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Cockayne Syndrome

Weber-Cockayne Syndrome

Cockayne syndrome is a rare autosomal recessive multisystem condition characterized by dwarfism, birdlike facies, premature aging, photosensitivity, progressive neurological dysfunction and intellectual deficit.


Presentation

Patients who have the Cockayne Syndrome show the following [4]:

Poor feeding

This is seen during infancy but in many cases, the diagnosis is not made at this point.

Photosensitive rashes

More than 75% of individuals with this condition exhibit photosensitivity. Other skin related findings include thin dry hair, dry scaly skin and decreased amount of subcutaneous tissue.

Cataracts

Severe form of CS I is what brings about the presence of cataracts in children who are younger than 3 years of age. This shows a poorer prognosis and in many cases it leads to early death.

General delay in psychomotor development

All individuals with category I Cockayne Syndrome exhibit mental retardation. This delay in psychomotor development becomes very visible around the age when speech and walking are expected to start developing.

Others

Generally, growth failure including progressive microcephaly is visible in most patients of the Cockayne type I within the first year.

According to neurologic examination patients show abnormal gait coupled with increased or decreased muscle tone and reflexes [5]. The abnormal gait is due to contractures of the ankles, knees and hips as well as leg spasticity and ataxia.

Another important characteristic of this disorder is pigmentary degeneration of the retina. Optic disk pallor and optic atrophy is also frequent. The changes in ophthalmology are often progressive.

Sensorineural hearing loss is present in more than 50% of patients with this condition. Dental caries is equally common as the root in permanent teeth of patients is often short [6]. Photodermatitis which leads to dry scaly skin is seen in most patients. The aged appearance is as a result of this disease process.

In some patients, there is decreased creatinine clearance but this rarely requires medical treatment. Structural irregularities in the renal system are not regularly reported. Testicular hypoplasia or cryptorchidism affects more than 30% of male patients [7]. Females menstruate but the cycles are not regular. Puberty is delayed in both sexes in certain cases.

Pediatric Disorder
  • As with other pediatric disorders, transition to adult services is problematic, not least because adults with CS are small, and many adult services are ill-equipped to manage patients of this stature.[nature.com]
Multiple Congenital Anomalies
  • A frequent multiple congenital anomaly/mental retardation syndrome of unknown etiology which affects 1/10,000 newborn infants.[icd10data.com]
Dental Caries
  • Criteria required for the diagnosis include poor growth and neurologic abnormality; other very common manifestations include sensorineural hearing loss, cataracts, pigmentary retinopathy, cutaneous photosensitivity, and dental caries.[ncbi.nlm.nih.gov]
  • Dental caries was associated with enamel defects, a high sugar/carbohydrate soft food diet, poor oral hygiene and dry mouth. Cephalometric analysis revealed mid-face hypoplasia, a small retroposed mandible and hypo-development of the skull.[ncbi.nlm.nih.gov]
  • Clinical features include failure to thrive, neurodevelopmental delay, cutaneous photosensitivity, pigmentary retinopathy, sensorineural hearing loss , dental caries , and cachectic dwarfism.[radiopaedia.org]
  • caries Bloom syndrome (p. 234) Roth m u nd Thomson syndrome (p. 238) Hartnup syndrome (p. 250) XP (p. 174) Progeria (p. 156) DNA analysis Blood serum UV irradiated cells with decreased DNA, RNA synthesis Brain computed tomography (CT) calcifications;[cram.com]
  • Dental caries is equally common as the root in permanent teeth of patients is often short. Photodermatitis which leads to dry scaly skin is seen in most patients. The aged appearance is as a result of this disease process.[symptoma.com]
Prognathism
  • Neurodevelopmental delay (progressive) · Mental deficiency (progressive) · Unsteady gait · Sunburns easily · Retinopathy and/or cataracts (progressive) · Hearing loss (progressive) · Dental caries · Typical facial appearance: Pinched facies Sunken eyes Beaked nose Prognathism[cockayne-syndrome.net]
Hepatomegaly
  • It also showed hepatomegaly and altered vertebral bodies. The ribs and clavicles were thinned with sclerosis at the margins. These images are characteristic of Cockayne syndrome. Figure 4. Right reticulo-nodular infiltrate and left atelectasis.[elsevier.es]
Dry Eyes
  • Dry eyes affect vision acuity. Hearing problems are common. These problems are caused by neurons that progressively deteriorate. This hearing deterioration is the same as occurs with normal aging.[mentalhelp.net]
  • They may also have cataracts, feeding difficulties in infancy, failure to thrive, hearing loss, cavities, and dry eyes. All of these problems are common in CS.[forgottendiseases.org]
Hyperpigmentation
  • […] patient hypersensitive to UV and leads to progressive neurodegeneration; overlap of XPB, XPD, XPG with Cockayne exists in small number of patients Skin Photosensitive eruption with erythema and scale in "butterfly" distribution on face may resolve with hyperpigmentation[cram.com]
  • Hyperpigmentation, varicose or spider veins ( telangiectasia ), [13] and serious sensitivity to sunlight are common, even in individuals without XP-CS. Often patients with Cockayne Syndrome will severely burn or blister with very little exposure.[en.wikipedia.org]
  • Thinning hair and skin hyperpigmentation have been noted in previous reports and are present in 46 and 29% of our cohort, respectively, but they have no clinical significance. There is no evidence to support routine dermatology input in CS.[nature.com]
Small Head
  • Cockayne syndrome (CS) is a rare disorder, characterised by small stature, microcephaly (having a small head) , developmental delay and premature pathological ageing.[amyandfriends.org]
  • The deep-set eyes and small head (microcephaly) are two common physical characteristic of children with CS. Knox was with us for 42 months, 2 weeks, and 4 days. He was born on July 14, 2010, and passed away on February 1, 2014.[bluepurpleandscarlett.com]
  • Their appearance of dwarfism with small head and prominent beaked nose strongly resembled that seen in the Seckel syndrome, but unlike patients with that syndrome they had a normal birth weight (for twins), thick cranial vaults, intracranial calcification[onlinelibrary.wiley.com]
Skeletal Dysplasia
Tremor
  • Status of tremors, ability to perform daily tasks, serial physical examinations, and results of handwriting samples. All 3 patients had a clear reduction in tremors and improvements in handwriting and manipulation of utensils and cups.[ncbi.nlm.nih.gov]
  • Other clinical problems in CS include hearing loss (of any type, but affecting both ears), cataracts, visual impairment due to retinal degeneration, tremor, walking and balance problems (ataxia), joint contractures, progressive loss of body fat and abnormal[amyandfriends.org]
  • It consists of: Treatment of specific signs and symptoms: Physiotherapy to loosen joints, correct posture defects, and keep muscles supple Medication to relax spastic muscles, and treat tremors Special education for learning difficulties Prevention of[news-medical.net]
Abnormal Gait
  • According to neurologic examination patients show abnormal gait coupled with increased or decreased muscle tone and reflexes. The abnormal gait is due to contractures of the ankles, knees and hips as well as leg spasticity and ataxia.[symptoma.com]

