Unilateral facial telangiectases suggest type 1 segmental manifestation of Osler‐Rendu‐Weber syndrome in an 11‐year‐old boy

ARTICLE

Auteur(s) : Pamela POBLETE-GUTIÉRREZ, Albert RÜBBEN, Hans F. MERK, Jorge FRANK

Department of Dermatology and Allergology, University Clinic of the RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany

Article accepted on 22/09/2003

Osler-Rendu-Weber Syndrome (ORWS), also known as hereditary hemorrhagic telangiectasia (OMIM 187300), is an autosomal dominant disorder first described at the end of the nineteenth century as a familial form of recurrent epistaxis associated with telangiectases of the skin and mucosa [1, 2]. Its most prominent feature is the presence of vascular abnormalities that can lead to serious bleeding, especially of the gastrointestinal tract. Histopathological examination of skin lesions shows dilated vessels that develop from postcapillary venules [3]. The disease affects up to 1:50,000 individuals with no sex difference. Diagnosis is established upon history of epistaxis combined with typical cutaneous and mucosal lesions and a skin biopsy is usually not necessary. In general, ORWS manifests at puberty or in early adult life. However, in some cases skin symptoms already develop in early infancy [2].
By haplotype analysis McDonald and colleagues demonstrated linkage of ORWS to chromosome 9q33-q34 [4]. In 1994, mutations in the endoglin gene, coding for a transforming growth factor-beta (TGF-β) binding protein, were identified in different affected individuals [5]. However, in other families revealing the clinical features of ORWS, no molecular defects could be found in this gene, thus indicating that ORWS is most likely a clinically and genetically heterogeneous disorder. Subsequently, different authors suggested that other genes may be involved in the pathogenesis of this disease and could be responsible for the broad clinical spectrum [6]. In 1997, this notion was supported by the identification of mutations in the activin receptor-like kinase 1 (ALK-1) gene located on chromosome 12q13 in several families with ORWS [7]. Here, we report an unusual case suggesting a type 1 segmental manifestation of this disorder.

Case report

An 11-year-old boy presented with a history of recurrent epistaxis over four years. Remarkably, the bleeding of the nose affected the left nostril exclusively and was self-limiting. His mother noted the appearance of the first skin lesions on the left cheek and left side of the lips shortly after birth. There was no history of gastrointestinal bleeding, pulmonary or cerebral complications.
The patient had one sister who was not affected. His parents were healthy and physical examination revealed no pathological cutaneous signs.
Upon clinical inspection of the boy, we observed multiple telangiectases confined to the left cheek and the left side of the lips (Fig. 1). Some vascular lesions were also present on the left side of the buccal area, on the oral mucosa of the left cheek, and on the left side of the gum.
An otorhinolaryngological examination revealed some telangiectases on the left nasal mucosa. The conjunctivae and eyelids were not affected. No other pathological findings of the skin were noted. Chest radiography, brain magnetic resonance imaging and abdominal computed tomography were normal. Examinations for occult blood in the feces repeatedly resulted negative. Routine laboratory studies showed normal values.

Discussion

To date, several families affected with ORWS have been published [8, 9]. The disease is inherited as an autosomal dominant trait with high penetrance and patients typically present epistaxis as the first manifestation in 90% of the cases [10]. The classical phenotype includes mucocutaneous telangiectases that can occur in a disseminated fashion on the nail beds, palms, lips, tongue, ears, face, chest, nasal mucosa, palate, and buccal mucosa. Besides these clinical signs affected individuals may develop complications due to vascular involvement of internal organs such as the central nervous system, lungs and gastrointestinal tract [11].
In the patient described herein, isolated telangiectases confined to the left inferior half of the face were noted. A corresponding involvement of the nasal mucosa, manifesting as unilateral epistaxis, and buccal mucosa were also present. No other anomalies could be detected and the family members did not reveal signs or symptoms of the disease. In contrast to the diffuse affection in the classical phenotype, the boy exhibited a distinct segmental pattern of involvement and the severity of lesions in the circumscribed region corresponded to that usually observed in the diffuse state. Besides the diffuse manifestation of autosomal dominant skin disorders, two different segmental phenotypes are currently distinguished: The type 1 manifestation reflects heterozygosity for a de novo postzygotic somatic mutation thus representing a true cutaneous mosaicism. The type 2 manifestation is the result of a germline mutation that gives rise to a diffuse distribution of skin lesions, combined with a postzygotic somatic mutation resulting in lost of heterozygosity in a segmental area. Clinically, this would be reflected by an increased severity of the segmental lesions that are superimposed on the ordinary diffuse phenotype [12].
Therefore, the segmental phenotype observed in our patient may represent a somatic mosaicism as the result of a postzygotic mutation and, thus, a type 1 segmental manifestation of ORWS. Previously, Happle made similar observations in other autosomal dominant skin disorders [13].
Interestingly, another condition referred to as unilateral nevoid telangiectasia also presents telangiectases in a limited unilateral region without systemic involvement [14]. In this disease, a congenital and acquired form are currently distinguished, the latter one being commonly observed in pregnancy and patients suffering from liver cirrhosis. A putative role of both increased estrogen and progesteron receptors in the skin and mucosa has thus been discussed [15]. However, the pathogenesis of this disease remains elusive because these findings are controversial and could not be confirmed in later studies. We propose that this disorder could reflect a segmental variant of ORWS. This notion is also supported by previous reports from other authors [14, 15]. It is possible that in individuals with segmental ORWS, skin lesions are accentuated under conditions accompanied by increased hormonal production, e.g. pregnancy and liver disease. In view of the identification of mutations in the endoglin and the ALK-1 gene underlying ORWS, future studies on the cellular and molecular level will clarify the genetic basis of our proposition. Because the mother refused a skin biopsy in the under-aged patient, we were not able to study the origin of the skin lesions on the molecular level.
The clinical aspect and the results of laboratory and radiological examinations allow for a favorable prognosis in the patient presented herein since epistaxis was always self-limiting and did not require special measures. Still, an annual dermatological control was recommended. n

References

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