Cutis Laxa, Autosomal Dominant 1

A number sign (#) is used with this entry because autosomal dominant cutis laxa-1 (ADCL1) is caused by heterozygous mutations in the elastin gene (ELN; 130160) on chromosome 7q11.

Description

Cutis laxa is a collection of disorders that are typified by loose and/or wrinkled skin that imparts a prematurely aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The skin lacks elastic recoil, in marked contrast to the hyperelasticity apparent in classic Ehlers-Danlos syndrome (see 130000). These properties are nearly always attributable to loss, fragmentation, or severe disorganization of dermal elastic fibers (summary by Davidson and Giro, 2002).

Autosomal dominant congenital cutis laxa (ADCL) is genetically heterogeneous and shows clinical variability. The characteristic loose skin may be accompanied by gastrointestinal diverticula, hernia, and genital prolapse. Rare manifestations are pulmonary artery stenosis, aortic aneurysm, bronchiectasis, and emphysema (summary by Graul-Neumann et al., 2008).

Loose, inelastic skin is a clinical feature of many disorders, e.g., geroderma osteodysplasticum (GO; 231070) and Costello syndrome (218040).

For a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).

Genetic Heterogeneity of Autosomal Dominant Cutis Laxa

Also see ADCL2 (614434), caused by mutation in the FBLN5 gene (604580) on chromosome 14q32, and ADCL3 (616603), caused by mutation in the ALDH18A1 (138250) gene on chromosome 10q24.

Clinical Features

Sestak (1962) reported a father and daughter with cutis laxa. Goltz (1966) studied a family with affected persons in successive generations. Balboni (1963) described a child with typical cutis laxa and multiple vascular anomalies including coarctation of the aorta. The father and a paternal uncle were thought to have the same condition. Beighton (1972) described 2 pedigrees with 2 or more generations affected. In each pedigree there was an instance of male-to-male transmission. In each case, however, the relevant males were not examined by the author. In the early report of Kopp (1888), the father had onset of cutis laxa at age 16, and in the son cutis laxa was present at birth. Other 'dominant' pedigrees were reported by Lewis (1948) (mother and daughter), Reidy (1963) (father and daughter), and Schreiber and Tilley (1961) (4 generations). (Another of the families reported by Schreiber and Tilley (1961), viz., no. 1, had the acromegaloid syndrome (102100).)

Damkier et al. (1991) described cutis laxa in 6 members of 5 generations. All were female except for the proband, a 17-year-old man in the most recent generation. The onset of skin manifestations occurred between puberty and early adulthood. In the man's mother and maternal grandmother, numerous gastrointestinal diverticula were demonstrated, and both had been operated on for abdominal hernia and genital prolapse. There were no cardiopulmonary symptoms. Marchase et al. (1980) described a mother and son with cutis laxa and concluded that there were abnormalities in both elastic tissue and collagen. The son had Klippel-Trenaunay-Weber syndrome (149000).

An acquired form of cutis laxa, called generalized elastolysis, has been described in at least 17 cases (Harris et al., 1978). In this disorder elastic fibers rather abruptly become fragmented, disorganized and scarce with resultant emphysema, aortic aneurysm and bowel diverticula, in addition to cutis laxa. An erythematous rash suggesting penicillin reaction occurred at the onset of elastolysis in some patients. Hiatal and other hernias and rupture of patellar tendons were also noted. It is well to remember that cutis laxa can be acquired as an autoimmune process (Tsuji et al., 1987). Other phenocopies of genetic disorders on the basis of autoimmune mechanisms are represented by acquired von Willebrand disease (see 193400) and congenital heart block (234700) occurring in the offspring of mothers with systemic lupus erythematosus.

Corbett et al. (1994) described a 51-year-old mother and her 23-year-old daughter with congenital cutis laxa and early-onset emphysema. Both mother and daughter had been smokers and were heterozygous (MZ) for alpha-1-antitrypsin deficiency (613490). Urban et al. (2005) provided follow-up on the family described by Corbett et al. (1994): the mother's pulmonary disease progressed to end-stage respiratory failure requiring double lung transplant, and she died at age 61 of renal failure secondary to immunosuppressant treatment. The maternal grandmother, originally reported by Beighton (1972), had congenital cutis laxa and later developed an inguinal hernia, uterine prolapse, dyspnea, and bronchiectasis. The maternal great-grandmother, an uncle, and a cousin were also reportedly affected by cutis laxa, but were unavailable for examination.

Tassabehji et al. (1998) reported a 37-year-old Caucasian woman with cutis laxa who underwent her first facial cosmetic surgery at 4 years of age, with 6 subsequent operations. Bilateral herniorraphies were performed at 7 years of age. A cardiac murmur was noted at 4 years of age, and when she presented with reduced exercise tolerance at 19 years, right ventricular hypertrophy was noted. Right ventricular angiography showed hypertrophy of the infundibulum with angiographic narrowing. There were multiple peripheral pulmonary stenoses, including stenoses in very small vessels. The father, described by Reidy (1963), had loose skin on his chest, forearms, and abdomen in addition to facial drooping, and had 2 cosmetic operations in his teenage years. He had required an inguinal herniorraphy, but apart from venous thrombosis at the age of 50 years, had remained in good health. The proband had suffered from Raynaud phenomenon since late adolescence.

