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Costello Syndrome

NORD is very grateful to Karen W. Gripp, MD, FAAP, FACMG, Chief, Division of Medical Genetics, A.I. duPont Hospital for Children, for assistance in the preparation of this report.

Synonyms of Costello Syndrome

  • faciocutaneoskeletal syndrome
  • FCS syndrome

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Costello syndrome is an extremely rare disorder that affects multiple organ systems of the body. This condition is characterized by growth delays after birth; short stature; extra loose skin on the neck, palms of the hands, fingers, and soles of the feet; noncancerous tumors (papillomata) around the face and anus; developmental delay and intellectual disability; and a characteristic facial appearance. Other physical features may include the development of dry hardened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis), abnormally deep creases on the palms and soles, and/or abnormally flexible joints of the fingers (hyperextensible). There is an increased incidence of congenital abnormalities of the heart and thickening of the heart muscle called a cardiomyopathy. Characteristic craniofacial features may include an abnormally large head (macrocephaly); course facial features; unusually thick lips; and/or abnormally wide nostrils (nares). Affected individuals have an increased lifetime risk to develop specific malignant tumors. Costello syndrome is an autosomal dominant genetic condition caused by mutations in the HRAS gene.

Symptoms

Infants with Costello syndrome typically have a normal or high birth weight, but exhibit poor sucking ability, have swallowing difficulties, and fail to grow and gain weight at the expected rate (failure to thrive). Growth delay after birth typically results in short stature during childhood and adulthood. Affected children may also have developmental delay or mild to moderate intellectual disability. In some cases, speech development and/or the ability to walk is significantly delayed. Children with Costello syndrome generally have warm, sociable personalities.

Individuals with Costello syndrome typically have loose skin (cutis laxa) on the neck, palms, fingers, and soles. The skin in these areas may lack elasticity and hang loosely; in addition, the skin may appear wrinkled and thickened. In some cases, certain areas of the skin may become unusually dark (hyperpigmentation). In addition, most patients with this disorder develop dry hardened patches of skin (hyperkeratosis) with unusually deep creases on the palms and soles. In some cases, affected individuals may also have skeletal abnormalities such as dislocated hips, abnormally flexible (hyperextensible) joints of the fingers, wrists bent toward the little finger (ulnar deviation) and/or unusual tightening of the fibrous cords on the back of the heels (Achilles tendon). Additional skeletal abnormalities include side-to-side curvature of the spine (scoliosis), front-to-back curvature of the spine (kyphosis), and reduced range of motion in the shoulder and elbows.

Children with Costello syndrome usually devlelop papillomata around the mouth and nostrils. Papillomata may develop as early as two years of age or at older ages. In some cases, these wart-like (verrucal) lesions may also be found near the anus. Papillomata usually become more apparent with age. Other benign tumors have also been reported.

Children with Costello syndrome have a distinctive facial appearance. Characteristic facial features may include an abnormally large head (macrocephaly); low-set ears with large, thick lobes; unusually thick lips; a large, depressed nasal bridge; abnormally wide nostrils (nares); and a coarse facial appearance. In addition, affected children may have unusually curly hair and/or sparse, thin hair on the front (anterior) of the head. Some children may also have folds of skin over the inner corners of the eyes (epicanthal folds).

In early childhood relative overgrowth of the hindbrain compared to the space available in the posterior fossa of skull cavity can result in crowding and neurologic problems. Because severe crowding requires surgical intervention, screening with brain and cervical spine MRI has been suggested.

Eye and vision changes are common and include nystagmus (rapid eye movements) in younger individuals, strabismus and rarely in older individuals keratoconus (abnormal thickening of the cornea).

Children with Costello syndrome often have certain heart abnormalities. These may include structural malformations of the heart that are present at birth (congenital heart defects); abnormal thickening of the muscular walls of the left lower chamber of the heart (hypertrophic cardiomyopathy); leakage of the valve between the left upper (atrial) and lower (ventricular) heart chambers (mitral valve prolapse); and/or other cardiac defects. Associated symptoms and findings may include abnormal heart sounds (heart murmurs) that may be detected by a physician through use of a stethoscope; shortness of breath, particularly upon exertion; faintness; chest pain; abnormal heart rhythms (arrhythmias); and/or other findings that may potentially lead to life-threatening complications without appropriate treatment.

