Cutis laxa recessive type 1
Cutis laxa recessive

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Description from OMIM

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 classical 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). The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to organ involvement and severity. Type I autosomal recessive cutis laxa (ARCL1) is a specific, life-threatening disorder with organ involvement, lung atelectasis and emphysema, diverticula of the gastrointestinal and genitourinary systems, and vascular anomalies. Associated cranial anomalies, late closure of the fontanel, joint laxity, hip dislocation, and inguinal hernia have been observed but are uncommon. Diminution of elastic fibers throughout the dermis and abnormal elastin components by electron microscopy are pathognomonic (summary by Morava et al., 2009). Classification of autosomal recessive cutis laxa is further divided into type II (ARCL2), associated with bone dystrophy, joint laxity, and developmental delay; and type III (ARCL3), or de Barsy syndrome, which presents very severe symptoms, with ocular involvement and mental retardation (summary by Davidson and Giro, 2002). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant cutis laxa, see 123700. Genetic Heterogeneity of Autosomal Recessive Cutis Laxa ARCL1A is caused by mutation in the FBLN5 gene. ARCL1B (614437) is caused by mutation in the EFEMP2 gene (604633), also known as FBLN4. ARCL1C (613177) is caused by mutation in the LTBP4 gene (614710). ARCL2A (219200) is caused by mutation in the ATP6V0A2 gene (611716). ARCL2B (612940) is caused by mutation in the PYCR1 gene (179035). ARCL2C (617402) is caused by mutation in the ATP6V1E1 gene (108746). ARCL2D (617403) is caused by mutation in the ATP6V1A gene (607027). ARCL3A (219150) is caused by mutation in the ALDH18A1 gene (138250). ARCL3B (614438) is caused by mutation in the PYCR1 gene (179035).



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List of symptoms



Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Cutis laxa integumentary 100 % 22829427 2014-04-24
Emphysema respiratory 92 % 22829427 2014-04-24
Peripheral pulmonary artery stenosis circulatory 50 % 22829427 2014-04-24
Hernia digestive 42 % 22829427 2014-04-24
Diaphragmatic hernia digestive 42 % 22829427 2014-04-24
Hypotonia nervous 42 % 22829427 2014-04-24
Prominent ears integumentary 42 % 22829427 2014-04-24
Inguinal hernia digestive 25 % 22829427 2014-04-24
Tricuspid valvular insufficiency circulatory 25 % 22829427 2014-04-24
Aortic valvular insufficiency circulatory 25 % 22829427 2014-04-24
Bossed forehead skeletal 25 % 22829427 2014-04-24
Broad nasal bridge skeletal 25 % 22829427 2014-04-24
Prominent veins integumentary 25 % 22829427 2014-04-24



List of references:


Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.
Bert Callewaert, Chi-Ting Su, Tim Van Damme, Philip Vlummens, Fransiska Malfait, Olivier Vanakker, Bianca Schulz, Meghan Mac Neal, Elaine C Davis, Joseph G H Lee, Aicha Salhi, Sheila Unger, Ketil Heimdal, Salome De Almeida, Uwe Kornak, Harald Gaspar, Jean-Luc Bresson, Katrina Prescott, Maria E Gosendi, Sahar Mansour, Gérald E Piérard, Suneeta Madan-Khetarpal, Frank C Sciurba, Sofie Symoens, Paul J Coucke, Lionel Van Maldergem, Zsolt Urban, Anne De Paepe,

Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.

Human mutation - Jan 2013