ARTICLE
Auteur(s) :, Ines BRAJAC*, Marija KAŠTELAN,
Franjo GRUBER, Zdravko PERIŠ
Department of Dermatology, University Hospital Centre Rijeka,
Krešimirova 42, 51000 Rijeka, Croatia
*Ines Brajac, Fax (+385) 51 658 281. E-mail:
ines.brajac@medri.hr
accepté le 7 Juin 2004
Hyalinosis cutis et mucosae (HCM), also known as Lipoidproteinosis
of Urbach and Wiethe (OMIM 247100) is an uncommon, autosomal
recessive inherited disease characterized by deposition of hyaline
material in skin, mucous membranes and internal organs. The first
clinical sign is hoarseness caused by infiltration of laryngeal
mucosa that may be present at birth or develop in the first years
of life.Yellow-white papules and nodules most commonly appear on
the face, axillae, neck, hands and scrotum. A classic sign is
bead-like papules along the margins of the eyelids. Infiltration of
the scalp often results in alopecia. Other common findings include
dental abnormalities, recurrent parotitis, and nail distrophy.
Extracutaneous features may include epilepsy and neuropsychiatric
abnormalities, sometimes in association with calcification in the
temporal lobes of the hippocampi [1-3].The disorder has recently
been shown to result from loss-of-function mutations in the
extracellular matrix protein 1 gene (ECM 1) on 1q21. ECM
1 has important physiological and biological roles in aspects
of epidermal differentiation, skin adhesion, wound healing, binding
of dermal collagens and proteoglycans, and regulation of
angiogenesis [4].Since the first descriptions of disease early in
the last century [5], numerous case reports have been published and
clinical features are discussed in detail. However, the course of
the disease as well as the therapeutic possibilities are still
being debated.Here, we report a 30 year follow up in a female
patient with HC. The report deals with the different treatment
modalities applied in the same patient, and the course of the
disease.
Case report
A 15 year-old girl was admitted to our Department for the
first time in 1972. She had been suffering from hoarseness since
birth. Rough, yellowish-white papular deposits in the skin and the
oral mucosa had developed in her first year of life. Her family
history was not remarkable. Also, there were no cases of hyalinosis
cutis et mucosae among relatives.
On admission, the extensive skin lesions were present on the
face and body. The yellowish-white papules, vesicles and crusted
plaques associated with atrophic areas and scars were noticed on
the trunk (( Fig 1 )). On the
elbows, knees, over the knuckles and sides of the hands verrucous
plaques were present. The papules and plaques were also observed on
the buccal mucosa, tonsils and pharynx. The tongue and lips were
enlarged; the frenulum was thickened, thus restricting speech. Her
face was hypomimic and coarse, with scars on the forehead, cheeks
and sides of the head. Multiple small waxy yellow papules were
found along the eyelids, and eyebrows (( Fig 2 )). Lesions on
the scalp caused alopecia and the patient wore a wig. The scull
X-rays revealed symmetric calcifications just lateral and superior
to sela turcica. Her quality of life was seriously impaired by the
disfiguring lesions and the permanent hoarseness. She was
depressed, reserved, unsociable, aggressive and almost completely
isolated from her peers.
The patient had almost identical lesions at the age of
12 years, when her parents had not yet decided to submit her
to dermabrasion. However, the girl felt wretched because of her
aged appearance and made her parents decide on the procedure.
After obtaining informed consent from her parents, face
dermabrasion was performed. Complete remission of the abraded
lesions was obtained after 10 days, and a full reversion of
the histological finding occurred within 2 months.
Regenerated, pink coloured skin had the clinical and histological
appearance of normal skin. Verrucous and atrophic lesions have
mostly disappeared and the skin was more elastic and movable.
A few months later, we abraded the lesions of the oral mucosa
rather deeply. After abrasion of the inner surfaces of the lips, a
completely normal mucous membrane was seen, both histological and
macroscopically. Regenerated mucous membrane lost its hardness and
regained normal elasticity.
In 1996, the patient came to our Department to the regular check
up. Previous dermabrasions had markedly improved the skin on
treated areas. However, prominent and disfiguring hyperkeratoses
were observed on the palmar and dorsal sides of her hands, as well
as on the elbows and knees. So, after an informed consent, the
patient was treated with etretinate 1.0 mg/kg daily for two
months and then with 0.75/mg/kg. After 4 months, the
examination revealed a substantial improvement of the verrucous
lesions on the knees, elbows and palms. The patient herself also
confirmed that her skin looked better and became more elastic.
However, as the plasma level of cholesterol, triglicerids and
transaminases increased, the therapy was stopped. Unfortunately,
after few months the lesions almost completely relapsed.
