Cutis laxa (ORPHA:209)
Cutis laxa (CL) is an inherited or acquired connective tissue disorder characterized by wrinkled, redundant and sagging inelastic skin associated with skeletal and developmental anomalies and, in some cases, with severe systemic involvement. Several different forms of inherited CL have been described, differentiated on the basis of the mode of inheritance and differences in the extent of internal organ involvement, associated anomalies and disease severity.
Epidemiology
Most cases of CL are inherited, with prevalence at birth being estimated at around 1/1,000,000 and only around 200 families being reported in the literature so far.
Clinical description
Autosomal recessive types of CL (ARCL) appear to be the most common forms with two subtypes being described: ARCL1 and ARCL2 (see these terms). ARCL1 is the most severe form of CL with generalized involvement leading to life-threatening complications (lung atelectesias and emphysema, vascular anomalies, and gastrointestinal and genitourinary tract diverticuli). ARCL2 appears to cover a spectrum of disorders ranging in severity from the wrinkly skin syndrome (see this term) to more severe disease associated with growth and developmental delay, and skeletal anomalies (classic ARCL2, Debré type; see this term). De Barsy syndrome and geroderma osteodysplastica (see these terms) also show significant clinical overlap with ARCL2. Occipital horn syndrome (X-linked cutis laxa (XRCL); see this term) is very similar to ARCL2; however, several patients present a more severe phenotype and systemic involvement. Autosomal dominant CL (ADCL) is generally a mild cutaneous disorder but systemic manifestations (hernias, cardiac valve anomalies, cardiovascular manifestations, gastrointestinal diverticuli and emphysema) have been noted in some cases.
Etiology
Although the underlying etiology remains unknown in many patients with the inherited forms of CL, several genes have been implicated: FBLN5 , EFEMP2 and LTBP4 in ARCL1 (14q32.1, 11q13 and 19q13.1-q13.2) , ATP6V0A2 and PYCR1 in ARCL2 (12q24.3 and 17q25.3), and ELN and FBLN5 in ADCL (7q11.2 and 14q32.1)). Homozygous ELNmutations have also been indentified in four patients with a mild form of ARCL.
Diagnostic methods
Diagnosis is often problematic due to the considerable clinical overlap between the hereditary forms. The diagnostic approach should include a detailed physical examination, family history, skeletal survey, developmental assessment, imaging studies, histological analysis, liver function tests and biochemical analysis, kidney ultrasound, and ophthalmological and cardiac evaluation.
Differential diagnosis
The main differential diagnosis is the Ehlers-Danlos syndromes (see these terms) but similar skin manifestations may also occur in patients with Williams syndrome, pseudoxanthoma elasticum, Hutchinson Gilford syndrome, Barber Say syndrome, Costello syndrome, Cardio-Facio-Cutaneous syndrome and Kabuki syndrome (see these terms). Inherited forms of CL should also be distinguished from acquired CL which is commonly preceded by urticaria, angioedema, local or generalized inflammatory skin disease or drug hypersensitivity reactions.
Antenatal diagnosis
Prenatal diagnosis is feasible by molecular testing for families in which the genetic anomaly has been identified.
Genetic counseling
Correct diagnosis of the hereditary forms is essential for providing adapted genetic counseling to affected families.
Management and treatment
There is no efficient treatment for CL and management is symptomatic. Plastic surgery is not generally indicated for the cutaneous manifestations in inherited forms.
Prognosis
Prognosis is variable, ranging from a usually fatal outcome in childhood in ARCL1 to a normal life expectancy in less severe forms.

                            Last update: 
                            July 2010


                            - Expert reviewer(s): 
                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS