kyphosis

Kahrizi Syndrome

Clinical Characteristics
Ocular Features: 

In an Iranian family with 3 affected sibs, cataracts (not further characterized) were noted in late adolescence.  Iris colobomas, unilateral in one sib and bilateral in another, were present.

Systemic Features: 

Children have severe psychomotor delays from birth and have severe mental retardation.  Speech and normal motor function never develop fully.  Thoracic kyphosis begins in late childhood and contractures develop in the elbows and knees.  A CAT scan in one patient revealed only normal findings.  Facial features have been described as ‘coarse’ with prominent lips, broad nasal bridge, and a bulbous nose.  Some individuals with this condition have lived into the 5th decade.  Ataxia is usually present although the cerebellum may be normal on MRI.

Genetics

This is an autosomal recessive condition resulting from homozygous mutations in the SRD5A3 gene (4q12).

Kahrizi syndrome is allelic to CDG1Q, or congenital disorder of glycosylation type Iq (612379), an autosomal recessive disorder with mutations in the same gene and a partially overlapping ocular phenotype.

At least 10 families have been reported with mutations in this gene considered important to glycosylation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this condition although physical therapy and cataract surgery might be considered in specific individuals.

References
Article Title: 

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Bl?omel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010 Jul 23;142(2):203-17.

PubMed ID: 
20637498

Cockayne Syndrome, Type B

Clinical Characteristics
Ocular Features: 

The eyes are deep-set.  Congenital cataracts are present in 30% of infants.  The aggressive course of this form of CS has precluded full delineation of the ocular features but infants have been described with microphthalmos, microcornea and iris hypoplasia. 

Systemic Features: 

Evidence of somatic and neurologic delays is present at birth or shortly thereafter with microcephaly and short stature.  Infants never develop normal milestones and may not grow in size beyond that of a 6 month-old child.  Communication skills are minimal.  They have a progeroid appearance, age rapidly, and most do not live beyond 5 years of age.   Feeding problems are common with considerable risk of aspiration, a common cause of respiratory infections and early death.  Severe flexion contractures develop early and may interfere with motor function.  Tremors and weakness contribute as well.  The skin is sensitive to UV radiation in some but not all patients.  However, the frequency of skin cancer is not increased.  Endogenous temperature regulation may be a problem. 

At least some cases with what has been called cerebro-oculo-facio-skeletal syndrome have been genotypically documented to have type B CS, the severe form of Cockayne syndrome.

Genetics

This is an autosomal recessive disorder resulting from mutations in ERCC6 (10q11) rendering the excision-repair cross-complementing protein ineffective in correcting defects during DNA replication.  Mutations in this gene account for about 75% of CS patients.  However, using date of onset and clinical severity, type A CS (216400) disease is far more common even though the ERCC8 mutations are found in only 25% of individuals.  Type A CS (216400) also has a somewhat later onset and is less severe in early stages.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation is type III is unknown.

Some patients have combined  phenotypical features of cerebrooculofacioskeletal syndrome (214150) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Feeding tubes may be necessary to maintain nutrition.  Protection from the sun is important.  Physical therapy can be used to minimize contractures.  Cataract surgery might be considered in selected cases as well as assistive devices for hearing problems but the limited lifespan should be considered. 

References
Article Title: 

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, Gibson L, Goodship JA, Jackson AP, Keng WT, King MD, McCann E, Motojima T, Murray JE, Omata T, Pilz D, Pope K, Sugita K, White SM, Wilson IJ. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2015 Jul 23. doi: 10.1038/gim.2015.110. [Epub ahead of print].

PubMed ID: 
26204423

Cockayne syndrome and xeroderma pigmentosum

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579

Cockayne Syndrome, Type A

Clinical Characteristics
Ocular Features: 

A progressive pigmentary retinopathy of a salt-and-pepper type and optic atrophy are commonly seen.  Retinal vessels are often narrowed and older patients can have typical bone spicule formation.  Night blindness, strabismus, and nystagmus may be present as well.  Enophthalmos, hyperopia, poor pupillary responses, and cataracts have been observed.  The lens opacities may in the nucleus or in the posterior subcapsular area and are often present in early childhood.  The ERG is often flat but may show some scotopic and photopic responses which are more marked in older individuals.  Vision loss is progressive but is better than expected in some patients based on the retina and optic nerve appearance.  The cornea may have evidence of exposure keratitis as many patients sleep with their eyes incompletely closed.  Recurrent corneal erosions have been reported in some patients.

The complete ocular phenotype and its natural history have been difficult to document due to the aggressive nature of this disease.

Ocular histopathology in a single patient (type unknown) revealed widespread pigment dispersion, degeneration of all retinal layers as well as thinning of the choriocapillaris and gliosis of the optic nerve.  Excessive lipofuscin deposition in the RPE was seen.

Systemic Features: 

Slow somatic growth and neural development are usually noted in the first few years of life.  Young children may acquire some independence and motor skills but progressive neurologic deterioration is relentless with loss of milestones and eventual development of mental retardation or dementia.  Patients often appear small and cachectic, with a 'progeroid' appearance.  The hair is thin and dry, and the skin is UV-sensitive but the risk of skin cancer is not increased.  Sensorineural hearing loss and dental caries are common.  Skeletal features include microcephaly, kyphosis, flexion contractures of the joints, large hands and feet, and disproportionately long arms and legs.  Perivascular calcium deposits are often seen, particularly in various brain structures while the brain is small with diffuse atrophy and patchy demyelination of white matter.  Peripheral neuropathy is characterized by slow conduction velocities.  Poor thermal regulation is often a feature. 

Type A is considered the classic form of CS.  Neurological deterioration and atherosclerotic disease usually lead to death early in the 2nd decade of life but some patients have lived into their 20s.  

Genetics

There is a great deal of clinical heterogeneity in Cockayne syndrome.  Type A results from homozygous or heterozygous mutations in ERCC8 (5q12).  CS type B (133540), is caused by mutations in ERCC6, and has an earlier onset with more rapidly progressive disease.  Both mutations impact excision-repair cross-complementing proteins important for DNA repair during replication.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation in type III is unknown. 

Some patients have combined phenotypical features of Cockayne syndrome (CS) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in nucleotide excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

There may be considerable overlap in clinical features and rate of disease progression among all types.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for Cockayne syndrome.  Supportive care for specific health problems, such as physical therapy for joint contractures, is important. 

Justification of cataract extraction should be made on a case by case basis.  Lagophthalmos requires that corneal lubrication be meticulously maintained.

References
Article Title: 

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, Gibson L, Goodship JA, Jackson AP, Keng WT, King MD, McCann E, Motojima T, Murray JE, Omata T, Pilz D, Pope K, Sugita K, White SM, Wilson IJ. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2015 Jul 23. doi: 10.1038/gim.2015.110. [Epub ahead of print].

PubMed ID: 
26204423

Ocular findings in Cockayne syndrome

Traboulsi EI, De Becker I, Maumenee IH. Ocular findings in Cockayne syndrome. Am J Ophthalmol. 1992 Nov 15;114(5):579-83.

PubMed ID: 
1443019

Cockayne syndrome and xeroderma pigmentosum

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579
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