Last year, we saw our patient one more time. She was married,
looking pretty good, had a healthy child, and was overall satisfied
with her life. The changes on her face but also on the trunk where
dermabrasion was not performed, were largely reversed. (( Fig 3 ) and ( Fig 4 )).
Discussion
In the patient described herein, clinical features and symptoms
were typical for HCM. The disease started in the first weeks of the
patient’s life with hoarseness. Later on, typical changes on mucous
membrane and skin developed as in majority of previously described
cases [6-9]. Since its first description by Urbach and Wiethe [5],
the spectrum of clinical features of HCM has been expanded. In
addition to patients with typical skin and mucous lesions and
hoarseness, cases that present clinically as acneiform lesions
[10], isolated mucosal changes [11, 12], gingival hyperplasia [13],
and ocular symptoms with epiphora as the leading symptom [14], have
been reported. However, there is a paucity of information regarding
the course of the disease due to the rare follow up of reported
patients.
The course of disease in our patient was protracted, with a
slight tendency to slow down in adult life. This tendency for
improvement is in accordance with some other reports [3], however,
Hofer et al. reported a progression of oral lesions with
increasing age [11].
The reason why not all but only certain patients with HCM
develop spontaneous improvement is still unclear. The differences
could exist between patients with early and late onset of the
disease as well as between patients with different severity of the
disease. So far, there is no clear association between the clinical
phenotype and the course of HC. We observed not only a therapeutic
but also a spontaneous improvement in our patient, suggesting that
early onset of the disease could lead to a slight improvement after
the age of 50. The natural course of the disease in our patient
with a tendency to spontaneous improvement was observed on the
trunk, where dermabrasion was not performed.
The decrease in severity in older age suggests that several
pathogenetic mechanisms might be involved in spontaneous
improvement such as the self-limited nature of the disease or
changes in the regenerative properties of skin cells in older age.
According to some authors, the disease is not likely to regress
either spontaneously nor with therapy [11, 15].
Carbon dioxide laser surgery of thickened vocal cords proved to
be effective for the treatment of hoarseness as reported by Haneke
et al. [16]. The skin changes could be largely reversed by
excising the hyaline material with no remission of lesions [17].
However, the use of surgical therapies is questionable because,
according to some authors, trauma has seemed to increase deposition
of hyaline in skin and mucous membranes [11].
Although the pathophysiology underlying these depositions is not
clear, one explanation might be that lack of ECM 1a leads to
defective protein binding. If ECM normally binds type IV collagen,
the lack of this potentially regulatory protein-protein interaction
in HCM could then result in increased type IV collagen expression
and typical histopathological changes [4]. In human skin ECM 1a
mRNA is expressed throughout the epidermis with the strongest
expression in the basal and first suprabasal cell layers, whereas
expression of ECM 1 b mRNA is predominantly found in spinous
and granular cell layers. Within the epidermis, ECM has a role in
the control of keratinocyte differentiation [18].
In our experience, the cutaneous lesions in HCM may be
completely removed by dermabrasion without deposition of hyaline
material, which is confirmed histologically and clinically during
the long follow up of the patient. This suggests that no
intervention was related to the development of new lesions as
proposed.
Various genodermatoses can be improved by dermabrasion.
Permanent success could be achieved in Darier’s disease and Morbus
Hailey-Hailey [19, 20], but only a slight improvement in black
ichthyosis or Mb. Pringle [21]. In our opinion, complete regression
is achieved in those disorders in which all cells that express the
intrinsic gene defect are removed by dermabrasion, and normal cells
of the skin adnexa can regenerate the deficient skin layers. In M.
Hailey-Hailey and M. Darier dermabrasion is effective, because deep
cells of the appendages do not express the gene defect.
Complete clinical remission of abraded regions in our patient
with HCM was immediately obtained, and a full reversion of the
histologic finding occurred within two months. Dermabrasion allows
for normal micro and macroreconstruction of the damaged layers to
occur shortly after the procedure, which could never occur
spontaneously in such a short time [17]. Namely, normal cells of
the skin appendages can regenerate the deficient skin layers, as
happened in our female patient with HCM.
The patient described here had also been treated with etretinate
for four months, but the therapy was stopped because of the
increasing levels of cholesterol, triglicerids and transaminases. A
few months after retinoid therapy the lesions almost completely
relapsed. Nevertheless, we clearly demonstrated that retinoids may
act on the cutaneous lesion in HCM. The observation that the skin
lesions respond to such a brief treatment period is encouraging,
and perhaps with a longer course of therapy a better improvement
with a longer period of remission could be seen.
There has been no promising treatment for HCM to date.