Workup

In situations where patients are suspected to have CS, the first step taken by professionals is to establish baseline renal function and deal with possibility of other conditions with the help of routine laboratory tests [8].

Chromosome analysis is the next step taken so as to remove karyotypic abnormalities associated with growth failure. Chromosome breakage studies may come in if Bloom Syndrome is considered in the differential diagnosis [9]. These studies coupled with mutation analysis are very important so as to remove the possibility of Bloom Syndrome or isolated xeroderma pigmentosum.

CT Scan and MRI scans can equally be used to search for white matter irregularities, cerebral atrophy, increased ventricular size and normal pressure hydrocephaly. Radiographs of the skeleton will also show vertebral body and pelvic abnormalities.

Other tests carried out include audiometry to determine sensorineural hearing loss, electroencephalography to look through any seizure activities and electroretinography to see if there are abnormalities in the electric potential of the retina.

Seizure Activity
  • Other tests carried out include audiometry to determine sensorineural hearing loss, electroencephalography to look through any seizure activities and electroretinography to see if there are abnormalities in the electric potential of the retina.[symptoma.com]

Treatment

Medical care is purely supportive and includes physiotherapy, photoprotection with sunscreens and clothing and hearing aids.

Prognosis

Cockayne syndrome is an autosomal recessive ailment which leads to neurologic dysfunction and growth failure. Patients with this condition die within the adolescent years but it is possible to survive deep into adulthood.

Etiology

Genetically, the Cockayne Syndrome and subtypes is classified as follows:

Type Gene
I ERCC8
II ERCC6
III not known

Cockayne Syndrome is caused by the mutations in the ERCC6 and ERCC8 genes [2]. These genes aid the repair of damaged DNA using the proteins they make, through the transcription-coupled repair mechanism. When the ERCC8 or ERCC6 gene is altered, DNA damage is not repaired. The accumulation of this damage is what results in the malfunctioning of cells and death of the cells.

Epidemiology

According to the office of rare diseases, the Cockayne Syndrome is a rare condition. This means that less than 2 in 100,000 people have any of the CS subtypes. The CS I is panethnic and since the condition is an autosomal recessive disorder, the male to female ratio is 1:1.

Since it is a progressive congenital disorder, clinical symptoms rarely surface until late infancy or early childhood.

Sex distribution
Age distribution

Pathophysiology

With all types of Cockayne Syndrome, aging prematurely is a cardinal feature [3]. The abnormality in growth and development become visible within the first two years of life. When the disease is at its peak, the head circumference, weight and height of the individual will be far below the fifth percentile.

