January 04, 2017
Years published: 1997, 2001, 2003, 2011, 2014, 2017
NORD gratefully acknowledges 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.
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); coarse 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.
Infants with Costello syndrome typically have a normal or high birth weight, but show 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 have developmental delay or mild to moderate intellectual disability. In some individuals, 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. Some 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 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 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.)
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.
Costello syndrome is a very rare disorder that affects males and females in relatively equal numbers. Approximately 350 affected individuals have been reported worldwide.
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.
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.
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: [email protected]
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
Email: [email protected]
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., short stature, intellectual disability, etc.].)
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