The Turkish Journal of Pediatrics
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Dyskeratosis congenita: report of two cases with distinct clinical presentations
Fatma Elif Demirgüneş, Gonca Elçin, Sedef Şahin
Department of Dermatology, Hacettepe University Faculty of Medicine, Ankara, Turkey
|Demirgüneş FE, Elçin G, Şahin S. Dyskeratosis congenita: report of
two cases with distinct clinical presentations. Turk J Pediatr 2008; 50: 604-607.|
Dyskeratosis congenita (DC) is a rare, inheritable disorder characterized by a
triad of abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia.
Inheritance is mainly X-linked recessive; however, autosomal dominant and
recessive forms have also been reported. Here, we report two cases of DC
with distinct clinical presentations together with different genetic screening
results, which emphasize the quite heterogeneous clinical as well as genetic
nature of DC.
dyskeratosis congenita, leukoplakia, nail disease, hyperpigmentation
|Dyskeratosis congenita (DC) was first described
by Zinsser in 1906. It was subsequently
described by Engman in 1926 and Cole in
1930. DC, which is also designated as Zinsser-
Engman-Cole syndrome, is a triad consisting
of nail dystrophy, mucosal leukoplakia and
abnormal skin pigmentation. In addition to
this clinical triad that defines DC, a severe
pancytopenia, a predisposition to malignancy
and a poorly defined immunodeficiency may
accompany the syndrome. Bone marrow failure
or aplastic anemia is the principal cause of
premature mortality in patients with DC[1-4].
Squamous cell carcinoma is the most common
malignancy, found in areas of leukoplakia such
as the mouth, tongue, nasopharynx, esophagus,
anus, cervix and rectum. In addition to its
clinical variability, the inheritance of the
condition is also variable. The most common
form is X-linked, but there are also families
showing autosomal dominant and autosomal
recessive inheritance. The major X-linked
form of the disease is due to DKC1 gene
mutation. DKC1 is encoding the protein
dyskerin, which is a component of ribosomal
RNA and telomerase complex. Recently, TERC
gene mutations were identified in the rarer
autosomal dominant subtype of DC. TERC is
one of the two core components of telomerase
and is essential for telomere maintenance. The
genetic basis for the autosomal recessive form
of the disease remains unknown.|
Herein, we describe two cases of DC, with
distinct clinical presenting features as well as
different genetic screening results, underlining
the wide spectrum of the genotype and the
|Case Presentation |
A five-year-old boy who had a four-year history
of ulcerated white plaque on his tongue, which
disturbed eating, and a six-month history of
easy splitting of the nails, was referred to our
department for further evaluation. He was born
at term (2250 g) to a marriage with third- degree
of consanguinity. His mother and father were 26
and 31 years old, respectively. A detailed family
history indicated that his uncle had suffered from
severe anemia and had died due to infection.
His brother and sister had no signs of systemic
infection or mucocutaneous abnormality.
Physical examination revealed reticulate hyperpigmentation
predominantly on the neck and the
inguinal areas, accompanied by dystrophic toeand
fingernails. The dystrophic fingernails are
shown in Figure 1. As shown in Figures 2 and 3,
evident leukokeratosis on the dorsum and sides
of the tongue and prominent dental caries were
noted. The patient had thin and sparse hair.
| ||Fig 1: Dystrophic fingernails observed in Case 1.|
| ||Fig 2: Evident leukokeratosis on the dorsum and
sides of the tongue.|
| ||Fig 3: Prominent dental caries.|
Laboratory tests were as follows: Complete
blood count with a white blood cell count
of 8900/mm3, with 80% neutrophils and 6% lymphocytes; red blood cell count 2950x103/µl;
hemoglobin 7.8 mg/dl; hematocrit 24%; and
platelet count 144x103/µl. Mild anisocytosis,
polychromasia and spherocytosis were noted
in the peripheral blood smear. Direct Coombs
test was negative and osmotic fragility test
result was normal.
