AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare, progressive bone marrow failure syndrome characterized by the triad of reticulated skin hyperpigmentation, nail dystrophy, and oral leukoplakia. Evidence exists for telomerase dysfunction, ribosome deficiency, and protein synthesis dysfunction in this disorder. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy.

Pathophysiology

DKC is genetically heterogeneous, with X-linked recessive (Mendelian Inheritance in Man [MIM] 305000), autosomal dominant (MIM 127550), and autosomal recessive (MIM 224230) subtypes. DKC is related to telomerase dysfunction^{1, 2}; all genes associated with this syndrome (ie, DKC1, TERT, TERC, NOP10) encode proteins in the telomerase complex responsible for maintaining telomeres at the ends of chromosomes. In the X-linked recessive form, the gene defect lies in the DKC1 gene (located at Xq28), which encodes for the protein dyskerin. Dyskerin is composed of 514 amino acids and has a role in ribosomal RNA processing and telomere maintenance.^{3, 4} In the autosomal dominant form, mutations in the RNA component of telomerase (TERC) or telomerase reverse transcriptase (TERT) are responsible for disease phenotype.^{2, 5, 6}

Defects in the NOP10 gene were found in association with autosomal recessive DKC.⁷ NOP10 encodes small nucleolar ribonucleoproteins (snoRNP) associated with the telomerase complex. In persons with autosomal dominant DKC and in terc-/- knockout mice, genetic anticipation (ie, increasing severity and/or earlier disease presentation with each successive generation) has been reported.⁸

Patients with DKC have reduced telomerase activity and abnormally short tracts of telomeric DNA compared with normal controls. Telomeres are repeat structures found at the ends of chromosomes that function to stabilize chromosomes. With each round of cell division, the length of telomeres is shortened and the enzyme telomerase compensates by maintaining telomere length in germline and stem cells. Because telomeres function to maintain chromosomal stability, telomerase has a critical role in preventing cellular senescence and cancer progression. Rapidly proliferating tissues with the greatest need for telomere maintenance (eg, bone marrow) are at greatest risk for failure. DKC1 has been found to be a direct target of the c-myc oncogene, strengthening the connection between DKC and malignancy.⁹

Analysis of 270 families in the DKC registry found that mutations in dyskerin (DKC1), TERT, and TERC only account for 64% of patients, with an additional 1% due to NOP10, suggesting that other genes associated with this syndrome are, as yet, unidentified.

Frequency

International

DKC is estimated to occur in 1 in 1 million people. More than 200 individuals have been reported in the literature.

Mortality/Morbidity

In an analysis of individuals with DKC, approximately 70% of patients died either directly from bone marrow failure or from its complications at a median age of 16 years. Eleven percent died from sudden pulmonary complications; a further 11% died of pulmonary disease in the bone marrow transplantation (BMT) setting. Seven percent died from malignancy (eg, Hodgkin disease, pancreatic carcinoma). Fatal opportunistic infections such as Pneumocystis carinii pneumonia and cytomegalovirus infection have been reported.

Race

No racial predilection has been reported. The DKC registry includes patients from all over the world, with families from at least 40 different countries currently in the registry.

Sex

The male-to-female ratio is approximately 3:1.

Age

Patients usually present during the first decade of life, with the skin hyperpigmentation and nail changes typically appearing first.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

The mucocutaneous features of DKC typically develop between ages 5 and 15 years. The median age of onset of the peripheral cytopenia is 10 years.

Physical

The triad of reticulated hyperpigmentation of the skin, nail dystrophy, and leukoplakia characterizes DKC. The syndrome is clinically heterogeneous; in addition to the diagnostic mucocutaneous features and bone marrow failure, affected individuals can have a variety of other clinical features.

