Forgotten Diseases Research Foundation

Cockayne syndrome (CS)


CS is a member of a group of diseases called DNA repair disorders. Patients with these diseases have mutations in genes that repair damaged DNA and/or are involved in DNA transcription. DNA is constantly damaged by many different agents, including ultraviolet light from the sun and other sources (e.g. flourescent lighhts), ionizing radiation from the cosmos and other sources, chemicals, internal mechanisms in cells, etc. Living things have evolved many systems that fix this damage. For example, there are proteins that recognize that DNA is damaged, enzymes that remove damaged DNA, enzymes that unzip a strand of DNA so that their molecules can get into it and repair damage, and enzymes that insert new lengths of undamaged DNA. This list is not exhaustive. Patients with DNA repair disorders have defects in these repair systems, and any of the molecules mentioned above may be defective. The result is inability or reduced ability to repair DNA. This situation greatly increases the risk of cancer.

CS is a member of a DNA repair disorder subgroup in which repair of UV-induced damage is defective. CS patients can be very prone to sunburn as a result, although not all patients have this problem. They also have a variety of medical problems that affect many systems in their bodies. CS is a progressive disorder, which means that it gets worse with time. Unlike most patients with UV-DNA repair disorders, most CS patients are not at increased risk of cancer. This fact may be due to the severity of CS.

Clinical information

Signs and symptoms

Cockayne syndrome is an extremely rare disorder that affects many body systems. Its incidence in four countries in Western Europe (France, Italy, UK, Netherlands) is estimated at 2.7 per million births in the overall population, and 1.8 per million births among indigenous Europeans (1). In Japan, incidence is 2.8 per million births (Kubota). Estimates have not been made for other countries, but the figures are likely the same, with the exception of individual areas and groups where incidence is higher (e.g., among certain aboriginal Canadians and in Saudi Arabia).

CS is present at birth, although it may not be fully evident until 1-2 years of age in mildly affected patients. In many moderate or mild patients, the first sign of the syndrome may be photosensitivity (ranging from mild to severe), or unusually tight joints caregivers may notice that the hips are stiff when changing diapers). Severely affected patients may be born with cataracts and other medical problems that make the presence of the syndrome more obvious. Feeding difficulties are also very common in CS patients, although these problems tend to be less severe in very mild cases of the disease. In severely affected patients, tube feeding has been credited by many parents as extending life. CS patients commonly have the following problems:

    Common problems in CS

  •  Brain abnormalities on CT or MRI scans (calcifications, white matter abnormalities, atrophy)
  •  Gait ataxia (a stiff, unbalanced gait) in those who can walk; nay walk on toes
  •  Intellectual disability (ranges from mild to profound)
  •  Delayed development of fine and gross motor skills
  •  Hearing loss, which can happen suddenly
  •  Pigmentary abnormalities in the retina
  •  Photosensitivity (easy sunburning)
  •  Abnormal curvature of the spine
  •  Microcephaly (very small head)
  •  Very short stature/dwarfism
  •  Many dental cavities
  •  Peripheral cyanosis
  •  High blood pressure
  •  A distinctive voice
  •  Joint contractures
  •  Hand tremors
  •  A happy, gentle, and/or outgoing personality

People with CS tend to have a similar facial appearance (see photos). The list below has features are often observed in this group. Note that some features may not be obvious in more mildly affected patients.

    Common facial features in CS

  •  Beaked nose (nose may have a bump that resemble a bird's beak)
  •  Receding jaw; typically in severely affected patients)
  •  Deep-set/sunken eyes (see photos on this page)
  •  Maloccluded/crowded teeth
  •  Small jaw
  •  Large ears

Severity groups

There are four primary severity groups in CS: severe, moderate, mild, and adult-onset. The syndrome may be thought of as occuring on a continuous scale, although most patients can be classified into a severity group relatively easily. In severely affected patients, the presence of a congenital disorder is generally present at birth. Severely affected CS patients are smaller: in a recent survey, the average height at age 6 years in severely affected patients was 79 cm, or 31", witha range of 75 - 87 cm (3). These children achieve relatively few milestones, and have very short life expectancy. They typically do not learn how to walk independently, with the most severely affected children also not developing an ability to sit independently. Severely affected children tend to have no speech or <10 words, although many be able to communicate to varying degrees via sign language.

Some patients with the severe form of CS have been diagnosed as having Cerebro-ocular facial syndrome (COFS). Many patients with COFS have mutations in the CSB gene (reviewed in reference 3), and COFS appears to be a very severe form of CS.

