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Summary

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Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous multisystem bone marrow failure disorder of telomere maintenance, which may present with dermatological features. The main cause of mortality is bone marrow failure, often developing in the second decade of life, although pulmonary disease and malignancies such as squamous cell carcinomas (SCCs) may also prove fatal. We report the case of a 28-year-old man with X-linked DC and confirmed DKC1 gene mutation. In addition to the classic triad of nail dystrophy, hyperpigmentation and oral leucoplakia, the patient had actinic keratosis (AK) and photodamaged skin, hitherto under-recognized features of this condition. Awareness of the clinical presentation of DC is important, as accurate clinical and molecular diagnosis affords patients and their families genetic counselling, cancer prevention and screening measures, and planning for complications such as bone marrow failure.

Dyskeratosis congenita (DC) is an inherited multisystem bone marrow failure disorder that predisposes to malignancy. Classically, patients exhibit a triad of mucocutaneous features, namely nail dystrophy, oral leucoplakia and reticulate skin pigmentation, but the clinical presentation is multifarious. Recent advances in the genetic understanding of this condition are unveiling the true clinical heterogeneity and associated complications of this disorder. Mutations in 10 genes have been identified as causing DC, and these can be X-linked, autosomal dominant or autosomal recessive. We describe a case of X-linked DC with a confirmed mutation, diagnosed at a relatively late stage in life.

Report

  1. Top of page
  2. Summary
  3. Report
  4. References
  5. CPD questions
  6. Instructions for answering questions

A 28-year-old man presented with red, dry skin on his face, neck, upper chest and arms, which had worsened in severity from early childhood. He had an 8-year history of persistently watery eyes and fragile nails. He also had excessive sweating on his forehead and axillae. He was otherwise well, and was born with normal skin. His parents were non-consanguineous. His medical history included oral leucoplakia affecting the buccal mucosa, which had since resolved, and a benign ventriculoseptal defect. His sister was unaffected, and there was no history of similar skin changes in the family. He had left school at 16 years of age, and had no learning difficulties, was a current smoker, and had one daughter whose skin, nails and eyes were normal. He was not taking any regular medications.

On physical examination, the patient was found to have photodamaged skin on photoexposed sites, with scaly erythematous patches (Fig. 1). There was reticulate hyperpigmentation with poikiloderma around the neck (Fig. 1). The eyes were constantly watery (epiphora), and bilateral ectropion was present (Fig. 2). Most of the nails were dystrophic, particularly the fingernails, which had longitudinal white lines, longitudinal ridges and onychoschizia (Fig. 2b). The oral mucosa was normal.

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Figure 1. Photodamaged skin on photoexposed sites: (a) forearm and (b), neck showing reticulate hyperpigmentation, historically referred to as ‘dirty neck’.

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Figure 2. (a) Epiphora due to stenosis of lacrimal drainage system, and bilateral ectropion (b) Nail dystrophy of the fingernails showing longitudinal white lines and ridging, and onychoschizia.

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On histological examination of a punch biopsy taken from representative skin of the forearm, alternating orthoparakeratosis was seen, along with a band-like inflammatory infiltrate, telangiectasia in the superficial vessels and epidermal atypia, compatible with AK (Fig. 3). A biopsy previously taken from areas of oral leucoplakia showed hyperkeratosis only. A diagnosis of DC was suspected clinically.

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Figure 3. (a) Actinic keratosis (AK) shouldering the acrosyringium, with band-like inflammatory infiltrate in areas of AK. Telangiectasia is visible in the superficial vascular plexus. (b) Basal atypia and dyskeratosis (abnormally premature keratinization in the suprabasal layer) typical of AK. Haematoxylin and eosin, original magnification (a) × 40; (b) × 100.

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Genetic testing revealed a mutation in the DKC1 gene (Ala353Val), confirming X-linked DC. Referrals were made to the haematology, ophthalmology and medical genetics departments. No features of bone marrow failure were found. His daughter was found to be a carrier for the DKC1 gene mutation. The patient was advised to use strict photoprotection and to cease smoking.

Advances in the genetic understanding of DC are exposing the clinical heterogeneity and associated complications of this condition. The classic clinical features, namely, reticulate skin pigmentation, oral leucoplakia and nail dystrophy, usually present in childhood. Abnormal skin pigmentation and nail changes usually appear first, often by 10 years of age. Bone marrow failure frequently develops by 20 years of age, and affects up to 80% of patients by 30 years of age.[1]

DC is a multisystem disease. Urogenital, ophthalmic, pulmonary, gastrointestinal and neurological complications can develop (Table 1). Clinical criteria for the diagnosis exist, with a minimum of two ‘major’ and two ‘somatic’ features needed to confirm the diagnosis.[1] Presentations of DC are multifarious, and can be subtle. The age at which the mucocutaneous and somatic features develop and their severity and extent varies greatly even within families, and patients may present with bone marrow failure alone.[2] Genotype–phenotype correlations are currently not well defined. Two severe variants of DC, which present in childhood with significant developmental delay, are Hoyeraal–Hreidarsson (HH) and Revesz (RZ) syndromes, typified by additional features of cerebellar hypoplasia and by bilateral exudative retinopathy with intracranial calcifications, respectively.[3, 4]

Table 1. Clinical features and diagnostic criteria of dyskeratosis congenita.
  1. a

    Adapted from Dokal.