The aging process is illustrated by bent standing posture, sunken eyes, thinning of the hair and skin and all the usual physical appearance of cachectic dwarfism. Additionally, there is an extensive and diffuse demyelination in both the central and peripheral nervous systems. 

Basal ganglia and precapillary calcifications are visible at a very age. Acute neuronal loss in the cerebellum and cerebral cortex is also present. All of these are consistent with the physiological changes associated with aging.

Prevention

There are no guidelines for prevention of Cockayne syndrome.

Summary

Cockayne Syndrome is a congenital autosomal recessive condition that has been categorized as rare. The common characteristics of this condition are stunted growth, under development of the nervous system, photosensitivity (abnormal sunlight sensitivity), progeria (fast paced aging) and early death [1].

The symptoms vary greatly in patients depending on the age at which the first signs appear. CS is part of a group referred to as the “leukodystrophies”. These are conditions which are characterised by the degeneration of white matter.

The disorder is basically a defect in the repair mechanism of DNA.
A couple known to be carriers of a single CS gene mutation has a 25% possibility of giving birth to a child with the Cockayne Syndrome condition. A child can only be affected by the condition if he inherits a mutation in a particular CS gene from the parents (both).

Since the symptoms of the Cockayne Syndrome vary significantly, the range of severity has been established by dividing the condition into three distinct types. They are as follows:

CS I

With this type of CS, the patient shows usual prenatal growth but at around one year of age, the developmental abnormalities begin to surface. Individuals with this CS type have an average lifespan of 10 to 20 years.

CS II

This CS type is known by the abnormalities and growth failure which begin at birth. Postnatal neurological development is poor and in many cases, absent. Individuals with this CS type have an average lifespan of 7 years.

CS III

This CS type sets in later than the previous two. It shows fewer symptoms and there is a slower rate of progression. There is no agreed average lifespan for people with this CS type but some patients live up to 50 years.

In some cases, the patient has a combination of Cockayne Syndrome and Xeroderma Pigmentosium. This is denoted by a variety of changes to the skin. Areas of skin exposed to sunlight may show mild freckling and in more severe cases, skin cancer.

Patient Information

Parents of the patient need to understand that treatment is symptoms-based and supportive. The neurologic and neurosensory abilities of the patient must be optimised in line with medical directions [10]. Such parents must also undergo genetic counselling as having one CS child means that there is a 25% chance of giving birth to another child with the condition.

The individual suffering from Cockayne syndrome must be made to understand the importance of protecting himself from sunlight with sunscreen and commensurate clothing so as to reduce cell damage.

References

Article

  1. Deschavanne P J, Diatloff-Zito C, Macieira-Coelho A, Malaise EP. Unusual sensitivity of two Cockayne's syndrome cell strains to both UV and gamma irradiation. Mutat. Res. 91: 403-406, 1981.
  2. Fujimoto WY, Greene M L, Seegmiller JE. Cockayne's syndrome: report of a case with hyperlipoproteinemia, hyperinsulinemia, renal disease, and normal growth hormone. J. Pediat. 75: 881-884, 1969.
  3. Hoeijmakers JH. DNA damage, aging, and cancer. N. Engl. J. Med. 2009 361 (15): 1475–85. doi:10.1056/NEJMra0804615
  4. Online 'Mendelian Inheritance in Man' (OMIM) Cerebrooculofacioskeletal Syndrome 1; COFS1 -214150
  5. Kleijer WJ, Laugel V, Berneburg M, Nardo T, Fawcett H, Gratchev A, Jaspers NG, Sarasin A, Stefanini M, Lehmann AR. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair (Amst). 2008 May 3;7(5):744-50.
  6. Weidenheim KM, Dickson DW, Rapin I. Neuropathology of Cockayne syndrome: Evidence for impaired development, premature aging, and neurodegeneration. Mech Ageing Dev. 2009 Sep;130(9):619-36.
  7. Khayat M, Hardouf H, Zlotogora J, Shalev SA. High carriers frequency of an apparently ancient founder mutation p.Tyr322X in the ERCC8 gene responsible for Cockayne syndrome among Christian Arabs in Northern Israel. Am J Med Genet A. Dec 2010;152A(12):3091.
  8. Laugel V, Dalloz C, Durand M, et al. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Hum Mutat. Nov 5 2009.
  9. Zhang H, Gao J, Ye J, Gong Z, Gu X. Maternal origin of a de novo microdeletion spanning the ERCC6 gene in a classic form of the Cockayne syndrome. Eur J Med Genet. Jul-Aug 2011;54(4):e389-93.
  10. Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. Sep 2004;114(3):889-94.

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Last updated: 2018-06-22 06:40