ARCL1
MCID: ATS393
MIFTS: 44

Autosomal Recessive Cutis Laxa Type I (ARCL1)

Categories: Blood diseases, Bone diseases, Cardiovascular diseases, Eye diseases, Fetal diseases, Gastrointestinal diseases, Genetic diseases, Mental diseases, Metabolic diseases, Muscle diseases, Nephrological diseases, Neuronal diseases, Rare diseases, Skin diseases

Aliases & Classifications for Autosomal Recessive Cutis Laxa Type I

MalaCards integrated aliases for Autosomal Recessive Cutis Laxa Type I:

Name: Autosomal Recessive Cutis Laxa Type I 12 15
Cutis Laxa, Autosomal Recessive, Type I 43 71
Autosomal Recessive Cutis Laxa Type 1 12 58
Autosomal Recessive Cutis Laxa with Severe Systemic Involvement 58
Autosomal Recessive Cutis Laxa, Pulmonary Emphysema Type 58
Cutis Laxa, Autosomal Recessive Type 1 52
Cutis Laxa, Autosomal Recessive 52
Cutis Laxa, Type 1 52
Arcl1 58

Characteristics:

Orphanet epidemiological data:

58
autosomal recessive cutis laxa type 1
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal; Age of death: adolescent,late childhood;

Classifications:

Orphanet: 58  
Rare circulatory system diseases
Rare skin diseases
Developmental anomalies during embryogenesis


Summaries for Autosomal Recessive Cutis Laxa Type I

NIH Rare Diseases : 52 The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 90349 Definition A generalized connective tissue disorder characterized by the association of wrinkled, redundant and sagging inelastic skin with severe systemic manifestations (lung atelectesias and emphysema, vascular anomalies, and gastrointestinal and genitourinary tract diverticuli). Epidemiology The prevalence of ARCL1 is unknown but around 60 cases have been reported in the literature so far. Clinical description The skin manifestations affect the whole body and are usually recognizable from birth. The excessive lax skin is particularly prominent around the axillae, groins and neck and on the face (giving patients an aged appearance with eyelid ptosis and drooping cheeks). Pulmonary emphysema develops early in life (during the neonatal period or by early childhood), often leading to respiratory failure. Common vascular anomalies include arterial aneurysms, fibromuscular artery dysplasia and stenosis leading to progressive heart failure. Genitourinary tract diverticuli lead to vesicoureteral reflux and recurrent infections. Less frequent findings include late closure of the fontanel, joint laxity, hip dislocation, inguinal hernia, arachnodactyly, bone fragility, vascular tortuosity and aortic aneurysm. Intelligence is normal. Etiology ARCL1 is genetically heterogeneous and, although the etiology remains unknown in the majority of cases, mutations have been identified in some patients in the FBLN5 (14q31) and EFEMP2 (11q13) genes , encoding the extracellular matrix proteins fibulin-5 and EGF-containing fibulin-like extracellular matrix protein 2 (Fibulin-4), respectively. Arachnodactyly, bone fragility, vascular tortuosity and aortic aneurysms are common findings in patients carrying EFEMP2 mutations. Diagnostic methods Detailed clinical evaluation and histological studies of skin biopsies (revealing a moth-eaten appearance, abnormal elastin fiber branching and lose microfibrils associated with reduced elastin synthesis) are usually diagnostic in ARCL1. Molecular testing, available on a research basis only, may confirm the diagnosis in carriers of FBLN5 and EFEMP2 mutations. Differential diagnosis The differential diagnosis should include other forms of CL (autosomal recessive type 2, autosomal dominant and X-lined CL) and related syndromes (gerodermia osteodysplastica, Cantu syndrome, wrinkly skin syndrome and De Barsy syndrome), together with the Ehlers-Danlos syndromes and Costello syndrome (see these terms). Genetic counseling Genetic counseling should be provided to affected families and prenatal diagnosis through molecular testing is feasible for families in which the disease-causing mutation has been identified. Management and treatment There are no effective therapeutic strategies available for ARCL1. Care should be multidisciplinary with symptomatic treatment of pulmonary emphysema, prophylactic therapy for infections and hernia repair. Prognosis The disease course in ARCL1 is severe, with most patients dying in childhood from cardiac or respiratory failure. Visit the Orphanet disease page for more resources.

