Are You Confident of the Diagnosis?
What you should be alert for in the history
CS can be diagnosed from a comprehensive history and physical exam. Patients are often normal at birth. Failure to grow appropriately, cachexia, characteristic facies, premature aging, and other clinical characteristics on exam as noted above together are suggestive of CS. The definitive diagnosis relies on molecular techniques in identifying the specific gene mutations.
Characteristic findings on physical examination
Cockayne syndrome (CS) is rare genetic disease with a spectrum of clinical features. Patients are typically characterized by profound neurologic abnormalities, increased sensitivity to the sun, growth failure leading to short stature with disproportionately long limbs, and premature aging. Other clinical characteristics include ocular and dental abnormalities. The classic CS patient has a “birdlike” appearance that includes a lack of subcutaneous facial fat (especially around the cheeks) with prominent accentuation of cheek bones, a thin bird-like nose and large ears.
Patients with CS are typically normal at birth but their central nervous system fails to mature and grow appropriately. Typically the initial presenting signs that alert a clinician to the possibility of CS are dwarfism and cachexia which may be evident before 1 year of age.
The neurologic abnormalities observed in patients with CS range from normal intelligence with normal psychomotor development to delayed psychomotor skills, progressive sensorineural deafness beginning with hearing loss in the high frequency range, peripheral neuropathies, and mental retardation. Patients offen have microcephaly and gait disturbances on physical examination. In addition, they may exhibit increased deep tendon reflexes. Despite these neurologic deficiencies, CS patients tend to be social individuals.
Dental abnormalities may include gingivitis, dental caries, enamel hypoplasia, absence of permanent teeth (oligodontia), and atrophy of the alveolar processes, while ocular abnormalities include dry eyes, optic atrophy, cataracts, retinal degeneration, and pigmentary retinopathy all of which may lead to progressive visual loss. Patients are photosensitive to UV light but are not at an increased risk for skin cancer.
Furthermore, many of the systemic complications in CS patients are attributed to premature aging (see section on Complications of the disease).
Expected results of diagnostic studies
Laboratory findings are often nonspecific; however, patients often may exhibit abnormal nerve conduction, abnormal brainstem auditory evoked response (BAER) and audiometry. Cerebral and cerebellar atrophy, basal ganglia calcification, enlarged ventricles, and a thickened skull may also be seen on computed tomography (CT), while an absence of myelin may be appreciated on magnetic resonance imaging (MRI). These studies all can aid in the diagnosis of CS in conjunction with the clinical examination.
When considering a diagnosis of CS, trichothiodystrophy (TTD) and xeroderma pigmentosum (XP) should be considered as well, because all three disease entities are characterized by defects in DNA excision repair. Similar to CS patients, TTD patients are not at an increased risk of developing skin cancer and do not develop pigmentary abnormalities. However, TTD patients have brittle hair characterized by a tiger-tail banding on polarized light microscopy, ichthyosis, and short stature.
XP patients have a dramatic sensitivity to the sun developing blistering burns with minimal exposure to UV light. These individuals are at an increased risk for numerous skin cancers at an early age. Finally, other rare diseases such as metabolic disorders, lysosomal storage diseases, fatty acid oxidation defects, porphyria, and Wilson’s disease should be included in thedifferential diagnose of a patient suspected of having CS.
Who is at Risk for Developing this Disease?
CS occurs with a frequency of approximately 1 in 100,000. A history of consanguinity is a risk factor for development of the syndrome.
CS has been historically divided into three subtypes differing on severity and age of onset. Type I (or classic) CS is characterized by the onset of symptoms in early childhood. Type II CS is a much more severe form of the disease often present at birth (congenital), characterized by minimal neurological development with early death. It has been referred to as cerebro-oculo-facial-skeletal (COFS) syndrome. Finally, Type III CS has the mildest of symptoms and occurs much later in life.
What is the Cause of the Disease?
CS is inherited in an autosomal recessive pattern and is one of several human diseases caused by defects in DNA repair. It is linked to mutations in ERCC8 (Excision Repair Cross-Complementing Group 8) and ERCC6 (Excision Repair Cross-Complementing Group 6), genes located on chromosomes 5 and 10q11 respectively. Patients with the ERCC8 mutation (20% of patients) are classified as CS complementation group A (CSA), wheras those patients with the mutation in the ERCC6 mutation (80% of patients) belong to complementation group B (CSB).