Nevertheless, the lesions, especially on face and other uncovered
areas of the body, should be removed or at least corrected as soon
as possible to enable the child a normal psychophysical
development. Fortunately, the face itself, because of the abundance
of small follicles, sweat and sebaceous glands, is the best area
for performing dermabrasion. The successful correction of the
defect could improve the overall quality of a child’s life.
The dermabrasion has excellent results, long-lasting effects and
no side effects. Not all of the lesions can be removed by single
act of dermabrasion, so the procedure has to be repeated. We should
avoid retinoid therapy in childhood because of side effects on bone
development. In the adult life, with a longer course of retinoids,
we can further improve skin appearance and life quality.
References
1 Lapiere Lipoid proteinosis Fitzpatrick , Eisen , Wolff ,
Freedberg , Austen Dermatology in general medicine 1993 McGraw Hill
New York 1825-1828
2 Hofer Urbach-Wiethe disease (lipoglycoproteinosis;
lipoid proteinosis; hyalinosis cutis et mucosae. A review Acta Derm
Venereol (Stockh) 53 1973 1-52
3 Kleinert , Cervos-Navarro , Kleinert , Walter , Steiner
Predominantly cerebral manifestation in Urbach-Wiethe syndrome
(lipoid proteinosis cutis et mucosae): a clinical and
patomorphological study Clin Neuropathol 6 1987 43-45
4 Hamada , McLean , Ramsay , et-al. Lipoid
proteinosis maps to 1q21 and is caused by mutations in the
extracellular matrix protein 1 gene (ECM1) Hum Mol Genet 11
2002 833-840
5 Urbach , Wiethe Lipoidosis cutis et mucosae Wirchows
Arch Path Anat 273 1929 285-
6 Szekeres , Korom Hyalinosis cutis et mucosae Hautarzt
34 1983 640-642
7 Leheup , Jeandel , Guedenet , et-al. Hyalinosis
cutis et mucosae. Ultrastructural histochemical aspects indicating
intracellular accumulation of glycosaminoglycans Ann Pathol 6 1986
53-59
8 Juberg , Winder , Turk A case of hyalinosis cutis et
mucosae (lipoid proteinosis of Urbach and Wiethe) with common
ancestors in four remote generations J Med Genet 12 1975
110-112
9 Kumar , Ramesh , Benna , Misra , Mukherjee Case 1:
lipoid proteinosis (Hyalinosis cutis et mucosae; Urbach-Wiethe
disease) Clin Exp Dermatol 27 2002 531-532
10 Cohen , Vardy , Cagnano , Zvulunov , Naimer A
17-year-old adolescent with acneiform skin changes Eur J Pediatr
158 1999 863-864 Diagnosis: lipoid proteinosis (Urbach-Wiethe
disease, Hyalinosis Cutis et Mucosae)
11 Hofer , Bergenholtz Oral manifestations in
Urbach-Wiethe disease (lipoglycoproteinosis;lipoid proteinosis;
hyalinosis cutis et mucosae) Odontol Revy 26 1975 39-57
12 Kautzky , Shenk , Bigenzahn , Rappersberg , Konrad
Hyalinosis cutis et mucosae of the ear-nose-throat
Laryngorhinootologie 68 1989 602-606
13 Bazopoulou-Kyrkanidou , Tosios , Zabelis ,
Charalampopoulou , Papanicolaou Hyalinosis cutis et mucosae:
gingival involvement J Oral Pathol Med 27 1998 233-237
14 Knorr , Meythaler , Naumann Epiphora as the leading
symptom of Urbach-Wiethe syndrome in a sibling pair Fortschr
Ophtalmol 88 1991 168-172
15 Anil , Philip , Jacob , Beena Hyalinosis cutis et
mucosae-a case report J Pierre Fauchard Acad 7 1993 89-92
16 Haneke , Hornstein , Meisel-Stosiek , Steiner
Hyalinosis cutis et mucosae in siblings Hum Genet 68 1984
342-345
17 Vukas Hyalinosis cutis et mucosae Dermatologica 144
1972 168-175
18 Smits , Poumay , Karperien , Tylzanovski , Wauters ,
Huylebroeck , Ponec , Merregaert Differentiation-dependent
alternative splicing and expression of the Extracellular Matrix
Protein 1 Gene in human keratinocytes J Invest Dermatol 114
2000 718-724
19 Periš Dermabrasion in Darier disease Acta Dermatol Iug
4 1991 223-226
20 Periš Dermoabrason-method of choice in treatment of
morbud Darier Acta Dermatovenereol APA 10 2001 111-116
21 Corrective dermatosurgery in childhood Acta
Dermatovenerol Croat 10 2002 227-234
|
Version imprimable
Version PDF
