looking for known mutations. Genetic abnormalities have only been found in about 50% of patients with DC so far. Mutations have been identified in six genes: DKC1, TERC, TERT, NOP10, NHP2, and TINF2. These are all genes associated with the telomere complex.

Diagnosis confirmation

When not presented with the classic clinical findings associated with DC, other conditions associated with bone marrow failure should be considered in the differential diagnosis. These diagnoses include Fanconi’s anemia, Diamond-Blackfan anemia, Schwachman Diamond syndrome, and acquired aplastic anemia. Of these entities, there are skin findings in Fanconi’s anemia that include guttate hypopigmentation, generalized hyperpigmentation, or cafe au lait macules, findings not typical of DC. The other entities do not have cutaneous or mucosal abnormalities that would be found in DC.

In addition to its strong predisposition to bone marrow failure and the cutaneous findings as noted previously, Fanconi’s anemia is also characterized by skeletal abnormalities including abnormal thumbs with or without hypoplastic radii, as well as hip, rib, or vertebral abnormalities. Patients with this rare autosomal recessive disorder may also present with short stature, microcephaly, microphthalmia, and other abnormalities involving the genitourinary, gastrointestinal, cardiac, and neurologic systems. Patients with Fanconi’s anemia are also at risk of developing solid tumors and leukemia.

Schwachman Diamond syndrome is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, congenital skeletal abnormalities, bone marrow failure, and a predisposition to the development of leukemia. Cutaneous findings include eczema and ichthyosis.

Who is at Risk for Developing this Disease?

DC is a very rare genetic disease involving mutations in the telomere complex. Family members of a pedigree with known DC are at risk of having the disease. All dyskeratosis congenita patients have shortened telomeres. To date, in those that have been genetically categorized, six mutations have been linked to DC. Five of these genes, DKC1, TERC, TERT, NOP10, NHP2, encode components of the telomerase complex and one gene, TINF2, encodes shelterin. There is considerable variation between patients with respect to age of onset and disease severity even within individual families.

What is the Cause of the Disease?

DC is a bone marrow failure syndrome that appears to be caused by mutations in genes that regulate telomere maintenance. The consistent feature in all patients with DC is abnormally shortened telomeres. To date, in those that have been genetically categorized, six mutations have been linked to DC. Five of these genes, DKC1, TERC, TERT, NOP10 and NHP2, encode components of the telomerase complex and one gene, TINF2, encodes shelterin, Inheritance patterns include X-linked recessive (XLR), autosomal dominant (AD), or autosomal recessive (AR), although there is also a high frequency of sporadic cases that are presumably due to new mutations in dominant genes. The XLR form of dyskeratosis congenita is the most common type.

Abnormalities in the telomeres secondary to these genetic mutations lead to telomere shortening causing cellular senescence, apoptosis, genomic instability or a reduction in cellular lifespan.

The first DC gene mapped was for dyskerin, DKC1, associated with the XLR form of DC. The dyskerin protein is involved in posttranscriptional pseudouridylation and forms a ribonucleoprotein (RNP) complex with three other proteins, NOP10, NHP2 and GAR1. AR inheritance in mutations in NOP10 or NHP2 (gene names NOLA3 and NOLA2, respectively) have been identified in three consanguineous families with DC.

Mutations in the TERC gene, a gene that serves as the reverse transcriptase template for the telomerase enzyme, has been found in an AD inheritance pattern in some DC patients. Abnormalities in the telomerase enzyme, TERT, has been found in patients with AD and AR DC.

Mutations in TINF2, a component of the shelterin complex that consists of six proteins that act as a cap at the telomere and regulate telomere length, have also been found to be present in some patients with DC.

Systemic Implications and Complications

Many organ systems may be involved in patients with DC. In addition to the aforementioned physical findings, below are findings in other organ systems that may be seen in DC patients.

Ophthalmic: epihoria secondary to nasolacrimal obstruction, blepharitis, conjunctivitis, pterygium formation, cataracts, strabismus, optic atrophy, and retinal abnormalities.

Pulmonary : Pulmonary fibrosis and abnormal pulmonary vasculature.

Gastrointestinal: Esophageal stenosis at times requiring dilatation, liver fibrosis and enteropathies that can result in poor growth.

Genitourinary: Hypogonadism and the development of urethral stenosis.

Musculoskeletal: Osteopenia, osteoporosis, and avascular necrosis of the hips and shoulders.

Developmental delay, learning disabilities, short stature, and microcephaly are also reported.

Bone marrow failure is common in patients with DC and may predate other clinical findings, Bone marrow failure often develops before the age of 20 years with up to 90% of patients by the age of 30 years showing signs of bone marrow failure. The main causes of mortality in patients with DC is bone marrow failure (60% to 70%), pulmonary complications (10% to 15%) and malignancy (10%).

Head and neck squamous cell carcinomas (SCCs) are the most common solid tumors seen in patients with DC, followed by skin and anorectal SCCs. Other cancers reported in DC include stomach cancers including adenocarcinomas, lung cancer including adenocarcinoma, esophageal SCC, Hodgkin lymphoma, non-Hodgkin lymphoma, pancreatic adenomas, liver adenoma, retinoblastoma, cervical SCC, myelodysplastic syndrome and AML. Most cancers seen in these patients developed at an age that was younger than expected for sporadic cancers.

