Dyskeratosis congenita in all its forms

Classic dyskeratosis congenita (DC) is an inherited disease characterized by the triad of abnormal skin pigmentation, nail dystrophy and mucosal leucoplakia ( Zinsser, 1906; Engman, 1926; Cole et al, 1930 ). A variety of non-cutaneous (dental, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary and skeletal) abnormalities have also been reported ( Sirinavin & Trowbridge, 1975; Drachtman & Alter, 1995; Dokal, 1996a; Knight et al, 1998a ). Bone marrow (BM) failure is the principal cause of early mortality with an additional predisposition to malignancy and fatal pulmonary complications. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. Since the annotation ( Dokal, 1996a), there have been significant advances in DC. These have been facilitated by the dyskeratosis congenita registry (DCR), established at the Hammersmith Hospital (London) in 1995. By November 1999, 92 DC families (Argentina, one; Australia, two; Austria, one; Belgium, two; Brazil, eight; Canada, two; Egypt, one; France, 11, Germany, three; Holland, two; Hong Kong, two; India, two; Ireland, five; Italy, four; New Zealand, one; Spain, two; Turkey, three; United Arab Emirates, two; UK, 14; and USA, 24) had been recruited. These 92 families from 20 different countries collectively comprised 148 (127 male and 21 female) patients. As well as confirming previous observations, the DCR has identified new features of DC and has been pivotal in the identification of the DKC1 gene which is mutated in X-linked DC. In 76 out of the 92 families, there were only males affected and these collectively comprised 118 patients. In 25 of these 76 families, there were two or more affected males with lack of male-to-male transmission, consistent with an X-linked recessive pattern of inheritance. In the 51 families with affected sporadic males, it is likely that many of these also represent the X-linked form of the disease, although some may represent autosomal forms of DC. Overall, out of the 148 patients, 127 (86%) were male and this confirms previous reports that the major form of DC is X linked. In 16 families out of the total of 92, there was one or more affected female. In 4 of these 16, the cases were sporadic with a history of parental consanguinity in two; in eight families, there were two affected members in the same generation with a history of parental consanguinity in two; in three families, there were affected cases in two different generations; finally, in one out of the 16 families, the two cases were first maternal cousins. Thus, collectively they are likely to represent different genetic subtypes. Some of these are likely to represent autosomal recessive forms of the disease and others autosomal dominant. These families therefore provide further evidence for autosomal recessive and dominant forms of the disease in addition to those published previously ( Sorrow & Hitch, 1963; Sirinavin & Trowbridge, 1975; Tchou & Kohn, 1982; Ling et al, 1985 ; Juneja et al, 1987 ; Pai et al, 1989a ; Drachtman & Alter, 1992; Joshi et al, 1994 ; Knight et al, 1998a ; Elliott et al, 1999 ). Somatic abnormalities A wide range of somatic abnormalities were seen as listed in Table I. DC may therefore be regarded as an inherited multisystem syndrome. In general, the abnormalities were not neonatal in manifestation, but developed progressively at a variable rate. The mucocutaneous features (skin pigmentation, nail dystrophy and leucoplakia; Fig 1) usually appeared between the ages of 5 and 10 years. The median ages of onset for abnormal skin pigmentation, nail dystrophy and leucoplakia were 8 years (range 0·5–21 years), 6 years (range 1–17 years) and 7 years (range 1–26 years) respectively. There was a wide age range over which these features developed and there were also significant qualitative differences in the skin pigmentation and the nail dystrophy; for example, some patients had a very florid rash involving most of the skin, others only had a localized rash and some patients had minimal nail changes, whereas some developed complete nail loss. In families with two or more affected members, the phenotypes among the different individuals tended to be similar. However, in some instances there was significant variability in the severity of the clinical phenotype in different members of the same family. This suggests that the phenotype may be modified by other genetic and/or environmental factors. Photographs of DC patients showing abnormal skin pigmentation (A, B, C and D), nail dystrophy of finger nails (E) and toe nails (F and G) and leucoplakia of tongue (H). A subset (20·3%) of patients developed pulmonary complications (Table I) with reduced diffusion capacity and/or restrictive defect. It has been possible to study some of these patients at several time points. For example, in one patient (aged 36 years) the diffusion capacity (TLCO) fell from 73% to 