MalaCards based summary : Autosomal Recessive Cutis Laxa Type I, also known as cutis laxa, autosomal recessive, type i, is related to cutis laxa, autosomal recessive, type iid and cutis laxa, autosomal recessive, type iiib. An important gene associated with Autosomal Recessive Cutis Laxa Type I is FBLN5 (Fibulin 5), and among its related pathways/superpathways are Phospholipase-C Pathway and Degradation of the extracellular matrix. Affiliated tissues include skin, lung and bone, and related phenotypes are emphysema and recurrent urinary tract infections

Disease Ontology : 12 A cutis laxa characterized by wrinkled, redundant and sagging inelastic skin and severe systemic manifestations particulary in the lungs, vasculature, and gastrointestinal and genitourinary systems.

Related Diseases for Autosomal Recessive Cutis Laxa Type I

Diseases in the Cutis Laxa family:

Cutis Laxa, Autosomal Dominant 1 Cutis Laxa, Autosomal Recessive, Type Ia
Cutis Laxa, Autosomal Recessive, Type Iiia Cutis Laxa, Autosomal Recessive, Type Iia
Cutis Laxa, Autosomal Recessive, Type Iib Cutis Laxa, Autosomal Recessive, Type Ic
Cutis Laxa, Autosomal Dominant 2 Cutis Laxa, Autosomal Recessive, Type Ib
Cutis Laxa, Autosomal Recessive, Type Iiib Cutis Laxa, Autosomal Dominant 3
Cutis Laxa, Autosomal Recessive, Type Iic Cutis Laxa, Autosomal Recessive, Type Iid
Autosomal Recessive Cutis Laxa Type Iii Autosomal Recessive Cutis Laxa Type I
Atp6v0a2-Related Cutis Laxa Efemp2-Related Cutis Laxa
Fbln5-Related Cutis Laxa Ltbp4-Related Cutis Laxa
Acquired Cutis Laxa Autosomal Recessive Cutis Laxa Type 2

Diseases related to Autosomal Recessive Cutis Laxa Type I via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 83)
# Related Disease Score Top Affiliating Genes
1 cutis laxa, autosomal recessive, type iid 33.9 RIN2 LTBP4 GORAB ATP6V0A2
2 cutis laxa, autosomal recessive, type iiib 32.8 PYCR1 LTBP4 GORAB EFEMP2 ATP6V0A2 ALDH18A1
3 cutis laxa, autosomal recessive, type iiia 32.5 RIN2 PYCR1 LTBP4 GORAB EFEMP2 ATP6V0A2
4 cutis laxa, autosomal recessive, type iib 32.1 RIN2 PYCR1 LTBP4 GORAB FBLN5 EFEMP2
5 cutis laxa, autosomal recessive, type iia 32.1 RIN2 PYCR1 LTBP4 GORAB FBLN5 EFEMP2
6 acquired cutis laxa 30.8 FBLN5 ELN
7 fbln5-related cutis laxa 30.6 FBLN5 ELN
8 cutis laxa, autosomal recessive, type ib 30.5 RIN2 PYCR1 LTBP4 GORAB FBLN5 EFEMP2
9 cutis laxa, autosomal dominant 1 30.3 SLC2A10 FBN1 FBLN5 ELN EFEMP2 ALDH18A1
10 cutis laxa, autosomal recessive, type ic 29.3 RIN2 PYCR1 LTBP4 LTBP3 GORAB FBLN5
11 arterial tortuosity syndrome 28.9 SLC2A10 LTBP4 FBN1 FBLN5 ELN EFEMP2
12 cutis laxa, autosomal recessive, type ia 28.9 SLC2A10 RIN2 PYCR1 LTBP4 GORAB FBN1
13 cutis laxa 26.7 TGFB1 RIN2 PYCR1 LTBP4 GORAB FBN1
14 cutis laxa, autosomal recessive, type iic 12.8
15 atp6v0a2-related cutis laxa 11.7
16 cutis laxa, autosomal dominant 3 11.2
17 wrinkly skin syndrome 10.3
18 doyne honeycomb retinal dystrophy 10.2 FBLN5 EFEMP2
19 macs syndrome 10.2 RIN2 FBLN5
20 efemp2-related cutis laxa 10.2
21 alacrima, achalasia, and mental retardation syndrome 10.1
22 bone disease 10.1
23 pulmonary emphysema 10.1
24 late-onset focal dermal elastosis 10.1 FBN1 ELN
25 pseudoxanthoma elasticum-like papillary dermal elastolysis 10.1 FBN1 ELN
26 diaphragmatic eventration 10.1 LTBP4 FBN1
27 aortic dissection 10.0 FBN1 ELN
28 chronic actinic dermatitis 10.0 FBN1 ELN
29 familial abdominal aortic aneurysm 10.0 FBN1 ELN
30 aortic aneurysm, familial thoracic 2 10.0 SLC2A10 FBN1
31 borderline glaucoma 9.9 PYCR1 GORAB
32 camurati-engelmann disease 9.9 TGFB1 LTBP3
33 mid-dermal elastolysis 9.9 FBN1 FBLN5 ELN
34 loeys-dietz syndrome 4 9.9 SLC2A10 FBN1
35 geleophysic dysplasia 1 9.9 LTBP3 FBN1
36 geleophysic dysplasia 2 9.9 LTBP3 FBN1
37 aortic valve insufficiency 9.9 FBN1 ELN EFEMP2
38 pelvic organ prolapse 9.9 FBN1 FBLN5 ELN
39 costello syndrome 9.9 FBN1 FBLN5 ELN
40 pneumothorax 9.9 FBN1 FBLN5 ELN
41 tracheal stenosis 9.8 LTBP3 FBN1
42 loeys-dietz syndrome 3 9.8 SLC2A10 FBN1 EFEMP2
43 inguinal hernia 9.8 FBN1 FBLN5 ELN
44 lymphoid interstitial pneumonia 9.8 TGFB1 FBN1 ELN
45 spastic paraplegia 9b, autosomal recessive 9.8 PYCR1 ALDH18A1
46 spastic paraplegia 9a, autosomal dominant 9.8 PYCR1 ALDH18A1
47 heart valve disease 9.8 TGFB1 FBN1 ELN
48 acromicric dysplasia 9.8 LTBP3 FBN1
49 megalocornea 9.8 LTBP3 FBN1
50 loeys-dietz syndrome 1 9.8 SLC2A10 FBN1

