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Cockayne syndrome type A(CSA)

MedGen UID:
155488
Concept ID:
C0751039
Disease or Syndrome
Synonyms: Cockayne syndrome type 1; Cockayne syndrome type I; Cockayne syndrome classic form; Cockayne syndrome classical; CSA; ERCC8-Related Cockayne Syndrome
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): ERCC8 (5q12.1)
OMIM®: 216400
Orphanet: ORPHA90321

Disease characteristics

Excerpted from the GeneReview: Cockayne Syndrome
Cockayne syndrome (referred to as CS in this GeneReview) spans a phenotypic spectrum that includes: CS type I, the "classic" or "moderate" form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal syndrome (COFS) or Pena-Shokeir syndrome type II; CS type III, a milder form; Xeroderma pigmentosum-Cockayne syndrome (XP-CS). CS type I (moderate CS) is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II (severe CS or early-onset CS) is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age seven years. CS type III (mild CS or late-onset CS) is characterized by essentially normal growth and cognitive development or by late onset. Xeroderma pigmentosum-Cockayne syndrome (XP-CS) includes facial freckling and early skin cancers typical of XP and some features typical of CS, including intellectual disability, spasticity, short stature, and hypogonadism. XP-CS does not include skeletal involvement, the facial phenotype of CS, or CNS dysmyelination and calcifications. [from GeneReviews]
Authors:
Vincent Laugel   view full author information

Additional description

From OMIM
Cockayne syndrome is characterized by abnormal and slow growth and development that becomes evident within the first few years after birth. 'Cachectic dwarfism' describes the outward appearance of afflicted individuals. Other features include cutaneous photosensitivity, thin, dry hair, a progeroid appearance, progressive pigmentary retinopathy, sensorineural hearing loss, dental caries, and a characteristic stance in the ambulatory patient. Patients often show disproportionately long limbs with large hands and feet, and flexion contractures of joints are usual skeletal features. Knee contractures result in a 'horse-riding stance.' There is delayed neural development and severe progressive neurologic degeneration resulting in mental retardation. The mean age at death in reported cases is 12.5 years, although a few affected individuals have lived into their late teens or twenties. Remarkably, in striking contrast with xeroderma pigmentosum, patients with CS have no significant increase in skin cancer or infection (Nance and Berry, 1992). Lowry (1982) noted that there is an early-onset form of Cockayne syndrome in which patients may show abnormalities at birth and have a shorter survival. Lowry (1982) thus suggested that CS could be divided clinically into the more common type I, with classic CS symptoms that manifest within the first few years or life, and the less common type II, with more severe symptoms that manifest prenatally. Mallery et al. (1998) found no correlation between genotype and phenotype among 16 patients with CS of varying severities, and concluded that clinical differences were based on other genetic backgrounds or the intrauterine environment. Genetic Heterogeneity of Cockayne Syndrome Cockayne syndrome is a genetically heterogeneous disorder, and certain types show some overlap with certain forms of xeroderma pigmentosum (XP), another disorder caused by defective DNA repair. See also Cockayne syndrome B (133540), caused by mutation in the ERCC6 gene (609413) on chromosome 10q11; XPG/CS (see 278780), caused by mutation in the ERCC5 gene (133530) on chromosome 13q33; XPB/CS (see 610651), caused by mutation in the ERCC3 gene (133510) on chromosome 2q21; and XPF/CS (see 278760), caused by mutation in the ERCC4 gene (133520) on chromosome 16p13. Rapin et al. (2000) reviewed the clinical, pathologic, and molecular features of Cockayne syndrome, xeroderma pigmentosum, and the XP-CS complex.  http://www.omim.org/entry/216400

