Alternative titles; symbols
SNOMEDCT: 59451000; ORPHA: 90349; DO: 0070135;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q32.12 | Cutis laxa, autosomal recessive, type IA | 219100 | Autosomal recessive | 3 | FBLN5 | 604580 |
A number sign (#) is used with this entry because autosomal recessive cutis laxa type IA (ARCL1A) is caused by homozygous or compound heterozygous mutation in the FBLN5 gene (604580) on chromosome 14q32.
Heterozygous mutation in the FBLN5 gene can cause an autosomal dominant form of cutis laxa (ADCL2; 614434).
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
Also see ARCL1B (614437), caused by mutation in the FBLN4 gene (EFEMP2; 604633); ARCL1C (613177), caused by mutation in the LTBP4 gene (FAM72A; 614710); and ARCL1D (620780), caused by mutation in the FBLN3 gene (EFEMP1; 601548).
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). ARCL2E (619451) is caused by mutation in the LTBP1 gene (150390).
ARCL3A (219150) is caused by mutation in the ALDH18A1 gene (138250). ARCL3B (614438) is caused by mutation in the PYCR1 gene (179035).
Goltz et al. (1965) described affected brothers and suggested recessive inheritance because of other reported instances of affected sibs as well as parental consanguinity. One child had multiple diverticula (esophagus, duodenum, ileum, bladder). The other had pulmonary emphysema and died at 18 months from cor pulmonale. The authors suggested 'generalized elastolysis' as a more satisfactory designation. Death from pulmonary emphysema was also described by Christiaens et al. (1954).
Hayden et al. (1968) described a 4-year-old patient with cutis laxa and congenital pulmonary artery stenosis. A deficiency of elastic fibers in the skin was reported.
Hajjar and Joyner (1968) described a 6-month-old Puerto Rican child with advanced pulmonary emphysema. Serum copper level was low and urinary excretion high, consistent with the theory that deficiency of serum copper produces a low elastase inhibitor substance with increased destruction of elastic fibers (Goltz et al., 1965). The patient of Maxwell and Esterly (1969) had pulmonary emphysema. Hernias have been an important feature of many cases (Schreiber and Tilley, 1961; Cashman, 1957; Goltz et al., 1965).
Welch et al. (1971) described 3 sons of a consanguineous mating who had features suggesting cutis laxa of the malignant form. Unusual features were tortuous arteries and arterial aneurysms. The father and many of his relatives had the benign hypermobile form of Ehlers-Danlos syndrome. Beighton (1972) reported a case with first-cousin parents and a case resulting from a father-daughter mating. Sestak (1962) reported affected brother and sister whose parents were first cousins once removed and who had a common ancestor of the 2 parents reported affected. One of these sibs was pictured by Cashman (1957). Dallaire et al. (1976) reported a leprechaunoid disorder in 3 male infants from 2 related and consanguineous pairs of parents of Italian origin. Many of the features suggested cutis laxa. All 3 boys died in the first year of life of severe cardiopulmonary complications.
Fitzsimmons et al. (1985) reported 3 affected brothers, 2 of whom had significant involvement of other organs. They emphasized that the skin changes may be rather inconspicuous.
One patient with cutis laxa diagnosed in the early years of life had by age 36 developed mild emphysema, despite the fact that she was a nonsmoker, and had hypertension for more than a decade due to fibromuscular dysplasia in both renal arteries. Fibromuscular dysplasia was demonstrated also in the right carotid artery (17:McKusick, 1972). In a 1-year-old child with cutis laxa, McKusick (1972) found evidence of multiple pulmonary artery stenoses, possibly due to fibromuscular dysplasia.
In 3 of 4 sibs (2 boys, 1 girl) from a consanguineous Irish-American mating, Anderson et al. (1984) described severe congenital hemolytic anemia of unknown cause and early-onset pulmonary emphysema. Two of the 3 affected sibs died of septic shock after splenectomy, at ages 7 and 3.5 years. The third sib, 20 years old at the time of report, demonstrated severe pulmonary emphysema and cutis laxa by age 15. Autopsy of the 2 deceased sibs showed bilateral hemorrhagic necrosis of the adrenals and pulmonary changes of emphysema. In the 7-year-old, extensive, diffuse giant cell infiltration was found in the lungs, bone marrow, lymph nodes and epicardium; the lungs of the 3.5-year-old showed scattered multinucleated giant cells.
In 3 sibs born of second-cousin Turkish parents, Van Maldergem et al. (1988) described severe congenital cutis laxa with pulmonary emphysema.
