AUTHOR INFORMATION

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Authored by Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine

Coauthored by Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine

Suzanne M Carter, MS, is a member of the following medical societies: American Bar Association

Edited by Elaine H Zackai, MD, Director of Clinical Genetics Center, Professor of Pediatrics, Department of Pediatrics, Division of Human Genetics and Molecular Biology, University of Pennsylvania, Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Suzanne M Carter, MS
Editor's Email:	Elaine H Zackai, MD

eMedicine Journal, February 2 2007, VOLUME 8, Number 2

INTRODUCTION

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Background: Cockayne syndrome (CS) spans a spectrum that includes CS type 1, the classic form; CS type 2, a more severe form with symptoms present at birth (ie, cerebrooculofacial-skeletal [COFS] syndrome, Pena-Shokeir type 2 syndrome); CS type 3, a milder form; and xeroderma pigmentosa–Cockayne syndrome (XP-CS). The discussion in this article is limited to CS types 1 and 2, also termed CS types A and B, respectively.

CS type 1 (CKN1; Online Mendelian Inheritance in Man [OMIM] number 216400) and CS type 2 (CSB; OMIM number 133540) are rare autosomal recessive disorders that feature growth deficiency, premature aging, and pigmentary retinal degeneration along with a complement of other clinical findings. CS type 1 presents at birth, whereas CS type 2 appears during early childhood. CKN1 was first reported in 1936. Fatality usually occurs in early adolescence, but some patients survive until early adulthood.

Pathophysiology: Premature aging is the cardinal feature of both types; however, within the first 2 years of life, growth and development become abnormal. By the time the disease has fully manifested, height, weight, and head circumference are far below the fifth percentile. The characteristic physical appearance of cachectic dwarfism with thinning of the skin and hair, sunken eyes, and a stooped standing posture illustrates the aging process. Pathologic studies reveal diffuse and extensive demyelination in the central and peripheral nervous systems. Patients demonstrate pericapillary calcifications in the cortex and basal ganglia at an early age; severe neuronal loss in the cerebral cortex and cerebellum also occurs. These changes correlate with the physiologic changes of aging.

Frequency:

• In the US: Incidence is less than 1 case per 250,000 live births.

Mortality/Morbidity: Patients are at risk for postnatal growth failure, pigmentary retinal degeneration, and premature death before adulthood.

• Postnatal growth failure: Profound growth failure begins within the first year of life. Weight is affected more than length, and cachectic dwarfism results. A rare subset of patients, classified as having severe CKN1, have low birth weight with almost no postnatal growth.

• Pigmentary retinal degeneration: This diagnostic criterion for CKN1 (salt-and-pepper appearance in the retinas) develops later in life. Cataracts are the second most common eye finding.

• Premature death: The characteristic appearance of aging in children with Cockayne syndrome is striking. The mean and median age of death is 12 years, and most patients die as a result of pneumonia or other respiratory infections.

Race: CNK1 is panethnic.

Sex: Male-to-female ratio is 1:1, which is consistent with an autosomal recessive disorder.

Age: As a progressive congenital disorder, clinical symptoms may not be manifested until late infancy or early childhood.

CLINICAL

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History: Patients present with delayed psychomotor development, poor feeding, photosensitive rashes, and cataracts.

• Delayed psychomotor development: All patients with CKN1 have mental retardation. The delay becomes apparent around the age when walking and speech should be developing.



• Poor feeding: Some patients present during infancy with weak or poor feeding; however, the diagnosis is usually not made at this time.



• Photosensitive rashes: More than 75% of patients have photosensitivity. Other skin findings include decreased amounts of subcutaneous tissue, dry scaly skin, and thin dry hair.



• Cataracts: The presence of cataracts in children younger than 3 years is associated with the severe form of CKN1, which demonstrates a poorer prognosis and results in death at an earlier age.

Physical: In the first year, all patients with CKN1 demonstrate growth failure, which includes progressive microcephaly in most patients.

• Neurologic examination shows increased or decreased muscle tone and reflexes. Ambulant patients present with an unusual gait resulting from leg spasticity, ataxia, and contractures of the hips, knees, and ankles.



