Dyskeratosis congenita: presentation of cutaneous triad in a sporadic case

Abstract

Dyskeratosis congenita (DKC) also known as Zinsser-Cole-Engman syndrome is a progressive genetic disease with a classical presentation characterised by a triad of reticulate pigmentation of skin, nail dystrophy and leukoplakia. It may be a multisystem disease with the involvement of haematological, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary and skeletal system. We report a sporadic case of DKC presenting with poikiloderma, nail dystrophy and oral leukoplakia.

Background

Dyskeratosis congenita (DKC) is a genetically heterogeneous disease of defective telomere maintenance with annual incidence of one per million.¹ Classical skin manifestations are in the form of a triad of reticulate pigmentation, nail dystrophy and oral leukoplakia.² Actively dividing cells of skin, oral mucosa and bone marrow (BM) are the most common affected sites, however, early degeneration of cells in other systems may be seen. BM failure is the leading cause of death.³ Here, we are reporting a case of sporadic DKC presenting at 26 years age with triad of poikiloderma, nail dystrophy, oral leukoplakia and epiphora without any systemic involvement

Case presentation

A 26-year-old man presented with roughening and discolouration of toe nails for the last 5 years, with partial involvement of finger nails. There was asymptomatic, slowly progressive pigmentation over his body for last 3 years which first appeared over neck and chest, progressing to lower limbs. He had persistent white patches over tongue for 6 months. He did not have a history of tobacco usage. The patient had episodes of watering from right eye for 5–6 months. There was no history of photosensitivity. His siblings were not affected and there was no history of similar complaint in the family. He was born to a non-consanguineous parent with unremarkable birth history and normal developmental milestones.

On general physical examination, he was a young man of average built with body mass index of 24.3 kg/m² (weight 72 kg, height 173 cm) corresponding 47th percentile. There was no pallor. On mucocutaneous examination, there was poikiloderma over neck, anterior chest, sides of face, pinnae with facial erythema and brown reticulate pigmentation over lower mid-back and bilateral lower limbs (figures 1 and 2). Leukoplakia on the dorsum of tongue with areas of discrete superficial erosions and violaceous pigmentation over buccal mucosa was present (figures 3 and 4). Teeth were normal. There was dystrophy of all the toe nails and longitudinal ridging of finger nails. Scaling on the medial part of right eye with lacrimation suggested chronic irritation due to tears. No other systemic abnormality was detected.

Figure 1.

Poikiloderma on face.

Figure 2.

Reticulate pigmentation on back.

Figure 3.

leukoplakia on tongue.

Figure 4.

Reticulate pigmentation on buccal mucosa.

Investigations

Routine haematological (haemoglobin—11.5 g/dL, total leucocyte count—4600×10⁹/L, platelet count—1.5 lac×10⁹/L³) and biochemical investigations were normal. Radiological examination of chest and abdomen was normal. Lingual biopsy showed hyperkeratosis, flattened rete ridges with fibrocollagenous tissue and proliferation of capillaries suggestive of leukoplakia. Chest X-ray, Ultrasonography abdomen/kidney ureter bladder region were normal.

Differential diagnosis

The patient was diagnosed as a sporadic case of DKC with no systemic involvement. A differential diagnosis of Fanconi’s anaemia, genetic reticulate pigmentary disorders and genetic photosensitive syndromes were kept. Presence of leukoplakia, nail changes and absence of dyschromatosis in our patient ruled out Fanconi’s anaemia. Similarly genetic reticulate pigmentary disorders are not associated with leukoplakia and nail changes. The main symptom in genetic photosensitive disorders is hypersensitivity to light which was absent in our case.

Treatment

The patient was referred to haematologist for further management.

Outcome and follow-up

No oral, haematological or systemic deterioration was seen at 6 months and 1 year of follow-up. He was advised for regular yearly follow-up.

Discussion

Dyskeratosis literally means the irreversible degeneration of skin tissue, and congenita means inborn. DKC is a complex multisystem disorder with genotypic as well phenotypic pleiotropism. It was first described by Zinsser and later by Engman and by Cole leading to the designation of Zinsser-Engman-Cole syndrome.⁴

DKC is related to telomerase dysfunction; all genes associated with this syndrome (CTC1, DKC1, TERC, TERT, TINF2, NHP2, NOP10 and WRAP53) encode proteins in the telomerase and shelterin complex (figure 5).² Telomerase acts as a template for repairing DNA, shelterin complex protects the terminus by formation of t-loops. The defective telomere maintenance results in chromosomal shortening and gene loss during cell replication which ultimately leads to cell apoptosis, particularly in highly proliferative tissues such as the haematological and dermatological systems.⁵ Different mutations manifest as autosomal dominant, autosomal recessive, X linked or sporadic DKC (figure 5), Whatever be the genetic basis shortening of telomere is always seen. In sporadic cases, Hoyeraal-Hreidarsson (HH), Revesz syndrome usually defects is in shelterin complex leading to defective chromosomal end repair and a severer and progressive disease. In sporadic DKC mutations are in dyskerin or TINF2.⁶ TERC and DKC1 mutations are the most common and lead to very short telomeres. TERT codes for enzyme component of telomere complex and mutation leads to variable clinical pattern ranging from classic DKC to single organ involvement. Clinical presentation of DKC is not dependent on severity of telomere shortening but depends on gene mutated, nature of mutation, generations of mutations, environmental factors and heterogeneity.