59% over a period of 6 months, suggesting that pulmonary abnormalities also progress with age and highlighting the need for regular monitoring. Postmortem studies on two patients who died suddenly from acute respiratory disease showed abnormal levels of pulmonary fibrosis and abnormalities in the pulmonary microvasculature. These histological changes correlate with the abnormalities in fibroblasts ( Scappaticci et al, 1989 ; Dokal et al, 1992 ; Kehrer & Krone, 1992; Kehrer et al, 1992 ) observed in DC skin biopsies and the telangiectatic vessels seen at the skin surface clinically. The development of pulmonary abnormalities highlighted by the DCR and previous reports ( Paul et al, 1992 ; Verra et al, 1992 ) may in part explain the high incidence of early and late fatal pulmonary complications after bone marrow transplantation (BMT) ( Berthou et al, 1991 ; Dokal et al, 1992 ; Langston et al, 1996 ; Yabe et al, 1997 ; Rocha et al, 1998 ). Haematological abnormalities Bone marrow failure resulting in peripheral cytopenias appears to be much more frequent than previously thought. As can be seen from Table II, 85·5% of patients had a peripheral cytopenia of one or more lineages, with 76·3% having a cytopenia of two or more lineages; in 80% of the patients who developed pancytopenia, the age of onset was less than 20 years (median 8 years), with 50% developing pancytopenia below the age of 10 years. Accepting that there may be some bias in the patients referred to the DCR, the actual probability of developing BM failure [one or more peripheral cytopenia(s)] is much higher than previously documented, approaching 94% by the age of 40 years ( Fig 2). This is also reflected in the causes of death (see below). It is noteworthy that one patient (aged 29 years) had approximately 10% myeloid blasts in the BM ( Dokal et al, 1992 ) and three others had hypocellular marrows with features of myelodysplasia (MDS). Thus, like Fanconi's anaemia (FA) ( Auerbach et al, 1998 ), although hypoplasia is the main abnormality seen in the BM there is a predisposition to both MDS and acute myeloid leukaemia (AML) in patients with DC. Probability of bone marrow failure in dyskeratosis congenita. The 16 families (DCR014, DCR0I9, DCR022, DCR024, DCR028, DCR039, DCR049, DCR063, DCR070, DCR073, DCR079, DCR082, DCR083, DCR086, DCR087 and DCR088) with affected females collectively comprised 21 female and nine male cases. Several of the men had features that were similar to those seen in families with affected males only (see above). Indeed, in two families (DCR019 and DCR024), the diagnosis of DC in the female members was facilitated by the diagnosis of the affected male patient. The phenotype in the female cases varied considerably. In family DCR014, the diagnosis in the case of the sporadic female case was based on the presence of the mucocutaneous triad associated with aplasia below the age of 10 years. In family DCR019, the female case was the daughter of a male patient. She developed BM failure at the age of 4 years without cutaneous features. In family DCR022, both females developed BM failure, they had fewer than two nails affected and had no skin pigmentation. In family DCR024, the female case died of BM failure aged 8 years; her brother was alive and had all the classic features seen in the male patients (see above). In family DCR028, the patient had skin pigmentation abnormalities, leucoplakia, thrombocytopenia and carcinoma of the larynx, but she had no nail dystrophy at the age of 46 years. In family DCR039 (previously published by Elliott et al, 1999 ), the male patient died from BM failure aged 8 years; his sister had mild skin pigmentation, leucoplakia and nail dystrophy. The parents of these two siblings were first cousins. In family DCR063, the 12-year-old girl had reticulate skin pigmentation, leukoplakia and hypocellular BM but no nail dystrophy; her 10-year-old brother had nail dystrophy as well as all the other features present in his older sister. In family DCR070, there were two affected sisters and one affected brother in one generation and their parents were first cousins. In family DCR073, the affected 3-year-old girl had skin pigmentation, hyperconvexed nails, dental caries, intracranial calcification, large cistern magna, liver dysfunction and hypocellular/dysplastic marrow. Her parents were first cousins. DCR079 was an Irish family in which there were two affected sisters with early onset of BM failure (associated with leucoplakia/tongue ulceration, short stature and ataxia), one of whom died from sepsis aged 2 years. In family DCR082, the affected members were a mother and daughter; the daughter had skin pigmentation and leucoplakia but no nail dystrophy, whereas the mother (aged 52 years) had skin pigmentation, macrocytic anaemia and a low CD4 count that had been associated with Pneumocystis carinii pneumonia. These two women therefore had