In 2 boys from separate families, Khakoo et al. (1997) described autosomal recessive cutis laxa and deficiency of lysyl oxidase (153455). Neither boy had the occipital osseous projections or abnormality of copper metabolism that are characteristic of the X-linked form (304150). Both showed wormian bones of the lambdoid sutures and osteoporosis of the lumbar vertebrae in addition to the characteristic feature of congenital cutis laxa. In 1 family, the mother showed partial deficiency of lysyl oxidase; in the other, the parents were first cousins.
Armstrong et al. (2003) described a form of cutis laxa in a 7.5-year-old boy with loose translucent skin, aortic dilatation, hyperextensible veins, recurrent respiratory problems, pectus excavatum, arthralgias, lax joints, mild epiphyseal dysplasia, and umbilical and inguinal hernias. He also had developmental delay, progressive bilateral sensorineural hearing loss, an unusual facial appearance, unusual radiographic changes in some of the phalanges, glanular hypospadias, shawl scrotum, and undescended testes. Electrophoresis of types I and III procollagens and collagens, and quantification of serum copper and ceruloplasmin, were normal. Armstrong et al. (2003) concluded that the patient had a previously unrecognized form of cutis laxa.
Olsen et al. (1988) found no qualitative difference between control and cutis laxa elastin mRNAs. However, quantitation of the elastin mRNA by slot blot hybridization showed markedly reduced levels in all 6 patients studied. This may account for the diminished elastin production in these patients. The patients varied from newborn to 36 months of age. The reduced elastin mRNA levels could result either from an alteration in the rate of transcription of the elastin gene (130160) or from instability of the cutis laxa elastin mRNAs, causing enhanced degradation. In some cases, enhanced degradation of elastin has been demonstrated (Uitto, 1985; Anderson et al., 1985), attesting to the molecular heterogeneity of cutis laxa.
In the case of a 27-month-old boy with this disorder, Kitano et al. (1989) found diminution of elastic fibers throughout the dermis and, by electron microscopy, globular and unstained elastin and relatively large amounts of the microfibrillar components of elastic fibers.
Loeys et al. (2002) studied a large consanguineous Turkish family, originally described by Van Maldergem et al. (1988), in which 4 patients were affected by autosomal recessive cutis laxa type I. An affected infant from this family manifested loose skin, poorly developed elastic fibers in skin (seen microscopically), supravalvular aortic stenosis, and flaccid trachea. She developed emphysema of the anterior segments of both lungs by age 6 months. Hemizygosity for an elastin deletion was excluded by FISH, and the locus was further excluded by linkage analysis. The authors demonstrated the presence of a homozygous missense mutation in the FBLN5 gene, resulting in a ser227-to-pro substitution (S227P; 604580.0001) in the fourth cbEGF-like domain of the FBLN5 protein.
Because missense mutations in the FBLN5 gene cause either autosomal recessive cutis laxa type I or ARMD3 (608895), Lotery et al. (2006) raised the possibility that patients with autosomal recessive cutis laxa caused by FBLN5 mutation may have early-onset ARMD, and that their parents (heterozygous for these mutations) may themselves be at higher risk of ARMD than the general population.
Hu et al. (2006) analyzed 2 disease-causing missense substitutions in fibulin-5, C217R (604580.0010) and S227P, and found evidence for misfolding, decreased secretion, and reduced interaction with elastin and fibrillin-1, resulting in impaired elastic fiber development. These findings supported the hypothesis that fibulin-5 is necessary for elastic fiber formation by facilitating the deposition of elastin onto a microfibrillar scaffold via direct molecular interactions.
Callewaert et al. (2013) analyzed the FBLN4 (604633), FBLN5, and LTBP4 (604710) genes in 12 families with type 1 ARCL, and identified homozygous mutations in the FLBN5 gene in 2 families (604580.0010 and 604580.0011). Homozygous or compound heterozygous mutations in LTBP4 were identified in 9 families (see, e.g., 604710.0005-604710.0008). 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.
Agha et al. (1978) suggested that there are 2 forms of recessive cutis laxa. In one type, congenital cutis laxa is associated with a generalized disorder of elastic tissue leading to diaphragmatic and other hernias, diverticula of the gastrointestinal and urinary tract, and infantile emphysema. Death usually occurs in the first year of life. Beighton (1972), Cashman (1957), Christiaens et al. (1954), Goltz et al. (1965), Hajjar and Joyner (1968), Maxwell and Esterly (1969) and Sestak (1962) reported cases. The second form is accompanied by prenatal and postnatal growth deficiency, large fontanels with delayed closure, congenital hip dislocation, and lax joints; see 219200.