Bone marrow aspirate was hypocellular and
revealed increased fat droplets, compatible
with aplastic anemia. A barium swallow
esophagography demonstrated a narrowed
proximal esophagus and web formation. A
biopsy specimen obtained from the tongue
revealed ulcerative inflammation and no
evidence of squamous cell carcinoma. He had
no respiratory symptoms and a chest X-ray
was within normal limits.
A diagnosis of DC was made with typical
skin lesions (reticulate hyperpigmentation),
leukoplakia of the tongue, dystrophic toe- and
fingernails, thin sparse hair, dental caries, and
esophageal web formation. Seven years after
his first admission, the X-linked nature of the
disease was confirmed by genetic screening,
which revealed DKC1 gene mutation. Denaturing
high performance liquid chromatography and
direct DNA sequence analysis of the DKC1
gene showed he was hemizygous for DKC1
gene mutation (a nucleotide transition of C to
T (1150 C--> T). In Figures 4 and 5, dystrophic
fingernails and leukokeratosis on the dorsum
and sides of the tongue are shown seven years
after his first admission.
| ||Fig 4: Dystrophic fingernails 7 years after the
first admission of Case 1.|
| ||Fig 5: Leukokeratosis on the dorsum and sides of the
tongue 7 years after the first admission of Case 1.|
Treatment with 30 mg/kg prednisolone orally
was considered for his anemia, which had
been gradually tapered and was discontinued after the follow-up visit one month later when
his hemoglobin was found to have reached
A 12-year-old boy presented with a two-year
history of easy bruising with trauma. A detailed
history revealed skin lesions that were first
noticed at the age of 8, nail abnormalities of
three-years’ duration and a white plaque on the
tongue that had appeared two months before.
The patient was the product of a full-term
pregnancy with cesarian section delivery due
to neonatal distress. His mother and father
were 32 and 41 years old, respectively, and
there was no consanguinity. There was no
remarkable medical problem in his family
and no history of significant infections, skin
pigmentation, or bone marrow failure in his
parents or other relatives.
On physical examination, reticulated hyperpigmentation
and atrophy on the neck, V area of
the chest and the posterior auricular sites were
noted, as shown in Figure 6. The longitudinal
ridging accompanied by distal dystrophy of the
nails is shown in Figure 7. Examination of the
mucosal sites revealed a white plaque on the
side of the tongue and hypoplastic conic teeth.
Figure 8 shows the white plaque on the side
of the tongue.
| ||Fig 6: Reticulated hyperpigmentation and atrophy on
the neck and V area of the chest.|
| ||Fig 7: Longitudinal ridging accompanied by distal
dystrophy of the nails.|
| ||Fig 8: White plaque on the side of the tongue.|
Laboratory tests were as follows: white blood cell
count of 4000/mm3 with 34% neutrophils, 54%
lymphocytes; red blood cell count 3170x103/µl;
hemoglobin 10.4 g/dl; hematocrit 34%; mean
corpuscular volume 98.2 fl; platelet count
72x103/µl; vitamin B1: 254 g/ml; and folic acid: 6.9 ng/ml. There was a mild polyclonal
gammopathy: IgA: 366.5 mg/dl (45-250 mg/dl)
and IgG: 1870 mg/dl (650-1600 mg/dl).
Ultrasound examination of the abdomen was
normal. The bone marrow aspirate revealed
hypocellularity and increased fat droplets and
was found compatible with aplastic anemia.
A cytogenic profile showed a 46 XY karyotype.
Genetic screening excluded both TERC and
DKC1 gene mutations.
|Dyskeratosis congenita is a very heterogeneous
disorder with respect to clinical and hematological
features and pattern of inheritance. The age of
onset, degree of bone marrow failure and range
of congenital abnormalities may vary. Three
distinct patterns of inheritance leading to the
general DC phenotype have been observed.
X-linked recessive inheritance appears to
account for over three-quarters of cases, and
the trait has been mapped to chromosome
Xq28 by linkage analysis. Since its inheritance
is predominantly X-linked recessive, DC is a
disease that occurs predominantly in males.
