Handbook of Genetic Counseling/Coffin-Lowry Syndrome

Coffin-Lowry Syndrome

Mode of Inheritance

• X-linked dominant

Chromosome Location

• Xp22.2-p22.1

Molecular Genetics

• 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

• 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

• 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

• 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

• • 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

• 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

• 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

• • • 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

• • 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

• Review session
• Answer final questions
• Give card

Notes

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