• Pigmentary degeneration of the retina is one hallmark of this disorder, with cataracts and optic atrophy or optic disk pallor as frequent findings.



• Ophthalmologic changes are progressive.



• More than one half of patients with CKN1 have mild-to-severe sensorineural hearing loss.



• Many patients have moderate-to-severe dental caries; permanent teeth have short roots.



• Most patients have photodermatitis that leads to dry scaly skin. Patients develop an aged appearance as a result of the disease process.



• Major structural anomalies of the renal system rarely occur. Some patients develop decreased creatinine clearance but usually do not require medical treatment.



• Cryptorchidism or testicular hypoplasia affects approximately one third of males. Females have menses, although cycles are irregular. Puberty may be delayed in both sexes.

Causes: CKN1 is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8) located on chromosome 5. Affected persons inherit 2 mutant genes, one from each parent. Cells carrying ERCC8 mutations are hypersensitive to UV light. They do not recover the ability to synthesize ribonucleic acid (RNA) after exposure to UV light. In addition, the cells cannot remove and degrade deoxyribonucleic acid (DNA) lesions from strands that have active transcription.

Mutations in the DNA excision repair gene ERCC6 located on band 10q11 cause CS type 2 (MIM number 133540; CSB). This gene encodes helicase, a protein that is presumed to have DNA unwinding function. Mutations include a deletion of exon 4, an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, and large deletion in the upstream region, including exon 1 of the CSA gene. The Q106P mutation could alter the propeller structure of the CSA protein, which is important for the formation of the CSA protein complex. Additionally, a missense mutation (A205P) and a nonsense (E13X) mutation have been identified, as well as a new common single nucleotide polymorphism in CKN1. No genotype-phenotype correlation exists.

DIFFERENTIALS

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Other Problems to be Considered:

Bloom syndrome
Rothmund-Thompson syndrome
Werner syndrome
Xeroderma pigmentosum

WORKUP

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Lab Studies:

• Perform routine laboratory tests to exclude other disorders and to establish baseline renal function.



• Request chromosome analysis to exclude any karyotypic abnormalities associated with growth failure.



• Request chromosome breakage studies if considering Bloom syndrome in the differential diagnosis. Patients with xeroderma pigmentosum (a differential diagnosis for CKN1) and Bloom syndrome demonstrate clinical phenotypes that overlap with those found in patients with Cockayne syndrome. Chromosome breakage studies and DNA mutation analysis are necessary to exclude Bloom syndrome and xeroderma pigmentosum.



• Cultured skin fibroblasts of patients with CKN1 lack the ability to form colonies when subjected to UV irradiation. Very few laboratory personnel have expertise in this technique.



• Mutational analysis of the gene associated with CS is available on a research basis only.

Imaging Studies:

• Computed tomography (CT) scan or magnetic resonance imaging (MRI) findings include increased ventricular size, cerebral atrophy, white matter abnormalities, and normal pressure hydrocephaly.



• Skeletal radiographs depict vertebral body and pelvic abnormalities.

Other Tests:

• Audiometry is used to determine if sensorineural hearing loss is present.



• Electroencephalogram is used to assess the patient for seizure activity.



• Electroretinogram reveals abnormalities in the electric potential of the retina.

For patients with sensorineural hearing loss, a significant loss of neurons occurs in the spiral ganglion and brainstem, with retrograde atrophy of the auditory pathways.

TREATMENT

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Medical Care: Treatment of patients with CKN1 depends solely on the presenting symptoms. Physical therapy helps prevent contractures and helps maintain ambulation. Sunscreen should be applied liberally, and excessive sun exposure should be avoided.

Consultations:

• Audiologist



• Geneticist



• Dentist



• Ophthalmologist



• Physical therapist

Diet: No special diet alters the prognosis. A gastrostomy tube may prevent malnutrition in patients who feed poorly.

Activity: Physical therapy is essential to enable patients to avoid joint contractures and to prolong ambulation.

MEDICATION

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Drug therapy currently is not a component of the standard of care for patients with CS (see Treatment).

FOLLOW-UP

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Further Inpatient Care:

• Use of a gastrostomy tube may prevent malnutrition in patients who feed poorly.