Clinical features

Anhidrosis
MedGen UID:
1550
Concept ID:
C0003028
Disease or Syndrome
Inability to sweat.
Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
A disorder in which there is abnormal electrical activity in the heart.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from CRANIAL NERVE DISEASES; NEUROMUSCULAR DISEASES; CEREBELLAR DISEASES; BASAL GANGLIA DISEASES; BRAIN STEM diseases; or diseases of the corticobulbar tracts (see PYRAMIDAL TRACTS). The cortical language centers are intact in this condition. (From Adams et al., Principles of Neurology, 6th ed, p489)
Intrauterine growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Sensorineural hearing loss
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Normal pressure hydrocephalus
MedGen UID:
42526
Concept ID:
C0020258
Disease or Syndrome
A form of compensated hydrocephalus characterized clinically by a slowly progressive gait disorder (see GAIT DISORDERS, NEUROLOGIC), progressive intellectual decline, and URINARY INCONTINENCE. Spinal fluid pressure tends to be in the high normal range. This condition may result from processes which interfere with the absorption of CSF including SUBARACHNOID HEMORRHAGE, chronic MENINGITIS, and other conditions. (From Adams et al., Principles of Neurology, 6th ed, pp631-3)
Hypermetropia
MedGen UID:
43780
Concept ID:
C0020490
Disease or Syndrome
A refractive error in which rays of light entering the eye parallel to the optic axis are brought to a focus behind the retina, as a result of the eyeball being too short from front to back. It is also called farsightedness because the near point is more distant than it is in emmetropia with an equal amplitude of accommodation. (Dorland, 27th ed)
Hypertension
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
Blood pressure that is abnormally high.
Hypogonadism
MedGen UID:
5711
Concept ID:
C0020619
Disease or Syndrome
A decreased functionality of the gonad.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Abnormally increased curvature of the thoracic portion of the spine.
Dental malocclusion
MedGen UID:
9869
Concept ID:
C0024636
Anatomical Abnormality
An inherited or acquired dental abnormality characterized by improper alignment of the teeth.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Retinitis pigmentosa
MedGen UID:
20551
Concept ID:
C0035334
Disease or Syndrome
Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited ocular diseases that result in a progressive retinal degeneration affecting 1 in 3,000 to 5,000 people (Veltel et al., 2008). Symptoms include night blindness, the development of tunnel vision, and slowly progressive decreased central vision starting at approximately 20 years of age. Upon examination, patients have decreased visual acuity, constricted visual fields, dyschromatopsia (tritanopic; see 190900), and the classic fundus appearance with dark pigmentary clumps in the midperiphery and perivenous areas ('bone spicules'), attenuated retinal vessels, cystoid macular edema, fine pigmented vitreous cells, and waxy optic disc pallor. RP is associated with posterior subcapsular cataracts in 39 to 72% of patients, high myopia, astigmatism, keratoconus, and mild hearing loss in 30% of patients (excluding patients with Usher syndrome; see 276900). Fifty percent of female carriers of X-linked RP have a golden reflex in the posterior pole (summary by Kaiser et al., 2004). Juvenile Retinitis Pigmentosa Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (see 204000), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). Autosomal recessive forms of juvenile retinitis pigmentosa can be caused by mutation in the SPATA7 (609868), LRAT (604863), and TULP1 (602280) genes (see LCA3, 604232, LCA14, 613341, and LCA15, 613843, respectively). An autosomal dominant form of juvenile retinitis pigmentosa (see 604393) is caused by mutation in the AIPL1 gene (604392).
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal enlargement of the spleen.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
Misalignment of the visual axes of the eyes. In comitant strabismus the degree of ocular misalignment does not vary with the direction of gaze. In noncomitant strabismus the degree of misalignment varies depending on direction of gaze or which eye is fixating on the target. (Miller, Walsh & Hoyt's Clinical Neuro-Ophthalmology, 4th ed, p641)
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Acquired Abnormality
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
A reduction in the strength of one or more muscles.
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Polyneuropathy
MedGen UID:
57502
Concept ID:
C0152025
Disease or Syndrome
A disease or disorder affecting more than one nerve.
Menstrual irregularities
MedGen UID:
56379
Concept ID:
C0156404
Finding
Deviations from the normal process; e.g. delayed, difficult, profuse, scanty, unusual bleeding, etc.
Hypoplasia of teeth
MedGen UID:
852449
Concept ID:
C0235357
Congenital Abnormality
Developmental hypoplasia of teeth.
Decreased lacrimation
MedGen UID:
116004
Concept ID:
C0235857
Finding
Abnormally decreased lacrimation, that is, reduced ability to produce tears.
Brain atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Micropenis
MedGen UID:
78603
Concept ID:
C0266435
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Dry hair
MedGen UID:
75809
Concept ID:
C0277960
Finding
Hair that lacks the lustre (shine or gleam) of normal hair.
Cutaneous photosensitivity
MedGen UID:
87601
Concept ID:
C0349506
Pathologic Function
An increased sensitivity of the skin to light. Photosensitivity may result in a rash upon exposure to the sun (which is known as photodermatosis). Photosensitivity can be diagnosed by phototests in which light is shone on small areas of skin.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Opacification of the corneal stroma
MedGen UID:
602191
Concept ID:
C0423250
Finding
Reduced transparency of the stroma of cornea.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Abnormality of visual evoked potentials
MedGen UID:
105509
Concept ID:
C0522214
Finding
An anomaly of visually evoked potentials (VEP), which are electrical potentials, initiated by brief visual stimuli, which are recorded from the scalp overlying the visual cortex.
Abnormal auditory evoked potentials
MedGen UID:
141758
Concept ID:
C0522216
Finding
An abnormality of the auditory evoked potentials, which are used to trace the signal generated by a sound, from the cochlear nerve, through the lateral lemniscus, to the medial geniculate nucleus, and to the cortex.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
A finding referring to walking difficulties.
Abnormality of the pinna
MedGen UID:
167800
Concept ID:
C0857379
Finding
An abnormality of the pinna, which is also referred to as the auricle or external ear.
Abnormality of skin pigmentation
MedGen UID:
224697
Concept ID:
C1260926
Finding
An abnormality in the formation or distribution of pigment in the skin, hair or nails.
Basal ganglia calcification
MedGen UID:
234651
Concept ID:
C1389280
Pathologic Function
The presence of calcium deposition affecting one or more structures of the basal ganglia.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Loss of facial adipose tissue
MedGen UID:
325251
Concept ID:
C1837767
Finding
Loss of normal subcutaneous fat tissue in the face.
Sparse hair
MedGen UID:
332942
Concept ID:
C1837770
Finding
Reduced density of hairs.
Delayed eruption of primary teeth
MedGen UID:
341477
Concept ID:
C1849538
Finding
Delayed tooth eruption affecting the primary dentition.
Square pelvis bone
MedGen UID:
337928
Concept ID:
C1849953
Anatomical Abnormality
An abnormally squared appearance of the bony pelvis, a normally rounded or basin-shaped structure.
Limitation of joint mobility
MedGen UID:
341696
Concept ID:
C1857108
Finding
A reduction in the freedom of movement of one or more joints.
Patchy demyelination of subcortical white matter
MedGen UID:
341813
Concept ID:
C1857638
Finding
Patchy loss of myelin from nerve fibers in the central nervous system.
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Severe postnatal growth retardation
MedGen UID:
347510
Concept ID:
C1857641
Finding
Severely slow or limited growth after birth, being four standard deviations or more below age- and sex-related norms.
Retinal pigment epithelial mottling
MedGen UID:
347513
Concept ID:
C1857644
Finding
Mottling (Spots or blotches with different shades) of the retinal pigment epithelium.
Slender nose
MedGen UID:
347514
Concept ID:
C1857645
Finding
Ivory epiphyses of the phalanges of the hand
MedGen UID:
346631
Concept ID:
C1857651
Finding
Sclerosis of the epiphyses of the phalanges of the fingers, leading to an increased degree of radiopacity (white or ivory appearance) in X-rays.
Thymic hormone decreased
MedGen UID:
341815
Concept ID:
C1857652
Finding
Reduced subcutaneous adipose tissue
MedGen UID:
387876
Concept ID:
C1857657
Finding
A reduced amount of fat tissue in the lowest layer of the integument. This feature can be appreciated by a reduced skinfold thickness.
Increased cellular sensitivity to UV light
MedGen UID:
346648
Concept ID:
C1857707
Finding
Progeroid facial appearance
MedGen UID:
341830
Concept ID:
C1857710
Finding
A degree of wrinkling of the facial skin that is more than expected for the age of the individual, leading to a prematurely aged appearance.
Thickened calvaria
MedGen UID:
346823
Concept ID:
C1858452
Finding
The presence of an abnormally thick calvaria.
Hypoplastic iliac wing
MedGen UID:
351279
Concept ID:
C1865027
Anatomical Abnormality
Underdevelopment of the ilium ala.
Hypoplastic pelvis
MedGen UID:
760700
Concept ID:
C3536734
Anatomical Abnormality
Underdevelopment of the bony pelvis.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Atypical scarring of skin
MedGen UID:
867415
Concept ID:
C4021786
Pathologic Function
Atypically scarred skin .
Peripheral dysmyelination
MedGen UID:
871139
Concept ID:
C4025610
Finding
Defective structure and function of myelin sheaths. Dysmyelination is distinguished from demyleination where there is destruction or damage of previously normal myelination.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Cockayne syndrome type A in Orphanet.

