Cutis Laxa of the autosomal recessive type in a consanguineous family

ARTICLE

Auteur(s) : Sofie DE SCHEPPER^a, Bart LOEYS^b, Anne DE PAEPE^b, Jo LAMBERT^a, Jean-Marie NAEYAERT^a

^a Department of Dermatology, Ghent University Hospital, De Pintelaan 185 B-9000 Ghent, Belgium
^b Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

Article accepted on 02/09/2003

Cutis laxa is a clinical entity found in a heterogeneous group of genetic and acquired disorders characterized by premature aging of the skin with normal wound healing.
Systemic involvement in certain forms of cutis laxa originates from elastic tissue abnormalities in blood vessels, heart valves, lungs, ligaments, etc.
During the last decade enormous progress has been made in the research for the genetic background of hereditary forms of cutis laxa. Mutations have been discovered in the elastin gene for the autosomal dominant form, in the ATP7A gene (encoding for a copper transporting ATPase) for X-linked recessive cutis laxa and recently also in the FBLN 5 gene, encoding for fibulin-5, a protein associated with the elastic fiber, in type 1 autosomal recessive cutis laxa.
Because of its heterogeneity and varying etiology it can be difficult to recognize cutis laxa clinically and to differentiate it from resembling conditions such as Ehlers-Danlos. Ehlers-Danlos patients, in contrast to cutis laxa, usually have hyperextensible, hyperelastic skin, increased joint mobility (seen only in type 2 autosomal recessive cutis laxa) and poor wound healing.
The mortality of cutis laxa is dependent on the severity of systemic complications but overall prognosis is poor because of the lack of adequate treatment.

Case report

The female proband in this large Turkish family was the fourth child of consanguineous parents. The girl was born at term after a normal pregnancy with a birth weight of 3290 g and length of 49 cm.
At the age of 1 month the girls' parents first noticed her abnormally loose skin. Clinical examination at that time showed a typical “sagged” facial appearance with redundant folds around the face and neck, sunset phenomenon of the eyes, downward slanting palpebral fissures, a broad flat nose, sagging cheeks and large ears (Fig. 1,  2,  3). The skin recoiled only slowly after stretching. A biopsy was performed which confirmed the elastin disorder in the skin. A special Von Gieson staining of the skin section showed sparse, clumped and granular degenerated elastin fibers (Fig. 4), especially obvious when compared to the histological examination of a skin specimen of a healthy Turkish patient of the same age (Fig. 5).
Because the possibility of cutis laxa was suggested, further investigations to detect systemic manifestations of the disease were necessary. An echocardiographic examination was performed showing a thickened aortic valve and supravalvular aortic stenosis. The results of a magnetic resonance imaging of the brain, radiography of the skeleton, abdominal ultrasound and ophthalmologic examination of the fundus were all normal. In her first months of life the girl was hospitalised several times because of recurrent lower respiratory tract infections resulting in emphysema. The lung damage was visualised with a CT examination of the thorax revealing emphysema of the anterior segments of both lungs. Hereupon a bronchoscopy was performed showing a flaccid trachea with small orificia towards the bronchi.
The familial history of our patient was negative with regard to her parents and three older sisters but genealogical study of the large Turkish family demonstrated three other affected individuals, second cousins once removed in relation to the proband, with approximately the same phenotype with cutis laxa and lung complications (Fig. 6). One girl also had pulmonary hypertension due to peripheral pulmonary artery hypoplasia, whereas a male family member had recurrent renal infections caused by bladder diverticula and uretero-hydronephrosis [1]. Unfortunately, all three had died following cardiorespiratory failure between the ages of 6 months and 22 years.
Taking into account her clinical and histological picture and pedigree the girl was diagnosed as having autosomal recessive cutis laxa type 1.
In the Center for Medical Genetics of the University Hospital Ghent she was further examined concerning the genetical background of her disease [2]. She had a normal female karyotype (46,XX). The elastin gene, responsible for some of the dominant forms of cutis laxa, was excluded as causative gene by linkage.
Following the demonstration of the role of fibulin-5 in elastogenesis in fibulin-5 knockout mice [3, 4], FBLN 5 was tested as the causative gene in this family and indeed a homozygous missense mutation was found in the fourth EGF-like domain of fibulin-5 [2]. Recently, a de novo heterozygous mutation in the FBLN-5 gene was found in a patient with cutis laxa without systemic involvement [5].
Unfortunately, the girl died due to systemic complications of her disease at the age of 20 months.

Discussion

Cutis laxa is a rare disorder of connective tissue comprising of congenital and acquired forms characterized by loose, sagging skin lacking elastic recoil [6-9].

