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 Drachtman 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 Sirinavin Tchou Ling et al, 1985 ; Juneja et al, 1987 ; Pai et al, 1989a ; Drachtman 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 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 in patients with DC. of bone marrow failure in dyskeratosis The 16 families and with affected collectively comprised 21 and male of the had features that were to those seen in families with affected males only (see in two families and the of DC in the members was facilitated by the of the affected male The phenotype in the cases In the in the of the sporadic was on the of the mucocutaneous triad with below the age of 10 years. In the was the of a male developed BM failure at the age of 4 years In both developed BM they had than two nails affected and had skin In the died of BM failure 8 was and had the features seen in the male patients (see In the patient had skin pigmentation and of the but had nail dystrophy at the age of years. In published by Elliott et al, 1999 ), the male patient died from BM failure 8 had skin pigmentation, leucoplakia and nail The of these two were first cousins. In the had skin pigmentation, and hypocellular BM but nail dystrophy; had nail dystrophy as well as the other features in In there were two affected and one affected in one generation and were first cousins. In the affected had skin pigmentation, and were first cousins. was an in which there were two affected with early onset of BM failure with and one of died from years. In the affected members were a and the had skin pigmentation and leucoplakia but nail whereas the (aged years) had skin pigmentation, anaemia and a that had been with These two therefore had disease which appeared to be as an autosomal dominant In there were three affected members in two a and and The died years from respiratory had skin pigmentation, pancytopenia and of the had and was and is to have died from The three members in this had mucocutaneous features and appeared to autosomal dominant of the clinical In there was one affected years and were first cousins. had leucoplakia and BM failure at age years. In there were three affected members in one two and had peripheral the also had significant In the two affected members were first cousins. The was a who at age 4 years with BM developed skin pigmentation, and the age of had nail dystrophy and maternal had anaemia which to and had very It can be seen that the clinical features in these families with cases are very In general, in families in which the appears to be autosomal recessive DCR and the phenotype is more than in those in which it appears to be autosomal dominant and This with previous Sorrow Ling et al, 1985 ; Juneja et al, 1987 ; Pai et al, 1989a ; Drachtman Joshi et al, 1994 ; Elliott et al, 1999 ; autosomal Tchou et al, 1985 ) and further evidence for autosomal recessive and dominant forms of DC. from the DCR that of from BM failure or from complications of died from pulmonary complications. In a further fatal pulmonary complications were seen in the of a died from malignancy and died of causes to DC and The of were to and these usually the of the of It is from patients on the DCR and from the previous reports that abnormalities reduced or reduced and/or and reduced or to can in a of patients with or BM Some from may be to than as and have been previously reported ( et al, ; to and have also been reported ( et al, ; et al, 1997 ). The main for anaemia is transplantation and there is some of both and has been in eight of the patients on the registry and some of these have been published previously ( Berthou et al, 1991 ; Dokal et al, 1992 ; et al, ; Knight et al, 1998a ; Rocha et al, 1998 ; et al, 1999 ). are three of had at one at 5 and one at 7 years after and the had an years There are also other reports of the of in patients with DC with some ( et al, 1992 ; Langston et al, 1996 ; Yabe et al, 1997 ; et al, 1999 ). of early and late fatal complications after ( Berthou et al, 1991 ; Dokal et al, 1992 ; Langston et al, 1996 ; Yabe et al, 1997 ; Knight et al, Rocha et al, 1998 ), the of have been less than in The of pulmonary disease in a significant of DC patients (Table I) the high incidence of fatal pulmonary complications in the of It also the need to which are with pulmonary as and to pulmonary is for As BM failure is the main cause of death in DC patients and is the only for the BM failure some to be on patients. the for are patients with pulmonary disease and who have appears to be in patients and may be in patients with DC. There is a need to new and for DC patients with studies ( et al, ; et al, 1985 ; et al, 1992; Dokal et al, 1992 ; et al, 1992 ) have reduced of myeloid and with and there is usually a with The to which the are reduced can from patient to patient and they can be reduced the is The appears to with a in the of and a reduced ( et al, 1999 ; The of abnormalities of and in fibroblasts suggests that the BM failure is likely to be a of abnormalities in both ( et al, 1985 ; et al, 1992 ) and DC has many features in with Fanconi's anaemia in which there is a to as C which is a Some have reported in ( or ( Pai et al, ; et al, ; et al, 1992 ), whereas others ( Sirinavin Drachtman Dokal et al, 1992 ; Kehrer Kehrer et al, 1992 ). In peripheral and BM from some patients in the of ( Dokal et al, 1992 ; et al, 1997 ). These studies provide evidence for a that DC to developing like may be regarded as a but with a predisposition to than the and seen in ( Dokal et al, 1997 ; et al, 1997 ). The of the pattern of X in suggests that the gene have a over those the a for in the of families at of DC. In 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 and it be to they are at a of developing BM failure than has been observed in one X-linked on the DCR ( Knight et al, 1998a ) levels were in 7 out of patients to ( Dokal et al, ; This suggests a predisposition to It is noteworthy that of the patients with had abnormalities of pulmonary diffusion capacity the with levels had diffusion capacity with three out of these patients below the age of 10 years. This may identification of patients who are more likely to pulmonary complications. levels have been to be in patients who developed fatal complications after ( Berthou et al, 1991 ). The for this predisposition to is It to a more in with high or the may be the of some as The (86%) of patients with DC on the DCR are male and provide further evidence that the X-linked recessive form of DC the of in one the DKC1 for X-linked was to ( Knight et al, ; et al, the DKC1 is The is a of with a of It is in that DKC1 is the of the gene the gene and gene ( et al, ; et al, 1999 ). studies of the and