Affected individuals have an approximately 15% lifetime risk to develop malignant tumors such as a cancer of the muscle tissue (rhabdomyosarcoma), a cancer of the nerve cells (neuroblastoma), and transitional cell carcinoma of the bladder.

In some cases, the symptoms and findings of Costello syndrome overlap with two similar disorders known as Noonan syndrome and cardiofaciocutaneous syndrome which are caused by mutations in different genes. (For more information on Noonan and Cardiofaciocutaneous syndromes, see the Related Disorders section below.

Causes

Costello syndrome is inherited as an autosomal dominant genetic condition and is caused my mutations in the HRAS gene. Mutations in this gene result in production of an abnormal H-Ras protein that leads to continuous cell growth and division.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Most individuals with Costello syndrome have the disorder as the result of a new mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

There have been a few reports of more than one sibling with Costello syndrome in a family. This is most likely due to germ cell mosaicism in which some of the parent's reproductive cells (germ cells) carry the HRAS gene mutation whereas others contain a normal gene. As a result, one or more of the parent's children may inherit the gene mutation, leading to manifestation of the autosomal dominant disorder, but the parent may have no apparent symptoms.

Affected Populations

Costello syndrome is a very rare disorder that affects males and females in relatively equal numbers. Approximately 350 affected individuals have been reported worldwide.

Related Disorders

Symptoms of the following disorders can be similar to those of Costello syndrome. Comparisons may be useful for a differential diagnosis:

Cardiofaciocutaneous (CFC) syndrome is an extremely rare inherited disorder characterized by multiple defects that affect various parts of the body. The major features of this disorder include growth failure; characteristic facial appearance; sparse hair; variable skin disease; heart defects; and/or mild to moderate mental retardation. Characteristic facial features may include an abnormally large head (macrocephaly) with a prominent forehead (frontal bossing), widely-spaced eyes (ocular hypertelorism), a short upturned nose, and/or unusually shallow eye socket ridges (hypoplastic orbital ridges). CFC syndrome is a dominant genetic disorder caused by a gene abnormality (mutation) in one of three genes that have been termed BRAF, MEK1 and MEK2. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC. (For more information on this disorder, choose cardiofaciocutaneous as your search term in the Rare Disease Database.)

Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations) in different genes: PTPN11, KRAS, SOS1, RIT1, SHOC2 and RAF1. Noonan syndrome is a genetic disorder that is typically evident at birth and is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low hairline in the back of the head; and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); vertical skin folds that may cover the eyes' inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a low nasal bridge; and low-set, prominent, abnormally rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, mild mental retardation, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. (For more information on this disorder, choose "Noonan" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
Costello syndrome is diagnosed by clinical examination and specific diagnostic criteria have been developed. Molecular genetic testing for mutations in the HRAS gene is available to confirm the diagnosis. Most clinically affected individuals have an identifiable HRAS mutation. Experts in the field suggested that individuals without an identifiable HRAS mutation should not be diagnosed with Costello syndrome, as they most likely have a related condition such as Noonan or cardiofaciocutaneous syndrome. The specific mutation in the HRAS gene, often referred to by the resulting amino acid change, is important to identify. While most individuals with Costello syndrome share a mutation that results in a change of the amino acid glycine in position 12 to serine, a number of changes have been seen. The prognosis for a patient is affected by the specific mutation, as some present with more severe medical problems than others.

Treatment
The treatment of Costello syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat abnormalities of the heart (cardiologists), physicians who diagnose and treat skeletal abnormalities (orthopedists), orthopedic surgeons, specialists who diagnose and treat abnormalities of the skin (dermatologists), speech pathologists, dietitians, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Individuals with cardiac abnormalities, such as hypertrophic cardiomyopathy, may be treated with certain medications (e.g., beta-blockers or calcium channel blockers, antiarrhythmic medications), surgical intervention, and/or other measures may be necessary. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.

Bracing, occupational and physical therapy may be used to treat ulnar deviation of the wrists. Surgery may be used to lengthen Achilles tendons. Facial papillomata can be removed with dry ice.

