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