Dyskeratosis congenita is a genodermatosis
characterized by hyperpigmentation of the skin, dystrophy of the nails,
leukoplakia of mucous membranes, and progressive pancytopenia.
Zinsser-Cole-Engman Syndrome; Dyskeratosis Congenita
Unknown, but approximately 200 cases have been
X-linked recessive disorder that affects
almost exclusively males (male-to-female ratio = 10:1). However, there are
rare case reports of autosomal recessive and autosomal dominant inheritance.
The mutant gene has been mapped to Xq28 and encodes for a 514-amino-acid
protein called dyskerin.
Dyskerin seems to have a major role in the
regulation of cell proliferation (biogenesis of ribosomes and
pseudouridylation of recombinant RNA messengers) and therefore primarily
affects rapidly proliferating tissues (e.g., skin, gastrointestinal mucosa,
and bone marrow).
The phenotype is highly variable; however, bone marrow
failure and the triad of reticulated hypopigmentation and hyperpigmentation
of the skin, nail dystrophy, and mucocutaneous leukoplakia is typical for
dyskeratosis congenita. The onset of skin and nail changes usually is around
age 10 years and precedes epiphora and mucocutaneous changes. Although signs
of bone marrow failure and malignancy begin to develop in the early to
mid-teens, manifestation before age 10 years is not uncommon.
Changes in skin pigmentation (reticulated
hypopigmentation and hyperpigmentation) often in combination with
telangiectases are more pronounced on the flexures of the big joints, neck,
and axillae, and along the inner thigh. Nail dystrophy is progressive and
initially may result in longitudinal ridges and finally in complete loss of
nails. The hair may be affected, leading to baldness. Leukoplakia most often
occurs in the mouth but also may affect other mucosal sites (e.g.,
esophagus, vagina, anus, urethral meatus, and lacrimal duct resulting in
strictures with dysphagia, dyspareunia, dysuria, and epiphora) and is
associated with an increased risk for malignancies (most often squamous cell
carcinoma). In male patients, testes often are undescended and hypoplastic.
Dental abnormalities (extensive cavities, premature loss) and increased
fragility of the bones caused by abnormal metaphyseal trabeculation and
osteoporosis have been reported. Lacrimal duct stenosis or atresia is
present in up to 80% of patients and leads to continuous epiphora. Up to
90% of patients suffer from bone marrow failure; rarely the diagnosis of
aplastic anemia precedes the diagnosis of dyskeratosis congenita. Some
patients develop myelodysplasia and acute myeloid leukemia. Pancytopenia
or complications related to bone marrow transplant (high rate of pulmonary
complications) are responsible for approximately 70% of the premature
deaths in this population. Approximately 20% of these patients show
pulmonary changes with progressive pulmonary fibrosis and restrictive lung
disease, arteriovenous shunting with microvascular changes, and reduced
diffusion capacity. It has been hypothesized that these underlying changes
are, at least in part, responsible for the high rate of pulmonary
complications in association with bone marrow transplant. Liver cirrhosis
with a nutmeg aspect may be present, and mucosal ulcerations may cause
gastrointestinal hemorrhage. Elevated immunoglobulin levels and increased
risk of opportunistic infections have been reported. Additional findings
(each in approximately 15-20% ...