Dyskeratosis Congenita

Dyskeratosis congenita (DKC), also called Zinsser-Cole-Engman syndrome,^[1][2]:570 is a rare progressive congenital disorder with a highly variable phenotype.^[3] The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, but these components do not always occur.^[3] DKC is characterized by short telomeres. Some of the manifestations resemble premature aging (similar to progeria). The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.^[3]

Characteristics

DKC can be characterized by cutaneous pigmentation, premature graying, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers, and predisposition to cancer. Many of these symptoms are characteristic of geriatrics, and those carrying the more serious forms of the disease often have significantly shortened lifespans.

Clinical features

Age: 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.

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

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 (e.g., 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 (e.g., 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 (i.e., 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, enteropathy, and cirrhosis.

Genitourinary system findings:: Hypospastic testes, hypospadias, and ureteral stenosis are reported.

Female carriers: Female carriers 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.

Pathophysiology

Main article: Ribosomopathy

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

 

To diagnose aplastic anemia, your doctor may recommend:

• Blood tests. Normally, red blood cell, white blood cell and platelet levels stay within a certain range. Your doctor may suspect aplastic anemia when all three of these blood cell levels are very low.
• Bone marrow biopsy. To confirm a diagnosis, you’ll need to undergo a bone marrow biopsy. In this procedure, a doctor uses a needle to remove a small sample of bone marrow from a large bone in your body, such as your hipbone. The bone marrow sample is examined under a microscope to rule out other blood-related diseases. In aplastic anemia, bone marrow contains fewer blood cells than normal.

Once you’ve received a diagnosis of aplastic anemia, you may need additional tests to determine an underlying cause.

Related

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• Blood transfusion
• Bone marrow biopsy
• Headache
• Nosebleeds
• Fatigue
• Shortness of breath
• Dizziness

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