mild disease which appeared to be segregating as an autosomal dominant trait. In family DCR083, there were three affected members in two generations, a sister and brother and their father. The sister died aged 30 years from respiratory complications; she had skin pigmentation, pancytopenia and squamous carcinoma of the tongue. Her brother, aged 47 years, had aplastic anaemia, severe acne and absent fingerprints. Their father was transfusion dependent and is said to have died from iron overload. The three members in this family had mild mucocutaneous features and appeared to show autosomal dominant transmission of the clinical phenotype. In family DCR086, there was one affected girl aged 2 years and her parents were first cousins. She had severe intrauterine growth retardation, microcephaly, developmental delay, ataxia, leucoplakia and severe BM failure at age 2 years. In DCR087, there were three affected members in one sibship, two sisters and their brother. They all had peripheral cytopenia, the brother also had significant atrioventricular (AV) malformation. In family DCR088, the two affected members were first cousins. The index case was a boy who presented at age 4 years with BM failure. He subsequently developed reticulate skin pigmentation, thin hair and extensive dental caries. At the age of 18 years, he still had no nail dystrophy and no leucoplakia. His maternal cousin had aplastic anaemia which responded to steroids and she had very thin hair. It can be seen that the clinical features in these families with female cases are very variable. In general, in families in which the inheritance appears to be autosomal recessive (e.g. DCR022, DCR024, DCR039, DCR 070, DCR079 and DCR086), the phenotype is more severe than in those in which it appears to be autosomal dominant (e.g. DCR019, DCR082 and DCR083). This agrees broadly with previous literature (autosomal recessive: Sorrow & Hitch, 1963; Ling et al, 1985 ; Juneja et al, 1987 ; Pai et al, 1989a ; Drachtman & Alter, 1992; Joshi et al, 1994 ; Elliott et al, 1999 ; autosomal dominant: Tchou & Kohn, 1982; Gasparini et al, 1985 ) and provides further evidence for autosomal recessive and dominant forms of DC. Analysis from the DCR shows that 67% of deaths resulted directly from BM failure or from complications of its treatment. Nine per cent died from sudden pulmonary complications. In a further 9%, fatal pulmonary complications were seen in the context of a BMT. Six per cent died from malignancy and 9% died of causes unrelated to DC and its treatment (rabies, myocardial infarction, road traffic accident). The majority of deaths were due to infection and these usually occurred (∼ 80%) before the end of the second decade of life. It is becoming increasingly recognized from patients on the DCR and from the previous reports that immunological abnormalities (including reduced or elevated immunoglobulin levels, reduced B- and/or T-lymphocyte numbers and reduced or absent responses to phytohaemagglutinin) can occur in a subgroup of patients with or without associated BM hypoplasia. Some deaths from infection may thus be attributable to immunodeficiency rather than aplastic anaemia. Fatal opportunistic infections such as Pneumocystis carinii pneumonia and cytomegalovirus have been previously reported ( Wiedemann et al, 1984 ; Rose & Kern, 1992) and this aspect, with special consideration of immunological abnormalities (see Table III), was recently reviewed by Solder et al (1998) . Malignancies developed in 13 (8·8%) out of the 148 patients. These included four cases of myelodysplasia (two patients with refractory anaemia and two patients with refractory anaemia with excess blasts), one which developed at age 10, one at 22, one at 27 and one at 29 years. There was also one case of Hodgkin's lymphoma (25 years) and eight cases of carcinoma: bronchus (56 years), colon (20 years), larynx (47 years), oesophagus (38 years), pancreas (29 years), skin (20 years) and tongue (one at 30 and one at 38 years). Of the 13 malignancies, three were in female patients (one case of MDS and two cases of carcinoma) and the majority of malignancies developed in the third decade or later. Treatment for severe BM failure in DC remains unsatisfactory. As in Fanconi's anaemia, the anabolic steroid oxymetholone can produce an improvement in haemopoietic function in many patients for a variable period of time ( Smith et al, 1979 ; unpublished observations). Transient successful responses to granulocyte–macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and erythropoietin have also been reported ( Russo et al, 1990 ; Alter et al, 1997 ). The main treatment for severe aplastic anaemia (SAA), however, is allogeneic stem cell transplantation (SCT) and there is some experience of using both sibling and alternative stem cell donors. To date, SCT has been performed in eight of the patients on the registry and some of these