Cerebrooculofacioskeletal Syndrome Clinical CharacteristicsOcular Features: Congenital cataracts and microphthalmia are frequent findings in this disorder. Delayed mental development and early death in childhood have limited full delineation of the ocular phenotype. Photosensitivity, nystagmus, optic nerve atrophy, and pigmentary retinopathy have been reported. The eyes may appear deeply-set. Systemic Features: Microcephaly, flexion contractures, prominent nasal root and an overhanging upper lip are common features. Severe developmental and growth delays are evident early followed by progressive behavioral and intellectual deterioration. Both hypotonia and hyperreflexia have been described. Kyphosis and scoliosis are common. CT scans may show intracranial calcifications and brain histology shows severe neurodegeneration with neuronal loss and gliosis. Respiratory distress may also occur and some individuals have died in the first decade of life. GeneticsHomozygous mutations in the ERCC6 gene (10q11) seem to be responsible for this autosomal recessive disorder. Several sets of parents have been consanguineous. Mutations in the same gene are responsible for Cockayne type B syndrome (133540) and some suggest that the variable phenotype represents a spectrum of disease rather than individual entities. Cerebrooculofacioskeletal syndrome represents the more severe phenotype in this spectrum. Pedigree: Autosomal recessiveTreatmentTreatment Options: No treatment is available for this disorder. ReferencesArticle Title: Ocular findings in cerebro-oculo-facial-skeletalsyndrome (Pena-Shokeir-II syndrome) Jonas JB, Mayer U, Budde WM. Ocular findings in cerebro-oculo-facial-skeletalsyndrome (Pena-Shokeir-II syndrome). Eur J Ophthalmol. 2003 Mar;13(2):209-211. PubMed ID: 28252747 Manitoba aboriginal kindred with original cerebro-oculo- facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene Meira LB, Graham JM Jr, Greenberg CR, Busch DB, Doughty AT, Ziffer DW, Coleman DM, Savre-Train I, Friedberg EC. Manitoba aboriginal kindred with original cerebro-oculo- facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene. Am J Hum Genet. 2000 Apr;66(4):1221-8. PubMed ID: 10739753 Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome Del Bigio MR, Greenberg CR, Rorke LB, Schnur R, McDonald-McGinn DM, Zackai EH. Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome. J Neuropathol Exp Neurol. 1997 Oct;56(10):1147-57. PubMed ID: 9329459 Read more about Cerebrooculofacioskeletal Syndrome
Ocular findings in cerebro-oculo-facial-skeletalsyndrome (Pena-Shokeir-II syndrome) Jonas JB, Mayer U, Budde WM. Ocular findings in cerebro-oculo-facial-skeletalsyndrome (Pena-Shokeir-II syndrome). Eur J Ophthalmol. 2003 Mar;13(2):209-211. PubMed ID: 28252747
Manitoba aboriginal kindred with original cerebro-oculo- facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene Meira LB, Graham JM Jr, Greenberg CR, Busch DB, Doughty AT, Ziffer DW, Coleman DM, Savre-Train I, Friedberg EC. Manitoba aboriginal kindred with original cerebro-oculo- facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene. Am J Hum Genet. 2000 Apr;66(4):1221-8. PubMed ID: 10739753
Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome Del Bigio MR, Greenberg CR, Rorke LB, Schnur R, McDonald-McGinn DM, Zackai EH. Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome. J Neuropathol Exp Neurol. 1997 Oct;56(10):1147-57. PubMed ID: 9329459
Refsum Disease, Adult Clinical CharacteristicsOcular Features: A retinitis pigmentosa-like retinopathy is the major ocular manifestation of this disease. There is typical night blindness and visual field constriction. Rod ERG responses are usually subnormal. However, central acuity is also reduced due to a degenerative maculopathy. Cataracts and optic atrophy are common. The macula may undergo progressive degeneration and optic atrophy is not uncommon. Some patients have defective pupillary responses. Systemic Features: Onset of symptoms is usually late in the first decade and sometimes into the third decade. There is usually a polyneuropathy with impaired motor reflexes and paresis in the limbs. A progressive sensorineural hearing loss occurs in many patients. Sensory deficits also occur. Some have ataxia and skin changes of ichthyosis. Anosmia is a near universal feature. Heart failure may occur and cardiac abnormalities such as conduction defects can occur. A variety of skeletal abnormalities such as pes cavus, short fourth metatarsals, and evidence of epiphyseal dysplasia have been reported. There is considerable clinical heterogeneity even within families. Phytanic acid oxidase activity as measured in fibroblasts is often low while serum phytanic acid is increased. The cerebrospinal fluid contains increased protein but no increase in cells. GeneticsThis disorder results from mutations in the PHYH (PAHX) gene (10pter-p11.2) encoding phytanoyl-CoA hydroxylase, or, more rarely in PEX7 (6q22-q24) encoding peroxin-7 resulting in an uncommon condition (10% of cases) sometimes called adult Refsum disease-2. Mutations in the latter gene also cause rhizomelic chondrodysplasia punctata type 1 (215100) which does not have all of the neurological features or the retinopathy. There is also so-called infantile form of Refsum disease (266510). Pedigree: Autosomal recessiveTreatmentTreatment Options: A diet low in phytanic acid can lead to improvement in the neurologic symptoms such as the ataxia and polyneuropathy but must be instituted in early stages of the disease. This approach may not be as beneficial for the visual or auditory symptoms. ReferencesArticle Title: Identification of PEX7 as the second gene involved in Refsum disease van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR, Wanders RJ. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet. 2003 Feb;72(2):471-7. PubMed ID: 12522768 Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease Jansen GA, Hogenhout EM, Ferdinandusse S, Waterham HR, Ofman R, Jakobs C, Skjeldal OH, Wanders RJ. Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease. Hum Mol Genet. 2000 May 1;9(8):1195-200. PubMed ID: 10767344 Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation Skjeldal OH, Stokke O, Refsum S, Norseth J, Petit H. Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation. J Neurol Sci. 1987 Jan;77(1):87-96. PubMed ID: 2433405 Read more about Refsum Disease, Adult
Identification of PEX7 as the second gene involved in Refsum disease van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR, Wanders RJ. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet. 2003 Feb;72(2):471-7. PubMed ID: 12522768
Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease Jansen GA, Hogenhout EM, Ferdinandusse S, Waterham HR, Ofman R, Jakobs C, Skjeldal OH, Wanders RJ. Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease. Hum Mol Genet. 2000 May 1;9(8):1195-200. PubMed ID: 10767344
Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation Skjeldal OH, Stokke O, Refsum S, Norseth J, Petit H. Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation. J Neurol Sci. 1987 Jan;77(1):87-96. PubMed ID: 2433405