Dyskeratosis Congenita

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Background

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, was first described in 1906. It 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.[1, 2]

Pathophysiology

To date, there are 14 genes that have been identified with DKC (ACD,DCK1, TERC, TERT, NOP10, NHP2, TINF2, USB1, TCAB1, CTC1, PARN,RTEL1, WRAP53, and C16orf57).[3, 4, 5] 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[6, 7] ; 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 regarding shortening length, protection, and replication.[8]

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.[9, 10, 11] Modification of dyskerin by SUMOylation has been shown to stabilize the protein. In addition, a mutation in the DKC1 gene is also found on exon 15, revealing a duplication, which adds a lysine residue on a polylysine tract on the C-terminus. All in all, there have been over 50 mutations found in DKC1.[12, 13, 14]

In the autosomal dominant form, mutations in the RNA component of telomerase (TERC) or telomerase reverse transcriptase (TERT) are responsible for disease phenotype.[7, 15, 16]

Defects in the NOP10 gene were found in association with autosomal recessive DKC.[17] 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.[18]

A heterozygous mutation was found on the conserved telomere maintenance component 1 gene (CTC1). This implication is also associated with a pleiotropic syndrome, Coats plus.[19]

Homozygous autosomal recessive mutations in RTEL1 lead to similar phenotypes that parallel with Hoyeraal-Hreidarsson (HH) syndrome. It is associated with short, heterogeneous telomeres. In the presence of functional DNA replication, RTEL1 mutations produce a large amount of extrachromosomal T-circles. Enzymes remove the T-circles and therefore shorten the telomere. RTEL1 has a role in managing DNA damage by increasing sensitivity; therefore, mutations on this gene cause both telomeric and nontelomeric causes of DKC.[20]

Patients with DKC have reduced telomerase activity and abnormally short tracts of telomeric DNA compared with normal controls.[21, 22] 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.[23]

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. In addition to the mutations that directly effect telomere length, studies also indicate that a DKC diagnosis should not be based solely on the length of the telomere, but also the fact that there are defects in telomere replication and protection.[8] In addition, revertant mosaicism has been a new recurrent event in DKC.[24]

Studies have also shown the significance of DNA methylation. A study in patients with DKC has shown changes in the CpG sites affiliated with the internal promoter region of the PR domain, specifically containing 8 (PRDM8) when compared with healthy control groups.[25]

Epidemiology

Frequency

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

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.

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.

In addition, studies have also found that not only are shortened telomeres associated with HH syndrome, but more so are telomere dysfunction and telomere protection.[14] The severe neurologic deficits in this severe form point to an important role of the DKC1 gene in brain function.

The biology of telomere shortening is not only associated with DKC, but it has comorbid associations with neuropsychiatric conditions. A cohort study with 6 pediatric and 8 adult subjects showed that 83% of the children and 88% of the adult had a comorbid neuropsychiatric condition. These conditions include schizophrenia, anxiety, intellectual disability, attention-deficit/hyperactivity disorder, adjustment disorder, mood disorders, or pervasive developmental disorders.[26]

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.

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.

The minimum requirement to diagnose DKS is the presence of 2 of 4 major features of the mucocutaneous triad and bone marrow failure 2 or more of the other somatic symptoms. Late diagnosis leads to inappropriate treatment and increased mortality/morbidity.[3]

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,[27] 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 retinal vasculopathy,[28] conjunctivitis, blepharitides, pterygium, proliferative retinopathy, frosted branch angiitis,[29] sparse eyelashes, ectropion, entropion and trichiasis.[4] Lacrimal duct stenosis resulting in epiphora (ie, excessive tearing) occurs in approximately 80% of patients.

Dental findings

DKC may also present with multiple dental changes, including caries, periodontal disease, and taurodontism.[4]

Skeletal system findings

Patients may have mandibular hypoplasia, osteoporosis, avascular necrosis, and scoliosis.

Gastrointestinal system findings

These may include esophageal webs, posterior pharyngeal wall squamous cell carcinoma, hepatic angiosarcoma,[30] hepatosplenomegaly, and cirrhosis.[31]

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.