Figure 5.

Mutations in telomerase—shelterin complex leads to exposure of telomeres leading to defective DNA damage repair mechanisms. Schematic diagram showing the mutations leading to different inheritance pattern. AA, aplastic anaemia; AD-DKC, autosomal dominant dyskeratosis congenita; AR-DKC, autosomal recessive dyskeratosis congenita; DF, Dominant Familial; ET, essential thrombocythaemia; HH, Hoyeraal-Hreidarsson syndrome; MDS, myelodysplastic syndrome; PF, pulmonary fibrosis; PNH, paroxysmal nocturnal haemoglobinurea; POT, protection of telomeres; RS, Revesz syndrome; S-DKC, sporadic dyskeratosis congenita; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase.

DKC classically presents as triad of reticulated skin hyperpigmentation (80%–90% cases), nail dystrophy (90% cases) and white oral plaques (80% cases).⁷ Milder form of disease may lack the classic triad and may have only skin, BM or any systemic findings. Nail changes appear earliest (usually by 10 years of age) followed by reticulate pigmentation and then leukoplakia. Other features occur with lower frequencies and involve virtually every organ system.⁷ Minimal clinical criteria for diagnosis of DKC include the presence of at least two of the four major features (abnormal skin pigmentation, nail dystrophy, leukoplakia and BM failure) and two or more of the other somatic features known to occur in DKC.⁸

Hyperpigmentation is seen in a reticulated pattern because of atrophy of epidermis, capillary hyperplasia and melanin pigment deposited near the blood vessels. Poikilodermatous changes with atrophy and telangiectasia may be seen. The sun-exposed areas, including the upper trunk, neck and face, are the most affected areas. Ectodermal abnormalities, such as alopecia of the scalp, eyebrows, and eyelashes, premature greying of the hair, hyperhidrosis, hyperkeratosis of the palms and soles and adermatoglyphia, are noticed. Nail dystrophy begins with ridging and longitudinal splitting which progresses resulting in small, rudimentary or absent nails. The fingernails are involved prior to toenails in most cases unlike in our case. Mucosal leukoplakia typically involves the buccal mucosa, tongue and oropharynx.⁹ There may be areas of erosions and ulceration are thought to be due to herpetic infection occurring secondary to immunocompromised state. Persistent erosions and leukoplakic areas show an increased risk of malignant transformation and hence require frequent monitoring. Constriction and stenosis at other mucosa, for example, oesophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina and anus leads to development of dysphagia, dysuria, phimosis and epiphora. Our patient also had history of epiphora.

Approximately 90% have peripheral cytopenia of one or more lineages with median age of presentation at 20 years. Adverse events include severe BM failure, myelodysplastic syndrome, acute myeloid leukaemia and solid tumours. BM failure is a major cause of death, with approximately 70% of deaths related to bleeding and opportunistic infections occurring as a result.¹⁰ Haematological system was not involved in our patient. Early diagnosis of DKC is helpful because before BM involvement harvesting and storage of cells can be done for later use.

Second major cause of death is malignancy occurring mainly on mucosal surfaces showing leukoplakia. Therefore, it is vital to recognise the increased risk of upper aerodigestive tract cancers in these patients (11-fold increase compared with general population).³ The prevalence of squamous cell carcinoma of the skin is also increased. Other malignancies reported include Hodgkin’s lymphoma, adenocarcinoma of the gastrointestinal tract, and bronchial and laryngeal carcinoma. Malignancy tends to develop in the third decade of life.¹¹ The skeletal, gastrointestinal and genitourinary systems also may be affected. Female carriers of DKC may have subtle clinical features.

Diagnosis of DKC was initially based on rigid diagnostic criteria of mucocutaneous triad with/without BM failure but with further advances in knowledge of disease we know that this syndrome is associated with wide spectrum of disorder. Telomere shortening leads to early ageing (premature grey hair, osteoporosis, dental loss), developmental (physical and mental) disorder, cancer syndrome, abnormal dentition and lung fibrosis.

Early age of onset of disease is normally seen in severe variants, with rapid progression and poor prognosis. Sporadic, HH syndrome, Revesz syndrome and X linked DKC have a presentation at early age and rapid progression while AD presents in adolescents or even later and have a slower progression. Malignant transformation is not dependent on time of onset or severity of disease. Our case was different because in spite of being sporadic the age of onset was relatively late and progression was slower with no haematological abnormalities until the age 27 years. Variable inheritance with variable expressivity may be responsible for this clinical picture.

For milder disease, supportive treatment is required only. Androgens (eg, oxymetholone) and haematopoietic growth hormones are used in DKC with BM failure.⁶

Conclusion

We are reporting this case because of classical presentation of DKC, rarity of the disorder, extensive cutaneous involvement and rare clinical features like epiphora in a patient with no history of similar complaint.

Learning points.

• Dyskeratosis congenita (DKC) is a multisystem disorder.

• There is genetic and clinical variability.

• Sporadic cases are rare.

• Early diagnosis helps because haematological harvesting can be done.

• Bone marrow failure/immunodeficiency, oral malignancy, pulmonary complications are common causes of death in DKC.