Both of our patients were male. However,
females can also be affected because many
of the remaining cases show evidence of
autosomal recessive or autosomal dominant
transmission[8-10]. By November 1999, 92 DC
families, comprising 148 (127 male, 21 female)
patients from 20 countries, had been recruited
to the DC registry. As well as confirming previous
observations, the DC registry has recently
identified new features of the DKC1 gene, which
is mutated in X-linked DC. Additionally, in
autosomal dominant DC patients, mutations in
the RNA telomerase component (TERC) have
been identified. TERC and DKC1 encoded protein
dyskerin are closely associated in the telomerase
complex, showing that DC may be a disease due
to defective telomerase activity. Although the
gene or genes involved in the recessive form
of the disease are not yet shown, they are very
likely the genes encoding proteins for telomere
maintenance. Genetic screening in the first case
revealed a DKC1 gene mutation confirming the
diagnosis of X-linked DC; the second case was
found to have a normal DKC1 and TERC screen.
The negative genetic findings and the healthy
status of the parents make autosomal recessive
inheritance likely in the second patient.|
Although similar to the genotype, the DC
phenotype is quite variable; the occurrence of
the clinical picture in DC seems to follow an
order. Cutaneous findings such as lacy reticulate
skin pigmentation, diffuse nail dystrophy and
mucosal leukoplakia, which were found in both
of our patients, are the most characteristic
features of the syndrome. These cutaneous features are not usually present at birth; rather
they develop progressively between the ages of
5 and 10 years. The oral leukoplakia in Case 1
and reticulate hyperpigmentation in Case 2 were
the first signs of the syndrome, which appeared
at 1.5 and 8 years of age, respectively.
Generally the nail dystrophy, which is present
in 83% of patients, is the first sign of the
disease and characterized by atrophy, shedding,
and ridging, and may progress to complete
nail loss. Although leukoplakia predominantly
involves the oral mucosa, it can involve any
Other cutaneous features include hyperhidrosis,
hyperkeratosis of the palms and soles, loss of
dermatoglyphics and occasionally bullae within
sun-exposed poikilodermatous areas.
Many other somatic abnormalities might be
seen in DC; thus, DC could be regarded as a
multisystem disorder. Esophageal stricture,
short stature, developmental delay, and thin
and sparse hair in Case 1 and extensive dental
caries found in both of our patients were some
of these somatic abnormalities.
Bone marrow failure is much more frequent than
previously suggested. By the age of 40 years, its
incidence approaches 94% of all patients. Since
the bone marrow failure is the main cause of
death, early diagnosis is important. Both of our
patients had mild aplastic anemia, which was
confirmed by bone marrow aspiration. Aplastic
anemia presented itself as anemia in Case 1 and
as mild thrombocytopenia in Case 2.
Squamous cell carcinoma is the most common
malignancy observed in patients with DC,
which is almost always found in areas of
leukoplakia. However, gastrointestinal tract
malignancies, such as signet ring carcinoma of
the rectum, adenocarcinoma of the rectum,
gastric adenocarcinoma[14,15], and malignancies
of other systems, such as primary bronchial
adenocarcinoma, adenocarcinoma of the
pancreas, and Hodgkin’s disease have also
In light of these two cases, we would like to
emphasize that the clinical presentation as well
as genetic nature of DC might be heterogeneous.
We believe it is reasonable to consider DC in
the differential diagnosis of a patient with any
features of the syndrome, regardless of gender.
In order to make early diagnosis, we should keep in mind that noncutaneous abnormalities may
precede characteristic classical mucocutaneous
features. Furthermore, DC should be considered
in any patient with aplastic anemia at any age.
Although diagnosis based on clinical criteria
alone is difficult, especially when noncutaneous
abnormalities precede classical mucocutaneous
features, identification of mutations in the DKC1
or TERC genes may help early diagnosis as well
as carrier detection.
We would also like to point out that all DC
patients require long-term follow-up for the
detection of associated malignancies. Since UV
irradiation accelerates telomere shortening, a
strict sun protection should be advised to all
We would like to thank Dr. Inderjeet Dokal and
his team for help with genetic screening.
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