dyskeratosis congenita in all its forms

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  • 768 q 2000 Blackwell Science Ltd



    Classic dyskeratosis congenita (DC) is an inherited diseasecharacterized 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, neuro-logical, ophthalmic, pulmonary and skeletal) abnormalitieshave also been reported (Sirinavin & Trowbridge, 1975;Drachtman & Alter, 1995; Dokal, 1996a; Knight et al,1998a). Bone marrow (BM) failure is the principal cause ofearly mortality with an additional predisposition to malig-nancy and fatal pulmonary complications. X-linked recessive,autosomal dominant and autosomal recessive forms of thedisease are recognized.

    Since the annotation (Dokal, 1996a), there have beensignificant advances in DC. These have been facilitated bythe dyskeratosis congenita registry (DCR), established at theHammersmith Hospital (London) in 1995. By November1999, 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 familiesfrom 20 different countries collectively comprised 148 (127male and 21 female) patients. As well as confirming previ-ous observations, the DCR has identified new features of DCand has been pivotal in the identification of the DKC1 genewhich is mutated in X-linked DC.


    In 76 out of the 92 families, there were only males affectedand these collectively comprised 118 patients. In 25 of these76 families, there were two or more affected males with lackof male-to-male transmission, consistent with an X-linkedrecessive pattern of inheritance. In the 51 families withaffected sporadic males, it is likely that many of these alsorepresent the X-linked form of the disease, although somemay represent autosomal forms of DC. Overall, out of the148 patients, 127 (86%) were male and this confirmsprevious reports that the major form of DC is X linked.

    In 16 families out of the total of 92, there was one ormore affected female. In 4 of these 16, the cases weresporadic with a history of parental consanguinity in two; ineight families, there were two affected members in the samegeneration with a history of parental consanguinity in two;

    in three families, there were affected cases in two differentgenerations; finally, in one out of the 16 families, the twocases were first maternal cousins. Thus, collectively they arelikely to represent different genetic subtypes. Some of theseare likely to represent autosomal recessive forms of thedisease and others autosomal dominant. These familiestherefore provide further evidence for autosomal recessiveand dominant forms of the disease in addition to thosepublished 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).

    Families with affected males onlySomatic abnormalities. A wide range of somatic abnorm-

    alities were seen as listed in Table I. DC may therefore beregarded as an inherited multisystem syndrome. In general,the abnormalities were not neonatal in manifestation, butdeveloped progressively at a variable rate. The muco-cutaneous features (skin pigmentation, nail dystrophy andleucoplakia; Fig 1) usually appeared between the ages of 5and 10 years. The median ages of onset for abnormal skinpigmentation, nail dystrophy and leucoplakia were 8 years(range 0521 years), 6 years (range 117 years) and7 years (range 126 years) respectively. There was a wideage range over which these features developed and therewere also significant qualitative differences in the skinpigmentation and the nail dystrophy; for example, somepatients had a very florid rash involving most of the skin,others only had a localized rash and some patients hadminimal nail changes, whereas some developed completenail loss. In families with two or more affected members, thephenotypes among the different individuals tended to besimilar. However, in some instances there was significantvariability in the severity of the clinical phenotype indifferent members of the same family. This suggests that thephenotype may be modified by other genetic and/orenvironmental factors.

    A subset (203%) of patients developed pulmonarycomplications (Table I) with reduced diffusion capacityand/or restrictive defect. It has been possible to studysome of these patients at several time points. For example, inone patient (aged 36 years) the diffusion capacity (TLCO)fell from 73% to 59% over a period of 6 months, suggestingthat pulmonary abnormalities also progress with age andhighlighting the need for regular monitoring. Postmortemstudies on two patients who died suddenly from acuterespiratory disease showed abnormal levels of pulmonary

    British Journal of Haematology, 2000, 110, 768779

    Correspondence: Dr Inderjeet Dokal, Department of Haematology,Imperial College School of Medicine (ICSM), Hammersmith Campus,

