Acrogeria of the Gottron type in a mother and son

ARTICLE

Acrogeria was described by Gottron [1] as a mild, nonprogressive, congenital form of skin atrophy, involving mainly the distal parts of the extremities. The essential feature is atrophy of the skin and subcutaneous tissue, giving an aged appearance. The disease must be differentiated from Werner's syndrome, also characterized by premature aging and disproportionately thin distal parts of the limbs. This syndrome differs however by the tautness of the skin, systemic involvement (premature senility, endocrine disturbances), and cataracts, which develop later in life [2]. Progeria Hutchinson-Gilford differs from acrogeria by generalized cutaneous lesions and the severe course of the disease, usually with fatal outcome before the age of 10-14 years due to severe athero-sclerosis and other symptoms of premature senility [2-4]. Some overlapping features of acrogeria with progeria or Werner's syndrome have been described as metageria or acrometageria [5]. The most important appears to be the relationship with Ehlers-Danlos syndrome type IV, i.e. a variant characterized by only slight skin hyperextensibility and joint hypermobility. This variant differs, however, from acrogeria clinically by a high incidence of rupture of great vessels and bowel, and biochemically by a total or partial lack of type III collagen [6], resulting from a structural defect in the alpha1 (III) chain, which enhances the susceptibility to proteinases [7]. The relation of acrogeria with Ehlers-Danlos syndrome type IV is still controversial although in acrogeria the production of type I and type III collagens was found to be normal [8, 9]. We present the results of collagen studies including the COL3A1 gene, in two typical cases of familial acrogeria. The occurrence of the disease in the mother and son speaks in favor of an autosomal dominant mode of inheritance.

Case reports

Case n° 1

The mother, 46-year-old at first examination, was born from a non-consaguineous marriage, and her siblings, one sister and two brothers, as well as their offsprings, both males and females, were not affected. Of her 2 sons, 24- and 20-year-old, only the younger showed a similar phenotype. The atrophy of the skin was noticed in early childhood. Except for disproportionately thin limbs, she had a normal stature, but the face showed striking features: beaked, pinched nose and micrognathia (Fig. 1A). The atrophic changes were most pronounced in the distal parts of the limbs, the skin of the hands and the fingers was thinned resembling crumpled cigarette paper, with violaceous-brownish mottled discolorations (Fig. 1B).

Since the age of 7 years she had noticed proneness to bruising with scar formation on the legs. Since the age of 40 years the atrophy of the distal limbs progressed, with more pronounced trophic nail changes, especially of the thumbs. The dorsa of the hands showed cyanotic and brownish pigmentations.

All routine laboratory studies and the neurological and ophtalmological examinations were normal. There were no signs of atherosclerosis or abnormal glucose tolerance. The bone densimetry of the legs showed 25% loss of the osseous tissue (osteoporosis).

Histological examination of a skin biopsy from the dorsum of the hand showed an extremely thin dermis with swollen and rarified collagen fibers and lacunae (Fig. 2A). The elastic fibers were disrupted, irregular, and in the lower parts of the dermis clumped. Focally elastic staining material was strikingly increased (Fig. 2B).

Case n° 2

The 20-year-old son, did not show any abnormality at birth. Skin atrophy of the distal limbs was noticed at the age of 3 years and somewhat later a tendency to bruising developed. The stature, face and cutaneous features were strikingly similar to those of his mother (Fig. 3A and 3B). There were no abnormalities in laboratory studies, and no signs of osteoporosis. The histological investigation showed identical changes as in the mother (Fig. 4A). In the biopsy from the leg less abundant irregular masses of orceinophilic material were seen (Fig. 4B).

Collagen study

Fibroblast cultures and labelling

Skin biopsies used for biochemical analysis were obtained from both patients and a skin fibroblast culture was established using standard procedures. (Pro)collagens produced by the dermal fibroblasts were metabolically labelled by the incorporation of C-proline [10]. After 20 h labelling, medium and cell layer were harvested separately and supplemented with proteinase inhibitors.

Protein analysis

Procollagen molecules were extracted, purified and enzymatically converted to collagen by a pepsin digestion. SDS-electrophoresis was performed using the Laemmli system [11]. The gels were processed for fluorography or for autoradiography, dried and exposed to a hyperfilm MP (Amersham).

