Dyskeratosis Congenita
Patient Information
Characteristics
Background and History
This is a group of conditions that have their onset at birth or shortly thereafter. Signs and symptoms are found throughout the body, many of which are life threatening. All are caused by rare gene mutations that impact the structure of chromosomes of a type often associated with aging.
Clinical Correlations
Evidence of this condition can be seen throughout the body, both internally and externally. However, there is considerable variability from patient to patient. Some children have evidence of the disease but the more serious manifestations are seen by young adulthood. Most individuals have signs of premature aging such as grey hair and hair loss at a young age. Far more serious, however, is the occurrence of bone marrow failure, scarring of the liver and lungs, and susceptibility to cancer, especially leukemia. The nails and teeth may fail to develop normally. There may be a lacy pattern to the normal pigmentation of the skin. The oral tissues often develop white plaques. The eyelids may become scarred and distorted and the cornea (windshield of the eye) likewise can become scarred and sometimes infected. The eyelashes can be sparse and often the lashes drag across the cornea causing severe discomfort and additional scarring. Most patients have normal intelligence but cognitive and developmental delays are present in a few individuals.
Genetics
Inheritance
Mutations in at least 7 genes can cause dyskeratosis congenita. It is inherited in three major patterns: autosomal dominant (in which the condition is passed from an affected parent to each child with a 50% risk), autosomal recessive (both parents carry a single copy of the mutation and their children have a risk of 25% that each child will inherit the condition), and sex-linked recessive (only mothers transmit the disorder to their sons and females do not inherit it).
Pedigree
Autosomal dominant
Autosomal dominant disorders require only one mutation for the disease to be expressed. Since an affected parent has two chromosomes, only one of which has the mutant gene, parents can expect that half (50%) of their children will receive that one and inherit the disease. It is common for individuals that inherit the mutation, however, to not have evidence of the disease (nonpenetrance).
Autosomal dominant inheritance leads to a vertical pattern of transmission
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
X-linked recessive, father affected
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the father, he has the disease since his only X chromosome is mutant and he has no normal X to blunt the effects of the abnormal gene. His sons only receive his Y chromosome and thus are all normal. However, all his daughters receive his one and only X chromosome and will be healthy 'carriers'. Thus such males will have no affected children but half their grandsons from those daughters will have the same disease as he does.
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the father, he has the disease since his only X chromosome is mutant and he has no normal X to blunt the effects of the abnormal gene. His sons only receive his Y chromosome and thus are all normal. However, all his daughters receive his one and only X chromosome and will be healthy 'carriers'. Thus such males will have no affected children but half their grandsons from those daughters will have the same disease as he does.
X-linked recessive, carrier mother
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the mother, she usually does not have the disease since the normal X chromosome without the mutation neutralizes the mutation in the abnormal X chromosome. However, half her sons will inherit the mutation-containing X chromosome and therefore have the X-linked disease. Half the daughters will inherit the mutation-bearing X chromosome and are usuallly healthy 'carriers'.
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the mother, she usually does not have the disease since the normal X chromosome without the mutation neutralizes the mutation in the abnormal X chromosome. However, half her sons will inherit the mutation-containing X chromosome and therefore have the X-linked disease. Half the daughters will inherit the mutation-bearing X chromosome and are usuallly healthy 'carriers'.
Diagnosis and Prognosis
The diagnosis is usually made by a multidisciplinary team of pediatricians, dermatologists, ophthalmologists, dentists, and many other specialists. Lifespan is limited but highly variable depending upon the organs involved. Among the life-threatening disabilities, failure of the bone marrow is the most responsible for premature death.
Patients with this condition require lifelong surveillance for cancer, eye disease, liver scarring and lung function. Stem cell bone marrow transplantation can be lifesaving but its effectiveness is sometimes limited to a finite period of time.
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