ARTICLE
Dyskeratosis congenita (DC), also called Zinsser-Cole-Engman syndrome,
is a rare disorder with an X-linked, recessive inheritance [1]. It is
characterized by the following triad of clinical symptoms: (1) dystrophy
of the nails with failure of the nails to form a nailplate, (2) whitish
thickening (leukokeratosis) of the oral and occasionally of the anal mucosa,
and (3) extensive areas of net-like pigmentation of the skin suggestive
of poikiloderma atrophicans vasculare [2, 3]. The majority of patients
with DC have pancytopenia or hypoplastic anemia [4]. In addition, DC patients
may display abnormalities of their gastrointestinal, musculoskeletal,
dental, neurologic, and immunological systems [5].
Histological examination shows atrophy of the epidermis, vacuolization
of basal cells and lymphocytic infiltration of the dermis in areas of
poikiloderma. Areas of reticular pigmentation show melanophages in the
upper dermis as the only constant feature. There have been many reports
on DC [4, 6-9], but there have been few ultrastructural studies characterizing
it. Therefore, we now present an ultrastructural study of DC and discuss
the pathogenesis of this disease.
Case report
A 46-year-old man visited our clinic on December 1st, 1989 for evaluation
of net-like pigmentation over his entire body, and nail deformities. The
net-like pigmentation probably appeared on his chest at about 3 years
of age and had gradually spread to his face, trunk and his extremities.
As a child, he had blisters on sun-exposured areas, especially bilaterally
on the back of his hands. Dystrophic changes of the nails were observed
before 1975 and had become gradually worse. Whitish thickening of his
oral mucosa was evident in 1986 and was treated by the oral surgery department
of our hospital.
Materials and methods
Biopsy specimens were obtained from oral mucosa and atrophic skin of
the patient's neck with net-like pigmentation. The specimen from the oral
mucosa was used only for light microscopy, while the neck specimen was
divided into two pieces for histological and ultrastructural studies.
Light microscopy
Tissue samples were fixed with 3.7% formaldehyde and embedded in paraffin.
Five µm thick tissue sections were prepared for light microscopic
observation.
Electron microscopy
Tissue samples for electron microscopy were fixed at 4° C in 2.5%
glutaraldehyde buffered with 0.1 M phosphate buffer (pH 7.4) for 2 hrs.
After postfixation in 1% buffered osmium tetroxide, sections were dehydrated
in graded ethanol solutions and propylene oxide and embedded in Epon 812.
Ultrathin sections were made with an MT-5000 Ultra Microtome (Sorvall,
Newtown, CT, USA) equipped with a diamond knife (Diatome, Bienne, Switzerland)
and were stained with 3.5% uranyl acetate and lead citrate. The sections
were examined at direct magnifications of 1,000-10000 times with an H-300
electron microscope (Hitachi, Tokyo, Japan) at an accelerating voltage
of 75 kV with a 0.03 mm objective aperture.
Results
Light microscopic findings
The oral biopsy section showed hyperkeratotic or parakeratotic thickening
of the horny layer and acanthosis with hypergranulosis. Lymphocytic exocytosis
was also present. Mononuclear cell infiltrates and capillary dilatation
with an increase of melanophages were observed in the upper dermis (Fig.
1a). The neck biopsy section showed atrophy of the epidermis,
disappearance of rete ridges and cleft formation at the dermo-epidermal
junction. Mild spongiosis and exocytosis of lymphocytes were also seen.
A mild inflammatory infiltrate was observed in the upper dermis (Fig. 1b).
Bandlike infiltration of lymphocytes and liquefaction degeneration were
not seen. Capillary dilatation and melanophages were observed. PAS positive
materials, which were localized under the cleft, were irregularly thickened.
Electron microscopic findings
Various sized vacuoles were observed in the cytoplasm of basal cells
and above the basal lamina. A large number of basal cells were linked
together by well-developed desmosomes (Fig.
2a). Exocytosis of lymphocytes was observed in the epidermis.
The basal lamina showed duplication or multiplication and partial breakdown.
A cleft was evident between the basal cells and the basal lamina. Anchoring
fibrils, which extended from dermis to the basal lamina, were clearly
visible, whereas anchoring filaments were broken and/or were missing (Fig.