Inheritance patterns include autosomal dominant, autosomal recessive and X-linked recessive forms. The inherited forms usually present at birth or develop soon afterwards and show a defect in the synthesis and/or assembly of elastic fibers. Acquired cutis laxa on the other hand results from destruction of normal elastic fibers and mostly occurs later in life.

Histopathologically elastin fibers may be reduced, absent, fragmented or dissociated from the microfibrillar components.

Autosomal Dominant Cutis Laxa [10, 11]

This is the mildest form of inherited cutis laxa and in most cases there is no evidence of consanguinity. Skin manifestations predominate and patients often have a normal life expectancy. Some cases are due to mutations in the elastin gene.

Autosomal Recessive Cutis Laxa [11, 12]

Autosomal recessive cutis laxa consists of at least three distinct types and is usually more severe. Most children have a typical facies due to skin laxity with downward slanting palpebral fissures, a broad flat nose, sagging cheeks and large ears.
Autosomal recessive cutis laxa type 1 (OMIM # 219100) is often fatal in the first years of life and combines skin manifestations with severe pulmonary emphysema, diverticula of gastrointestinal and urinary tracts and cardiovascular abnormalities. Recently molecular analysis showed the first evidence of a genetic defect in the fibulin-5 gene being responsible for this type of autosomal recessive cutis laxa [2, 5]. It is most likely that other genes are also involved.
The type 2 cutis laxa (OMIM # 219200) is accompanied by bone dystrophy, mental retardation and congenital hip dislocation that often results in growth retardation. The molecular basis of this type is unknown.
The De Barsy syndrome (OMIM # 219150) is the third type of autosomal recessive cutis laxa, which typically presents with a clinical triad of lax skin, corneal “clouding” due to degradation of elastic fibers in the Bowman membrane of the cornea and mental retardation. The causative gene has not yet been elucidated.

X-linked Cutis Laxa

The X-linked recessive form of cutis laxa, formerly considered as Ehlers-Danlos type IX, is now called the Occipital Horn Syndrome and is a copper transport disorder. Here the cutis laxa phenotype is accompanied by effects on collagenous tissues (ligamentous laxity), poor wound healing (wound healing is normal in all other cutis laxa types) and a variety of systemic symptoms such as bladder diverticula, diarrhea, osteoporoses, mild mental retardation, etc. A distinctive characteristic are the bony “horns” symmetrically situated on each side of the foramen magnum and pointing caudal, which are demonstrable radiographically. This disorder is caused by mutations in the Cu^2 + -transporting ATPase alpha polypeptide (ATP7A), resulting in reduced activity of lysyl oxidase, an enzyme essential to cross-linking of both collagen and elastin [13]. The ATP7A gene is located on the long arm of the X-chromosome and the disease is allelic to Menkes kinky hair disease (OMIM # 309400).

Acquired Cutis Laxa [14, 15]

The acquired forms of cutis laxa are even more heterogeneous than the inherited ones and can appear generalized or localized. The principal feature is the loss of skin elasticity with late (adult) onset but internal organs including lungs, gastrointestinal and cardiovascular system may become involved.
Generalized acquired cutis laxa can be postinflammatory (with childhood onset!) and is then often preceded by urticarial or papular eruptions, but can also be associated with malignancy (multiple myeloma, Hodgkin, etc.) or medication intake (penicillin, penicillamine, etc.) [16-22].
Localized cutis laxa occasionally occurs in cutaneous T-cell lymphoma (granulomatous slack skin) and in Sweet syndrome. Postinflammatory (acrodermatitis chronica atrophicans) and even idiopathic (middermal elastolysis) localized forms of cutis laxa are also possible [23-25].

Etiopathogenesis

It is clear that inherited forms of cutis laxa harbour a defect in synthesis and/or assembly of elastic fibers, whereas the acquired forms result from destruction of normal elastin. Concerning the pathogenesis of cutis laxa several hypotheses have been made.

It could be that an increase in activity of neutral proteases with degradation of tropoelastin, a decreased elastin production by fibroblasts or a defective assembly of the elastin fiber components is responsible. The decreased serum copper levels could also result in dysfunction of elastase inhibitors with destruction of elastin fibers especially in the lungs but the definitive role of an altered serum copper concentration as a biochemical defect in congenital cutis laxa has not yet been proven.

Especially for autosomal recessive cutis laxa type III, it is postulated that a combined defect in elastin and collagen fibers causes the symptoms.

Treatment

Thus far, treatment of cutis laxa is disappointing.
A blepharoplasty or facelift often brings symptomatic relief, but permanent satisfying results are rare. n

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