details have been published previously ( Berthou et al, 1991 ; Dokal et al, 1992 ; Forni et al, 1993 ; Knight et al, 1998a ; Rocha et al, 1998 ; Lau et al, 1999 ). Four are currently alive, three of whom had sibling donors (one now at 4, one at 5 and one at 7 years after SCT) and the fourth had an unrelated SCT 3 years ago. There are also other reports of the use of SCT in patients with DC with some long-term survivors ( Philips et al, 1992 ; Langston et al, 1996 ; Yabe et al, 1997 ; Ghavamzadeh et al, 1999 ). Unfortunately, because of early and late fatal pulmonary/vascular complications after SCT ( Berthou et al, 1991 ; Dokal et al, 1992 ; Langston et al, 1996 ; Yabe et al, 1997 ; Knight et al, 1998a; Rocha et al, 1998 ), the results of allogeneic SCT have been less successful than in FA. The presence of pulmonary disease in a significant proportion of DC patients (Table I) perhaps now explains the high incidence of fatal pulmonary complications in the setting of SCT. It also highlights the need to avoid drugs which are associated with pulmonary toxicity (such as busulphan) and to use pulmonary shielding if radiotherapy is used for SCT. As BM failure is the main cause of premature death in DC patients and SCT is currently the only curative option for the BM failure (with some long-term survivors), SCT should continue to be performed on carefully selected patients. Perhaps the best candidates for SCT are patients with no pre-existing pulmonary disease and who have sibling donors. SCT using fludarabine-based protocols appears to be giving encouraging results in FA patients and may be worth exploring in patients with DC. There is a great need to develop new and better treatment strategies for DC patients with SAA. Haemopoietic progenitor studies ( Colvin et al, 1984 ; Friedland et al, 1985 ; Alter et al, 1992; Dokal et al, 1992 ; Marsh et al, 1992 ) have shown reduced numbers of all progenitors (erythroid, myeloid and megakaryocytic) compared with controls and there is usually a downward decline with time. The degree to which the progenitors are reduced can vary from patient to patient and they can be reduced even when the PB count is normal (unpublished observations). The haemopoietic system appears to undergo 'premature ageing' with a reduction in the proliferative potential of clonogenic progenitors and a reduced subplating cloning efficiency ( Marley et al, 1999 ; unpublished data). The demonstration of abnormalities of growth and chromosomal rearrangements in fibroblasts suggests that the BM failure is likely to be a consequence of abnormalities in both haemopoietic stem cells ( Friedland et al, 1985 ; Marsh et al, 1992 ) and stromal cells. DC has many features in common with Fanconi's anaemia in which there is a hypersensitivity to clastogenic agents such as mitomycin C (MMC), which is a DNA alkylator. Some authors have reported excessive chromosome breakage in DC, either spontaneous ( Morrison, 1974) or induced ( Pai et al, 1989b ; DeBauche et al, 1990 ; Ning et al, 1992 ), whereas others disputed their findings ( Sirinavin & Trowbridge, 1975; Drachtman & Alter, 1992) with the result that, until recently, confusion existed over the susceptibility of DC cells to clastogenic agents. Coulthard et al (1998) chose a range of agents, based on previous reports suggesting susceptibility, to determine which agents would produce an increased level of breakage in DC lymphocytes over that seen in normal controls. This study demonstrated that there was no significant difference in chromosomal breakage between DC and normal lymphocytes with or without the use of bleomycin, diepoxybutane (DEB), MMC and γ-irradiation. This conclusive study now enables DC patients to be distinguished from FA. Primary DC skin fibroblasts are abnormal both in morphology and in growth rate. Furthermore, they show unbalanced chromosomal rearrangements (dicentrics, tricentrics, translocations) in the absence of any clastogenic agents ( Scappaticci et al, 1989 ; Dokal et al, 1992 ; Kehrer & Krone, 1992; Kehrer et al, 1992 ). In addition, peripheral blood and BM metaphases from some patients show numerous unbalanced chromosomal rearrangements in the absence of any clastogenic agents ( Dokal et al, 1992 ; Demiroglu et al, 1997 ). These studies provide evidence for a defect that predisposes DC cells to developing chromosomal rearrangements. DC, like FA, may thus be regarded as a chromosomal instability disorder, but with a predisposition to chromosomal rearrangements rather than the gaps and breaks seen in FA ( Dokal & Luzzatto, 1994). The demonstration of chromosomal instability suggests that cells of tissues with a high turnover, such as the BM, skin and gastrointestinal tract, may accumulate progressive DNA damage. This could in part account for the high frequency of BM failure and the epithelial abnormalities seen in these patients. X-chromosome inactivation patterns (XCIPs) have been studied in PB cells of women from X-linked DC families by investigating a methylation-sensitive restriction enzyme site in the polymorphic human at women to be of DC showed complete in in addition, women to be on the of genetic also had ( et al, 1997 ; et al, 1997 ; et al, 1997 ). The presence of the pattern of X inactivation in PB cells suggests that cells the gene have a over those the normal Furthermore, a provides for use in the of families at of DC. In addition, may to an inherited from a in sporadic male DC as well as autosomal from X-linked forms of the This also suggests that X-linked may have a reduced haemopoietic and it be to they are at a of developing BM failure than normal controls. has been observed in one X-linked on the DCR ( Knight et al, 1998a ) factor levels were in 7 out of 13 patients studied to ( Dokal et al, ; unpublished observations). This suggests a predisposition to It is noteworthy that of the patients with had abnormalities of pulmonary diffusion capacity the with normal levels had normal diffusion capacity (unpublished with three out of these patients below the age of 10 years. This may identification of patients who are more likely to develop pulmonary complications. levels have been to be in patients who developed fatal complications after SCT ( Berthou et al, 1991 ). The for this predisposition to is It could to a more in all cells with high or the may be the of some such as The majority (86%) of patients with DC on the DCR are male and provide further evidence that the X-linked recessive form of DC the majority of cases. in one large the DKC1 for X-linked DC, was to ( & et al, ). additional families this and a of the was with with no ( et al, 1993 ). To further the of the DKC1 in the families in the DCR have been in DCR families the DKC1 gene to be more a DKC1 was between and in ( Knight et al, 1996 ). the use of genetic and this to be to between and ( Knight et al, ). with from this resulted in the of a in one DC patient and of the gene for X-linked dyskeratosis congenita DKC1 ( et al, 1998 ). The DKC1 gene is of ( et al, 1999 ; Knight et al, ; et al, the DKC1 is The is a of with a of It is in that DKC1 is the human of the gene the gene and gene ( et al, 1993 ; & Philips et al, 1998 ; et al, 1999 ). studies of the and that is a in and/or Furthermore, in and its a also present in the and of was identified ( et al, 1997 ; et al, 1998 ). the of to in The and have been shown to ( et al, 1997 ; et al, 1999 ) and thus is to be a of the using either with an immunoglobulin ( et al, 1999 ) or with ( et al, 1999 ) or with a (unpublished have its to the The different abnormalities associated with DC are variable from patient to patient both in severity and age of It is possible to of abnormality as a with there also in the of such abnormalities in a patient. The severity of the DC phenotype may be by the age of onset of the BM failure and the of associated somatic those with onset of BM failure below the age of 10 years in with several somatic abnormalities can be regarded as having the whereas those who develop abnormalities after the age of 20 years have the It is that those with early onset of BM failure early and not to develop some of the other complications of the Thus, pulmonary myelodysplasia and malignancy are seen in patients who It be to it is possible to of Furthermore, it is that DKC1 may result in phenotypes which with DC, but which have been other disease Indeed, one such has been The is a severe multisystem characterized by microcephaly, growth of immunodeficiency and aplastic anaemia ( et al, ; et al, ; et al, 1994 ; et al, ; et al, 1997 ; et al, 1997 ). The that had been reported only in and the presence of in these patients the that may be due to in To was to DC, the DKC1 gene was in two families, one of which was the family by et al In one a at in 5 to an of at in was in both affected in the other a at in 3 to an of at 47 in was in the affected The of these two in two families with all the features of that is a severe of X-linked DC ( Knight et al, ). It also shows that in DKC1 can to a much more clinical phenotype than previously hypoplasia and severe immunodeficiency lymphocytes and which have not previously been regarded as an part of the DC phenotype. The severe developmental and hypoplasia in families an of in The demonstration that is a severe of X-linked DC suggests that DKC1 may to a very wide clinical of patients. This may not have been recognized previously because clinical due to in DKC1 that resulted in death fatal infections because of severe below the age of 10 years would not have been as DC or as these patients not to develop the mucocutaneous features of classic DC or have all the features of This suggests that with severe clinical phenotypes who have some features of DC or (e.g. or but who lack the skin and

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