Early intervention is important to ensure that children with Costello syndrome reach their potential. Services that may be beneficial include special remedial education, speech therapy, special social support, and other medical, social, and/or vocational services.

Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.

Investigational Therapies

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.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

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/

Contact for additional information about Costello syndrome:

Karen W. Gripp, MD, FAAP, FACMG
Chief, Division of Medical Genetics
A.I. duPont Hospital for Children
1600 Rockland Rd.
Wilmington, DE 19803
Phone: 302-651-5916
Fax: 302-651-5033
Email: kgripp@nemours.org

Organizations related to Costello Syndrome

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., short stature, mental retardation, etc.].)

References

TEXTBOOKS
Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:122, 124-25.

JOURNAL ARTICLES
Aoki Y, Niihori T, Banjo T et al. Gain of function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013; Jul 11;93(1):173

Detweiler S, Thacker M, Hopkins E, Conway L, Gripp KW. Orthopedic manifestations and implications for individuals with Costello Syndrome. Am J Med Genet Part A. 2013;161A:1940-1949.

Gripp KW, Demmer LA. Keratoconus in Costello syndrome. Am J Med Genet Part A. 2013;161:1132-1136.

McCormick EM, Hopkins E, Conway L, Catalano S, Hossain J, Sol-Church K, Stabley DL, Gripp KW. Assessing genotype-phenotype correlation in Costello syndrome using a severity score. Genetics in Medicine. 2013;15:554-557.

Schwartz DD, Katzenstein JM, Hopkins E, Stabley DL, Sol-Church K, Gripp KW, Axelrad ME. Verbal memory functioning in adolescents and young adults with Costello syndrome: Evidence for relative preservation in recognition memory. Am J Med Genet Part A. 2013; 61A:2258-2265.

Gripp KW, Lin AE. Costello Syndrome: A Ras/MAPK pathway syndrome (Rasopathy) resulting from HRAS germline mutations. Genet Med. 2012;14:285-292.

Sammon M, Doyle D, Hopkins E, Sol-Church K, Stabley D, McGready J, Schulze K, Alade Y, Hoover-Fong J, Gripp KW. Normative growth charts for individuals with Costello syndrome. Am J Med Genet, Am J Med Genet Part A. 2012;158: 2692-2699.

Axelrad ME, Schwartz DD, Katzenstein JM, Hopkins E, Gripp KW Neurocognitive, adaptive and behavioral functioning in individuals with Costello syndrome: A review. Am J Med Genet Part C, 2011; 157C:115-122.

Gripp KW, Stabley DL, Geller PL, Hopkins E, Stevenson DA, Carey JC, Sol-Church K. Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome. Am J Med Genet Part A. 2011;155A:2263-2268.

Gripp KW, Hopkins E, Sol-Church K, et al. Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C. Am J Med Genet Part A, 2011; 155A:706-716.

Lin AE, Alexander ME, Colan SD, et al. Clinical, pathological and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK Pathway syndrome. Am J Med Genet Part A, 2011;155A:486-507.

Hopkins E, Lin AE, Krepkovich KE, et al. Living with Costello syndrome: Quality of life issues in older individuals. Am J Med Genet Part A, 2010; 152A:84-90.

Rauen KA, Schoyer L, McCormick F, et al. Proceedings from the 2009 Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back. Am J Med Genet Part A, 2010; 152A:4-24.

Gripp KW, Hopkins E, Doyle D, Dobyns WB High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: Brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities. Am J Med Genet Part A, 2010; 152A:1161-1168.

Gripp KW, Innes MA, Axelrad MEet al Costello syndrome associated with novel germline HRAS mutations: An attenuated phenotype? Am J Med Genet 2008; 146A:683-690.

Rauen KA, Hefner E, Carrillo K, Taylor J, Messier L, et al Molecular aspects, clinical aspects and possible treatment modalities for Costello syndrome: Proceedings from the 1st International Costello Syndrome Research Symposium 2007. Am J Med Genet A. 2008;146A(9):1205-1217.

Kerr B, Allanson J, Delrue MA, Gripp KW, Lacombe D, Lin AE, Rauen KA. The diagnosis of Costello syndrome: Nomenclature in Ras/MAPK pathway disorders.
Am J Med Genet A. 2008;146A(9):1218-1220.

