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366 Part IV Disorders of Hematopoietic Cell Development

with a severe form of DC. However, heterozygosity for mutations in first; mucosal leukoplakia and excessive ocular tearing appear later;
TERT is associated with a milder phenotype, late presentation, severe and by the mid-teens, the serious complications of BM failure and
aplastic anemia without physical malformations, isolated pulmonary malignancy begin to develop. In a portion of the patients, BM
fibrosis, isolated hepatic fibrosis, or a combination of these clinical abnormalities appear before or without the skin manifestations.
manifestations. Heterozygosity for mutations in TERC is associated The DC Registry data from England have detailed the prevalence
with a milder phenotype, late presentation and severe aplastic anemia, of somatic abnormalities in families with classic DC. Cutaneous
or MDS without physical malformations. Coats plus syndrome is findings are a typical feature of the syndrome. Lacy reticulated skin
caused by mutations in the CTC1 gene. It is characterized by retinal pigmentation affecting the face, neck, chest, and arms is a common
telangiectasia and exudates, intracranial calcification, leukodystrophy, finding (89%). The degree of pigmentation increases with age and
brain cysts, osteopenia, gastrointestinal bleeding, and portal hyper- can involve the entire skin surface. There may also be a telangiectatic
tension caused by the development of vasculature ectasias in the erythematous component. Nail dystrophy of the hands and feet is
stomach, small intestine, and liver. Some patients with this disease the next most common finding (88%) (Fig. 29.4). It usually starts
have the additional manifestations of DC, which include sparse and with longitudinal ridging, splitting, or pterygium formation and may
gray hair, dystrophic nails, and anemia. Telomeres are short. progress to complete nail loss. Leukoplakia usually involves the oral
DC cells are characterized by very short telomeres. In several mucosa (78%), especially the tongue (Fig. 29.5), but may also be seen
acquired and IBMFSs, telomeres are short compared with those from in the conjunctiva, anal, urethral, or genital mucosa. Hyperhidrosis
age-matched control participants. However, because the telomerase of the palms and soles is common, and hair loss is sometimes seen.
function is profoundly impaired in DC, the telomeres in this disease Eye abnormalities are observed in approximately 50% of cases. Exces-
are very short (lower than the first percentile of the normal range). sive tearing (epiphora) secondary to nasolacrimal duct obstruction is
Shortening of telomeres results in cellular senescence, apoptosis (“cel- common. Other ophthalmologic manifestations include conjunctivi-
lular crisis”), or chromosome instability. However, some cells may tis, blepharitis, loss of eyelashes, strabismus, and cataracts and optic
survive the crisis by harboring compensatory genetic mutations that atrophy. Abnormalities of the teeth, particularly an increased rate of
confer proliferative advantage and neoplastic potential. dental decay and early loss of teeth, are common. Skeletal abnormali-
DC is a chromosome “instability” disorder of a different type than ties such as osteoporosis with recurrent long bone fractures, avascular
FA. Results of clastogenic stress studies of DC cells are typically necrosis, abnormal bone trabeculation, scoliosis, and mandibular
normal. There is no significant difference in chromosomal breakage hypoplasia are seen in approximately 20% of cases. Genitourinary
between patient and normal lymphocytes with or without exposure abnormalities include hypoplastic testes, hypospadias, phimosis, and
to bleomycin, DEB, MMC, or γ-radiation. This contrasts sharply urethral stenosis and horseshoe kidney. Gastrointestinal findings,
with FA cells and distinguishes one disorder from the other. However, such as esophageal strictures, hepatomegaly, or cirrhosis, are seen in
metaphases of cultured patient peripheral blood cells, BM cells, and 10% of cases. A subset of patients develops pulmonary fibrosis with
fibroblasts show numerous spontaneous unbalanced chromosome reduced diffusion capacity or a restrictive defect. In fatal cases, lung
rearrangements such as dicentrics, tricentrics, and translocations. tissue shows pulmonary fibrosis and abnormalities of the pulmonary
These are probably caused by short telomeres. vasculature. Hepatic fibrosis may also occur. Vasculopathy of the gut,
Most studies of the pathogenesis of the aplastic anemia in DC kidneys, liver, chest, or other organs is seen in severe cases and may
have shown a marked reduction or absence of CFU-GEMM, BFU-E, cause massive bleeding.
CFU-E, and CFU-GM. Long-term DC BM cultures have shown that
hematopoiesis is severely defective in all patients with a low frequency
of colony-forming cells. The function of DC BM stromal cells is Laboratory Findings
normal in their ability to support growth of hematopoietic progeni-
tors from normal BM, but generation of progenitors from DC BM Peripheral Blood, Bone Marrow, and
cells seeded over normal stroma is reduced, suggesting that the defect Immunologic Findings
in DC is of stem cell origin. Telomerase is activated in HSCs and The incidence of cytopenias caused by BM failure has been reported
might be necessary for HSC self-renewal capacity and prevention of in up to 90% of patients. Severe aplastic anemia occurs in about 50%
senescence. The BM failure in this disorder may be a result of a of patients. When BM failure is evident, most patients already have
progressive attrition and depletion of HSCs. This is supported by physical manifestations of DC, but this is variable. The initial hema-
−
+
studies showing reduced number of CD34 /CD38 in patients’ bone tologic change is usually thrombocytopenia, anemia, or both followed
marrows. Alternatively, the BM dysfunction may represent a failure by full-blown pancytopenia caused by aplastic anemia. The RBCs are
of replication, maturation, or both. often macrocytic, and the HbF can be elevated. It is noteworthy that
iPSCs from patients with DC have been shown to have defects in early BM specimens and biopsies may be normocellular or hypercel-
telomere elongation during programming in a mechanism that is lular; however, with time, the cellular elements decline with a sym-
concordant with the mutated gene in the patients. In iPSCs from metric decrease in all hematopoietic lineages. Ferrokinetic studies at
patients with heterozygous mutations in TERT, telomerase activity is this point are consistent with aplastic anemia. Some patients with
directly affected. iPSCs from patients with mutant DKC1 manifest DC, particularly those with DKC1 mutations, have immunologic
reduced telomerase activity because of impaired telomerase assembly. abnormalities, including reduced immunoglobulin levels, reduced
iPSCs from a patient with TCAB1 mutations are characterized by B- or T-lymphocyte numbers, and reduced or absent proliferative
mislocalization of telomerase from Cajal bodies to nucleoli. It was responses to PHA. Severe immunodeficiency necessitating HSCT has
also shown that extended culture of DKC1-mutant iPSCs leads to also been described.
progressive telomere shortening and eventual loss of self-renewal. In On imaging studies, a small-sized cerebellum may give a clue to
contrast, another group studied telomerase reactivation and TERC the diagnosis in patients with atypical presentations. Imaging of the
regulation during reprogramming and showed that reprogramming skeleton usually shows nonspecific osteopenia.
restores telomere elongation in DC cells despite genetic lesions affect- Telomere length is a useful screening testing for DC. In the vast
ing telomerase. This group showed that TERC upregulation is a majority of patients, the telomeres are very short (i.e., lower than the
feature of the pluripotent state and that several telomerase compo- first percentile adjusted to age).
nents are targeted by pluripotency associated transcription factors.
Cancer Predisposition
Clinical Features
Cancer develops in about 10% to 15% of patients, usually in the
Clinical manifestations in dyskeratosis congenita often appear during third and fourth decades of life. Similar to FA, patients with DC can
childhood. The skin pigmentation and nail changes typically appear develop solid tumors as well as MDS/AML. However, the incidence