• Cutaneous findings
• • The primary finding is abnormal skin pigmentation, with tan-to-gray hyperpigmented or hypopigmented macules and patches in a mottled or reticulated pattern. Reticulated pigmentation occurs in approximately 90% of patients. Poikilodermatous changes with atrophy and telangiectasia are common.
  • The cutaneous presentation may clinically and histologically resemble graft versus host disease. The typical distribution involves the sun-exposed areas, including the upper trunk, neck, and face.
  • Other cutaneous findings may include alopecia of the scalp, eyebrows, and eyelashes; premature graying of the hair; hyperhidrosis; hyperkeratosis of the palms and soles; and adermatoglyphia (loss of dermal ridges on fingers and toes).
• Nail findings
• • Nail dystrophy is seen in approximately 90% of patients, with fingernail involvement often preceding toenail involvement.
  • Progressive nail dystrophy begins with ridging and longitudinal splitting. Progressive atrophy, thinning, pterygium, and distortion eventuate in small, rudimentary, or absent nails.
• Mucosal findings
• • Mucosal leukoplakia occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx. The leukoplakia may become verrucous, and ulceration may occur. Patients also may have an increased prevalence and severity of periodontal disease.
  • Other mucosal sites may be involved (eg, esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus). Constriction and stenosis can occur at these sites, with subsequent development of dysphagia, dysuria, phimosis, and epiphora.
• Bone marrow failure
• • Approximately 90% have peripheral cytopenia of one or more lineages. In some cases, this is the initial presentation, with a median age of onset of 10 years.
  • Bone marrow failure is a major cause of death, with approximately 70% of deaths related to bleeding and opportunistic infections as a result of bone marrow failure.
• Pulmonary complications
• • Approximately 20% of individuals with DKC develop pulmonary complications, including pulmonary fibrosis and abnormalities of pulmonary vasculature.
  • The recommendation is that DKC patients avoid taking drugs with pulmonary toxicity (eg, busulfan) and that they have their lungs shielded from radiation during BMT.
• Increased risk of malignancy
• • Patients have an increased prevalence of malignant mucosal neoplasms, particularly squamous cell carcinoma of the mouth, nasopharynx, esophagus, rectum, vagina, or cervix. These often occur within sites of leukoplakia.
  • The prevalence of squamous cell carcinoma of the skin is also increased. Other malignancies reported include Hodgkin lymphoma, adenocarcinoma of the gastrointestinal tract, and bronchial and laryngeal carcinoma.
  • Malignancy tends to develop in the third decade of life.
• Neurologic system findings: Patients may have learning difficulties and mental retardation.
• Ophthalmic system findings: DKC reportedly is associated with conjunctivitis, blepharitides, and pterygium. Lacrimal duct stenosis resulting in epiphora (ie, excessive tearing) occurs in approximately 80% of patients.
• Skeletal system findings: Patients may have mandibular hypoplasia, osteoporosis, avascular necrosis, and scoliosis.
• Gastrointestinal system findings: These may include esophageal webs, hepatosplenomegaly, and cirrhosis.
• Genitourinary system findings: Hypospastic testes, hypospadias, and ureteral stenosis are reported.
• Female carriers: Female carries of DKC may have subtle clinical features. One study showed that 3 of 20 female carriers had clinical features that included a single dystrophic nail, a patch of hypopigmentation, or mild leukoplakia.

Causes

Mutations in DKC1 have been shown to cause the X-linked form of DKC. The inheritance pattern of most cases of DKC is X-linked recessive, but autosomal dominant and recessive patterns have been reported. Autosomal dominant DKC is associated with TERC and TERT mutations in some cases, and NOP10 has been associated with some cases of autosomal recessive DKC.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Fanconi Syndrome

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

Perform appropriate tests to screen for bone marrow failure, pulmonary disease, neurologic disease, and mucosal malignancies. Specific tests depend on the clinical findings and may include a CBC count, chest radiography, pulmonary function tests, and stool tests for occult blood. Elevated von Willebrand factor levels have been associated with fatal vascular complications after BMT and may be a marker for patients with a predisposition for endothelial deterioration.

Mutational analysis may be useful in confirming the diagnosis. Mutations in the TERC gene and in the TERT gene, the gene for telomerase reverse transcriptase (another member of the ribonucleoprotein complex), have been identified in a subset of patients with aplastic anemia.¹⁰ Genetic testing for occult DKC should be considered in patients with aplastic anemia. However, a 2006 genetic analysis of the TERC gene among 284 children with either aplastic anemia or myelodysplastic syndrome found only 2 mutations in the TERC gene.¹¹

Patients and family members without a known mutation can be screened with a new test, leukocyte subset flow fluorescence in situ hybridization, which can identify very short telomeres in both clinically apparent and silent disease.¹²

Imaging Studies

Several reports note that radiographs show calcification of the basal ganglia.

Histologic Findings

Skin biopsy specimens from the areas of reticulated pigmentation typically show nonspecific changes, including mild hyperkeratosis, epidermal atrophy, telangiectasia of the superficial blood vessels, and melanophages in the papillary dermis. Interface changes have also been reported, with mild basal layer vacuolization and a lymphocytic inflammatory infiltrate in the upper dermis.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Short-term treatment options for bone marrow failure in patients with DKC include anabolic steroids (eg, oxymetholone), granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin¹³; however, the only long-term, curative option is hematopoietic stem cell transplantation (SCT).

