In the evaluation of patients with aplastic anemia in which an inherited disease is suspected and FA has been ruled out, the next syndrome to consider is DC (MIM 305000, 127550, 224230). As with FA, the first descriptions involved physical findings. In fact, DC was considered a form of ectodermal dysplasia, and was called “Zinsser-Cole-Engman” syndrome after the physicians who provided the first descriptions from 1910–1930. Many case reports followed in the dermatologic literature, and only in the 1960s was an association made between DC and hematologic problems. As discussed below, the definition of DC continues to evolve.
The male:female ratio was 3.2:1 among 550 cases in the literature; it was 4.2:1 for those cases reported from 1910 through 1999, and 2.4:1 for those in the last decade (p = 0.009), reflecting the bias that DC was considered to be an X-linked recessive disorder until the recent discovery of autosomal dominant and recessive genes (see below). Seventy-five % of the cases in the literature had some physical abnormality. The diagnostic triad, defined from the beginning, includes dystrophic nails, lacy reticular pigmentation, and oral leukoplakia (, ). These findings in literature cases comprised 70%, 67%, and 47% respectively, and 75% of reported patients had at least one of these; 46% had all 3. The next most common physical problems were constant tearing from lacrimal duct stenosis, sparse and/or early grey hair and eyebrows, poor dentition, and developmental delay. An important early sign is esophageal stenosis in 8%, requiring dilatation. Osteopenia and early hip replacement due to avascular necrosis in unusually young adults occurred in up to 10%. Important but less frequently noted problems include pulmonary fibrosis, meatal stenosis, and neurologic findings. Major ophthalmologic findings include proliferative and exudative retinopathy, both of which can lead to retinal detachment.11,21,22
Most of the physical findings in DC are age-dependent, and thus their absence in a young patient by no means eliminates DC from consideration.
Figure 8 Features of the diagnostic triad in DC. Left, dystrophic nails on hands and feet. Middle, lacy reticular pigmentation on neck and upper thorax. Right, oral leukoplakia on tongue and buccal mucosa. Some of the figures are from Savage and Alter.36
There are two very severe subsets of DC. Patients with Hoyeraal-Hreidarsson (HH, MIM 300240) syndrome have cerebellar hypoplasia () with resultant ataxia and developmental delay, as well as microcephaly, immunodeficiency, intrauterine growth retardation, and early onset severe aplastic anemia. The diagnosis of Revesz syndrome (RS, MIM 268130) applies to young children with bilateral exudative retinopathy (similar to acquired unilateral Coats' retinopathy), intrauterine growth retardation, aplastic anemia, and central nervous system (CNS) calcifications. We have suggested that the appellation of HH requires cerebellar hypoplasia, and that of RS requires exudative (not hemorrhagic) retinopathy, in association with other features of DC. Recent discovery of mutated genes, as well as very short telomeres (see later) in these subsets of patients validates their inclusion in the DC category.23–25
Figure 9 Cerebellar hypoplasia in the Hoyeraal-Hreidarsson variant of DC. Magnetic resonance image of brain; arrow indicates very small cerebellum.36
The median age at diagnosis of patients with DC was 14 years, range birth to 75 years, more than double the age in FA (). The very young subset includes patients with HH or RS, while the older subset may include parents in families with autosomal dominant inheritance where the proband was a child. There was no sex difference in the age at diagnosis. Several patients were diagnosed as DC only after they had failed to respond to immunosuppressive treatment of their aplastic anemia.33
In contrast with FA, patients with DC do not have a childhood peak hazard rate for aplastic anemia, but rather a steady increase from 1% up to age 20 to almost 10% per year at age 50. Similar to FA, however, patients with DC have a cumulative incidence of severe aplastic anemia of around 50% by age 50.34
The diagnosis of DC may be suspected in the presence of features of the clinical triad, and/or other pathognomonic physical findings, with or without hematologic or neoplastic complications. It has been suggested that one of the triad, plus a hypoplastic marrow, plus any two of the other physical findings would lead to a diagnosis of DC.35
However, we have identified individuals who have none of these findings, but are family members who share the mutated DC gene of the proband, and have very short telomeres..36
These may be “silent carriers”, but warrant close observation for any of the complications that may arise in DC. There are also patients who present as adults with what appears to be acquired aplastic anemia, but who turn out to have mutations in the DC genes TERT
In addition, a subset of patients with familial pulmonary fibrosis had mutations in TERT
The DC equivalent of the chromosome breakage test for FA is detection of very short telomeres (less than the 1st
percentile for age in a large number of normal controls) in blood leukocyte subsets ().31
This assay has high sensitivity and specificity for identification of patients with FA, distinction of those patients from their unaffected (and mutation-negative) relatives, and from patients with any IBMFS that is not DC. In fact, very short telomeres was used as the case definition for the genetic linkage study that identified TINF2
as a new but quite common DC gene.24
At this time it appears that documentation of very short telomeres in several leukocyte subsets is the most useful “screening test” for a diagnosis of DC, although further studies may refine this suggestion. Telomere biology will be discussed below.
Figure 10 Telomere length in blood lymphocytes according to age in patients with DC and their relatives (left), and patients with other IBMFS and their relatives (right). Vertical axis indicates telomere length in kilobases. Lines indicate the first, tenth, 50 (more ...)
While most patients with DC present to the hematologist with aplastic anemia, others may have MDS or AML as their first hematologic sign, and still others may have familial pulmonary fibrosis.28,30,32–36
Whatever the presentation, these individuals are at risk of any of the complications described in DC. In particular, they have a high risk for cancer, similar in order of magnitude of relative risk (11-fold compared with SEER) and in type as seen in FA.37
Bone marrow findings in patients with DC who have cytopenias are similar to those seen in FA, i.e. hypocellularity, decreased megakaryocytes, and some dyspoieses, which often may not be sufficient to make the diagnosis of MDS. Cytogenetic clones have not been a feature of the literature case reports, although we have seen them in a few patients. As in our prior experience in patients with FA38
, we have observed stable or fluctuating clones over many years in patients with DC, and do not use clones alone as the determinant for SCT in DC.
The median age for survival free of cancer in cases in the literature was 68 years, much older than in FA, but the most frequent solid tumor was the same, HNSCC, and the other tumors were similar, involving the gastrointestinal and anogenital areas (, ). AML and MDS were less frequent in DC than in FA, but there is concern about whether many cases of DC are not diagnosed as such when they present as adults with no or minimal physical findings; definitive diagnosis may require analysis of telomeres, and sequencing of the known DC genes (see later).
Overall survival of cases in the literature is older than in FA, i.e. 34 years in those reported from 1910 through 1999, and 49 years for those in the past decade (). As in FA, however, there is a recent cohort effect (p = 0.009), reflecting the combination of better medical and transplant management, as well as diagnosis of milder or even clinically healthy affected individuals. The causes of the reported deaths were similar to FA, i.e. complications of aplastic anemia, SCT, and cancer. In addition, pulmonary fibrosis was a cause of death unique to DC. Almost 90% of the patients reported recently were 18 years of age or older, i.e. adults. Unlike in FA, where there is decreased fertility in both sexes, there is no obvious problem with fertility in DC, although this has not been examined rigorously.