Paula and Bobby
Parents of Lillie
What is Cerebrooculofacioskeletal syndrome?
This rare disease is a congenital, degenerative genetic condition.
It affects the brain, spinal cord and eyes of affected individuals.
Individuals with the syndrome have a life expectancy of no more than 5 years.
Xeroderma Pigmentosum Vii; Xp7 Xp, Group G; Xpgc
What gene changes cause Cerebrooculofacioskeletal syndrome?
Current research has identified mutations in the ERCC1, ERCC2, ERCC5 and ERCC6 genes as causes of the syndrome.
The syndrome is inherited in an autosomal recessive pattern.
Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
What are the main symptoms of Cerebrooculofacioskeletal syndrome?
The syndrome mainly affects the brain, spinal cord and eyes of affected individuals. This leads to severe intellectual disability, hypotonia (low muscle tone), and impairment of the reflexes which may include clenched fists.
Individuals will have very small eyes and congenital cataracts (a clouding of the eyes present at birth). Involuntary eye movements are also a feature of the syndrome.
Other physical features include large and low-set ears, a very small head (microcephaly) and very small jaw (micrognathia).
Individuals may also suffer from medical conditions related to their skull, limbs, heart and kidneys.
Possible clinical traits/features:
Microcephaly, Rocker bottom foot, Camptodactyly of finger, Death in childhood, Cutaneous photosensitivity, Autosomal recessive inheritance, Scrotal hypoplasia, Cataract, Deeply set eye, Microphthalmia, Micrognathia, Micropenis, Kyphoscoliosis, Large beaked nose, Intrauterine growth retardation, Hearing impairment, Global developmental delay
How does someone get tested for Cerebrooculofacioskeletal syndrome?
The initial testing for Cerebrooculofacioskeletal syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Cerebrooculofacioskeletal syndrome
This diagnosis should be considered in infants presenting with microcephaly, cataracts and joint contractures. There is often early death, or, in those who survive, severe failure to thrive. The facial appearance is characteristic, in that the nasal root is prominent and the forehead slopes sharply backwards. Both the jaw and the eyes are small.
Pena et. al. (1974) described two sisters with severe camptodactyly, clubfeet, knee and hip ankylosis, facial anomalies (low-set malformed ears, hypertelorism, depressed tip of the nose, small mouth, high palate), and pulmonary hypoplasia, that died in the perinatal period.
The condition is probably heterogeneous. Note the similarity with the Neu-Laxova syndrome (see separate entry). There is good evidence that some infants diagnosed initially as COFS subsequently develop Cockayne syndrome including the sunken eye appearance, sensorineural deafness, photosensitivity, and basal ganglia calcification. McKusick lists COFS as separate from the cases reported by Lowry et al., (1971), Dolman and Wright, 1978, Scott-Emuakpor et al., (1977), giving these the designation CAMAK or CAMFAK, however it seems likely that they all fall into the COFS-Cockayne spectrum. See also the report by Talwar and Smith (1989).
Del Bigio et al., (1997) studied the brains of eight cases. They noted severe microencephaly with mild ventriculomegaly. Cerebral myelination was delayed in one case. There was cortical neural loss, patchy or diffuse absence of myelin and gliosis in the white matter and pericapillary and parenchymal mineralisation in the globus pallidus, putamen and cerebral cortex. The cerebellum in older children showed severe degenerative changes involving the internal granular layer and Purkinje cell layer.
Jaeken et al., (1989) reported three infants with the COFS phenotype in whom Vermeulen et al., (1993) later demonstrated biochemical abnormalities consistent with xeroderma pigmentosum complementation group G. Meira et al., (2000) showed that the pateints with COFS syndrome from the same tribe originally reported by Pena and Shokeir (1974) had a mutation in the Cockayne syndrome group B (CSB/ERCC6). Graham et al., (2001) reported two patients with features of COFS syndrome with UV sensitivity. Mutations in the xeroderma pigmentosum group D (XPD) gene were demonstrated. Nucleotide excision repair (NER) requires ERCC! (an endonuclease) for its function, and mutations in ERCC1 were found by Jaspers et al., (2007) in a patient with a severe phenotype but only moderate hypersensitivity to UV and mitomycin C.
Temtamy et al., (1996) reported a case wth COFS syndrome associated with a familial (1;16)(q23;q13) translocation.
The diagnosis in the case reported by Sakai et al., (1997) is not absolutely certain, as there was corneal clouding and no clinical photographs were published, nevertheless the authors do provide a good review of the neuropathology in this condition. The patient reported by Longman et al., (2004) presented like someone with a congenital muscular dystrophy. Biopsy revealed that his muscle was almost entirely replaced by fat. A patient with posterior polar cataract, microphthalmos and optic atrophy was reported by Jonas et al., (2003).
Rarely, ichthyosis occurs (Suzumura et al., 2006).
Laugel et al., (2008) described 3 additional cases and found CSB mutations in all three. All had feeding difficulties truncal hypotonia, but peripheral spasticity. The sib of one (not examined) was said to be similarly affected and had retinitis pigmentosa and deafness.
A large family, with 5 affected fetuses were reported by Drury et al., (2014). The phenotype was severe with microcephaly, akinesia and contractures. Cerebellar hypoplasia was a feature in 2. They suggest that the ERCC5 mutation as found in this family might convey severe disease.
Hosseini et. al. (2015) reviewed the nucleotide excision repair-related (NER) disorders. There is overlap between COFS and Trichotiodystrophy, and type 1 is allelic to Cockayne syndrome type B.
Yew et. al. (2016) reviewed photodermatoses associated with defective DNA repair. Overlapping may also be with Warburg micro syndrome or Martsolf syndrome.
* This information is courtesy of the L M D
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