• Approximately 50% of patients experience a temporary increase in blood counts with androgen therapy; the duration of treatment is limited by adverse effects; in addition, reports have described splenic peliosis and rupture in patients treated concomitantly with androgens and granulocyte colony-stimulating factor.¹⁴
• The success rate of SCT is limited because of a high prevalence of fatal pulmonary complications, which likely reflect preexisting pulmonary disease in these patients.
• Drugs that cause pulmonary toxicity (eg, busulfan) and exposure to unnecessary radiation should be avoided in these patients.
• Nonmyeloablative hematopoietic SCT conditioning regimens (ie, reduced-intensity conditioning) with fludarabine may offer better outcomes. A 2007 review showed a 22% mortality rate with reduced-intensity conditioning in DKC treatment versus a  71% mortality rate with traditional myeloablative regimens.¹⁵
• The best candidates for transplantation may be patients with sibling donors and with no preexisting pulmonary disease.

The elucidation of the genetic basis of X-Iinked DKC enables prenatal testing and carrier detection. Early diagnosis of DKC through genetic analysis also may help identify patients for early harvest and storage of their bone marrow for use after anticipated marrow failure. In the future, patients with DKC may be candidates for hematopoietic gene therapy.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Colony-stimulating factors

Used to stimulate bone marrow in patients with cytopenia of one or more cell lineage.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Complications

Patients with DKC should avoid drugs with pulmonary toxicity (eg, busulfan) and should have their lungs shielded from radiation during BMT. Additionally, some authorities recommend routine endoscopic surveillance beginning at age 30 years in known cases of DKC, along with general precautions like sun and tobacco avoidance.

Prognosis

DKC is a multisystem disorder that carries a poor prognosis (mean survival of 30 y), with most deaths related to infections, bleeding, and malignancy. In the DKC registry, approximately 70% of affected individuals died of bone marrow failure or its complications, and these deaths occurred at a median age of 16 years. Therapeutic interventions are mostly palliative, but BMT and SCT for aplastic anemia have been tried with variable success. Wide variation in clinical phenotype may occur in individuals, suggesting that other genetic or environmental factors may be contributory. The prognosis is worse for the X-linked and autosomal forms compared with the autosomal dominant form.

Hoyeraal-Hreidarsson (HH) syndrome is also associated with mutations in DKC1. Mutations in this gene have been described in patients with HH syndrome, which is characterized by intrauterine growth restriction, microcephaly, mental retardation, cerebellar malformation, and progressive bone marrow failure. Mucosal ulcerations have been found in a few patients, and some authorities hypothesize that HH syndrome may be a severe variant of DKC in which affected individuals die before the development of mucocutaneous findings. One study found that patients with HH syndrome have significantly shorter telomeres than those with the milder form of disease. The severe neurologic deficits in this severe form point to an important role of the DKC1 gene in brain function.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to offer prenatal or postnatal testing in appropriate individuals
• Failure to avoid the administration of drugs with pulmonary toxicity (eg, busulfan) and to shield the lungs of affected patients from radiation during BMT

Special Concerns

• DNA testing of the genes responsible for the X-linked and autosomal dominant forms of DKC makes several options possible, including prenatal testing, early diagnosis via postnatal testing (which may, in turn, enable harvesting of the patient's bone marrow before marrow failure), and carrier detection. Testing is available through the DKC registry and through  GeneDx. The following other resources may be helpful:
• • Dyskeratosis Congenita Registry: This contains the largest collection of DKC patients, with clinical and genetic information on more than 200 families from 40 different countries, comprising more than 350 affected individuals. The address is Hammersmith Hospital, Commonwealth Building, 4th Floor, Du Cane Road, London W12 ONN, United Kingdom. 
  • Dyskeratosis Congenita Society: The address is Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine and Dentistry, 4 Newark Street, London E1 2AT United Kingdom.
  • National Organization for Rare Disorders: The address is 55 Kenosia Avenue, PO Box 1968, Danbury, CT 06813-1968.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Editor-in-Chief, William James, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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12. Alter BP, Baerlocher GM, Savage SA, Chanock SJ, Weksler BB, Willner JP, et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood. Sep 1 2007;110(5):1439-47. [Medline].
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14. Giri N, Pitel PA, Green D, Alter BP. Splenic peliosis and rupture in patients with dyskeratosis congenita on androgens and granulocyte colony-stimulating factor. Br J Haematol. Sep 2007;138(6):815-7. [Medline].
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19. Mochizuki Y, He J, Kulkarni S, Bessler M, Mason PJ. Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. Proc Natl Acad Sci U S A. Jul 20 2004;101(29):10756-61. [Medline].
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Article Last Updated: Jan 28, 2008