Disease group Connective tissue disorders
Synonymous -
Estimated prevalence -
OMIM 123700, 614434, 616603, 219100, 614437, 219200, 612940, 219150, 304150
Inheritance Autosomal recessive, autosomal dominant, X-linked recessive
Gene (s) ATP7A (300011), Elastin gene (160160), Fibuline-4 (604633), Fibuline-5 (604580)


Cutis laxa (CL) is a heterogeneous group of inherited connective tissue disorders characterized by loose, sagging and inelastic skin. Both autosomal recessive, dominant and X-linked inheritance have been described.


Clinical Description

Patients with Hereditary Cutis Laxa may present with loose, redundant skin visible at birth, resulting in an appearance of skin that is too large for the body. This can be demonstrated by a lack of recoil when the skin is stretched from its resting position, which cannot be evoked in patients with Ehlers-Danlos syndrome.

Complications can include extracutaneous manifestations such as pulmonary emphysema, aortic root dilatation, hernias, and diverticuli of the gastrointestinal and urinary tracts.

Hereditary Cutis Laxa is categorized into several subtypes, including autosomal dominant (ADCL), autosomal recessive (ARCL), X-linked (Occipital Horn Syndrome), and others such as Urban-Rifkin-Davis syndrome (URDS), macrocephaly-alopecia-cutis laxa-scoliosis syndrome (MACS), and arterial tortuosity syndrome (ATS).


CL hereditary types1-13


Clinical features (in addition to cutis laxa)



Cutaneous features prominent; pulmonary and cardiovascular manifestations less common than in other forms; present at birth or until early adulthood





Progeroid features; cataract; corpus callosum agenesis, atheroid movements;



Most severe form (death in first few years of life); hernias (e.g. inguinal, umbilical, oesophageal)

1A: Supravalvular aortic stenosis, pulmonary emphysema, recurrent respiratory infections

1B: Arterial tortuosity, pulmonary emphysema and bone fragility - often with fractures at birth

1C: Severe pulmonary, gastrointestinal and genitourinary manifestations




ARCL1C Urban-Rifkin-Davis syndrome



Growth and developmental delay, abnormal glycosylation of serum proteins, strabismus, central nervous system defects (e.g. microcephaly, pachygyria), delayed closure of anterior fontanelle



Growth and developmental delay, triangular face, progeroid features, normal glycosylation, hip dislocation


ARCL3A De Barsy syndrome

Growth and developmental delay, bilateral corneal opacities, athetoid movements


XLCL Occipital Horn syndrome

Occipital exostoses; skin folds tend to disappear with aging; mild mental retardation; inguinal hernias, bladder diferticula; functional copper deficiency (low serum ceruloplasmin and copper levels)



Macrocephaly, alopecia, scoliosis, joint hypermobility



Elongation and tortuosity of major arteries, diaphragmic hernia, scoliosis, bony exostoses


  *also causes Menkes disease (OMIM 309400) (severe neurological deficits, seizures, hypotonia, death in the first few years of life)14



Histopathology of the skin might reveal loss and/or fragmentation of elastic fibers. The light microscopic appearance of elastic fibers is generally not discriminative between the subtypes. The underlying pathophysiological mechanisms are not fully understood. Molecular defects in CL (see table for causative genetic mutations) may impair any step in elastic fiber assembly. They may directly affect elastic fiber components or may disturb metabolic pathways that interfere with synthesis, postā€translational modification, and/or transport of its components.1



The diagnosis of a cutis laxa syndrome is primarily based on clinical assessment of the typical skin features, and the associated extracutaneous findings. Light microscopy of skin biopsies, using a Verhoeff-von Giesson stain for elastin, might reveal an absence or disruption of elastic fibers. For Occipital Horn Syndrome (X-linked CL), determining levels of copper and ceruloplasmin is diagnostic. Molecular analysis (see involved genes in the table) can help to confirm the diagnosis.1,2,6



The management of cutis laxa syndrome involves addressing both cosmetic and medical concerns. In terms of skin manifestations, plastic surgery, lipofilling, or botox infiltration may provide temporary cosmetic improvement. However, it is important that patients avoid activities that may worsen skin laxity such as sunbathing and tobacco smoking.

For extracutaneous manifestations, a multidisciplinary approach is necessary to prevent and manage potential complications. This may include regular echocardiography to monitor for cardiovascular issues and MRI scans (especially in patients with mutations in ARCL1B, ARCL3B, ADCL2, XLCL, ATS) to assess for aneurysm formation. To minimize the risk of life-threatening complications such as pulmonary emphysema and aortic root dilatation, early intervention and ongoing monitoring are crucial.1,4,12




1.    Beyens A, Boel A, Symoens S, Callewaert B. Cutis laxa: A comprehensive overview of clinical characteristics and pathophysiology. 2021; 99(1):53-66.
2.    Morlino S, Nardella G, Castellana S, Micale L, Copetti M, Fusco C, et al. Review of clinical and molecular variability in autosomal recessive cutis laxa 2A.2020.
3.    Beyens A, Moreno-Artero E, Bodemer C, Cox H, Gezdirici A, Yilmaz Gulec E, et al. ATP6V0A2-related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype.  2019; 28(10):1142-5.
4.    Fischer B, Callewaert B, Schröter P, Coucke PJ, Schlack C, Ott CE, et al. Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1. Mol Genet Metab 2014; 112(4):310-6.
5.    Callewaert B, Su CT, Van Damme T, Vlummens P, Malfait F, Vanakker O, et al. Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa. Hum Mutat 2013; 34(1):111-21.
6.    Dimopoulou A, Fischer B, Gardeitchik T, Schröter P, Kayserili H, Schlack C, et al. Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Mol Genet Metab 2013; 110(3):352-61.
7.    Callewaert B, Renard M, Hucthagowder V, Albrecht B, Hausser I, Blair E, et al. New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations. Hum Mutat 2011; 32(4):445-55.
8.    Kaler SG. ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol 2011; 7(1):15-29.
9.    Kornak U, Reynders E, Dimopoulou A, van Reeuwijk J, Fischer B, Rajab A, et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet 2008; 40(1):32-4.
10.    Van Maldergem L, Yuksel-Apak M, Kayserili H, Seemanova E, Giurgea S, Basel-Vanagaite L, et al. Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type. Neurology 2008; 71(20):1602-8.
11.    Hucthagowder V, Sausgruber N, Kim KH, Angle B, Marmorstein LY, Urban Z. Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet 2006; 78(6):1075-80.
12.    Beyens A, Albuisson J, Boel A, Al-Essa M, Al-Manea W, Bonnet D, et al. Arterial tortuosity syndrome: 40 new families and literature review. Genet Med 2018; 20(10):1236-45.
13.    Kaler SG, Gallo LK, Proud VK, Percy AK, Mark Y, Segal NA, et al. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet 1994; 8(2):195-202.
14.    Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet 2010; 18(5):511-8.