Geroderma Osteodysplasticum

A number sign (#) is used with this entry because of evidence that geroderma osteodysplasticum (GO) is caused by homozygous or compound heterozygous mutation in the GORAB gene (607983) on chromosome 1q24.

Clinical Features

As the name indicates, the features of this disorder include changes in the skin suggesting precocious aging and osseous changes including osteoporosis and multiple lines like growth rings of trees. The disorder was first described by Bamatter et al. (1950) in 5 members of a Swiss family. Boreux (1969), whose report was based on the same family, concluded that the disorder was inherited as an X-linked recessive with occasional manifestation in heterozygous females. A report by Klein et al. (1968) was also based on this family.

Hunter et al. (1978) reported 2 families with 6 affected children. Consanguinity (including incest) and full manifestation of the disorder in 2 females among the 6 strongly indicated autosomal recessive inheritance. One kindred with 4 affected in 2 sibships was Dutch-Russian-Mennonite. The second family was also Mennonite. The faces of the affected persons had a 'droopy, jowled, prematurely aged appearance.' The bones were osteoporotic and susceptible to fracture, particularly the vertebrae, which showed compression with anterior wedging and biconcavity. Lisker et al. (1979) reported 3 affected brothers. Hall (1983) presented the cases of 2 unrelated males.

Hunter (1988) described a mildly affected French Canadian girl and raised the question of underdiagnosis of this disorder. In this patient, a diagnosis of Ehlers-Danlos syndrome had been made. Hunter (1988) emphasized the droopy, jowly face with a degree of malar hypoplasia and mandibular prognathism. He also pointed out the lax but not hyperelastic skin, most marked over the extremities, and osteoporosis which may be associated with fractures and vertebral collapse. Patients reported by Patton et al. (1987) and by Sakati and Nyhan (1983) (see 219200) were judged by Hunter (1988) to have GO. The patients reported by Patton et al. (1987) were later found to have Costello syndrome (218040). The patient reported by Hunter (1988) had wormian bones.

In a Jewish family from Morocco, Lustmann et al. (1993) described the disorder in 2 boys and 2 girls out of 7 children of healthy parents related as first cousins. The initial diagnosis had been Ehlers-Danlos syndrome. Dental and facial abnormalities, including maxillary hypoplasia and mandibular prognathism, were described in 2 of the sibs, a 23-year-old woman and a 30-year-old man at the time of report.

Eich et al. (1996) described 2 sibs with GO who, in addition to the known clinical and radiologic manifestations of the disorder, presented a metaphyseal peg indenting the epiphysis of the long bones, particularly at the knees. The peg was visible only at the age of 4 to 5 years but was invisible in infancy and following physeal closure. Eich et al. (1996) suggested that this age dependence may be the reason that the anomaly was not described in previous reports of 23 patients in 11 families. They speculated that the metaphyseal peg represents a primary, age-dependent alteration of bone shape and hence a new genetic bone marker apparently specific to GO.

Al-Torki et al. (1997) reported a Bedouin family in which 2 sisters had this disorder. The parents were second cousins. A deceased brother of the paternal grandfather was said to have had the same disorder. Both sisters were 'surgically managed' for bilateral congenital hip dislocation at the age of 11 months. At age 9 the older sib had a prematurely aged face with loose and wrinkled skin, joint laxity, and platyspondyly and osteoporosis involving the thoracolumbar vertebrae. The younger sister had a more pronounced phenotype.

Rajab et al. (2008) reported on 22 Omani patients from 11 consanguineous families with the diagnosis of WSS or GO. Eight individuals from 3 families were diagnosed with GO. Distinctive features of GO included skin wrinkling limited to the dorsum of the hands, feet, and abdomen, normal-sized fontanels, normal teeth, bowed long bones, and osteopenia with frequent fractures. Adult patients with GO appeared prematurely aged. Unlike the patients with WSS, all 4 patients with GO had normal isoelectric focusing of serum transferrin.