Further Outpatient Care:

• Monitor patients for hypertension, renal function, hearing loss, and dental caries.



• Physical therapy delays the onset of joint contractures.

Transfer:

• Consider transfer or referral to a facility with expertise in cultured skin fibroblasts because very few laboratory personnel have expertise in this technique.

Deterrence/Prevention:

• Advise patients to avoid excessive sun exposure and to use sunscreen liberally when outdoors.

Complications:

• Mental retardation



• Growth failure



• Progressive pigmentary retinopathy



• Sensorineural hearing loss



• Joint contractures and ataxia



• Hypertension



• Photosensitivity



• Premature death

Prognosis:

• CNK1 is an autosomal recessive disorder resulting in growth failure and progressive neurologic dysfunction.



• Death usually occurs during adolescence, but survival into adulthood is possible.

Patient Education:

• Recommend genetic counseling because each sibling subsequently born to the parents of an affected child will have a 25% risk of having CNK1.



• Not only are cultured cells from CS patients hypersensitive to the lethal effects of UV but also the normal recovery in DNA and RNA synthesis after UV exposure does not occur. Measuring RNA synthesis and the secondary DNA synthesis of cultured amniocytes after irradiation with UV light has been successful in the prenatal diagnosis of CS. Prenatal diagnosis based on molecular analysis in future pregnancies may also be possible if the mutations in the affected child are known.



• Advise parents that treatment is supportive and based on symptoms.



• Optimize neurologic and neurosensory abilities in the patient.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to make the diagnosis and offer genetic counseling to parents of an affected child

Special Concerns:

• A severe form of CKN1 presents within the first 2 years of life. These children have low birth weight, congenital cataracts, microcephaly, and severe neurologic deficits at younger than 1 year.

TEST QUESTIONS

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CME Question 1: Which of the following complications is not known to occur in patients with Cockayne syndrome type 1?

A: Cutaneous photosensitivity
B: Growth failure
C: Cataracts
D: Gait abnormalities
E: Cardiac abnormality

The correct answer is E: A cardiac abnormality is not a common finding in patients with Cockayne syndrome type 1. Any cardiac workup should be based on clinical symptoms.

CME Question 2: Which of the following figures indicates the subsequent risk that the parents of a child with Cockayne syndrome type 1 will have another child affected by the disorder?

A: 100%
B: 50%
C: 25%
D: 10%
E: 3-5%

The correct answer is C: Cockayne syndrome is an autosomal recessive disorder; therefore, the risk of having another affected child is 25%.

Pearl Question 1 (T/F): Ophthalmologic abnormalities are common in patients with Cockayne syndrome type 1.

The correct answer is True: Progressive retinal pigmentary degeneration is noted most often, followed by cataracts and optic atrophy.

Pearl Question 2 (T/F): Cockayne syndrome type 1 does not have a genetic etiology.

The correct answer is False: Cells of patients with Cockayne syndrome type 1 are hypersensitive to UV light. Following irradiation, the cells are unable to synthesize ribonucleic acid (RNA) and cannot repair damage to deoxyribonucleic acid (DNA) undergoing active transcription.

Pearl Question 3 (T/F): Children with Cockayne syndrome type 1 demonstrate normal findings on brain imaging studies.

The correct answer is False: MRI or CT scan findings depict brain abnormalities such as cerebral atrophy, normal pressure hydrocephaly, or increased ventricular size.

Pearl Question 4 (T/F): Xeroderma pigmentosum is in the differential diagnosis for Cockayne syndrome type 1.

The correct answer is True: Patients with xeroderma pigmentosum and Bloom syndrome demonstrate clinical phenotypes that overlap with those found in patients with Cockayne syndrome type 1. Chromosome breakage studies and DNA mutation analysis are necessary to exclude the 2 disorders.

BIBLIOGRAPHY

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• Greenhaw GA, Hebert A, Duke-Woodside ME, et al: Xeroderma pigmentosum and Cockayne syndrome: overlapping clinical and biochemical phenotypes. Am J Hum Genet 1992 Apr; 50(4): 677-89[Medline].
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