2b). Several macrophages were observed which had melanin in their
cytoplasm between or under the duplicated basal lamina. Several microvilli
were present in the intracellular spaces. Tonofilaments in the basal cells
with vacuoles were decreased in size and in number compared with those
in normal basal cells. Lipid droplets were not observed in the cytoplasm
of basal cells.
Discussion
DC is an X-linked disorder associated with cutaneous, mucosal, ocular
and hematologic abnormalities and an increased incidence of cancer [2].
Our case was diagnosed as DC from clinical findings of reticular pigmentation
on the trunk, leukokeratosis of the oral mucosa, dystrophic changes of
the nails, and histological characteristics. To date, there have been
few electron microscopic studies involving DC. Mckay et al. [10]
described ultrastructural findings only concerning mucosal lesions of
DC. Aso et al. [11] reported the presence of lipid droplets in
the cytoplasm of epidermal cells and multiplication of basal lamina and
suggested that these findings were related to the degeneration of epidermal
cells. In the present study, we observed multiplication of the basal lamina
as previously described by Aso et al. [11], and vacuoles in the
cytoplasm of basal cells and in the lamina lucida which had never been
previously reported. Histologically cleft formation at the dermo-epidermal
junction seems to be identical to the vacuolar structures observed on
electron microscopy. It seems that reduplication of basal lamina is a
secondary phenomenon and is commonly caused by various tumors or benign
inflammatory skin reactions [12, 13]. Thus we consider that it does not
play a key role in the pathogenesis of this disease.
In contrast with those changes of the basal lamina, the vacuoles and
clefts between the basal cells and basal lamina may be significant in
the pathogenesis of DC. Vacuolar degeneration of basal cells has been
demonstrated in various cutaneous disorders such as vitiligo [14, 15],
pityriasis rosea [16], and photodamaged skin [17, 18]. Moreover, Forman
et al. [19] reported a case of Kindler's syndrome, which is characterized
by blister formation in childhood, poikiloderma and diffuse cutaneous
atrophy and is accordingly considered to be a congenital disorder similar
to DC. They demonstrated ultrastructurally the reduplication of the lamina
densa and focal clefts below degenerating cytolytic basal cells. These
findings seems to be similar to those observed in our case. So certain
characteristics common to both diseases may be induced by the same mechanism.
In fact, clinically and histologically, both diseases have several features
in common. But acrokeratoses and blister formation are prominent features
in Kindler's syndrome, although not in DC. In addition, mucous membrane
lesions are not common in Kindler's syndrome. From these characteristics
the diagnosis of Kindler's syndrome can be excluded in our patient, although
both diseases are included in the category of congenital poikiloderma.
Yamamoto et al. [17] demonstrated electron-lucent degeneration
and vacuoles in basal keratinocytes of photodamaged skin and suggested
that these were characteristic markers for photodamage. From these considerations,
vacuolar degeneration and cleft formation, at least in this case of DC,
seemed to be closely related to photosensitivity and may correspond with
the past history of this patient who had suffered as a child from blisters
on sun-exposured areas, especially on the backs of his hands. Sakamoto
and Kitamura [20] examined the characteristics of many cases of DC and
reported blister formation in some cases. Therefore, it seems that blisters
are formed clinically when clefts are highly developed. However, blister
formation did not appear as our patient grew older and the reason for
this is still unknown. Thus, degeneration of basal cells seems to be the
initial skin manifestation of DC and therefore, may play an important
role in pathogenesis of this disease.
Histologically and ultrastructurally, lymphocytic exocytosis was observed
in the specimen of atrophic skin. There have been some reports describing
the presence of lymphocytic exocytosis [21]. Others have not described
it [6, 22]. The histological characteristics of the skin of DC described
in the literature vary from case to case. Thus it seems to be difficult
to explain the significance of lymphocytic exocytosis satisfactorily although
it might be the result of the degeneration of basal cells.
CONCLUSION
We suggest that the disappearance of rete ridges and atrophy of the epidermis
in DC result from vacuolar degeneration of basal cells and that duplication
of the basal lamina is caused by degeneration of basal cells. Moreover,
we speculate that clinical reticular pigmentation, which seems to correspond
to the venous line, is related to dermal melanophages filled with melanin
as a result of pigmentary incontinence.
