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
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Notes

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