Classic/major features
Reticular pigmentation, especially around the neck
Nail dystrophy
Oral leucoplakia
Bone marrow failure
Somatic/multisystem features
OphthalmologicaaEpiphoria, ectropion, entropion, sparse eyelashes
RespiratoryPulmonary fibrosis/malignancy
GastrointestinalOesophageal stenosis, liver fibrosis, peptic ulceration, malignancy
OralCaries, malignancy
NeurologicalAtaxia, cerebellar hypoplasia (HH), intracranial calcifications (RZ), learning difficulties, developmental delay, microcephaly
UrogenitalUrethral stricture, phimosis, hypogonadism, undescended testes
DermatologicalPremature hair loss, greying, hyperhidrosis
OtherDeafness, immunodeficiency, osteopenia, osteoporosis, avascular necrosis of hip and shoulder, intrauterine growth retardation, short stature

DC can be inherited as X-linked, autosomal dominant and recessive forms. X-linked DC is the most common form of DC, accounting for around 30% of patients.[1] The Ala353Val DKC1 gene mutation is a common recurrent cause of X-linked DC. Currently, mutations in 10 genes are known to cause DC (Table 2), but in around 40% of cases, no mutation can currently be identified.

Table 2. Genes affected in dyskeratosis congenita.
GeneOMIM numberType of inheritance
  1. Biallelic mutations have also been noted in TERT.

X-linked DKC#305000X-linked
TERC #127550Autosomal dominant
TERT #613989
TINF2 #613990
NOP10 #224230Autosomal recessive
NHP2 #613987
TCAB1 #613988
RTEL1 #615190
C16orf57/USB1 *613276
CTC1 *613129

The majority of the mutations known to cause DC result in defective telomere maintenance and significantly short-for-age telomeres. The exception to this are C16orf57 mutations, which cause DC but without significantly reduced telomere length. Greater telomere shortening is associated with more severe and earlier-onset disease.[5-7] Mutations in the DKC1 gene lead to defective dyskerin protein, a core component of telomerase, and this results in reduced telomerase activity. Telomerase is a replication enzyme that maintains telomere length by adding TTAGGG repeats to the 3′ end of chromosomal DNA after replication. Pathophysiologically, it is thought that critically shortened telomeres no longer protect chromosomal ends from cellular DNA damage-repair pathways. The resultant premature cell death and chromosome instability could with increasing age lead respectively to stem cell depletion (causing features such as bone marrow failure) and development of malignancies.[1] Environmental factors such as ultraviolet light exposure and smoking may contribute to the latter.

Histological findings in DC are nonspecific, and include hyperkeratosis, epidermal atrophy, prominent telangiectasia of superficial vessels, pigmentary incontinence and possibly an interface dermatitis. Histological features of AK have not previously been reported, to our knowledge, in DC. This serves as a warning sign in patients with DC, as actinic damage is a risk factor for the development of cutaneous SCCs.[8]

The median age at death in DC is the early to mid-40s, excluding those with the severe HH and RZ syndromes, who are not reported to survive past their 20s.[9] The main causes of mortality in DC are bone marrow failure (up to 70%), pulmonary disease (up to 15%) and malignancies occurring at an earlier age than in the general population (up to 10%).[1, 9] The median age of those affected by cutaneous SCC is 21 years of age.[9] Overall, an 11-fold increase in malignancy is seen in patients with DC compared with the general population.[9] The risk of developing tongue cancer, myelodysplastic syndrome or acute myeloid leukaemia is especially high.[9]

It is important to recognise both the classic and more subtle presentations of DC, and to be aware of the possible complications. The only long-term cure for the haematopoietic abnormalities in DC is allogenic haematopoietic stem cell transplantation, which carries a significant mortality risk.[1] Accurate clinical and molecular diagnosis affords patients and their families access to timely genetic counselling, cancer prevention and screening measures, and planning for complications such as bone marrow failure.

Learning points
  • The classic clinical features of DC are nail dystrophy, oral leucoplakia and reticulate skin pigmentation, but the presentation can be highly variable.
  • DC is a multisystem disease with multifarious complications, and bone marrow failure develops in over 80% of cases.
  • There is an increased risk of malignancy at a relatively young age in DC, especially for cutaneous SCCs, head and neck SCCs and acute myeloid leukaemia, and of developing myelodysplastic syndrome.
  • If DC is suspected, genetic testing may help confirm the diagnosis.

References

  1. Top of page
  2. Summary
  3. Report
  4. References
  5. CPD questions
  6. Instructions for answering questions

CPD questions

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  2. Summary
  3. Report
  4. References
  5. CPD questions
  6. Instructions for answering questions

Question 1

In approximately what percentage of patients can a gene mutation currently be identified?

  1. a)
    20%.
  2. b)
    40%.
  3. c)
    60%.
  4. d)
    30%.
  5. e)
    90%.

Question 2

What is the most common cause of mortality in dyskeratosis congenita?

  1. a)
    Bone marrow failure.
  2. b)
    Cutaneous squamous cell carcinoma.
  3. c)
    Pulmonary fibrosis.
  4. d)
    Liver disease.
  5. e)
    Haematological malignancy.

Instructions for answering questions

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