Feeding difficulties and failure to thrive are universal or near-universal in this group, with cachexia being a significant problem. Children with severe CS typically need feeding tubes. Parents note that the tubes can help with weight gain and ease the administration of medicines and vitamins (personal communications to the author of this article). It is important to note that children with severe CS are prone to weight loss in the event of gastrointestinal infections. Any CS patient with such an infection should be seen by a doctor quickly and monitored closely.

Moderately affected CS patients tend to live longer and be bigger than children in the severe group. For example, the average height at age 6 in the study referenced above was 99 cm (39"), with a range of 91 - 107 cm (3). At age 16, these patients averaged 104 cm (~41"), with a range of 91-107 cm. In general, members of this group also achieve more milestones, with independent walking and self-feeding being common in this group. Coginitively, moderately affected patients typically learn to speak, although a minority may not. Some moderately affected patients acquire enough language to combine words/speak in phrases.

Feeding difficulties and failure to thrive are also very common in this group, with cachexia also being a significant problem. Many moderately affected children eat by mouth for many years. Soft foods such as yoghurts are the easiest for them to eat, while foods with mixed textures (e.g. crunchy cereal in milk) may be problematic. Many of these children benefit from feeding tubes, which offer the advantages noted in the previous paragraph. As with severe CS, it is important to note that moderately affected children are prone to weight loss in the event of gastrointestinal infections. Any CS patient with such an infection should be seen by a doctor quickly and monitored closely.

Those with the mild form of CS tend to be larger than those in the moderate group. Average height at age 6 in the study noted above was 104 cm (~41"), with heights at age 16 averaging 128 cm (50.4"; range: 107 - 148 cm; 2). In addition to being larger, these individuals may not have failure to thrive, may learn to speak in sentences and may learn to read, write, swim, ski, or ride a bike. These patients have the longest life expectancy.

The adult-onset form of CS has only been documented in a single case in Japan (4).

The table below shows average life expectancy for the severe, moderate, and mold forms of CS.

Mean life expectancy

      Range

Severe

        5.1 years

0.6 - 11 years

Moderate

       15.9 years

11 - 22 years

Mild

       30.6 years 

22 - 47 years


CS is a progressive disorder, which means that it gets worse with time. Regardless of severity group, the course of the disease is the same in all affected individuals. Patients initially grow and gain skills, plateau, and then go through a period of decline during which skills are lost and medical problems increase. The length of each stage is correlated with severity. Growth and skill acquisition are shortest in the most severely affected, and longest in the most mildly affected, while skill loss is the most rapid in severe CS and slowest in mildly affected patients. Anxiety may develop as a result of skill loss. Hearing loss is a particularly common reason for the development of this problem. Cochlear implants have been transformative for some patients in that regard (3, 5).

Dysphagia (swallowing difficulties) can be a significant problem in declining CS patients. This problem can lead to aspiration of food, airway blockage, or aspiration pneumonia. It may be advisable to avoid firm chokable foods such as apples, etc. in patients with dysphagia. Soft foods such as yoghurts may be more easily tolerated, and feeding tubes may also be recommended by physicians.

Prenatal growth and birthweight in CS

CS has been described as involving post-natal growth failure, with prenatal growth in children in the moderate and mild groups being normal, and growth faltering after birth (6).

As part of a research project involving clinical aspects of CS, the Forgotten Diseases Research Foundation found that on average, children with CS weigh less at birth than their unaffected siblings. Data on birthweight and gestational age was obtained from parents who provided informed consent. Percentiles were determined by using data from two large studies of birthweight percentiles by gesational age (7, 8). One study was performed in the United States and lists birthweight percentiles for singletons by gestational age and sex (7). The other was performed in Australia and provides similar data for twins (7), and was used for a pair of twins (one CS, one non-CS).

The bar graphs below show average birthweight percentiles for 23 groups of siblings (25 CS patients and 32 unaffected siblings). Within families, birthweight percentiles for the unaffected siblings were higher than the percentiles for unaffected siblings. The data in the top graph show data for newborns in all severity groups. The lower graph shows data for moderately and mildly affected patients only (14 CS patients and 20 unaffected siblings). The average birthweight for gestational age was only slightly higher in the moderate/mild group, with the sibling average being almost identical to the average in the upper graph. Thus, the data implies that prenatal growth in CS may indeed be affected by the syndrome. The vast majority of infants in both groups were born at term, with one child in the unaffected siblings having been born before 37 completed weeks of gestation and one CS patient being born post-term (after 42 weeks completed gestation).