Agha, A., Sakati, N. O., Higginbottom, M. C., Jones, K. L., Jr., Bay, C., Nyhan, W. L. Two forms of cutis laxa presenting in the newborn period. Acta Paediat. Scand. 67: 775-780, 1978. [PubMed: 102106] [Full Text: https://doi.org/10.1111/j.1651-2227.1978.tb16260.x]
Anderson, C. E., Finklestein, J. Z., Nussbaum, E., Larson, E. J., Halpern, R., Uitto, J., Tanaka, K. R. Association of hemolytic anemia and early-onset pulmonary emphysema in three siblings. J. Pediat. 105: 247-251, 1984. [PubMed: 6747755] [Full Text: https://doi.org/10.1016/s0022-3476(84)80121-3]
Anderson, L., Oikarinen, A., Ryhanen, L., Anderson, C. E., Uitto, J. Characterization and partial purification of a neutral protease from the serum of a patient with autosomal recessive pulmonary emphysema and cutis laxa. J. Lab. Clin. Med. 105: 537-546, 1985. [PubMed: 3886813]
Armstrong, L., Jimenez, C., Hunter, A. G. W. A boy with developmental delay, malformations, and evidence of a connective tissue disorder: possibly a new type of cutis laxa. Am. J. Med. Genet. 119A: 57-62, 2003. [PubMed: 12707960] [Full Text: https://doi.org/10.1002/ajmg.a.10175]
Beighton, P. H., Bull, J. C., Edgerton, M. T. Plastic surgery in cutis laxa. Brit. J. Plast. Surg. 23: 285-290, 1970. [PubMed: 5469601] [Full Text: https://doi.org/10.1016/s0007-1226(70)80057-1]
Beighton, P. H. The dominant and recessive forms of cutis laxa. J. Med. Genet. 9: 216-221, 1972. [PubMed: 5046633] [Full Text: https://doi.org/10.1136/jmg.9.2.216]
Callewaert, B., Su, C.-T., Van Damme, T., Vlummens, P., Malfait, F., Vanakker, O., Schulz, B., Mac Neal, M., Davis, E. C., Lee, J. G. H., Salhi, A., Unger, S., and 16 others. Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa. Hum. Mutat. 34: 111-121, 2013. [PubMed: 22829427] [Full Text: https://doi.org/10.1002/humu.22165]
Cashman, M. E. Cutis laxa. Proc. R. Soc. Med. 50: 719-720, 1957.
Christiaens, L., Marchand-Alphant, A., Fovet, A. Emphyseme congenital et cutix laxa. Presse Med. 62: 1799-1801, 1954. [PubMed: 13237122]
Dallaire, L., Cantin, M., Melancon, S. B., Pereault, G., Potier, M. A syndrome of generalized elastic fiber deficiency with leprechaunoid features: a distinct genetic disease with an autosomal recessive mode of inheritance. Clin. Genet. 10: 1-11, 1976. [PubMed: 949858] [Full Text: https://doi.org/10.1111/j.1399-0004.1976.tb00001.x]
Davidson, J. M., Giro, M. Cutis laxa and premature aging syndromes. In: Royce, P. M.; Steinmann, B. (eds.): Connective Tissue and its Heritable Disorders: Molecular, Genetic, and Medical Aspects. (2nd ed.) New York: Wiley Liss (pub.) 2002. Pp. 525-560.
