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Autosomal recessive cutis laxa type 2
A spectrum of connective tissue disorders characterized by the association of wrinkled, redundant and sagging inelastic skin with growth and developmental delay, and skeletal anomalies. The spectrum ranges from patients with classic autosomal recessive cutis laxa type 2 (ARCL2, Debré type) to patients with a milder form of the disease, wrinkled skin syndrome (WSS).
ORPHA:90350Classification level: Group of disorders
- Cutis laxa with joint laxity and developmental delay
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Infancy, Neonatal
- ICD-10: Q82.8
- OMIM: -
- UMLS: C0432337
- MeSH: -
- GARD: -
- MedDRA: -
Around 40 patients with classic ARCL2 have been reported so far.
Patients with ARCL2 present with generalized cutis laxa at birth but the skin manifestations become less pronounced and may disappear completely with age. Pre- and postnatal growth delay is common. Patients have a characteristic facial appearance (down-slanting palpebral fissures, a broad flat nasal bridge and short nose with anteverted nostrils, large ears and a small mouth). The most common ocular anomalies are strabismus and myopia. Congenital hip dislocation, increased joint laxity, congenital or progressive microcephaly, delayed closure of large fontanels, osteoporosis and decreased bone density are frequent findings. Developmental delay is observed in the majority of patients (mainly due to muscle hypotonia and joint laxity) but congenital brain anomalies are rare (although developmental anomalies such as cobblestone-like brain dysgenesis have been reported in some patients). Intellectual deficit and seizures have been reported in older patients. The systemic manifestations are mild in ARCL2 and pulmonary emphysema and cardiac anomalies are rare.
The underlying etiology in the majority of ARCL2 cases remains unknown. However, a combined disorder of N- and O-linked glycosylation (congenital disorder of glycosylation type II) has been detected in some patients and is associated with mutations in the ATP6V0A2 gene (12q24.31). Mutations in ATP6V0A2 have also been identified in patients with WSS. There are no specific clinical features that distinguish ARCL2 patients with glycosylation defects from those without any metabolic anomalies. Mutations in the PYCR1 gene have recently been identified in patients with ARCL2 and in patients with a phenotype (wrinkly skin, osteopenia and progeroid features) overlapping with classic ARCL2 and WSS, and the closely related syndromes, gerodermia osteodysplastica (GO) and de Barsy syndrome (DBS; see these terms).
Diagnosis is made on the basis of physical and developmental examination, skeletal surveys, imaging studies, histological analysis of skin biopsies (decreased amounts of structurally abnormal elastin fibers) and biochemical tests (plasma transferrin and apolipoprotein CIII isoelectric focusing for detection of abnormal glycosylation). Molecular testing is available on a clinical basis for families with ATP6V0A2 mutations.
Differential diagnoses should include other forms of CL (ARCL type 1, autosomal dominant CL and X-linked CL), as well as the clinically overlapping entities GO and DBS (see these terms).
Genetic counseling should be proposed 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 ARCL2 and care should be multidisciplinary with symptomatic management of the ocular and skeletal manifestations, and supportive and educational care for developmental and learning problems.
The prognosis for patients is variable: life expectancy is generally not reduced. Although the skin manifestations improve with age, cognitive decline has been reported in some older patients.