Al-Dosari and Alkuraya (2009) reported 4 apparently unrelated consanguineous Saudi Arabian families with a total of 7 patients with GO. Based on the findings in their patients and a review of previously published GO patients, the authors noted that almost all patients had an oblique furrowing extending from the lateral border of the supraorbital ridge to the scalp hairline superolaterally and to the outer canthus inferomedially, resulting in the impression of fullness in the lateral part of the upper eyelid. The mandibular labial frenulum was either absent or hypoplastic in all patients. Consistent with previous reports, their patients showed intra- and interfamilial variation in severity.

Mapping

Using autozygosity mapping to analyze 4 Pakistani families and 1 Libyan family with GO, Newman et al. (2008) identified a 4-Mb candidate region on chromosome 1q24 between rs9286879 and rs1200150. All families were consanguineous. Affected members of the Pakistani families shared the same haplotype, suggesting a common founder effect, whereas affected members from the Libyan family had a different haplotype. There was no evidence of shared homozygosity across the locus on chromosome 12q24 encompassing ATP6V0A2 (611716), thus excluding this locus and excluding the notion that GO is allelic to wrinkly skin syndrome.

In 2 families with GO, Rajab et al. (2008) excluded several loci described in cutis laxa and wrinkly skin phenotypes on 2q31, 5q23-q31 (LOX, 153455 and ADAMTS2, 604539), 7q11 (ELN; 130160), 11q13 (EFEMP2; 604633), and 14q32 (FBLN5; 604580).

Hennies et al. (2008) performed genomewide linkage analysis involving 12 affected individuals from 4 unrelated Mennonite families with geroderma osteodysplastica from Germany, Mexico, and Canada, 1 of which was previously reported by Hunter et al. (1978), and identified a homozygous region on chromosome 1q24 with a combined multipoint lod score of 12.0. The shared homozygous haplotype in all affected persons from the Mennonite pedigrees was consistent with a founder effect and defined a 5.1-cM (5.7-Mb) candidate region between markers D1S1569 and D1S218 containing 102 genes.

Al-Dosari and Alkuraya (2009) identified one block of homozygosity spanning about 3 Mb on chromosome 1q that was shared by all 7 patients with GO osteodysplastica from 4 apparently unrelated Saudi Arabian families. Consistent with their similar geographic origin, the 3 families from the Central Province had a similar haplotype at the minimal region of overlap that was distinct from the haplotype in the family from the Southern Province. Linkage analysis produced several peaks but only one that had the expected lod score corresponding to the shared block of homozygosity. This locus contained 38 genes including GORAB.

Molecular Genetics

Using systematic sequencing in a 5.7-Mb candidate region on chromosome 1q24, Hennies et al. (2008) identified a homozygous nonsense mutation in the GORAB gene (607983.0001) in 12 affected individuals from 4 Mennonite pedigrees with geroderma osteodysplastica (GO), including a Mennonite family previously reported by Hunter et al. (1978). Subsequent analysis of GORAB in 9 additional unrelated patients with GO, including an Omani patient from 'family B' previously reported by Rajab et al. (2008), revealed homozygosity or compound heterozygosity for 8 different mutations, respectively (see, e.g., 607983.0002-607983.0005). Obligatory carriers were all heterozygous for the respective mutation, and the mutations were not found on 100 ancestry-matched control chromosomes. GORAB protein was completely absent from available fibroblasts from affected individuals, indicating a loss-of-function effect of the identified mutations. 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).

In affected members of 4 apparently unrelated consanguineous Saudi Arabian families segregating GO, Al-Dosari and Alkuraya (2009) identified homozygous mutations in the GORAB gene. Three families from the Central Province had the same frameshift mutation, whereas the family from the Southern Province had a missense mutation (A220P; 607983.0006). The segregation pattern was consistent with both mutations being pathogenic. Neither mutation was identified in a panel of at least 96 Saudi controls.

Nomenclature

Wiedemann (1978) pointed out that 'derma' is neuter; hence, the designation for this disorder should be 'geroderma osteodysplasticum' or 'gerodermia osteodysplastica.' Geroderma osteodysplasticum may be the correct form; cf. xeroderma pigmentosum (VAM).

In the first report of this disorder, Bamatter et al. (1950) noted a similarity of the phenotype to Walt Disney creations and used the designation 'Walt Disney dwarfs.'