Graphical network of the top 20 diseases related to Autosomal Recessive Cutis Laxa Type I:



Diseases related to Autosomal Recessive Cutis Laxa Type I

Symptoms & Phenotypes for Autosomal Recessive Cutis Laxa Type I

Human phenotypes related to Autosomal Recessive Cutis Laxa Type I:

58 31 (show all 32)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 emphysema 58 31 hallmark (90%) Very frequent (99-80%) HP:0002097
2 recurrent urinary tract infections 58 31 hallmark (90%) Very frequent (99-80%) HP:0000010
3 atelectasis 58 31 hallmark (90%) Very frequent (99-80%) HP:0100750
4 bladder diverticulum 58 31 hallmark (90%) Very frequent (99-80%) HP:0000015
5 redundant skin 58 31 hallmark (90%) Very frequent (99-80%) HP:0001582
6 congenital diaphragmatic hernia 58 31 hallmark (90%) Very frequent (99-80%) HP:0000776
7 premature skin wrinkling 58 31 hallmark (90%) Very frequent (99-80%) HP:0100678
8 arterial fibromuscular dysplasia 58 31 hallmark (90%) Very frequent (99-80%) HP:0005313
9 renal diverticulum 58 31 hallmark (90%) Very frequent (99-80%) HP:0100877
10 inguinal hernia 58 31 frequent (33%) Frequent (79-30%) HP:0000023
11 full cheeks 58 31 frequent (33%) Frequent (79-30%) HP:0000293
12 ptosis 58 31 frequent (33%) Frequent (79-30%) HP:0000508
13 joint hyperflexibility 58 31 frequent (33%) Frequent (79-30%) HP:0005692
14 arterial stenosis 58 31 frequent (33%) Frequent (79-30%) HP:0100545
15 delayed cranial suture closure 58 31 frequent (33%) Frequent (79-30%) HP:0000270
16 aortic aneurysm 58 31 frequent (33%) Frequent (79-30%) HP:0004942
17 ileus 58 31 frequent (33%) Frequent (79-30%) HP:0002595
18 hypothyroidism 58 31 occasional (7.5%) Occasional (29-5%) HP:0000821
19 arrhythmia 58 31 occasional (7.5%) Occasional (29-5%) HP:0011675
20 congestive heart failure 58 31 occasional (7.5%) Occasional (29-5%) HP:0001635
21 osteoporosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0000939
22 arachnodactyly 58 31 occasional (7.5%) Occasional (29-5%) HP:0001166
23 vesicoureteral reflux 58 31 occasional (7.5%) Occasional (29-5%) HP:0000076
24 recurrent fractures 58 31 occasional (7.5%) Occasional (29-5%) HP:0002757
25 pulmonic stenosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0001642
26 wormian bones 58 31 occasional (7.5%) Occasional (29-5%) HP:0002645
27 respiratory distress 58 31 occasional (7.5%) Occasional (29-5%) HP:0002098
28 bowel diverticulosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0005222
29 hernia 58 Frequent (79-30%)
30 prematurely aged appearance 58 Very frequent (99-80%)
31 aneurysm 58 Frequent (79-30%)
32 cutis laxa 58 Very frequent (99-80%)

