Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity

Abstract

Background: Elastin gene mutations have been associated with a variety of phenotypes. Autosomal dominant cutis laxa (ADCL) is a rare disorder that presents with lax skin, typical facial characteristics, inguinal hernias, aortic root dilatation and pulmonary emphysema. In most patients, frameshift mutations are found in the 3' region of the elastin gene (exons 30-34) which result in a C-terminally extended protein, though exceptions have been reported.

Methods: We clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient.

Results: Molecular analysis showed C-terminal frameshift mutations in exon 30, 32, and 34 of the elastin gene and identified a mutational hotspot in exon 32 (c.2262delA). This cohort confirms the previously reported clinical constellation of skin laxity (100%), inguinal hernias (51%), aortic root dilatation (55%) and emphysema (37%).

Conclusion: ADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account. Regular cardiovascular and pulmonary evaluations are imperative in the clinical follow-up of these patients.

Figure 1

Pedigrees of the families described in this study. Round symbol, female; square, male; filled symbol, affected; open symbol, normal; slash line, deceased.

Figure 2

Clinical aspects of affected patients. Facial characteristics include large ears, a long, coarse face, blepharochalasis, ptosis, a beaked nose and a large philtrum. Note the variability of skin phenotype at different ages. (A-C) Typical facial characteristics, slightly hyperextensible skin, mild rimpling and sagging of the abdominal skin in patient F3:I-2. (D-F) Typical facial characteristics, slightly hyperextensible skin, and small redundant skin folds of the axillar folds in patient F3:II-1. (G-I) Typical facial characteristics, manifest loose, redundant and sagging skin folds of the abdominal skin and slightly hyperextensible skin of the limbs in patient F3:II-2. (J) Patient S1:II-2 at the age of 1 year presenting with typical facial characteristics and generalized, loose, redundant skin folds. (K-L) Facial characteristics and skin hyperextensibility in patient F6:II-1.