A number sign (#) is used with this entry because of evidence that autosomal recessive cutis laxa type IC (ARCL1C) is caused by homozygous or compound heterozygous mutation in the LTBP4 gene (604710) on chromosome 19q13.

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).

Patients with autosomal recessive cutis laxa type IC exhibit generalized cutis laxa in association with impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development (summary by Callewaert et al., 2013).

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

Urban et al. (2009) described 4 unrelated patients with a syndrome that disrupted pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All patients had severe respiratory distress, with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Three of the 4 patients died of respiratory failure. Cardiovascular lesions were mild, limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis and enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide fontanelles. All patients had cutis laxa. Urban et al. (2009) proposed the name Urban-Rifkin-Davis syndrome (URDS) for this disorder.

Callewaert et al. (2013) studied affected individuals from 9 families with cutis laxa and mutations in the LTB4 gene (see MOLECULAR GENETICS). Involvement of facial skin, resulting in a coarse and aged appearance, was present in most probands, but varied in severity. In some individuals, the skin was hyperextensible or appeared translucent with a prominent venous pattern. A few patients had thin and slowly growing hair. Inguinal and diaphragmatic hernias were frequent and the latter often required surgical correction. Pulmonary involvement with emphysema was universally present, and the emphysematous changes were severe in most cases. Upper airway involvement with tracheomalacia aggravated respiratory symptoms. In the majority of patients, cardiovascular involvement was limited to peripheral pulmonary artery stenosis. Bladder diverticula occurred in more than half of all patients and caused inadequate voiding with urinary tract infections. Fragility of gastrointestinal tissues was demonstrated by diverticula and rectal prolapse. Craniofacial dysmorphism included sloping forehead, sparse hair temporally, large ears, hypertelorism, low nasal bridge, beaked nose, sagging cheeks, and retrognathia. Neurologic status seemed normal, although assessment was complicated because many patients were very young and critically ill. Overall the prognosis was poor, with a mortality rate over 80%; mean age at death was 4 years, and most succumbed to respiratory failure.

Urban et al. (2009) confirmed autosomal recessive inheritance of this disorder by the finding of causative homozygous and compound heterozygous mutations in the LTBP4 gene.

In 4 of 6 unrelated patients with cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities, Urban et al. (2009) identified homozygous or compound heterozygous mutations in the LTBP4 gene (604710.0001-604710.0005). Four of the 5 identified mutations were predicted to lead to premature termination codons and one was a missense mutation. Four of the mutations were located in a hybrid or an 8-cysteine domain, domains known to have long-range effects on fibrillin and LTBP conformation. Two of the 6 patients studied were negative for LTBP4 mutations, indicating genetic heterogeneity.

Callewaert et al. (2013) analyzed the FBLN4 (604633), FBLN5 (604580), and LTBP4 genes in 12 families with type I ARCL and identified homozygous or compound heterozygous mutations in the LTBP4 gene in 9 families (see, e.g., 604710.0005-604710.0008). Homozygous mutations in FLBN5 were identified in 2 families (604580.0010 and 604580.0011). No mutations were found in the FBLN4 gene, and no mutations were detected in 1 family in which the proband had cutis laxa and bladder diverticula without obvious emphysema. Callewaert et al. (2013) noted that the FBLN5 and LTBP4 mutations caused a very similar phenotype associated with severe pulmonary emphysema in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seemed to be more severe in patients with LTBP4 mutations.

Urban et al. (2009) demonstrated that impaired synthesis and lack of deposition of LTBP4 into the extracellular matrix (ECM) caused increased TGF-beta activity in cultured fibroblasts and defective elastic fiber assembly in all tissues affected by this disorder. The LTBP4 defects were associated with blocked alveolarization and airway collapse in the lung. Urban et al. (2009) suggested that coupling of TGF-beta signaling and ECM assembly is essential for proper development and is achieved in multiple human organ systems, including the lung, intestines, and urinary tract, by multifunctional proteins such as LTBP4. They also suggested that given the potential similarities in disease mechanisms between this syndrome and the Marfan syndrome (154700), pharmacologic intervention for normalization of TGF-beta signaling may be a treatment option.