Immunological defects

Decreased B cells, decreased natural killer (NK) cells, and dysgammaglobulinemia result in frequent infections. Immune defects are commonly found in conjunction with other DKC symptoms, but they have also been found to precede these symptoms.[12]  There has also been an association with hypothyroidism and hypogonadism.[32]

Causes

Mutations in DKC1 have been shown to cause the X-linked form of DKC. Specifically, the presence of a missense mutation on DKC1 in females has been shown to compromise telomerase RNA levels, putting them at increased risk for penetrant telomere phenotypes that may be associated with increased clinical morbidity.[33]

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,TERT, and TINF2 mutations in some cases, and NOP10, TERT, NHP2, and RTEL1 mutations have been associated with some cases of autosomal recessive DKC. Fifty percent of DKC patients with the clinical phenotypes have a mutation in their genes.[12]

Laboratory 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.[34] 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.[35]

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.[36]

The flow-FISH (fluorescent in situ hybridization) technique is also a cost-effective method that can also be used to measure telomere length.[37]

Imaging Studies

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

Dermoscopic Findings

The dermatoscope is another useful tool used to examine cutaneous findings associated with DKC. The image seen is typically described as pigmented lines made up of brown dots and globules arranged in a netlike pattern.[38]

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.

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 erythropoietin[39] ; however, the only long-term, curative option is hematopoietic stem cell transplantation (SCT). A 2016 study has shown that reduced-intensity conditioning, meaning chemotherapy without radiation for those receiving SCT, has improved overall survival post treatment.[40]

Oxymetholone has a 70% respond rate, yet adversely affects female patients through its strong masculinizing side effects. An androgen derivative drug that functions similarly to oxymetholone is danazol. This drug has been reported to have good hematological response and a better side effect profile for women.[3]

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.[41]

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.[42]

Drugs that cause pulmonary toxicity (eg, busulfan) and exposure to unnecessary radiation should be avoided in these patients.

Many DKC patients are at high risk of cancer; therefore, proton therapy has been a better treatment option than strong radiation, because of its ability to spare normal tissue and deliver a nontoxic form of radiation therapy.[43]

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.[44]

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.

Findings have shown that the internal fragment of dyskerin, GSE24.2, has been able to reduce the pathological effects caused by the DKC1 mutation.[45]

An association with sirtuins, specifically SIRT6, is another important target for DKC patients. It was found that sirtuins have properties to increase the longevity of proteins. Specifically with DKC patients, they has proven the ability to protect the telomeric chromatin shortening from deacetylation of histones at the replication sites.[46]

Surgical Care

To date, the only curative therapy is bone marrow transplantation; however, surgical preparation in itself can cause harm to the patient.[47]

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.

Patients who undergo hematopoietic stem cell transplantation (HSCT) for treatment should be warned of the increase risk of posttransplantation lymphoproliferative disorders.[48] A special case reported a patient with the TINF2 mutation treated with HSCT who experienced irreversible leukoencephalopathy.[49]

Medication Summary

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

Erythropoietin (Epogen, Procrit)

Clinical Context:  Erythropoietin stimulates division and differentiation of erythroid progenitor cells.

Filgrastim (Neupogen)

Clinical Context:  Filgrastim activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.

Class Summary

These agents are used to stimulate bone marrow in patients with cytopenia of one or more cell lineage.

Author

David T Robles, MD, PhD, FAAD, Director, Dermatology Division, Chaparral Medical Group

Disclosure: Nothing to disclose.

Coauthor(s)

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Jacquiline Habashy, DO, MSc, Resident Physician, Department of Dermatology, Western University of Health Sciences College of Osteopathic Medicine of the Pacific

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Additional Contributors

Jean Paul Ortonne, MD, Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France

Disclosure: Nothing to disclose.

Philip Fleckman, MD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington

Disclosure: Nothing to disclose.

Acknowledgements

Jonathan M Olson, MD Fellow, Division of Dermatology, University of Washington Medical Center

Jonathan M Olson, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

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