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Handbook of Genetic Counseling/Coffin-Lowry Syndrome

< Handbook of Genetic Counseling

Coffin-Lowry Syndrome

Mode of Inheritance

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  • X-linked dominant

Chromosome Location

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  • Xp22.2-p22.1

Molecular Genetics

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  • Coffin-Lowry gene is a growth factor regulated serine-threonine kinase (RPS6KA3 or RSK)
    • Kinase activation in a number of pathways
    • Plays a role in stimulation of the cell cycle between G0 and G1
    • Activates CREB (cAMP response element binding protein)
      • Involved in neuronal survival
      • Involved in conversion from short term to long term memory
    • Cells in patients with CLS have defective EGF stimulated phosphorylation of S6
  • There are normal variants/polymorphisms
  • Normal gene product: ribosomal protein S6 kinase alpha 3
    • Mutations in the RPS6KA3 give rise to CLS and XLMR

Penetrance

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  • In males with the disease-causing mutation: 100% will be affected
  • In females with the disease-causing mutation are carriers and are at high risk for developmental delay and mild physical signs of CLS

Incidence and Carrier Frequency

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  • No estimate of prevalence has been reported.
    • Estimate of A. Hunter et al., Children's Hospital Ontario: 1/40,000 to 1/50,000

Clinical Features

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  • Growth Failure
    • Prenatally, growth is normal
    • Postnatal growth failure occurs early
      • Males usually fall below 3rd percentile in height
      • Microcephaly can be seen, but not in all cases
  • Dental Anomalies are common
    • Small teeth
    • Malpositioning
    • Hypodontia
    • Delayed eruption
    • Premature loss
    • Palate is high
    • Retrognathia in young children is replaced by prognathia
  • Neuropsychiatric
    • Patients are generally happy and pleasant
    • Severe MR occurs which may inhibit detailed neurologic assessment
    • Neurologic findings:
      • Loss of strength and muscle mass
      • Both decreased and increased deep tendon reflexes
      • Sleep Apnea
      • Stroke
      • Progressive spasticity
      • Progressive paraplegia with loss of the ability to walk
        • Due to calcification of the ligamenta flava
        • And Congenital stenosis of the spinal canal
      • "Drop Attacks"
        • Affect 10-20% of patients
        • Unexpected tactile or auditory stimuli/excitement trigger EMG silence in the lower limbs
  • Results in a brief collapse, but no loss of consciousness
        • Frequency of attacks may cause the need for a wheelchair to prevent injury
    • Cardiovascular
      • ~14% of males and ~5% of females have cardiovascular disease
        • Abnormalities of the mitral, tricuspid, and aortic valves
        • Short chordae
        • Cardiomyopathy
        • Congestive heart failure
        • Dilatation of the aorta and pulmonary artery
      • Cardiac anomalies may contribute to premature death
    • Musculoskeletal
      • Progressive kyphoscoliosis
        • At least 47% of affected males have this (32% of females)
        • Respiratory compromise can happen due to this
    • Hearing and Vision
      • Some patients have been reported to have hearing loss (14/89 males and 1/22 females)
        • Clustering of hearing loss in families may occur
      • Significant vision problems are uncommon
        • Cataracts, retinal pigment atrophy, and optic atrophy have been reported
        • Incidence of chronic eyelid irritation may be increased
    • Miscellaneous Findings
      • Singles cases:
        • Rectal prolapse
        • Uterine Prolapse
        • Unilateral renal agenesis
        • Pyloric stenosis
        • Jejunal diverticuli
        • Colonic diverticuli
        • Popiteal ganglion
        • Anteriorly placed anus
        • Increased facial pigment
        • Enlarged trachea

Lifespan

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    • Mortality
      • Early mortality is increased in CLS
        • 13.5% of males/4.5% of females mean age of death 20.5 years
      • Complicating factors include:
        • Cardiac anomalies
        • Panacinar emphysema
        • Respiratory complications
        • Progressive Kyphoscoliosis
        • Seizure-associated aspiration

