Zinsser-Engman-Cole syndrome, DKC, Hoyeraal-Hreidarsson syndrome, bone marrow failure, congenital dyskeratosis, reticular skin hyperpigmentation, nail dystrophy, oral leukoplakia, pancytopenia, testicular atrophy



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 305000), autosomal dominant (MIM 127550), and autosomal recessive (MIM 224230) subtypes. DKC is related to telomerase dysfunction; both genes associated with this syndrome (DKC1 and TERC) 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. In the autosomal dominant form, mutations in the RNA component of telomerase (TERC) are responsible for disease phenotype. In persons with autosomal dominant DKC and in terc-/- knockout mice, genetic anticipation (ie, increasing severity with each successive generation) has been reported.



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.



An analysis of 228 families in the DKC registry found that in 63% of patients, mutations could not be found in either dyskerin or DKC1, suggesting that other genes associated with this syndrome are as yet, unidentified.





Frequency:





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

Mortality/Morbidity: In a recent 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.

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. A recent 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.