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.