MGI Mouse Phenotypes related to Autosomal Recessive Cutis Laxa Type I:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 integument MP:0010771 9.56 ALDH18A1 ATP6V0A2 EFEMP2 FBLN5 FBN1 GORAB
2 respiratory system MP:0005388 9.23 EFEMP2 FBLN5 FBN1 GORAB LTBP3 LTBP4

Drugs & Therapeutics for Autosomal Recessive Cutis Laxa Type I

Search Clinical Trials , NIH Clinical Center for Autosomal Recessive Cutis Laxa Type I

Cochrane evidence based reviews: cutis laxa, autosomal recessive, type i

Genetic Tests for Autosomal Recessive Cutis Laxa Type I

Anatomical Context for Autosomal Recessive Cutis Laxa Type I

MalaCards organs/tissues related to Autosomal Recessive Cutis Laxa Type I:

40
Skin, Lung, Bone, Heart, Testes

Publications for Autosomal Recessive Cutis Laxa Type I

Articles related to Autosomal Recessive Cutis Laxa Type I:

(show all 14)
# Title Authors PMID Year
1
Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa. 6 61
22829427 2013
2
Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. 61 6
20389311 2010
3
Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis. 6
22943132 2012
4
EFEMP2-Related Cutis Laxa 6
21563328 2011
5
Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin-4 gene mutation. 6
19664000 2009
6
FBLN5-Related Cutis Laxa 6
20301756 2009
7
A p.C217R mutation in fibulin-5 from cutis laxa patients is associated with incomplete extracellular matrix formation in a skin equivalent model. 6
18185537 2008
8
Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa. 6
17937443 2007
9
Fibulin-5 mutations: mechanisms of impaired elastic fiber formation in recessive cutis laxa. 6
17035250 2006
10
Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. 6
16685658 2006
11
Long tortuous aorta in a child with Larsen syndrome. 6
15776121 2005
12
Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. 6
12189163 2002
13
Clinicopathologic findings in congenital aneurysms of the great vessels. 6
8985490 1996
14
Severe congenital cutis laxa with pulmonary emphysema: a family with three affected sibs. 6
3232707 1988

Variations for Autosomal Recessive Cutis Laxa Type I

ClinVar genetic disease variations for Autosomal Recessive Cutis Laxa Type I:

