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Coffin-Lowry syndrome (CLS) is a rare genetic disorder characterized by intellectual disability; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature; and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears, and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by changes (mutations) in the RPS6KA3 gene and is inherited in an X-linked dominant pattern. Males are usually more severely affected than females.
The symptoms of Coffin-Lowry syndrome tend to be more severe in males, although symptoms in affected females can range from none to the same severity seen in males. The characteristic facial features seen in affected males become more easily identifiable in late childhood and adulthood. The face is characterized by a prominent forehead and eyebrows, narrowing of both temples, scarce hair on the scalp, thickened eyebrow ridges, downslanting eyelid slits, wide-set eyes, thickened upper eyelids, a broad nasal bridge with a thick dividing cartilage (septum), thick prominent lips, an open mouth, prominent chin and ears.
Limb abnormalities may include large soft hands with double-jointed thick fingers that taper toward the tips, an unusual prominent transverse crease (hypothenar) and a shortened big toe. In males, the skin is loose and may stretch easily. Many bone abnormalities may also occur such as thickening of facial bones, shortening of the long bones, and pointed or sunken breast bone. Abnormal front-to-back and side-to-side curvature of the spine may also be present (kyphosis and scoliosis) and progresses with age. Affected individuals usually have short stature. A smaller than average head size (microcephaly) and dental abnormalities are common. Hearing loss is sometimes associated with Coffin-Lowry syndrome. In rare cases, vision loss may occur. Heart problems may be present and can be life threatening.
Affected males may have severe to profound intellectual disability. Intelligence in affected females ranges from normal to profound intellectual disability. Severely affected children may have no speech development.
Some affected individuals experience episodes of brief collapse without loss of consciousness (drop attacks) that occur following an unexpected noise or emotional event.
Coffin-Lowry syndrome is caused by changes (mutations) in the RPS6KA3 gene on the X chromosome. Some individuals with Coffin-Lowry syndrome do not have a detectable mutation in the RPS6KA3 gene.
Coffin-Lowry syndrome is inherited in an X-linked dominant pattern. About 70-80% of those affected have no family history of the condition. Males with a RPS6KA3 gene mutation will be affected with Coffin-Lowry syndrome and females with a RPS6KA32 gene mutation have a high risk for developmental delay and mild physical symptoms of the disease.
Coffin-Lowry syndrome affects as many males as females. However, symptoms may be more severe in males.
X-ray and neuroimaging studies may be helpful in confirming a diagnosis of Coffin-Lowry syndrome. Decreased ribosomal S6 kinase activity in cultured fibroblast or transformed lymphoblast cells from a male indicates Coffin-Lowry syndrome. Studies of enzyme activity cannot be used to diagnose an affected female.
Molecular genetic testing on a blood specimen or cells from a cheek swab is available to identify mutations in the RPS6KA3 gene. This testing can be used to confirm but not rule out the diagnosis of Coffin-Lowry syndrome because not all affected individuals have a detectable mutation.
Treatment
Treatment for Coffin-Lowry syndrome is symptomatic and supportive. Affected individuals should have regular cardiac, hearing and visual examinations. Patients should be monitored for progressive kyphoscoliosis which can be life threatening if the cardiorespiratory system becomes compromised. Antiepileptic medications such as clonazepam may be used to treat drop attacks.
Genetic counseling is recommended for families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Harum KH and Johnson MV. Coffin-Lowry syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:171-172.
JOURNAL ARTICLES
Delaunoy JP, Abidi F, Zeniou M, et al. Mutations in the X-linked RSK2 gene (RPS6KA3) in patients with Coffin-Lowry syndrome. Hum Mutat 2001;17:103-116.
Gilgenkrantz S, Mujica P, Gruet P, et al. Coffin-Lowry syndrome: a multicenter study. Clin Genet 1988;34:230-245.
Stevenson RE, Schwartz CE, Schroer RJ. X-linked mental retardation. New York: Oxford University Press, 2000.
Hanauer A, Young ID. Coffin-Lowry syndrome: clinical and molecular features. J Med Genet. 2002;39:705-13.
Bird H, et al. Crossover analysis in a British family suggests that Coffin-Lowry syndrome maps to a 3.4-cM interval in Xp22. Am J Med Genet. 1995;59:512-6.
Trivier E, et al. Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature. 1996;384:567-70.
Biancalana V, et al. Confirmation and refinement of the genetic localization of the Coffin-Lowry syndrome locus in Xp22.1-p22.2. Am J Med Genet. 1992;50:981-7.
Vles JS, et al. Early clinical signs in Coffin-Lowry syndrome. Clin Genet. 1984;26:448-52.
Hersh JH, et al. Forearm fullness in Coffin-Lowry syndrome: a misleading yet possible early diagnostic clue. Am J Med Genet. 1984;18:195-9.
Wilson WG, et al. Brief clinical report: early recognition of the Coffin-Lowry syndrome. Am J Med Genet. 1981;8:215-20.
INTERNET
Rogers RC, Abidi FE. Coffin-Lowry Syndrome. 2002 Jul 16 [Updated 2018 Feb 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1346/ Accessed Dec 2, 2019.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:303600; Last Update: 11/11/2019. https://omim.org/entry/303600. Accessed Dec 2, 2019.
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