Testing

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  • Ribosomal S6 kinase enzyme assay
    • Performed on cultured fibroblasts or transformed lymphoblasts
    • Available on a clinical basis in males
    • Not as useful in females due to broad range of enzyme activity resulting from X-chromosome inactivation
  • Molecular Genetic Testing
    • Uses of testing
      • Confirmatory diagnostic testing
      • Carrier testing
      • Prenatal diagnosis
    • Test Methods
      • Mutation Scanning
        • SSCP analysis (followed by squencing of abnormal exons)
  • Available on a clinical basis
  • In CLS patients, mutations were identified in 34% who had a clinical diagnosis
  • A negative study does not rule out the diagnosis of CLS
      • Protein Truncation testing
        • ~60% of 71 mutations idenitifed caused protein truncation
        • Western blot then sequencing of variants
        • Performed on cultured lymphoblasts
        • Is available clinically for affected males
      • Linkage Analysis
        • For families in which direct testing has not identified a mutation
  • Assesses probability that at-risk individuals have inherited a familial mutation
        • Acurracy dependent on:
  • Accurracy of clinical diagnosis of CLS
  • Informativeness of genetic markers in the family
        • Samples are required from multiple family members to perform analysis
    • Laboratories offering clinical testing
      • Universite Louis Pasteur
Institut Genet Biologie Molec/Cellulaire Illkirch , France
Director: Pierre Chambon
Contact: Andre Hanauer, PhD
email: Email: andre@titus.u-strasbg.fr
phone: (+33) 3-88-65-34-00 fax: (+33) 3-88-65-32-46
Methodology: Direct DNA analysis, Linkage, Enzyme Assay, Protein Analysis
Additional Testing Provided: Prenatal diagnosis
    • Laboratories offering research testing
      • JC Self Research Institute
Center for Molecular Studies Greenwood, SC
Director: Charles Schwartz, MS, PhD
Contact: Cindy Skinner, RN
email: cindy@ggc.org
phone: (800) 939-1920 phone2: (864) 941-8115 fax: (864) 388-1707
Description of Research: Mutational analysis using SSCP or DHPLC, is done on all exons of RSK2 in males suspected to have CLS. Contact prior to sending samples.

Surveillance, Management, Treatment

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  • No specific therapy for CLS
  • Need for development of communication skills and self-care
  • Vision and hearing testing is appropriate
  • Cardiac studies should be done in childhood
    • Repeated every 5-10 years
  • Monitor for the development of progressive kyphoscoliosis
    • Intervention to prevent progression is appropriate
  • Should be suspicion for narrowing of spinal canal
    • Attention to gait
    • Bowel/bladder habits
    • Expression of pain
    • Focal neurological changes
    • Clonus
    • Abnormal tendon reflexes
    • Awareness of "drop attacks"
      • Allows early intervention to minimize occurrence of triggering stimuli
    • Trial of antiepileptic medication may be indicated
  • Significant social resources may be required to support women with CLS

Differential Diagnosis

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      • Borjeson-Fossman-Lehmann Syndrome (BFLS)
        • X-linked recessive disorder
        • Severe MR
        • Hand findings
        • Short anteverted nose with thick septum
        • Small nares
        • Kyphoscoliosis
      • Facial appearances similar to CLS:
        • Williams Syndrome
        • FG syndrome
        • X-linked alpha-thalassemia MR

Resources/Support

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    • NINDH Coffin-Lowry Information Page
http://www.ninds.nih.gov/health_and_medical/disorders/coffin_lowry.htm
      • Coffin-Lowry Syndrome Foundation
3045 255th Avenue SE
Sammamish, WA 98075
CLSFoundation@yahoo.com
http://clsf.info
Tel: 425-427-0939 (M-F after 6pm PST
      • National Organization for Rare Disorders (NORD)
P.O. Box 1968
(55 Kenosia Avenue)
Danbury, CT 06813-1968
orphan@rarediseases.org
http://www.rarediseases.org
Tel: 203-744-0100 Voice Mail 800-999-NORD (6673)
Fax: 203-798-2291
      • National Institute of Child Health and Human Development (NICHD)
National Institutes of Health
Bldg. 31, Rm. 2A32
Bethesda, MD 20892-2425
NICHDClearinghouse@mail.nih.gov
http://www.nichd.nih.gov
Tel: 301-496-5133 800-370-2943
      • National Institute of Mental Health (NIMH)
6001 Executive Blvd.
Rm. 8184, MSC 9663
Bethesda, MD 20892-9663
nimhinfo@nih.gov
http://www.nimh.nih.gov
Tel: 301-443-4513 TTY: 301-443-8431 Depression Info: 800-421-4211 Anxiety Info: 88-88-ANXIETY (269-4389) Panic Info: 888-64-PANIC (64-72642)
Fax: 301-443-4279
      • The Arc of the United States
1010 Wayne Avenue
Suite 650
Silver Spring, MD 20910
Info@thearc.org
http://www.thearc.org
Tel: 301-565-3842
Fax: 301-565-3843 or -5342
      • March of Dimes Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, NY 10605
askus@marchofdimes.org
http://www.marchofdimes.org
Tel: 914-428-7100 888-MODIMES (663-4637)
Fax: 914-428-8203

Conclusions

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  • Review session
  • Answer final questions
  • Give card

Notes

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The information in this outline was last updated in April 2003.

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