Fitzsimmons, J. S., Fitzsimmons, E. M., Guibert, P. R., Zaldua, V., Dodd, K. L. Variable clinical presentation of cutis laxa. Clin. Genet. 28: 284-295, 1985. [PubMed: 4064367] [Full Text: https://doi.org/10.1111/j.1399-0004.1985.tb00402.x]
Goltz, R. W., Hult, A. M., Goldfarb, M., Gorlin, R. J. Cutis laxa, a manifestation of generalized elastolysis. Arch. Derm. 92: 373-387, 1965. [PubMed: 5835325] [Full Text: https://doi.org/10.1001/archderm.92.4.373]
Hajjar, B. A., Joyner, E. N. Congenital cutis laxa with advanced cardiopulmonary disease. J. Pediat. 73: 116-119, 1968. [PubMed: 5658618] [Full Text: https://doi.org/10.1016/s0022-3476(68)80048-4]
Hayden, J. G., Talner, N. S., Klaus, S. N. Cutis laxa associated with pulmonary artery stenosis. J. Pediat. 72: 506-509, 1968. [PubMed: 5647293] [Full Text: https://doi.org/10.1016/s0022-3476(68)80341-5]
Hu, Q., Loeys, B. L., Coucke, P. J., De Paepe, A., Mecham, R. P., Choi, J., Davis, E. C., Urban, Z. Fibulin-5 mutations: mechanisms of impaired elastic fiber formation in recessive cutis laxa. Hum. Molec. Genet. 15: 3379-3386, 2006. [PubMed: 17035250] [Full Text: https://doi.org/10.1093/hmg/ddl414]
Khakoo, A., Thomas, R., Trompeter, R., Duffy, P., Price, R., Pope, F. M. Congenital cutis laxa and lysyl oxidase deficiency. Clin. Genet. 51: 109-114, 1997. [PubMed: 9111998] [Full Text: https://doi.org/10.1111/j.1399-0004.1997.tb02430.x]
Kitano, Y., Nishida, K., Okada, N., Mimaki, T., Yabuuchi, H. Cutis laxa with ultrastructural abnormalities of elastic fiber. J. Am. Acad. Derm. 21: 378-380, 1989. [PubMed: 2754071] [Full Text: https://doi.org/10.1016/s0190-9622(89)80039-8]
Loeys, B., van Maldergem, L., Mortier, G., Coucke, P., Gerniers, S., Naeyaert, J.-M., de Paepe, A. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum. Molec. Genet. 11: 2113-2118, 2002. [PubMed: 12189163] [Full Text: https://doi.org/10.1093/hmg/11.18.2113]
Lotery, A. J., Baas, D., Ridley, C., Jones, R. P. O., Klaver, C. C. W., Stone, E., Nakamura, T., Luff, A., Griffiths, H., Wang, T., Bergen, A. A. B., Trump, D. Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa. Hum. Mutat. 27: 568-574, 2006. [PubMed: 16652333] [Full Text: https://doi.org/10.1002/humu.20344]
Maxwell, E. S., Esterly, N. B. Cutis laxa. Am. J. Dis. Child. 117: 479-482, 1969. [PubMed: 5773419] [Full Text: https://doi.org/10.1001/archpedi.1969.02100030481018]
McKusick, V. A. Heritable Disorders of Connective Tissue. (4th ed.) St. Louis: C. V. Mosby (pub.) 1972. Pp. 382-386.
McKusick, V. A. Personal Communication. Baltimore, Md. 1972.
Morava, E., Guillard, M., Lefeber, D. J., Wevers, R. A. Autosomal recessive cutis laxa syndrome revisited. Europ. J. Hum. Genet. 17: 1099-1110, 2009. [PubMed: 19401719] [Full Text: https://doi.org/10.1038/ejhg.2009.22]
Olsen, D. R., Fazio, M. J., Shamban, A. T., Rosenbloom, J., Uitto, J. Cutis laxa: reduced elastin gene expression in skin fibroblast cultures as determined by hybridizations with a homologous cDNA and an exon 1-specific oligonucleotide. J. Biol. Chem. 263: 6465-6467, 1988. [PubMed: 3360789]
Schreiber, M. M., Tilley, J. C. Cutis laxa. Arch. Derm. 84: 266-272, 1961. [PubMed: 13748595] [Full Text: https://doi.org/10.1001/archderm.1961.01580140092012]
Sestak, Z. Ehlers-Danlos syndrome and cutis laxa: an account of families in the Oxford area. Ann. Hum. Genet. 25: 313-321, 1962. [PubMed: 13910947] [Full Text: https://doi.org/10.1111/j.1469-1809.1962.tb01768.x]
Uitto, J. Elastic fibers in cutaneous diseases. Curr. Concepts Skin Dis. 6: 19-23, 1985.
Van Maldergem, L., Vamos, E., Liebaers, I., Petit, P., Vandevelde, G., Simonis-Blumenfrucht, A., Bouffioux, R., Kulakowski, S., Hanquinet, S., Van Durme, P., Laporte, M., Ledoux-Corbusier, M. Severe congenital cutis laxa with pulmonary emphysema: a family with three affected sibs. Am. J. Med. Genet. 31: 455-464, 1988. [PubMed: 3232707] [Full Text: https://doi.org/10.1002/ajmg.1320310226]
Welch, J. P., Aterman, K., Day, E., Roy, D. L. Familial aggregation of a 'new' connective-tissue disorder: a nosologic problem. Birth Defects Orig. Art. Ser. VII(8): 204-213, 1971. [PubMed: 5173261]