Recent clinical studies

Etiology

Conte C, D'Apice MR, Botta A, Sangiuolo F, Novelli G
Genet Test Mol Biomarkers 2009 Feb;13(1):127-31. doi: 10.1089/gtmb.2008.0092. PMID: 19309286
Ridley AJ, Colley J, Wynford-Thomas D, Jones CJ
J Hum Genet 2005;50(3):151-4. Epub 2005 Mar 3 doi: 10.1007/s10038-004-0228-2. PMID: 15744458
Cao H, Williams C, Carter M, Hegele RA
J Hum Genet 2004;49(1):61-3. Epub 2003 Dec 6 doi: 10.1007/s10038-003-0107-2. PMID: 14661080

Diagnosis

Ben Chehida A, Ghali N, Ben Abdelaziz R, Ben Moussa F, Tebib N
Iran J Kidney Dis 2017 May;11(3):253-255. PMID: 28575888
Conte C, D'Apice MR, Botta A, Sangiuolo F, Novelli G
Genet Test Mol Biomarkers 2009 Feb;13(1):127-31. doi: 10.1089/gtmb.2008.0092. PMID: 19309286

Prognosis

Ben Chehida A, Ghali N, Ben Abdelaziz R, Ben Moussa F, Tebib N
Iran J Kidney Dis 2017 May;11(3):253-255. PMID: 28575888

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