Molecular collagen studies

Genomic DNA and total RNA from the patients was isolated from dermal fibroblasts using the Easy-DNA kit (invitrogen) and Trizol (life technology), respectively. Total RNA was converted to cDNA, using M-MLV reversed transcriptase (life technologies) according to the manufacturer's instructions. PCR was performed using primers for the complete COL3A1 coding region in 12 overlapping fragments. These were investigated for the presence of a possible mutation using a combination of different mutation detection methods, i.e. confirmation sensitive gel electrophoresis (CSGE) [12], single strand conformation polymorphism analysis (SSCP) and heteroduplex analysis (HA).

Results

Biochemical analysis

Biochemical analysis of the (pro)collagen molecules showed in both patients normal profiles for type I, III and V collagen in the medium as well as in the cell layer, compared to normal control. In particular, no abnormalities either in the intensity or in the electrophoretic mobility of the alpha1 (III) chains was seen.

Molecular analysis

Mutation analysis of the COL3A1-cDNA sequences was performed. Each amplified fragment was investigated by CSGE, SSCP and HA but in none of them was evidence found for the presence of a mutation.

Discussion

The family presented here shows all the characteristics of acrogeria, together with proneness to bruising, which is one of the features of Ehlers-Danlos syndrome type IV. However, bruising as well as scar formation are not infrequent findings in acrogeria [9, 13]. Micrognathia and a pinched thin nose, present in both the mother and the son, were also reported in several patients with acrogeria.

Acrogeria is a rare disease with few familial cases reported. Therefore the mode of inheritance is not fully established. The first cases described by Gottron [1] were siblings, offsprings of non-affected parents, which was compatible with a recessive mode of transmission. However our cases and the familial acrogeria reported by others [13, 14] also suggest a possible autosomal dominant inheritance.

Although both sexes can be affected, there is a high prevalence of women [9, 15]. The relationship between acrogeria and Ehlers-Danlos syndrome type IV was indicated by some authors [16, 17], whereas others stressed the features evidently separating both diseases [18-20]. The absence of alterations in type I and type III collagen does not favor a close link with the Ehlers-Danlos syndrome. However, as postulated by Bruckner-Tuderman et al. [8], acrogeria of the Gottron type might be associated with various biochemical defects of connective tissue resulting in either purely dermatological symptoms or in multisystem disorders overlapping with other connective tissue diseases. The occurrence of acrogeria and metageria in members of one family [5] and presence of some symptoms of Werner's syndrome in patients with acrogeria indicate that these two disorders are related, and metageria could be regarded as a more severe variant of acrogeria.

The pathogenesis of acrogeria is not clear. The biochemical and morphological studies did not disclose any collagen defect. The histological and electron microscopic studies vary considerably [13]. In some, the collagen fibers were found to be swollen [13], tightly packed and homogeneous, decreased in number [8]. The ultrastructural studies showed a considerably widened, rough, endoplasmic reticulum and vacuoles within fibroblasts and a smaller than normal diameter of collagen fibrils, both in cases recognized as EDS type IV with some clinical features of acrogeria [17, 22, 23] and typical acrogeria [16]. The distended fibroblast cytoplasm and vacuoles filled with granulofilamentous substance, also present outside fibroblasts [16], would suggest a defect in collagen synthesis, secretion or storage [24]. In a great number of reported cases the decrease and degeneration of elastic fibers was more characteristic than the abnormality of collagen bundles [15]. Elastic fibers showed striking alterations consisting in the formation of irregular clumps and pseudoelastin substance [13, 20] with overproduction of orceinophilic masses [18]. However, other studies showed only collagen abnormalities [8] with slight fragmentation and clumping of the elastic fibers, absent in the upper parts of the dermis. The involvement of the elastica in acrogeria is also evidenced by a not infrequent coexistence of elastosis perforans [13, 14, 20] or late onset focal dermal elastosis [9]. Although no biochemical abnormality of elastica has been disclosed [9], more studies are needed to find a possible defect of elastin.

CONCLUSION

In summary, the reported familial cases are typical of acrogeria of the Gottron type. The normal collagen synthesis and absence of structural defects of type III collagen strongly indicate that acrogeria is not a variant of Ehlers-Danlos syndrome type IV but a separate entity. It is however possible that acrogeria might be heterogeneous and a subgroup of the patients could harbor a mutation in type III collagen. Differentiation from Ehlers-Danlos syndrome and premature aging syndromes is of clinical importance due to the different course, management and prognosis.

Article accepted on 7-9-99.

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