Cutis Laxa, Autosomal Recessive, Type Iib

A number sign (#) is used with this entry because of evidence that autosomal recessive cutis laxa type IIB (ARCL2B) is caused by homozygous or compound heterozygous mutation in the PYCR1 gene (179035) on chromosome 17q25.

Description

The phenotype of autosomal recessive cutis laxa type II (ARCL2) includes cutis laxa of variable severity, abnormal growth, developmental delay, and associated skeletal abnormalities (summary by Morava et al., 2009). No specific clinical features distinguish ARCL2A (219200), which includes a glycosylation defect, and ARCL2B, in which abnormal glycosylation has not been reported (Morava et al., 2009; Guernsey et al., 2009).

For a phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).

Clinical Features

Al-Gazali et al. (2001) reported 5 children from 2 consanguineous families, of Palestinian and Syrian origin, respectively, with features overlapping both geroderma osteodysplastica (GO; 231070) and wrinkly skin syndrome (WSS; 278250). All 5 children had similar dysmorphic facial features, consisting of broad and prominent forehead, hypotelorism with epicanthal folds, prominent bulbous nose, flat malar region, and large protruding ears. All had wrinkling of the skin, more marked on the dorsum of the hands, feet, and abdomen; hyperextensibility of joints, particularly of the hands; and an aged appearance. Intrauterine growth retardation, subsequent failure to thrive, developmental delay, and a variable degree of osteoporosis were also present in all 5. The 3 older children developed progressive prognathism. The authors suggested that GO and WSS represent variable manifestations of the same disorder.

Hamamy et al. (2005) described a 2-year-old girl, born of consanguineous Palestinian parents, with congenital wrinkly skin on the dorsa of the hands and feet and anterior abdominal wall, prominent veins on the chest, and hyperextensibility of the small joints of the hands and feet. She had a triangular senile-looking face with hypotelorism, a prominent bulbous nose, large protruding ears, and brachycephaly. MRI revealed agenesis of the corpus callosum with absence of the cingulate gyrus and sulcus, and a high third ventricle with colpocephaly. The authors noted that corpus callosum agenesis was also reported in 2 sibs with WSS from a Syrian family described by Al-Gazali et al. (2001).

Nanda et al. (2008) reported 3 children from 2 unrelated consanguineous Kuwaiti families with congenital cutis laxa who displayed overlapping features of GO And WSS. All 3 patients had dysmorphic facial features, wrinkled skin that was more marked on the hands and feet, hyperextensible joints, intrauterine growth retardation, developmental delay, congenital dislocation of hips, and osteoporosis.

Rajab et al. (2008) reported 3 sibs from a consanguineous Omani family with congenital cutis laxa, microcephaly, osteopenia, and mental retardation. The authors described the affected sibs as having 'typical GO features' including a 'droopy' face with deep-set eyes, maxillary hypoplasia, relative mandibular hypoplasia, bowing of the long bones, and frequent fractures due to osteopenia.

Guernsey et al. (2009) reported a Maritime Canadian family of French Acadian descent in which 4 individuals had a phenotype consistent with cutis laxa type II. Another patient from a presumably unrelated family was also affected. All patients displayed lax, wrinkled skin with reduced elasticity, lax joints, and mild craniofacial dysmorphic features. The loose skin was most prominent over the dorsum of the hands and feet. Craniofacial dysmorphism included microcephaly, broad and prominent forehead, prominent ears, blue sclerae, and sagging cheeks. The patients looked substantially older than their chronologic ages. Joint laxity was most prominent in the small joints of the hands and feet, and 2 patients had congenital hip dislocation. All patients had intrauterine growth retardation with some degree of postnatal growth deficiency, and all showed developmental delay. Two affected individuals had demonstrated agenesis of the corpus callosum, and 1 other had been found to have enlarged ventricles. There were no obvious metabolic abnormalities.

Mapping

Reversade et al. (2009) performed homozygosity mapping in 5 consanguineous families segregating autosomal recessive cutis laxa, including the Palestinian family and 1 of the Kuwaiti families previously described by Hamamy et al. (2005) and Nanda et al. (2008), respectively, and identified a 2.8-Mb minimal candidate region on chromosome 17q25 between markers rs8065431 and rs1046896 containing 59 genes.

Molecular Genetics

In affected members of 2 Maritime Canadian families of French Acadian descent with ARCL2B, Guernsey et al. (2009) identified a homozygous mutation in the PYCR1 gene (179035.0001), resulting in loss of protein function.

In patients with autosomal recessive cutis laxa, including those previously described by Al-Gazali et al. (2001), Hamamy et al. (2005), Nanda et al. (2008), and Rajab et al. (2008) with clinical features of geroderma osteodysplastica and/or wrinkly skin syndrome, Reversade et al. (2009) sequenced the PYCR1 gene and identified homozygosity or compound heterozygosity for 6 missense mutations, 1 frameshift mutation, 5 splice site mutations, and a 22-bp deletion (see, e.g., 179035.0002-179035.0008). Altered mitochondrial morphology, membrane potential, and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals.