SNOMEDCT: 238875009; ORPHA: 2834, 357058; DO: 0112171;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.31 | Wrinkly skin syndrome | 278250 | Autosomal recessive | 3 | ATP6V0A2 | 611716 |
A number sign (#) is used with this entry because of evidence that at least some cases of the wrinkly skin syndrome (WSS) are caused by homozygous or compound heterozygous mutations in the ATP6V0A2 gene (611716) on chromosome 12q24.
The occurrence of mutations in the same gene in autosomal recessive cutis laxa type IIA (ARCL2A; 219200) indicates that wrinkly skin syndrome and some cases of autosomal recessive cutis laxa type IIA represent variable manifestations of the same genetic defect.
Wrinkly skin syndrome (WSS) evolves during early childhood and includes generalized and excessive skin wrinkling, dental problems, herniae, foot deformities, hip dislocations, growth retardation, and a large anterior fontanel. The facial gestalt is characterized by a broad nasal bridge, hypertelorism, and downslanting palpebral fissures (summary by Rajab et al., 2008).
In 2 and possibly 3 offspring of first-cousin parents, Gazit et al. (1973) described a disorder they called the wrinkly skin syndrome. It was characterized at birth by wrinkled skin of the hands and feet with an increased number of wrinkles on the palms and soles. Skeletal musculature was poorly developed and hypotonic with winging of the scapulas. The venous pattern was prominent over the anterior thorax. The patients of Gazit et al. (1973) were Iraqi Jews.
Karrar et al. (1983) described WSS in 2 Saudi Arabian sibs, a brother and sister whose parents were first cousins. Casamassima et al. (1987) reported a case indicating that mental retardation and microcephaly are components of the syndrome. Skin biopsy showed elastic fiber abnormalities. An atrial septal aneurysm was demonstrated on echocardiography. Hurvitz et al. (1990) reported another case.
Kreuz and Wittwer (1993) reported a mother and her 2 sons with an interstitial deletion involving band q32 of chromosome 2 and compared their phenotypes with those of 20 previously reported individuals with the same deletion. All individuals had small size at birth, retarded growth and development, craniofacial dysmorphism, and skeletal and ocular anomalies. The mother and sons reported by Kreuz and Wittwer (1993), however, also showed features of the wrinkly skin syndrome, including wrinkling of the abdominal skin and the skin of the dorsum of the hands and feet, decreased elastic recoil of the skin, an increased number of palmar and plantar creases, musculoskeletal anomalies, microcephaly, mental retardation, and an old appearance. Broken elastic fibers were evident on light microscopy of the skin biopsies. The boys demonstrated a peculiar grimacing. Their serum copper and ceruloplasmin (117700) levels were slightly raised. The occurrence of WSS in association with heterozygosity for the deletion may be inconsistent with the presumed recessive inheritance of WSS.
Azuri et al. (1999) found reports of 9 cases of wrinkly skin syndrome and also pointed to the 3 patients reported by Kreuz and Wittwer (1993) who showed some manifestations of WSS. They presented the case of a 2.5-year-old girl, the daughter of healthy, first-cousin Muslim parents, who had WSS associated with prominent neurologic involvement manifested by mental retardation, microcephaly, and an episode of epilepticus.
In a letter, Zlotogora (1999) noted that Gazit et al. (1973) described the wrinkly skin syndrome in 2 girls and their newborn brother born to consanguineous Jews originating from Iraq. This report was written without the knowledge that the same 2 girls had been reported by Reisner et al. (1971) as one of the first examples of the syndrome of cutis laxa with growth and developmental delay (219200). The report of affected sibs by Ogur et al. (1990) supported the suggestion that the 2 disorders represent variable presentations of the same syndrome. A boy was severely affected with the classic form of cutis laxa and developmental delay, while his sister showed improvement over the years and at the age of 6.5 years presented with a relatively mild disease, including cutaneous manifestations similar to those found in the wrinkly skin syndrome.
