Continuing Education Activity

Dyskeratosis congenita, also known as Zinsser-Engman-Cole syndrome, is an uncommon genodermatosis classically associated with the triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Most affected by the syndrome have a defect in the dyskeratosis congenita 1 (DKC1) gene which encodes the dyskerin protein involved in telomere maintenance. Inheritance is most commonly x-linked recessive, and subsequently, males are affected three times more frequently than females. Clinical findings vary widely and may include atrophic wrinkled skin, eye disease, and bone marrow failure. Treatment is difficult and largely depends on an interprofessional approach. This activity describes the pathophysiology, evaluation, and management of dyskeratosis congenita and highlights the role of the interprofessional team in the care of affected patients.

Objectives:

• Describe the pathophysiology of dyskeratosis congenita.
• Review the presentation of dyskeratosis congenita.
• Outline the treatment options for dyskeratosis congenita.
• Explain the importance of improving coordination amongst the interprofessional team to enhance care for patients affected by dyskeratosis congenita.

Introduction

Dyskeratosis congenita (DKC), which is also known as Zinsser-Engman-Cole syndrome, is a genodermatosis originally described by Zinsser in 1906.[1] It is an uncommon syndrome classically associated with the triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation.[2] The majority of people affected by the syndrome have a defect in the DKC1 gene encoding the dyskerin protein which is involved in telomere maintenance.[3] Inheritance is most commonly x-linked recessive, and subsequently, males are three times more likely to be affected than females. Clinical findings vary widely and may include atrophic wrinkled skin, eye disease, and bone marrow failure. Treatment is difficult and largely requires an interprofessional approach.

Etiology

The defective preservation of telomeres causes dyskeratosis congenita.[3] Telomeres are sequences of nucleotides at the ends of chromosomes that protect the chromosomes from progressively shortening after multiple rounds of DNA replication. The genes found to be defective in DKC are all related to telomere preservation.[4] The most common gene, DKC1, encodes for dyskerin protein and is inherited in an x-linked recessive fashion. Dyskerin is directly involved in stabilizing an enzyme called telomerase that is responsible for catalyzing a reaction that sustains the length of telomeres.[5][6][7] Without proteins like dyskerin, the telomeres progressively shorten which causes the cells involved to undergo apoptosis or senescence. The instability of telomeres may also induce carcinogenesis, especially in rapidly dividing cells. Numerous genes, including TINF2, TERC, TERT, C16orf57, NOLA2, NOLA3, WRAP53/TCAB1, and RTEL1 are mutated in DKC.

Epidemiology

Males are affected more than females in a ratio of approximately 3:1, which corresponds with x-linked recessive being the most common inheritance pattern.[8][9] Female carriers have been reported to have milder phenotypes, although more severe phenotypes have also been reported in carriers.

Pathophysiology

The clinical phenotype produced by telomere shortening with subsequent senescence, apoptosis, or carcinogenesis in dyskeratosis congenita varies greatly. Classically the triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation is seen.[10] Nail dystrophy usually consists of thin dystrophic nails with longitudinal ridging, and may eventually develop dorsal pterygium.[11] Reticular hyperpigmentation is usually in a fine, lace-like pattern and frequently occurs on the face, upper trunk, and upper arms. Areas of hyperpigmentation may be surrounded by hypopigmented areas, as well as telangiectasias and atrophic patches of skin. Oral leukoplakia is a premalignant condition commonly seen on the tongue (but may occur on other parts of mucosa) in those with DKC.[9] Up to 90% may also be affected by bone marrow failure.

Histopathology

Histologic findings of dyskeratosis congenita are generally non-specific. Commonly, there are telangiectasias seen superficially, along with hyperkeratosis and atrophy of the epidermis.[12] It is not uncommon to see many melanophages in the superficial dermis. Infrequently there is a vacuolar change in the basal layer of the epidermis, along with a mild interface lymphocytic infiltrate. Fibrotic changes may also be seen in the superficial dermis.

History and Physical

Generally, patients with dyskeratosis congenita first develop presenting signs of dystrophic nails between the ages of 5 to 13 years.[2] Nail dystrophy usually consists of longitudinal ridging, and may eventually develop dorsal pterygium. During late childhood, skin changes start to develop. Reticular hyperpigmentation is usually in a fine lace-like pattern and frequently occurs on the face, upper trunk, and upper arms. However, other areas such as the thighs may also develop pigmentation changes. Areas of hyperpigmentation may be surrounded by hypopigmented areas, as well as telangiectasias and atrophic patches of skin.[13] Hyperhidrosis, acrocyanosis, keratoderma, the atrophic wrinkled skin of bony prominences as well as face and genitals, as well as thin graying hair may also be seen. Premalignant leukoplakia, along with blisters, erosions, and tooth decay may affect the mouth. The development of the musculoskeletal and neurological systems may be affected by short stature and developmental delay, respectively.[14] Osteoporosis and avascular necrosis have also been described. Eyes may develop ectropion or entropion with subsequent corneal abrasions. Gastrointestinal and genitourinary systems sometimes are affected by stenosis, malignancy, or hepatic fibrosis.[9] Lungs can also develop fibrosis. Bone marrow failure, myelodysplastic syndrome, or leukemia can cause changes in blood counts.[15]

Evaluation

Evaluation and diagnosis is mainly a combination of history and physical examination, biopsies of skin, mucosa, or bone marrow, and flow-fluorescence in situ hybridization (FISH). Biopsies of skin and mucosa show histological characteristics listed above along with possible malignancy-associated changes. Bone marrow biopsy shows associated bone marrow failure, myelodysplastic, or leukemia changes.[16] FISH shows telomere shortening in leukocytes. Genetic analysis may reveal one of the correlated genetic defects listed above.

Treatment / Management

Treatment often involves an interprofessional approach. Surveillance for associated complications is paramount. Lifelong annual skin screening, as well as sun protection, is warranted to detect and protect from cutaneous squamous cell carcinoma. Dental examinations twice per year are recommended by a dental professional to screen for oral malignancies. Yearly examinations by an otolaryngologist may be warranted to screen for squamous cell carcinoma. Gastroenterologists' involvement with screening endoscopies of the esophagus and/or colon for strictures or malignancies may be beneficial. Bone marrow examination should be performed at the time of diagnosis, and then accordingly pending biannual blood counts to screen for bone marrow failure or malignancy changes. Pulmonary function tests should be done yearly to screen for signs of fibrosis. Calcium and vitamin D levels should be regularly checked and treated accordingly to prevent osteoporosis and/or fractures. Eyes may develop complications like a corneal abrasion secondary to associated eye problems like ectropion. Thus, regular eye examinations may be beneficial. Ultrasound of the liver should be done regularly, along with annual liver function tests.

Transfusions may help intermittently alleviate bone marrow failure.  Medical treatment of bone marrow failure with stem cell transplantation is done when severe, but stem cell transplantation still has a poor long-term survival rate.[17] Androgens, as well as granulocyte colony-stimulating factors (G-CSF), are sometimes used before stem cell transplantation. However, androgens are associated with tumors of the liver, and added G-CSF increases the risk of splenic rupture.[18]

Patients should be encouraged to not participate in any carcinogenic habits or practices such as smoking, alcohol, or unprotected sun exposure. Surgical interventions should be acted upon accordingly.

Differential Diagnosis

Rothmund-Thomson syndrome and epidermolysis bullosa simplex with mottled pigmentation have similar poikiloderma. Dermatopathia pigmentosa reticularis, as well as Naegeli-Franceschetti-Jadassohn syndrome, may have similar reticulate hyperpigmentation. Fanconi anemia has a similar presentation to DKC but is due to chromosomal rearrangement and breakage. Patients with graft-versus-host disease have poikiloderma, and mucosal changes are lichen planus-like.

There are also a few variants of DKC that have findings of DKC with a few other specific characteristics. Hoyeraal-Hreidarsson syndrome is like DKC but also has cerebellar hypoplasia and intrauterine growth restriction.[19] Cerebellar hypoplasia and exudative retinopathy distinguish Revesz syndrome.

Prognosis

Patients with dyskeratosis congenita have a shortened lifespan. Causes of death from most to least common are bone marrow failure, lung disease, and malignancies.

Enhancing Healthcare Team Outcomes

Dyskeratosis congenita is best managed by an interprofessional team that includes oncology nurses. Because of the high risk of malignancy, patients must not only be screened regularly but should be educated on the harms of nicotine, alcohol, and too much sunlight.