Above: Birthweight percentiles in newborns with CS and their unaffected siblings.
See text above for details.



Diagnosis, Testing, and Clinical Trials

Diagnosis

CS is confirmed by testing for mutations in the genes CSA/ERCC8 and CSB/ERCC6, and for XP-CS (see below), XPB, and XPD. The US National Institutes of Health maintains a list of laboratories that do testing (see link at right). If you are not a doctor and suspect that your child has CS, check with your family physician, who will compare your child's signs and symptoms with those known to occur in this syndrome. If your child's doctor isn't familiar with CS, the information sources on this page may help. Your doctor can obtain a sample from your child and send it to a testing center.

Clinical trials

Since 1999, the National Institutes of Health has been running a large study of people with TTD, Cockayne syndrome, and xeroderma pigmentosum. The study is called Examination of Clinical and Laboratory Abnormalities in Patients with Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy. The goal of the study is to document health problems occuring in people with these diseases in order to understand them as completely as possible. More information about the study, including contact information, is available at clinicaltrials.gov.

Differential Diagnosis

The differential diagnosis for CS includes XP-CS, which is effectively the same disease as CS, as strategies for management and outcomes are generally the same. The primary difference between the two is that XP-CS patients, because they have xeroderma pigmentosum in addition to CS, tend to have numerous solar lentigines on skin that has been exposed to the sun.

sensitivity to UV light, short stature, intellectual disabilities, and other problems that commonly occur in CS. The primary difference between the two is that TTD patients generally have dry, very brittle hair that has a tiger-tail pattern when viewed under polarizing microscopy. When a hair sample from a person with TTD is examined closely under a standard light microscope, a small number of individual strands generally have breaks that look like the ends of paintbrushes (see our TTD page for a photo). Hair from CS patients does not have this problem. Like CS and many other conditions, the severity of TTD ranges from mild to severe. Severely affected patients may be as small as CS patients, while mildly affected patients may grow to be several inches taller.

References

  1. 1. Kleijer WJ et al. (2008) Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair (Amst) 17(5):744-750. Abstract on PubMed.
  2. 2. Kubota M et al. (2015) Nationwide survey of Cockayne syndrome in Japan: Incidence, clinical course and prognosis. Pediatr Int 57(3):339-347. Full text from Forgotten Diseases.
  3. 3. Natale V (2011) A comprehensive description of severity groups in Cockayne syndrome. Am J Med Genet Part A 155A(5):1081-1095. Full text from Forgotten Diseases Research Foundation.
  4. 4. Hashimoto S et al. (2008) Adult-onset neurological degeneration in a patient with Cockayne syndrome and a null mutation in the CSB gene. J Invest Derm 128:1597-1599. Abstract on PubMed.
  5. 5. Morris DP et al. (2007) Cochlear implantation in Cockayne syndrome: our experience of two cases with different outcomes. Laryngoscope 117(5):939-43. Abstract on PubMed.
  6. 6. Laugel V (2000) Cockayne Syndrome Updated June 14, 2012. GeneReviews [Internet] Pagon RA et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2016. Full text.
  7. 7. Oken E et al. (2003) A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC Pediatr 3:6. doi:10.1186/1471-2431-3-6 Full text on PubMed.
  8. 8. Roberts CL et al. (1999) National birthweight percentiles by gestational age for twins born in Australia. J Paediatr Child Health 35(3):278-282. doi:10.1186/1471-2431-3-6. Abstract on PubMed.
  9. 9. Batra PS et al. (2008) Infantile onset of Cockayne syndrome in two siblings. Indian J Dermatol Venereol Leprol 74(1):65-67. Full text from publisher.
  10. 10. Ghaffar TYA et al. (2011) Cholestasis in patients with Cockayne syndrome and suggested modified criteria for clinical diagnosis. Orphanet J Rare Dis 6:13. Full text on PubMed.
  11. 11. Source: Mundaganur P (2012) A rare case of Cockayne syndrome-MRI features. J Clin Diagn Res 6(9):1582-1583. Full text on PubMed.

Above: A 7-year-old boy with CS from India. He was sensitive to sunlight and developmentally delayed. He also had brain calcifications and brain atrophy, optic nerve atrophy, retinal degeneration and hearing loss. Photograph from reference 9.


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Above: Three Egyptian CS patients. Photograph from reference 10.

Below: Brain imaging in CS, showing cerebral atrophy with prominence of ventricular
system and calcification of basal ganglia. Image from reference 10.


Page last modified on 10 May 2017.