Disease group Connective tissue disorders
Synonymous -
Estimated prevalence -
OMIM 123700, 219100, 219200, 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

In some patients the clinical findings are limited to the loose and redundant skin present at birth; however, some cases are associated with extracutaneous manifestations such as pulmonary emphysema, aortic root dilatation, umbilical and inguinal hernias, gastro-intestinal and vesico-urinary tract diverticuli. Autosomal recessive CL type 1 (ARCL-I) is characterized by generalized cutis laxa and pulmonary emphysema. The disorder is often lethal before the age of two due to cardiorespiratory failure. In autosomal recessive CL type 2 (ARCL-2) the facial skin is typically not affected and patients have widely persistent fontanels and developmental delay. Familial history in ARCL is often remarkable for consanguinity. Patients with autosomal dominant CL (ADCL) have generalized loose skin folds and sometimes mild pulmonary emphysema. Recently, aortic root dilatation was also described in some of these patients. X-linked CL, now reassigned as Occipital Horn Syndrome, is characterized by loose skin folds which tend to disappear with aging. These patients have mild mental retardation and typical occipital osseous horns can be seen. Besides these 4 major types, several unclassified variants exist.


Histopathology of the skin can reveal loss, fragmentation or both of elastic fibers. The pathophysiological mechanisms leading to these changes however are not fully understood. In a family with ARCL-I, characterized by pulmonary emphysema and supravalvular aortic stenosis, a missense mutation in the fibulin 5 gene (FBLN5 on chrom. 14q32.1) has been reported. A homozygous missense mutation in the fibulin 4 gene (FBLN4 on chrom. 11q13) has been reported in a patient with pulmonary emphysema, multiple bone fractures and severe cardiovascular involvement (vascular tortuosity, ascending aortic aneurysm). Several patients however do not seem to harbour mutations in these genes, implying a considerable genetic heterogeneity.
The genetic defect of ARCL-II is presently unknown while ADCL is caused by frameshift mutations at the 3’ end of the elastin gene (ELN on chrom. 7q11.2), resulting in an extended protein. So far, only 9 such mutations have been reported. These patients are characterized by severe pulmonary disease (emphysema) and important cardiovascular involvement (aortic root dilatation, peripheral pulmonary artery stenosis).
One missense mutation in FBLN5 was reported in an ADCL patient with mild cardiovascular involvement (mitral valve regurgitation) and no pulmonary emphysema.
The defective enzyme in Occipital Horn Syndrome or X-linked CL is a copper-transporting ATPase (encoded by the ATP7A gene on chrom. Xq13.2-q13.3), which also causes Menkes disease (OMIM# 309400). As a result, decreased levels of copper and ceruloplasmin can be found in the serum of patients. Copper is an essential cofactor of lysyloxidases, a family of enzymes necessary for cross-linking fibrillar collagens and elastin.


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 a skin biopsy, using a Verhoeff-von Giesson stain for elastin, can reveal the absence or disruption of elastic fibers. For Occipital Horn Syndrome (X-linked CL), determining levels of copper and ceruloplasmin is diagnostic. Molecular analysis can help to confirm the diagnosis.


There is no causal therapy known for any of the cutis laxa syndromes. In those cases where the clinical manifestations are limited to the skin, there is a primarily cosmetic concern. In some patients, plastic surgery can be beneficial, although often operations need to be repeated due to recurrence of skin laxity. When extracutaneous manifestations are present, the management is focused on the treatment of complications: e.g. reduction of hernias. In these cases, close follow-up is required to anticipate problems and guarantee timely action; this is especially true for possible life-threatening complications such as pulmonary emphysema and aortic root dilatation. Patients with developmental delay need to be followed neurologically.