Kornak et al. (2008) noted that an association of a cutis laxa phenotype with a congenital disorder of glycosylation (CDG) had been described (Morava et al., 2005) and that wrinkly skin had been observed in an individual with a defect in the conserved oligomeric Golgi (COG) complex (Wu et al., 2004). On the basis of these observations, Kornak et al. (2008) investigated glycosylation of serum proteins isolated form individuals with ARCL2 and WSS and found that they showed a CDG type II pattern, which corresponds to a defect of N-glycosylation at the level of processing in the Golgi apparatus. Reduced sialic acid content of the glycans from affected individuals indicated that sialylation, a terminal step of glycan synthesis, was particularly impaired. A strict correlation between phenotype and degree of glycan abnormality was not seen.
Phenotypic Overlap with Geroderma Osteodysplasticum
Rajab et al. (2008) reported on 22 Omani patients from 11 consanguineous families with the diagnosis of wrinkly skin syndrome or geroderma osteodysplastica (231070) and concluded that the 2 disorders are distinct. Fourteen patients from 8 families had WSS. The WSS phenotype includes generalized, excessive skin wrinkling, dental problems (small teeth, delayed eruption, caries), hernia, congenital hip dislocation, failure to thrive, and large anterior fontanel. Isoelectric focusing of serum transferring revealed a sialotransferrin type 2 pattern in all 4 WSS patients studied, suggesting that WSS is related to an N-protein glycosylation defect, probably at the level of processing (CDG II).
By homozygosity mapping in consanguineous families diagnosed with WSS or ARCL2, Kornak et al. (2008) found linkage to chromosome 12q24 (maximum lod = 3.2) in 12 families, including 4 with WSS.
The transmission pattern of WSS in the families reported by Kornak et al. (2008) was consistent with autosomal recessive inheritance.
Kornak et al. (2008) found loss-of-function mutations in the ATP6V0A2 gene (see 611716.0003) in affected members of 4 consanguineous families from Oman diagnosed with wrinkly skin syndrome. They also found 8 different mutations in this gene (see 611716.0001-611716.0002) in patients diagnosed with autosomal recessive cutis laxa type II in 8 families living in other areas. The findings indicated a mechanism leading to a congenital glycosylation defect and showed that WSS and ARCL2 are variable manifestations of the same genetic defect. Rajab et al. (2008) stated that they reported the clinical features of 5 Omani families (families D, E, F, G, and H) with WSS that were found to have a mutation in the ATP6V0A2 gene by Kornak et al. (2008).
In 1 of the Omani families originally reported by Rajab et al. (2008) with clinical features consistent with GO, Reversade et al. (2009) identified homozygosity for a missense mutation in the PYCR1 gene (179035.0008; see ARCL2B, 612940).
Exclusion Studies
In 3 families segregating WSS and 2 families segregating geroderma osteodysplastica, Rajab et al. (2008) excluded loci that had been described in cutis laxa and WSS phenotypes on 2q31, 5q23-q31 (LOX, 153455 and ADAMTS2, 604539); 7q11 (ELN, 130160), 11q13 (EFEMP2, 604633), and 14q32 (FBLN5, 604580).
Azuri, J., Mizrachi, A., Weintraub, S., Lerman-Sagie, T. Neurological involvement in a child with the wrinkly skin syndrome. Am. J. Med. Genet. 82: 31-33, 1999. [PubMed: 9916839]
Casamassima, A. C., Wesson, S. K., Conlon, C. J., Weiss, F. H. Wrinkly skin syndrome: phenotype and additional manifestations. Am. J. Med. Genet. 27: 885-893, 1987. [PubMed: 3321993] [Full Text: https://doi.org/10.1002/ajmg.1320270415]
Gazit, E., Goodman, R. M., Katznelson, M. B., Rotem, Y. The wrinkly skin syndrome: a new heritable disorder of connective tissue. Clin. Genet. 4: 186-192, 1973. [PubMed: 4765201] [Full Text: https://doi.org/10.1111/j.1399-0004.1973.tb01141.x]
Hurvitz, S. A., Baumgarten, A., Goodman, R. M. The wrinkly skin syndrome: a report of a case and review of the literature. Clin. Genet. 38: 307-313, 1990. [PubMed: 2268976] [Full Text: https://doi.org/10.1111/j.1399-0004.1990.tb03585.x]
Karrar, Z. A., Elidrissy, A. T. H., Al Arabi, K., Adam, K. A. The wrinkly skin syndrome: a report of two siblings from Saudi Arabia. Clin. Genet. 23: 308-310, 1983. [PubMed: 6851222] [Full Text: https://doi.org/10.1111/j.1399-0004.1983.tb01882.x]
Kornak, U., Reynders, E., Dimopoulou, A., van Reeuwijk, J., Fischer, B., Rajab, A., Budde, B., Nurnberg, P., Foulquier, F., ARCL Debre-type Study Group, Lefeber, D., Urban, Z., and 9 others. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H(+)-ATPase subunit ATP6V0A2. Nature Genet. 40: 32-34, 2008. [PubMed: 18157129] [Full Text: https://doi.org/10.1038/ng.2007.45]
Kreuz, F. R., Wittwer, B. H. Del(2q)--cause of the wrinkly skin syndrome? Clin. Genet. 43: 132-138, 1993. [PubMed: 8500259] [Full Text: https://doi.org/10.1111/j.1399-0004.1993.tb04437.x]
Morava, E., Wopereis, S., Coucke, P., Gillessen-Kaesbach, G., Voit, T., Smeitink, J., Wevers, R., Grunewald, S. Defective protein glycosylation in patients with cutis laxa syndrome. Europ. J. Hum. Genet. 13: 414-421, 2005. [PubMed: 15657616] [Full Text: https://doi.org/10.1038/sj.ejhg.5201361]
Ogur, G., Yuksel-Apak, M., Demiryont, M. Syndrome of congenital cutis laxa with ligamentous laxity and delayed development: report of a brother and sister from Turkey. Am. J. Med. Genet. 37: 6-9, 1990. [PubMed: 1700609] [Full Text: https://doi.org/10.1002/ajmg.1320370103]
Rajab, A., Kornak, U., Budde, B. S., Hoffmann, K., Jaeken, J., Nurnberg, P., Mundlos, S. Geroderma osteodysplasticum hereditaria and wrinkly skin syndrome in 22 patients from Oman. Am. J. Med. Genet. 146A: 965-976, 2008. [PubMed: 18348262] [Full Text: https://doi.org/10.1002/ajmg.a.32143]
Reisner, S. H., Seelenfreund, M., Ben-Bassat, M. Cutis laxa associated with severe intrauterine growth retardation and congenital dislocation of the hip. Acta Paediat. Scand. 60: 357-360, 1971. [PubMed: 5579863] [Full Text: https://doi.org/10.1111/j.1651-2227.1971.tb06672.x]
Reversade, B., Escande-Beillard, N., Dimopoulou, A., Fischer, B., Chng, S. C., Li, Y., Shboul, M., Tham, P.-Y., Kayserili, H., Al-Gazali, L., Shahwan, M., Brancati, F., and 35 others. Mutations in PYCR1 cause cutis laxa with progeroid features. Nature Genet. 41: 1016-1021, 2009. Note: Erratum: Nature Genet. 54: 213 only, 2022. [PubMed: 19648921] [Full Text: https://doi.org/10.1038/ng.413]
Wu, X., Steet, R. A., Bohorov, O., Bakker, J., Newell, J., Krieger, M., Spaapen, L., Kornfeld, S., Freeze, H. H. Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nature Med. 10: 518-523, 2004. [PubMed: 15107842] [Full Text: https://doi.org/10.1038/nm1041]
Zlotogora, J. Wrinkly skin syndrome and the syndrome of cutis laxa with growth and developmental delay represent the same disorder. (Letter) Am. J. Med. Genet. 85: 194 only, 1999. [PubMed: 10406678] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990716)85:2<194::aid-ajmg19>3.0.co;2-p]