History of DC:
1906- German Dr.'s report "poiklodermia vascularis atrophicans"
1908-
Jacobi reports "abnormal skin, sparse hair, lattice work rash"
1910-Zinser reports on two brothers with
skin and oral abnormalities
1926- report by Engmart
1930-report by Cole/ Dyskeratosis Congenita
1956-report
by Costello and Bunche
*to this point DC seen as dermatological disease*
1963- first female patient recorded
1969-
first autosomal dominant family recorded
Literature Reviews of DC:
Number of
patients:470
Families: 313
Males only affected: 215
Two or more affected: 51 (x linked)
Sporadic
affected female: 164
One or more females: 98 (autosomal)
Zinnser (1910)- Engman- Cole note skin pigmintation/
nail dystrophy/ and leukoplakia
Bone marrow failure rate 85.5%
Leukoplakia 78%
Skin abnormalities
89%
Nail abnormalities 88%
The probability of getting cancer increases with age.
There was a
good reponse to ozymethalone for transplant patients.
DC is a disorder of stem cell function.
Skin fibroblast
are abnormal.
Chromosomal rearrangements can lead to cancer.
Genentic Characteristics:
X
linked recessive (boys)
1986 Michael Conner thought disease might be located at _____ (missed this).
1998....there
are many mutations of gene.
Hayerall Hreidarsson Syndrome (H.H.) might be a severe DC variant
DKC1 makes
keratin.
Dyskerin goes along with TERT
DKC1 helps with telomere maintenance. Early loss of cells
leads to premature aging.
DC has features of Aplastic Anemia
5% of DC patients have A.A.
DC
is very heterogeneous.
Classic DC (1910), H.H (1999), and combination of A.A., MDA, Pulmonary Fibrosis (2007) PNH
(2004) make a triad for diagnosis...difficult because some elements are cyrptic
15 patients older than 15 when diagnosed
17
patients younger than 15 when diagnosed
14 patients with DC and A.A.
11 with H.H.
TERT- telomerase
reverse transcripts
Mutations in TINF2 are clusetered in very short telomeres.
Pure telomerease
difficiency causes mose severe H.H. syndrome.
Shelterin protects ends of chromosomes.
Deffective telomere
maintenance in humans leads to premature aging, bone marrow failure, and increased malignancy.
In TINF2 , all but
one case was sporadic.
Therapies and Surveillance:
Bone Marrow Failure, MDS, AML, Solid
Tumors, Pulmonary Fibrosis, Osteopenia/ Osteoperosis, Hip and Shoulder Replacement...all problems associated with DC
1910-literature
2008-
44 cancers at substancially younger than average age
DC- patients with DC are 10 times more likely to get all cancers
and 7 times more likely to get solid tumors.
50%- Bone marrow failure is the first event....starts earlier than
patients with Fanconi's Anemia
When to Treat: Counts are low, leukemia, MDS
Stem Cell Transplant:
androgens, GCSF, transfusions, gene therapy in the future
Patients don't respond to: ATG or CSA (immunosuppresents),
androgens at high doses, androgens and GCSF together
Types of cancer DC patients are succeptible to: dental, nasal,
anogenital
Monitoring of healthy DC patients: blood counts every 4-6 months, annual bone marrow, liver enzymes every
4-6 months (androgens), ultrasounds