REFERENCES
1. Fulk CS. Primary disorders of hyperpigmentation. J Am Acad Dermatol
1984; 10: 1-16.
2. Kramer KH. Heritable diseases with increased sensitivity to cellular
injury. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Frank Austen
K. eds. Dermatology in General Medicine. 4th ed. New York: McGraw-Hill,
1993: 1974-91.
3. Lever WF, Schaumburg-Lever G. Congenital diseases In: Lever WF, Schaumburg-Lever
G, eds. Histopathology of the Skin. 7th ed. Philadelphia: JB Lippincott,
1989: 65-102.
4. Tchou Ping-K, Kohn T. Dyskeratosis congenita: an autosomal dominant
disorder. J Am Acad Dermatol 1982; 6: 1034-9.
5. Sirinavin C, Trowbride AA. Dyskeratosis congenita: clinical and genetic
aspects. J Med Genet 1975; 12: 339-54.
6. Dodd HJ, Devereux S, Sarkany I. Dyskeratosis congenita with pancytopenia.
Clin Exp Dermatol 1985; 10: 73-8.
7. Connor JM, Teague RH. Dyskeratosis congenita report of a large
kindred. Br J Dermatol 1981; 105: 321-5.
8. Aguilar-Martinez A, Lautre-Ecenarro MJ, Urbina-Gonzalez F, et
al. Cytogenetic abnormalities in dyskeratosis congenita report
of five cases. Clin Exp Dermatol 1988; 13: 100-4.
9. Gutman A, Frumkin A, Adam A, et al. X-linked dyskeratosis
congenita with pancytopenia. Arch Dermatol 1978; 114: 1667-71.
10. Mckay GS, Ogden GR, Chisholm DM. Lingual hyperkeratosis in dyskeratosis
congenita: ultrastructural findings. J Oral Pathol Medicine 1991;
20: 196-9.
11. Aso K, Sato N, Hozumi Y. Dyskeratosis congenita. Jpn J Clin Dermatol
1985; 27: 211-7 (in Japanese).
12. Oguchi M, Komura J, Ofuji S. Ultrastructural studies of epidermis
in acute radiation dermatitis. Arch Dermatol Res 1978; 262: 73-81.
13. Ghadially FH. Cell membrane and coat In: Ghadially FH, ed. Ultrastructural
Pathology of the Cell and Matrix. 3rd ed. London: Butterworths, 1988:
1043-97.
14. Bhawan J, Bhutani LK. Keratinocyte damage in vitiligo. J Cutan
Pathol 1983; 10: 207-12.
15. Moellmann G, Klein-Angerer S, Scollay DA, et al. Extracellular
granular material and degeneration of keratinocytes in the normally pigmented
epidermis of patients with vitiligo. J Invest Dermatol 1982; 79:
321-30.
16. Takai Y, Miyazaki H. Cytolytic degeneration of keratinocytes adjacent
to Langerhans cells in pityriasis rosea (Gibert). Acta Derm Venereol
1976; 56: 99-103.
17. Yamamoto O, Bhawan J, Hara M, et al. Keratinocyte degeneration
in human facial skin: documentaion of new ultrastructural markers for
photodamage and their improvement during topical tretinoin therapy. Exp
Dermatol 1995; 4: 9-19.
18. Toyoda M, Bhawan J. Ultrastructural evidence for the participation
of Langerhans cells in cutaneous photoaging processes: a quantitative
comparative study. J Dermatol Sci 1997; 14: 87-100.
19. Forman AB, Prendiville JS, Esterly NB, et al. Kindler syndrome:
report of two cases and review of the literature. Pediatric Dermatol
1989; 6: 91-101.
20. Sakamoto K, Kitamura W. Cole-Engman syndrome. Jpn J Clin Dermatol
1970; 24: 441-52 (in Japanese).
21. Ling NS, Fenske NA, Julius RL, et al. Dyskeratosis congenita
in a girl simulating chronic graft-vs-host disease. Arch Dermatol
1985; 121: 1424-8.
22. Kawaguchi K, Sakamaki H, Onozawa Y, et al. Dyskeratosis congenita
(Zinsser-Cole-Engman syndrome). Virchows Archiv A Pathol Anat 1990;
417: 247-53.
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