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Chapter 29 Inherited Bone Marrow Failure Syndromes 365

conditioning regimen; (2) increased sensitivity to chemotherapy and reported as males. However, with better understanding and broaden-
radiation, resulting in massive apoptosis in various organs; or (3) ing of the clinical spectrum of the disease and with more autosomal
performing HSCT relatively late and at an advanced disease stage. cases being identified, the proportion of males is much lower.
Results of reduced-intensity HSCT regimens have been published
by two groups. In a study from Cincinnati published in 2008, six
patients with severe cytopenia with or without clonal BM cytogenetic Pathobiology
abnormalities and one patient with AML in remission were trans-
planted. The conditioning regimen included Campath-1H, fludara- Multiple genes have been associated with DC (see Table 29.1). DC
bine, and melphalan. Four patients received matched related MB, genes encode components of the telomerase complex (TERT, DKC1,
two received unrelated peripheral blood, and one had unrelated BM. TERC, NOP10, and NHP2), T-loop assembly protein (RTEL1),
All patients engrafted and were alive at a median follow-up of 548 telomere capping (CTC1), the telomere shelterin complex (TINF2),
(range, 93–920) days. In another study from Hannover, three patients and the telomerase trafficking protein (TCAB1); all are critical for
received conditioning with fludarabine, treosulfan, and melphalan in telomere maintenance. The X-linked recessive disease is a common
addition to Campath-1H or rabbit ATG. Donor sources were form of DC. It was originally estimated to comprise as many as 75%
matched sibling BM, matched unrelated BM, or 9/10 matched cord of DC cases, but with the identification of more DC genes and more
blood. The indications were severe BM failure (n = 2) and MDS (n patients with autosomal dominant inheritance, the true incidence is
= 1). The patients who received BM cells survived at 9 and 20 months approximately 30%. The X-linked disease is caused by mutations in
posttransplant. The other patient died of idiopathic pneumonitis. DKC1 on chromosome Xq28. DKC1 encodes for the protein dys-
kerin. Dyskerin associates with the H/ACA class of RNA. Dyskerin
binds to the 3′ H/ACA small nucleolar RNA-like domain of the
Future Directions TERC component of telomerase. This stimulates telomerase to syn-
thesize telomeric repeats during DNA replication. Dyskerin is also
Mutant SBDS causes SDS in 90% of clinically diagnosed patients. involved in maturation of nascent rRNA. It binds to small nucleolar
The hunt for additional causative mutant genes in the other 10% is RNA through the 3′ H/ACA domain and catalyzes the isomerization
still underway. Identification of such gene(s) may expand our under- of uridine to pseudouridine through its pseudouridine synthase
standing of pathogenesis. Several other clinical and basic research homology domain. This might be the mechanism for impaired
questions in SDS must be addressed. First, the various biochemical translation from internal ribosome entry sites seen in mice and
functions of the SBDS gene require further study. How SBDS protein human DC cells.
maintains normal hematopoiesis and protects from apoptosis as well Several genes are mutated in families with autosomal dominant
as cancer is unclear. The natural history, and risk factors for the inheritance. TINF2 is probably the most commonly mutated gene in
development of complications need to be determined. There is also this group and accounts for approximately 11% to 25% of the DC
a need to understand the mechanism for the heightened sensitivity families. TINF2 protein is part of the shelterin protein complex that
of patients with SDS to chemotherapy and irradiation and to develop binds to and protects telomeres by allowing cells to distinguish
low-intensity regimens for HSCT. Research should continue on the between telomeres and regions of DNA damage. In the complex,
efficacy of innovative drugs such as antiapoptotic agents in increasing TINF2 binds to TRF1, TRF2, POT1, TPP1, and RAP1.
the growth potential of HSCs and relieving the severity of cytopenia. Heterozygous mutations in TERT also results in autosomal domi-
Determining risk factors and molecular events during malignant nant disease. TERT encodes for the enzyme component of telomerase.
myeloid transformation might prompt strategies for prevention and Telomerase is a ribonucleoprotein polymerase that maintains telomere
screening for complications. ends by synthesis and addition of the telomere repeat TTAGGG at
the 3′-hydroxy DNA terminus using the TERC RNA as a template.
Heterozygous mutations in the TERC gene are another cause of
Dyskeratosis Congenita autosomal dominant DC. TERC encodes for the RNA component
of telomerase and has a 3′ H/ACA small nucleolar RNA-like domain.
Background The autosomal recessive forms of DC are caused by biallelic
mutations in NOP10, NHP2, TERT, or TCAB1. Interestingly, bial-
DC is an inherited multisystem disorder of the mucocutaneous and lelic mutations in TERT and TERC have also been associated with a
hematopoietic systems in association with a wide variety of other DC. In the latter families, parents might be affected with a milder
somatic abnormalities. Originally, it was considered a dermatologic disease. In the telomerase complex, the H/ACA domain of nascent
disease and was termed Zinsser-Cole-Engman syndrome. The tradi- human telomerase RNA forms a preribonucleoprotein with NAF1,
tional diagnostic ectodermal triad consists of reticulate skin pigmen- dyskerin, NOP10, and NHP2. Initially, the core trimer dyskerin-
tation of the upper body, mucosal leukoplakia, and nail dystrophy. NOP10-NHP2 forms to enable incorporation of NAF1, and efficient
The skin and nail findings usually become apparent during the first reverse transcription of telomere repeats. NOP10 and NHP2 also
10 years of life, but the oral leukoplakia is observed later. These play an essential role in the assembly and activity of the H/ACA class
manifestations tend to progress as patients get older. of small nucleolar ribonucleoproteins that catalyze the isomerization
Hematologic manifestations were subsequently recognized to be of uridine to pseudouridine in rRNAs.
a major component of the syndrome and are responsible for substan- TCAB1 facilitates trafficking of telomerase to Cajal bodies. Muta-
tial morbidity and mortality. Indeed, the full diagnostic dermatologic tions in this gene impair this trafficking activity and lead to misdirec-
triad is present only in about 46% of patients, but BM failure of tion of telomerase RNA to nucleoli; thereby preventing elongation
varying severity is reported in up to 90% of cases. With the recent of telomeres by telomerase.
advances in understanding the molecular basis of the disease, patients DC with hemizygous mutations in the DKC1 on the X chromo-
with hematologic abnormalities but without dermatologic findings some, or heterozygous TINF2 and biallelic TERT mutations can
have been identified that dramatically changed the historical defini- result in a severe form of DC called Hoyeraal-Hreidarsson syn-
tion of the disease. Patients with DC also have a predisposition to drome. It is characterized by hematologic and dermatologic manifes-
develop solid tumors and MDS/AML. tations of DC in addition to cerebellar hypoplasia. Immune deficiency
is common when this syndrome is caused by DKC1 mutations.
Revesz syndrome is a combination of classical manifestations of DC
Epidemiology and exudative retinopathy. It is caused by mutations in TINF2 and
is an autosomal dominant form of the disease. TINF2 mutations have
The estimated incidence of DC in childhood is about 4 cases per also been found in children with severe aplastic anemia without
million per year. In older literature, most patients with DC were physical anomalies. Biallelic mutations in TERT are also associated