The proteins normally encoded by these genes assist RNA polymerase III in dealing with transcription blocks caused by DNA damage by helping to recruit nuclear excision proteins to remove the damage. Defective ERCC6 and ERCC8 gene products lead to defective DNA repair and presumably allows the accumulation of reactive oxygen species in cells and DNA damage, ultimately leading to premature aging.
Systemic Implications and Complications
The most important systemic complications of CS are neurological. Patients often develop progressive neurological decline (including progressive sensorineural hearing loss), cognitive deficits, and mental retardation. Patients may have difficulty with both language and motor skills. Ataxia, peripheral neuropathy, and spasticity are relatively common, while epilepsy and other movement disorders may also be present.
Patients with CS often have dental abnormalities, such as absence of permanent teeth (oligodontia), atrophy of the alveolar processes, mandibular prognathism, condylar hypoplasia, dental caries, and gingivitis. Ophthalmological diseases such as retinal degeneration, pigmentary retinopathy, cataracts, and optic atrophy may also complicate patients with CS.
Over time, patients with CS develop signs of premature aging. Patients may become cachectic from a failure to feed themselves, and eventually may require feeds through a gastric tube. All the associated diseases associated with premature aging such as Type II diabetes, atherosclerotic disease, cardiovascular disease, cerebrovascular disease, renal disease, hypertension, hyperlipidemia, osteopenia, kyphosis, hair thinning, and skin atrophy are hallmarks of progressive disease.
In addition, patients with CS appear to be prone to liver disease, particularly cholestatic liver disease. In one study, seven out of nine patients with CS had liver abnormalities ranging from mild liver enzyme elevation to cholestatic liver disease and liver failure. CS patients also have other endocrine complications, such as immature sexual development and hypogonadism. Female patients often experience menstrual irregularities.
Although CS patients are sensitive to sun exposure, they are not at an increased risk for skin cancer or other forms of cancer as compared to the general population.
Management strategies for complications associated with Cockayne syndrome are summarized in Table I.
|General management strategies||– Emphasize healthy living (regular exercise, healthy eating, no smoking/drugs/alcohol) as way of preventing many of the complications observed in CS as listed below.|
|Cardiovascular disease||– Healthy living (regular exercise, healthy eating, no smoking/drugs/alcohol)|
|– Routine follow up with primary care physician and cardiologist|
|Dental abnormalities (caries, gingivitis, etc.)||– Meticulous daily dental care|
|– Routine check ups with dentist|
|Diabetes / Endocrinological abnormalities||– Routine follow-ups with endocrinology / gynecology|
|– Daily calcium and vitamin D supplements to protect against osteopenia/osteoporosis|
|– Weight-bearing exercises on a routine basis|
|Hypertension/Hyperlipdemia||– Routine follow up with primary care physician and cardiologist|
|Liver disease / Renal disease||– Routine follow up with primary care physician, gastroenterologist, or nephrologist|
|Neurological abnormalities / Hearing loss / Epilepsy||– Routine neurological exams with neurologist|
|– Annual comprehensive hearing tests|
|Ophthalmological abnormalities (cataracts / pigmentary retinopathy / dry eyes / etc).||– Routine exams with ophthalmology|
|– Artificial tears for dry eyes|
|Sun sensitivity||– Sun avoidance|
|– Utilize chemical and mechanical means of sun protection|
|– Routine visits with dermatology to evaluate for skin changes/pre-malignant lesions|
Optimal Therapeutic Approach for this Disease
The management of CS relies on a multidisciplinary approach. Pediatricians, geneticists, dermatologists, ophthalmologists, neurologists, gastroenterologists, cardiologists, endocrinologists, gynecologists, and dentists may all be involved in the patient’s care.
Patients with CS need to follow up closely with their primary care physicians so that they can be monitored for all the potential complications that they are at an increased risk for, such as hypertension, hyperlipidemia, cardiovascular disease, diabetes, liver disease, and renal disease.
At an early age, patients should be evaluated and followed by a neurologist who can monitor for signs of neurological decline. Comprehensive hearing tests should also be performed routinely to screen for sensorineural hearing loss.
CS patients often have ophthalmological abnormalities and should be followed closely by ophthalmologists. Routine eye exams should be performed to screen for cataracts, retinal degeneration, pigmentary retinopathy, etc. For patients who experience chronic dry eyes, the use of artificial tears can help alleviate their symptoms.