Lin AE, Rauen KA, Gripp KW, Carey JC. Clarification of previously reported Costello syndrome patients. Am J Med Genet A. 2008;146(7):940-3.

Tartaglia M, et al. Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noona, cardio-facio-cutaneous and Costello syndromes. Clin Genet. 2003;63:423-6.

Hennekam RC. Costello syndrome: an overview. Am J Med Genet. 2003;117C:42-8.

Yassier WK, et al. Costello syndrome: orthopaedic manifestations and functional health. J Pediatr Orthop. 2003;23:94-8.

Delrue MA, et al. Costello syndrome: clinical aspects and tumor risk. Arch Pediatr. 2002;9:1059-63.

Lin AE, et al. Further delineation of cardiac abnormalities in Costello syndrome. Am J Med Genet. 2002;111:115-29.

Gripp KW, et al. Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for tumor screening protocol. Am J Med Genet. 2002;108:80-7.

Moroni I, et al. Costello syndrome: a cancer predisposing syndrome? Clin Dysmorphol. 2000;9:265-8.

van Eeghen AM, et al. Costello syndrome: report and review. Am J Med Genet. 1999;82:187-93.

Franceschini P, et al. Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review. Am J Med Genet. 1999;86:174-79.

Siwik ES, et al. Cardiac disease in Costello syndrome. Pediatrics. 1998;101:706-09.

Johnson JP, et al. Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause. J Pediatr. 1998;133:441-48.

Costello JM. Costello syndrome: update on the original cases and commentary [letter]. Am J Med Genet. 1996;62:199-201.

Torrelo A, et al. Costello syndrome. J Am Acad Dermatol. 1995;32:904-07.

Umans S, et al. Costello syndrome: the natural history of a true postnatal growth retardation syndrome. Genet Couns. 1995;6:121-25.

Davies SJ, et al. Costello syndrome: natural history and differential diagnosis of cutis laxa. J Med Genet. 1994;31:486-89.

Vila Torres J, et al. Pathology of the elastic tissue of the skin in Costello syndrome. An image analysis study using mathematical morphology. Anal Quant Cytol Histol. 1994; 16:421-29.

Fryns JP, et al. Costello syndrome: a postnatal growth retardation syndrome with distinct phenotype. Genet Couns. 1994;5:337-43.

Costa T, et al. What syndrome is this? Costello syndrome. Pediatr Dermatol. 1994;11:277-79.

Teebi AS. Costello or facio-cutaneous-skeletal syndrome [letter]? Am J Med Genet. 1993;47:172-73; discussion 174.

Teebi AS, et al. Further delineation of Costello syndrome. Am J Med Genet.. 1993; 47:166-68.

Zampino G, et al. Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology. Am J Med Genet. 1993;47:176-83.

Say B, et al. The Costello syndrome. Am J Med Genet. 1993;47:163-65.

Yoshida R, et al. The Costello syndrome: are nasal papillomata essential? Jpn J Hum Genet. 1993;38:437-44.

Kondo I, et al. The Costello syndrome: report of a case and review of the literature. Jpn J Hum Genet. 1993;38:433-36.

Borochowitz Z, et al. New multiple congenital anomalies: mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement. Am J Med Genet. 1992;43:678-85.

Martin RA, et al. Delineation of the Costello syndrome. Am J Med Genet. 1991;41:346-49.

Berberich MS, et al. Resolution of the perinatal and infantile failure to thrive in a new autosomal recessive syndrome with the phenotype of a storage disorder and furrowing of palmar creases [abstract]. Proc Greenwood Genet Center. 1991;10:78.

Der Kaloustian VM, et al. Costello syndrome. Am J Med Genet. 1991;41:69-73.

Costello JM. A new syndrome: mental subnormality and nasal papillomata. Aust Paediat J. 1977;13:114-18.

INTERNET
Gripp KW, Lin AE. Costello Syndrome. 2006 Aug 29 [Updated 2012 Jan 12]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1507/ Accessed Feb 24, 2014.

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Report last updated: 2014/03/04 00:00:00 GMT+0

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