that is a in and/or in and a also in the and of was identified ( et al, 1997 ; et al, 1998 ). the of to in The and have been to ( et al, 1997 ; et al, 1999 ) and is to be a of the with an ( et al, 1999 ) or with ( et al, 1999 ) or with a have to the The different abnormalities 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 abnormalities in a The severity of the DC phenotype may be by the age of onset of the BM failure and the of 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 abnormalities after the age of 20 years have the It is that those with early onset of BM failure early and not to 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 it is that DKC1 may in phenotypes which with but which have been other disease one has been The is a multisystem characterized by of and 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 of in these patients the that may be to in was to the DKC1 gene was in two families, one of which was the by et In one a at in 5 to an of at in was in both affected in the other a at in to an of at in was in the affected The of these two in two families with the features of that is a of X-linked DC ( Knight et al, ). It also that in DKC1 can to a much more clinical phenotype than previously hypoplasia and and which have not previously been regarded as an part of the DC The and hypoplasia in families an of in The that is a of X-linked DC suggests that DKC1 may to a very wide clinical of patients. This may not have been previously clinical to in DKC1 that in death fatal of below the age of 10 years not have been as DC or as these patients not to the mucocutaneous features of DC or have the features of This suggests that with clinical phenotypes who have some features of DC or or but who lack the skin and nail changes, be for in the DKC1 on the previous the DCR and the that is a of X-linked it is possible to the in Fig In this dyskeratosis congenita has been X-linked and autosomal it is possible to X-linked and autosomal forms of a with two patients who had the clinical features of have been reported ( et al, 1998 ) and are of other cases of one can that there are likely to be patients who not DC or but clinical features are to in DKC1 or in for autosomal is likely to be some patients. It is noteworthy that in of the DCR families male members have died of the age of 8 years and the of DC was only of the to the mucocutaneous of these families has been published previously ( et al, ) There are also other reports in the in which patients were to have bone marrow and developed features of DC ( et al, ; et al, 1992 ; et al, ). of clinical and genetic between dyskeratosis congenita (DC) and syndrome. The DC phenotype is in autosomal and X-linked The phenotype is in which is also autosomal and X-linked The disease by in the DKC1 gene is by The for additional clinical by in DKC1 which not DC or is in The wide range of abnormalities seen in patients with and DC that has a in many and this is by the of the DKC1 gene ( et al, 1998 ). It is of that the affected (skin and have a high This clinical with the abnormalities of of reduced and the in suggests that the DC gene may have a in having the on with a high The of DKC1 in the and in this gene to the clinical the BM is As highlighted that is a in and/or It is that a have on with a high need to be to this for have identified DKC1 in of the DCR The of ( Fig identified have been ( et al, 1998 ; Knight et al, ; et al, et al, ). DKC1 have been suggesting that may be In and have been to be It different in the same gene can to clinical studies are to the of and different It is noteworthy that the in 5 in one of the families, which can be regarded as the most phenotype ( Knight et al, ), the first DKC1 the ( Fig which on studies on the is to have a in in ( et al, 1998 ; et al, 1998 ; et al, 1999 ). It is that this is with a in the of than the in the DKC1 This is a of the of the DKC1 gene with the and The with is a which has been in different The were in patients with the syndrome. In addition to the two C a G) and a are also of showing the of some possible The is the of which is with and the ( et al, The ( and is a ( Dokal et al, 1992 ; Kehrer Kehrer et al, 1992 ; Dokal et al, 1998 ; et al, 1998 ). The and both the and of the and have been to be This therefore be for It also suggests that some of the in DC may from to other In this it is of that the of the ( et al, ). may to a in resulting in a of et have that DC from two families have a of levels of and have than have from 36 DC patients from different families and have that they also have than A in explain some of the clinical features of DC as to a in may the capacity of somatic ( et al, ). This suggests that although the in DC is a genetic abnormality inherited Knight et al, ). of abnormal or abnormal of of may to the of in may the in may explain the and seen in some patients. The resulting may to those of X-linked DC had clinical features a of pigmentation, and and the clinical phenotype in some patients is less ( Knight et al, 1998a ). This the that some of the patients who have been the autosomal forms of DC may out to have in However, to have not DKC1 in cases This the for autosomal DC for DC patients developing ( Dokal, for the subset of patients who have the are very of a high incidence of fatal pulmonary complications. There is therefore a clinical need to new for patients developing As DC is a gene recessive and the that need to be are DC is a for gene there is evidence from studies and from in DC that with the gene have with the an also be from the of in studies in DC there is of the there is a in the of and a reduced of DKC1 of of DKC1 in of DC in form the of developing a of gene for DC patients. The for these studies on advances in and that are in many In on the of the DKC1 and the of a DC may the development of an gene These may also have for the of patients with the first to be identified that is in the of and have a possible for the be in in which is are which with may out to be in the not only of autosomal but also of some of DC is a multisystem with mortality usually to BM for which forms of are The of patients are showing a X-linked recessive pattern of inheritance. The identification of the DKC1 gene and an that early in patients with features as the patients with anaemia or and who are below the age of 10 years be for DC. The over the years is to the of in the and The DKC1 gene also a to the for autosomal and some of anaemia or As have that has a in this may of not only the with DC but also that in other patients with This in to new for patients who be by to and has been over the 5 years. other and at the Hammersmith who have and to the clinical and of the DC also to for in the dyskeratosis congenita registry and to the and for