6 (show all 18) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 FBLN5 NM_006329.3(FBLN5):c.1201_1202del (p.Ser401fs)deletion Pathogenic 689758 14:92336713-92336714 14:91870369-91870370
2 EFEMP2 NM_016938.5(EFEMP2):c.169G>A (p.Glu57Lys)SNV Pathogenic 5423 rs119489101 11:65638826-65638826 11:65871355-65871355
3 EFEMP2 NM_016938.5(EFEMP2):c.835C>T (p.Arg279Cys)SNV Pathogenic 5424 rs119489102 11:65635993-65635993 11:65868522-65868522
4 EFEMP2 NM_016938.5(EFEMP2):c.1070_1073dup (p.Asp359fs)duplication Pathogenic 5425 rs193302865 11:65635428-65635429 11:65867957-65867958
5 FBLN5 NM_006329.3(FBLN5):c.679T>C (p.Ser227Pro)SNV Pathogenic 5475 rs28939370 14:92353597-92353597 14:91887253-91887253
6 FBLN5 NM_006329.3(FBLN5):c.1171G>T (p.Glu391Ter)SNV Pathogenic 21451 rs80338767 14:92343845-92343845 14:91877501-91877501
7 FBLN5 NM_006329.3(FBLN5):c.649T>C (p.Cys217Arg)SNV Pathogenic 21454 rs80338766 14:92353627-92353627 14:91887283-91887283
8 EFEMP2 NM_016938.5(EFEMP2):c.1189G>A (p.Ala397Thr)SNV Pathogenic 39009 rs193302868 11:65634532-65634532 11:65867061-65867061
9 EFEMP2 NM_016938.5(EFEMP2):c.376G>A (p.Glu126Lys)SNV Pathogenic 39011 rs193302867 11:65638121-65638121 11:65870650-65870650
10 EFEMP2 NM_016938.5(EFEMP2):c.377A>T (p.Glu126Val)SNV Pathogenic 39012 rs193302869 11:65638120-65638120 11:65870649-65870649
11 EFEMP2 NM_016938.5(EFEMP2):c.577del (p.Gln193fs)deletion Pathogenic 39013 rs193302870 11:65637622-65637622 11:65870151-65870151
12 EFEMP2 NM_016938.5(EFEMP2):c.608A>C (p.Asp203Ala)SNV Pathogenic 39014 rs193302864 11:65637447-65637447 11:65869976-65869976
13 EFEMP2 NM_016938.5(EFEMP2):c.800G>A (p.Cys267Tyr)SNV Pathogenic 39016 rs193302866 11:65636028-65636028 11:65868557-65868557
14 FBLN5 NM_006329.3(FBLN5):c.604G>A (p.Gly202Arg)SNV Conflicting interpretations of pathogenicity 21453 rs80338765 14:92357580-92357580 14:91891236-91891236
15 FBLN5 NM_006329.3(FBLN5):c.1183C>T (p.Arg395Trp)SNV Uncertain significance 417872 rs372650987 14:92343833-92343833 14:91877489-91877489
16 EFEMP2 NM_016938.5(EFEMP2):c.775A>G (p.Ile259Val)SNV Benign 39015 rs601314 11:65636053-65636053 11:65868582-65868582
17 EFEMP2 NM_016938.5(EFEMP2):c.1226G>A (p.Arg409Gln)SNV Benign 39010 rs61893867 11:65634495-65634495 11:65867024-65867024
18 FBLN5 NM_006329.3(FBLN5):c.1090G>T (p.Asp364Tyr)SNV Benign 21450 rs1802492 14:92343926-92343926 14:91877582-91877582

Expression for Autosomal Recessive Cutis Laxa Type I

Search GEO for disease gene expression data for Autosomal Recessive Cutis Laxa Type I.

Pathways for Autosomal Recessive Cutis Laxa Type I

GO Terms for Autosomal Recessive Cutis Laxa Type I

Cellular components related to Autosomal Recessive Cutis Laxa Type I according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 extracellular region GO:0005576 9.8 TGFB1 LTBP4 LTBP3 FBN1 FBLN5 ELN
2 extracellular matrix GO:0031012 9.35 TGFB1 LTBP4 FBN1 FBLN5 ELN
3 collagen-containing extracellular matrix GO:0062023 9.17 TGFB1 LTBP4 LTBP3 FBN1 FBLN5 ELN
4 elastic fiber GO:0071953 9.16 FBLN5 ELN

Biological processes related to Autosomal Recessive Cutis Laxa Type I according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 transforming growth factor beta receptor signaling pathway GO:0007179 9.5 TGFB1 LTBP4 LTBP3
2 aortic valve morphogenesis GO:0003180 9.4 TGFB1 ELN
3 regulation of transforming growth factor beta receptor signaling pathway GO:0017015 9.37 TGFB1 LTBP4
4 cellular response to insulin-like growth factor stimulus GO:1990314 9.26 TGFB1 FBN1
5 L-proline biosynthetic process GO:0055129 9.16 PYCR1 ALDH18A1
6 proline biosynthetic process GO:0006561 8.96 PYCR1 ALDH18A1
7 elastic fiber assembly GO:0048251 8.8 LTBP3 FBLN5 EFEMP2

Molecular functions related to Autosomal Recessive Cutis Laxa Type I according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 calcium ion binding GO:0005509 9.55 LTBP4 LTBP3 FBN1 FBLN5 EFEMP2
2 integrin binding GO:0005178 9.43 LTBP4 FBN1 FBLN5
3 transforming growth factor beta binding GO:0050431 9.32 LTBP4 LTBP3
4 extracellular matrix structural constituent GO:0005201 9.26 LTBP4 FBN1 ELN EFEMP2
5 extracellular matrix constituent conferring elasticity GO:0030023 8.8 FBN1 FBLN5 ELN

Sources for Autosomal Recessive Cutis Laxa Type I

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