143 Cutis Laxa

Cutis laxa can be inherited or acquired and there are subclassifications of each type. A self-limited congenital form has also been described. The author has also observed acquired, localized cutis laxa in two children, one with involvement limited to the intertriginous skin without evidence of cutaneous T-cell lymphoma and another confined to the upper eyelids, similar to blepharochalasis reported in adults (unpublished data).

Inherited Types

An autosomal dominant, three autosomal recessive forms and an X-linked recessive form, previously designated Ehlers–Danlos syndrome type IX or occipital horn syndrome, are the best characterized. There are several other autosomal recessive types with varied associated features and other disorders in which cutis laxa occurs in addition to other more conspicuous anomalies. Facial dysmorphism with hooked nose, short columella, everted nostrils and long philtrum is quite characteristic of the inherited forms of cutis laxa.

The rare autosomal dominant form (OMIM #123700), which has been linked to mutations in either fibulin or elastin genes [6], has primarily cutaneous involvement, with few systemic manifestations, a relatively benign course and a normal life expectancy [33–35]. It may appear at any age from birth to adulthood, but generally has a later onset than the recessive forms. It most likely displays incomplete penetrance [34]. Bronchiectasis, emphysema, diverticula, hernias, uterine prolapse [33], hoarseness, mitral valve prolapse, dilation of the sinuses of Valsalva [35], pulmonary artery stenosis [34], dilation and tortuosity of the carotid artery, presenting as a pulsating mass in the lateral neck [34], and aortic aneurysm with or without rupture [36] have been associated with this form [33]. Facial involvement is universal and cosmesis is usually the main concern, as most affected individuals lack systemic involvement.

Autosomal recessive cutis laxa type I (OMIM #219100) is the rarest and most severe form, associated in some with mutations in the gene for the fibulin-5 [1], and is associated with emphysema, which may develop in the first months of life [33]. Cutis laxa is present at birth, involves nearly the entire body surface and, unlike other forms, can worsen over time. A hoarse, low-pitched voice is thought to result from lax, redundant vocal cords. Diaphragmatic hernia may cause respiratory distress in the neonatal period [8]. Diverticula of the oesophagus, stomach, small intestine and rectosigmoid as well as inguinal, obturator and umbilical hernias are common. Bladder diverticula present with symptoms of enuresis and frequency but are largely asymptomatic. Some patients have developed renal failure associated with heavy chain disease [37]. At least one infant was reported to have co-existent congenital hypothyroidism due to isolated thyroid-stimulating hormone (TSH) deficiency [38]. Emphysema is associated with recurrent pulmonary infections, resulting in cor pulmonale and death in the first few years of life.

Autosomal recessive cutis laxa type II (OMIM #219200) is also called Debré type or cutis laxa with growth and developmental delay as this variant is a multisystemic disorder. Cutis laxa, nearly always present at birth, may or may not involve the face but appears to be especially severe over the hands, feet and abdomen. In this variant the skin manifestations appear to improve over time [13]. Variably, infants may present with congenital dislocation of the hips and generalized laxity of the joints [15] Affected infants exhibit wide sutures and a large anterior fontanelle with delayed closure. Other craniofacial abnormalities include microcephaly, broadening of the nasal bridge, short nose, with hypertelorism, long philtrum, downslanting palpebral fissures, epicanthal folds, small mouth, low-set ears and a high-arched or cleft palate [15]. Other inconstant findings are macular coloboma, myopia, iris hypoplasia, reversed-V eyebrows, simian crease, cleft lip [39], osteoporosis [40], Dandy–Walker malformation, cobblestone-like brain dysgenesis [13], minor heart and osseous defects [41] and common variable-like immunodeficiency syndrome [42]. Most have developmental delay with transient feeding intolerance and, at least in some cohorts, seizures develop during childhood. A few of the children have died as a result of the associated seizure disorder [13]. Some patients have been products of consanguineous marriages, supporting an autosomal recessive inheritance.

De Barsy syndrome (OMIM #219150) has recently been categorized as autosomal recessive cutis laxa type III. It comprises intrauterine growth retardation, wrinkled atrophic skin, open sutures, somatic and mental retardation and hypermobility of small joints. It can be differentiated from recessive cutis laxa type II by the presence of corneal opacification due to degeneration of the Bowman membrane, muscular hypotonia, athetoid posturing and brisk tendon reflexes. This form is postulated to result from decreased elastin synthesis.

X-linked cutis laxa (OMIM #304150) is now classified in the group of copper transport diseases and appears to be related genetically to Menkes disease. Both diseases have mutations affecting the copper-transporting P-type ATPase [43]. Patients affected have the typical cutaneous features of cutis laxa but also exhibit joint laxity, hydronephrosis, chronic diarrhoea, soft mildly hyperextensible skin, a long thin face with high forehead and long philtrum, occipital horn exostoses and mental deficiency. In addition, serum copper and caeruloplasmin are decreased.

Acquired Types

Acquired elastolysis presents as a generalized insidious disease, typically associated with internal manifestations in all adults and infrequently in children. It usually begins in adulthood but has been reported in children [9,16,18,20,44,45]. Laxity varies in distribution and is progressive over several years. Only the facial and ear involvement has been reported in patients less than 10 years of age [16,18,45], with more generalized, adult presentation in older children [9,20]. Most reported patients have been male. A host of various inflammatory skin lesions, such as generalized vesicular eruptions [16], erythema multiforme, urticaria, angio-oedema, erythema multiforme and dermatitis herpetiformis-like eruptions [20], occur before or concurrent with cutaneous laxity. Associated internal disorders include emphysema, GI and genitourinary diverticula, inguinal hernias and rectal prolapse. The GI manifestations are most common and often asymptomatic.

Death from emphysema and aortic rupture has been reported. Increased serum IgA was reported in two children, but its significance is unknown [20,45]. Of the few cases reported in children, only one had systemic involvement (tracheobronchiomegaly) and one death resulted. This suggests a better prognosis for those developing this type of acquired cutis laxa in childhood. However, there have been no reports of spontaneous resolution. Its association with recent drug therapy, particularly penicillin [20] and isoniazid [18], and evidence of tuberculosis in two children [18,44] suggests a hypersensitivity reaction as a possible aetiology.

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