Patients must also obtain routine dental exams because they are prone to both developmental abnormalities of their dental structures and the development of dental caries and gingivitis.
Although CS patients are not at an increased risk of skin cancer, they are particularly photosensitive. As a result, patients should utilize both mechanial and chemical forms of sunscreen and follow up with their dermatologists on a routine basis.
Teach patients and their families the characteristics and complications of CS so that they can better monitor their own health. Explain to patients that although there is currently no cure, measures can be taken to prevent complications and to improve their quality of life significantly. It is imperative that patients follow up with their medical providers on a routine basis.
Teach patients the importance of following up with their primary care physicians so that they can be adequately monitored for all the systemic complications associated with the disease. Teach patients the signs and symptoms of specific complications so that they can personally monitor for them and seek appropriate care early on. For example, patients should learn that the signs and symptoms of liver disease may include yellowing of the skin, mucous membranes and conjunctivae,increased fatigue, easy bruising, generalized pruritus, dark urine, and pale stools.
Encourage patients to lead a healthy lifestyle by exercising routinely, eating healthy, not smoking, and drinking in moderation. These efforts can help slow down and even prevent some of the complications associated with premature aging.
Encourage patients to visit their ophthalmologists on a routine basis and more frequently if they notice changes in their vision. Advise patients to use artificial tears if they experience chronic dry eyes.
Teach patients to perform meticulous dental care on a daily basis and to visit their dentists routinely.
Because CS patients are extremely sensitive to UV light, advise patients to use adequate mechanical and chemical sun protection. Patients should apply sunscreen to all sun-exposed areas routinely and wear protective clothing.
Unusual Clinical Scenarios to Consider in Patient Management
Cockayne syndrome is characterized by a wide spectrum of clinical phenotypes. It is therefore not surprising that some patients have clinical features that overlap with other similar conditions. For example, patients with xeroderma pigmentosum/Cockayne syndrome complex have the dermatological (pigmentary changes secondary to UV light) and ocular manifestations of XP and the neurological manifestations of CS. These patients also develop progressive neurological deterioration.
What is the Evidence?
Abdel Ghaffar , TY, Elsobky , ES, Elsayed , SM. “Cholestasis in patients with Cockayne syndrome and suggested modified criterial for clinical diagnosis”. Orphanet J Rare Dis. vol. 6. 2011. pp. 13(The authors of this study found that seven of nine patients with CS had evidence of liver dysfunction ranging from mild elevation of liver enzymes to cholestatic liver disease.)
Kraemer , KH, Patronas , N, Schiffmann , R, Brooks , B, Tamura , D, DiGiovanna , J. “Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship”. Neuroscience . vol. 145. 2007. pp. 1388-96. (A summary of xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome is presented in this excellent review article.)
Nance , MA, Berry , SA. “Cockayne syndrome: Review of 140 cases”. Am J Med Genet . vol. 42. 1992. pp. 68-84. (This review provides a summary of the important clinical features observed in a large cohort of CS patients.)
Ozdirim , E, Topcu , M, Ozon , A, Cila , A. “Cockayne syndrome: review of 25 cases”. Ped Neurol. vol. 15. 1996. pp. 312-316. A review of 25 cases of CS is presented detailing the common clinical and laboratory findings among these patients.
Rapin , I, Weidenheim , K, Lindenbaum , Y, Rosenbaum , P, Merchant , S, Krishna , S, Dickson , D. “Cockayne syndrome in adults: review with clinical and pathologic study of a new case”. J Child Neurol . vol. 21. 2006. pp. 991-1006. (The authors present an excellent review of CS with a detailed pathological discussion of the disease entity.)
Sonmez , FM, Celep , F, Ugur , SA, Tolun , A. “Severe form of Cockayne syndrome with varying clinical presentation and no photosensitivity in a family”. J Child Neurol . vol. 21. 2006. pp. 333-337. (The authors report six cases of CS Type B without photosensitivity as a clinical feature.)
Sordo , M, Zamora , E, Perez , L, Barrios , B. “Cockayne's syndrome: a case report. Literature review”. Med Oral Pathol Oral Cir Bucal. vol. 11. 2006. pp. E236-38. (A case report of CS is presented with a detailed discussion and review of the oral pathologies associated with the disease.)
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