Zhang et al. (1999) provided clinical information on a patient with cutis laxa in whom Zhang et al. (1997) had identified heterozygosity for a 2012G deletion in the ELN gene (130160.0008). Loose skin, stridor, and feeding difficulties were apparent from birth. Additional clinical findings ascertained during infancy included moderate subglottic stenosis with floppy airway structures, redundant mitral and tricuspid valves, mild dilatation of the proximal aorta and great vessels, and umbilical and inguinal hernias. He underwent inguinal herniorrhaphies at ages 7 months, 3 years, and 14 years. At age 17 years, his height and weight were at the 75th percentile. Physical examination showed an aged appearance, with smooth, loose skin lacking elastic recoil; tortuous, pulsatile external carotid arteries; and a hoarse voice. He complained of fatigue, dyspnea on exertion, and shortness of breath. Aortic root dilatation was described as minimal. Pulmonary function testing showed reduced expiratory flow, suggestive of fixed or collapsible upper airway obstruction. Histologically, dermal collagen fibers appeared normal, but elastic fibers appeared fragmented with a paucity of amorphous elastin in the matrix. Tropoelastin production in cultured fibroblasts from this patient was the lowest of 6 cutis laxa patients studied (Sephel et al., 1989), and an apparent nonspecific increase in type VI collagen (120220) production was noted.

Szabo et al. (2006) reported a 3-generation family of Japanese and German ancestry and an unrelated Singaporean girl of Chinese descent with cutis laxa and aortic aneurysmal disease. The proband in the Japanese-German family was an 11-year-old girl who, along with her paternal grandmother, had a mildly dilated aortic root, mild aortic insufficiency, and obvious cutis laxa. Her 38-year-old father had a large aneurysm of the sinuses of Valsalva and ascending aorta, requiring grafting and valve replacement; he had barely noticeable skin laxity. His brother, the proband's uncle, died at age 26 of aortic dissection with no other apparent systemic involvement or skin laxity. Histologic examination of aneurysmal tissue from this patient revealed medial degeneration characterized by a dramatic loss of the elastic lamellae and smooth muscle cells and a lack of atherosclerotic and inflammatory lesions. The daughter of the deceased brother, the proband's cousin, had cutis laxa and mild aortic dilation. The proband and her father and grandmother all had inguinal hernias repaired surgically. The unrelated Singaporean girl, who had no family history of cutis laxa, was noted at birth to have marked laxity of the skin. An echocardiogram at age 5 showed significant dilation of the aortic root at the level of the sinuses of Valsalva. Szabo et al. (2006) concluded that severe aortic disease may be present in patients with cutis laxa and that regular cardiac monitoring is necessary to avert fatal aortic rupture.

Graul-Neumann et al. (2008) described a boy with autosomal dominant severe cutis laxa, severe congenital pulmonary disease, which had not previously been reported in ADCL, and supravalvular pulmonary artery stenosis. He was the first child born to unrelated parents. Physical examination at birth revealed generalized loose skin, inguinal and umbilical hernias, and hypotonia. Immediately after birth, he developed respiratory distress syndrome characterized by repeated pneumothoraces and emphysema. At 7 months of age, he developed infantile spasms (308350). At 15 months, he was able to vocalize but could only sit with support. His father had a grade 1 aortic valvular insufficiency but did not show any signs of cutis laxa with normal elasticity and recoil of the skin. Electron microscopy of the proband's skin demonstrated only mild rarefication of elastic fibers (in contrast to most recessive cutis laxa types). No mutations were found in the FBLN4 (604633) or FBLN5 genes. A novel heterozygous splice site mutation in the ELN gene (130160.0019) was detected in the proband and his clinically healthy father. Graul-Neumann et al. (2008) concluded that the variable processing of an identically mutated gene (dominant-negative in the child and haploinsufficiency in the father) caused the highly variable clinical appearance of ADCL in this family.

Molecular Genetics

Zhang et al. (1997, 1999) and Tassabehji et al. (1998) independently described patients with autosomal dominant cutis laxa and mutations in the elastin gene (see 130160.0008-130160.0010).

In the mother and daughter with cutis laxa and severe pulmonary disease described by Beighton (1972) and Corbett et al. (1994), Urban et al. (2005) identified no mutations in the elastin gene by direct sequencing, but detected an abnormal protein in cultured dermal fibroblasts using metabolic labeling and immunoprecipitation. Mutation and gene expression analyses established the presence of a complex tandem duplication in the elastin gene (130160.0016). Immunoprecipitation showed that the mutant tropoelastin was partially secreted and partially retained intracellularly; a polyclonal antibody raised against a unique peptide in the mutant molecule showed both intracellular and matrix staining. Urban et al. (2005) concluded that mutations in the elastin gene can cause cutis laxa associated with a severe pulmonary phenotype.

In affected members of a 3-generation family of Japanese and German ancestry and an unrelated Singaporean girl of Chinese descent with cutis laxa and aortic aneurysmal disease, Szabo et al. (2006) identified heterozygosity for a 25-bp deletion (130160.0017) and a 1-bp deletion (130160.0018) in the ELN gene, respectively.

History

Wiener (1925) reported dominant inheritance of cutis laxa, but Beighton (1972) concluded that the family reported by Wiener (1925) had the Ehlers-Danlos syndrome.