# 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.