There are two severe subsets of DC, the Hoyeraal-Hreidarsson Syndrome (HH) and Revesz Syndrome (RS). Patients with HH have cerebellar hypoplasia, microcephaly, developmental delay, immunodeficiency, intrauterine growth retardation, and bone marrow failure. These patients have short telomeres and mutations in DKC1, TINF2, or TERT have been identified.

RS is associated with exudative retinopathy and bone marrow failure. Most patients also had cerebral calcifications. Nail dystrophy and oral leukoplakia have also been reported in RS syndrome. These patients also have abnormally short telomeres, and mutations in the TINF2 gene have been identified. Survival appears to be particularly shortened in patients with these subsets.

Treatment Options

There is no known cure for patients with DC. Treatment is aimed at management of complications associated with the disease.

Optimal Therapeutic Approach for this Disease

There are no known treatments for the dermatologic changes associated with DC. As the cutaneous changes tend to occur on sun-exposed areas, it is very prudent for the dermatologist to emphasize the importance of photoprotection, which can be achieved through the use of sunscreen and photoprotective clothing.

Bone marrow failure

A trial of androgens may be tried in patients with DC who present with BMF. It is very important to be aware of the fact that patients with DC are very sensitive to androgens and should be started at lower dosages than other BMF syndromes, and they should be monitored very closely for side effects.

Hematopoietic growth factors such as erythropoietin and G-CSF are occasionally used but should not be used in conjunction with androgens. Splenic rupture has been reported with the combined use of G-CSF and androgens.

Hematopoietic stem cell transplant (HSCT) is the treatment of choice for BMF or leukemia in patients with DC. Patients with DC who have BMF do not respond to immunosuppressive therapy and are at high risk of HSCT-related complications due to underlying pulmonary and liver disease. Drugs that cause pulmonary toxicity, such as busulfan, as well as unnecessary radiation should be avoided in patients with DC.


The treatment of specific cancers in patients with DC should be determined by the type of cancer. It is important to take into consideration that these patients may have prolonged cytopenias when undergoing chemotherapy.

Patient Management

DC can involve multiple organ systems and usually requires the involvement of many medical specialties to care for these patients. In addition, signs and symptoms develop at different ages and rates, making it important that these patients are under constant surveillance for the development of complications associated with the disease.

  • –A comprehensive examination of skin, nails and oral mucosa is required to look for any evidence of cancer.

  • –If the diagnosis is considered based on physical findings, prompt referral to a hematologist is recommended to confirm the diagnosis and to follow closely for evidence of cytopenias indicating BMF and to follow for the development of cancers.

  • –Patients should be monitored by otolaryngologists to monitor for leukoplakia and the development of head and neck cancers.

  • –Close dental follow-up to maintain good oral hygiene and to monitor for leukoplakia and oral squamous cell cancers.

  • –Annual pulmonary function tests.

  • –Gynecologic evaluation for females is recommended starting by the age of 16 years or when sexually active.

  • –A comprehensive review of systems and physical examination will dictate the need for referral to other specialists.

  • –A relative with signs or symptoms suggestive of DC or one that is being evaluated as a potential HSCT donor should have telomere-length testing or molecular genetic testing if the mutation in the family is known.

Unusual Clinical Scenarios to Consider in Patient Management

DC does not always present to the dermatologist in its classic presentation. Dermatologists should be alerted to the patient with unusual skin or nail findings who has myelodysplasia or BMF. The diagnosis should be considered in unusual presentations of poikiloderma associated with nail abnormalities. As more genetic mutations are identified, the clinical spectrum of DC may broaden.

What is the Evidence?

Savage, SA, Pagon, RA, Bird, TD, Dolan, CR, Stephens, K. “Dyskeratosis congenita”. GeneReviews[Internet]. 1993-2009. (This is an excellent, comprehensive, up to date review on all aspects of DC.)

Alter, BP, Giri, N, Savage, SA, Rosenberg, PS. “Cancer in dyskeratosis congenita”. Blood. vol. 113. 2009. pp. 6549-57. (This article summarizes an extensive literature review of reported cancers in patients with DC as well as reports on a prospective study of an NCI cohort.)

Savage, SA, Dokal, I, Armanios, M, Aubert, G, Cowen, EW, Domingo, DL. “Dyskeratosis congenita: the first NIH clinical research workshop”. Pediatr Blood Cancer. vol. 53. 2009. pp. 520-3. (Report on an NIH clincial workshop that gives guidelines for following patients with DC.)

Savage, SA, Alter, BP. “Dyskeratosis congenita”. Hematol Oncol Clin North Am. vol. 23. 2009. pp. 215-31. (Excellent concise reiveiw of clinical findings and management of patients with DC.)

Walne, AJ, Dokal, I. “Advances in the understanding of dyskeratosis congenita”. Br J Haematol. vol. 145. 2009. pp. 164-72. (Review of DC, concentrating on the genes and the genetic defects associated with DC.

Alter, BP. “Diagnosis, genetics, and management of inherited bone marrow failure syndromes”. Hematology Am Soc Hematol Educ Program. 2007. pp. 29-39.. (This excellent review compares the clinical and molecular findings in inherited BMF syndromes including DC, Fanconi anemia, Diamond Blackfan anemia, Schwachman Diamond syndrome and severe congenital neutropenia.)

Vulliamy, TJ, Dokal, I. “Dyskeratosis congenita: the diverse clinical presentation of mutations in the telomerase complex”. Biochimie. vol. 90. 2008. pp. 122-30. (An in depth review of the genetic mutations associated with DC, concentrating on the molecular findings.)