    Du Cane Road, London W2 0NN, UK. E-mail: i.dokal@ic.ac.uk

  • fibrosis and abnormalities in the pulmonary microvascu-lature. These histological changes correlate with theabnormalities in fibroblasts (Scappaticci et al, 1989; Dokalet al, 1992; Kehrer & Krone, 1992; Kehrer et al, 1992)observed in DC skin biopsies and the telangiectatic vesselsseen at the skin surface clinically. The development ofpulmonary abnormalities highlighted by the DCR andprevious reports (Paul et al, 1992; Verra et al, 1992) may

    in part explain the high incidence of early and late fatalpulmonary complications after bone marrow transplanta-tion (BMT) (Berthou et al, 1991; Dokal et al, 1992; Langstonet al, 1996; Yabe et al, 1997; Rocha et al, 1998).

    Haematological abnormalities. Bone marrow failure result-ing in peripheral cytopenias appears to be much morefrequent than previously thought. As can be seen fromTable II, 855% of patients had a peripheral cytopenia ofone or more lineages, with 763% having a cytopenia of twoor more lineages; in 80% of the patients who developedpancytopenia, the age of onset was less than 20 years(median 8 years), with 50% developing pancytopenia belowthe age of 10 years. Accepting that there may be some biasin the patients referred to the DCR, the actual probability ofdeveloping BM failure [one or more peripheral cytopenia(s)]is much higher than previously documented, approaching94% by the age of 40 years (Fig 2). This is also reflected inthe causes of death (see below). It is noteworthy that onepatient (aged 29 years) had approximately 10% myeloidblasts in the BM (Dokal et al, 1992) and three others hadhypocellular 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 BMthere is a predisposition to both MDS and acute myeloidleukaemia (AML) in patients with DC.

    Families with affected femalesThe 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 andnine male cases. Several of the men had features that weresimilar to those seen in families with affected males only (seeabove). Indeed, in two families (DCR019 and DCR024), thediagnosis of DC in the female members was facilitated by thediagnosis of the affected male patient.

    Table I. Somatic abnormalities/complications in DC families with

    affected males only (n 118).

    Abnormality % of patients

    Abnormal skin pigmentation 890

    Nail dystrophy 880

    Bone marrow failure 855

    Leucoplakia 780Epiphora 305

    Learning difficulties/developmental delay/

    mental retardation


    Pulmonary disease 203

    Short stature 195

    Extensive dental caries/loss 169

    Oesophageal stricture 169Hair loss/grey hair/sparse eyelashes 161

    Hyperhiderosis 153

    Malignancy 76

    Intrauterine growth retardation 76Liver disease/peptic ulceration/enteropathy 73

    Ataxia 68

    Hypogonadism/undescended testes 59Microcephaly 59

    Urethral stricture/phimosis 51

    Osteoporosis/aseptic necrosis/scoliosis 51

    Deafness 08

    Fig 1. Photographs of DC patients showing abnormal skin pigmentation (A, B, C and D), nail dystrophy of finger nails (E) and toe nails (F andG) and leucoplakia of tongue (H).

    q 2000 Blackwell Science Ltd, British Journal of Haematology 110: 768779

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  • The phenotype in the female cases varied considerably. Infamily DCR014, the diagnosis in the case of the sporadicfemale case was based on the presence of the muco-cutaneous triad associated with aplasia below the age of10 years. In family DCR019, the female case was thedaughter of a male patient. She developed BM failure at theage of 4 years without cutaneous features. In familyDCR022, both females developed BM failure, they hadfewer than two nails affected and had no skin pigmentation.In family DCR024, the female case died of BM failure aged8 years; her brother was alive and had all the classicfeatures seen in the male patients (see above). In familyDCR028, the patient had skin pigmentation abnormalities,leucoplakia, thrombocytopenia and carcinoma of thelarynx, but she had no nail dystrophy at the age of46 years. In family DCR039 (previously published by Elliottet al, 1999), the male patient died from BM failure aged8 years; his sister had mild skin pigmentation, leucoplakiaand nail dystrophy. The parents of these two siblings werefirst cousins. In fa