Information on the following diseases can be found in the Related Disorders section of this report:

• Cardio-Facio-Cutaneous Syndrome
• Cantu Syndrome
• De Barsy Syndrome
• Noonan Syndrome
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Costello syndrome is characterized by growth delays after birth (postnatal) leading to short stature; the presence of excessive, loose skin (cutis laxa) that lacks elasticity on the neck, palms of the hands, fingers, and soles of the feet; the development of benign (non-cancerous) growths (papillomata) around the mouth and nostrils (nares); mental retardation; and/or a distinctive facial appearance.

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 (postnatally) typically results in short stature during childhood and adulthood. Affected children may also have mild to moderate mental retardation. 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 infants with this disorder develop dry hardened patches of skin (hyperkeratosis) with unusually deep creases on the palms and soles. In some cases, affected infants may also have skeletal abnormalities such as dislocated hips, abnormally flexible (hyperextensible) joints of the fingers, and/or unusual tightening of the fibrous cord(s) on the back of the heel(s) (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.

As children with Costello syndrome age, they usually develop benign growths (papillomata) around the mouth (perioral) and nostrils (nares). Papillomata may develop as early as two years of age or as late as about 15 years of age. In some cases, these wart-like (verrucal) lesions may also be found near the anus (perianal). Papillomata usually become more apparent as a child ages. Other benign tumors have also been reported. Some individuals have developed malignant tumors. Individuals with Costello syndrome may be at a greater risk than the general population of developing certain types of cancer. The most common malignant tumor associated with Costello syndrome is rhabdomyosarcoma.

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/or 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).

As noted above, Costello syndrome may also be associated with certain heart (cardiac) abnormalities. These may include certain 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.

In some cases, the symptoms and findings of Costello syndrome overlap with two similar disorders known as Noonan syndrome and Cardiofaciocutaneous syndrome. The exact relationship between these three similar disorders is unknown. (For more information on Noonan and Cardiofaciocutaneous syndromes, see the Related Disorders section below.
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The exact cause of Costello syndrome is unknown. Most cases appear to occur randomly for unknown reasons (sporadically) with no apparent family history of the disorder. Many such cases are thought to represent new (sporadic) genetic changes (mutations) that theoretically may be transmitted as an autosomal dominant trait (i.e., new dominant gene mutation).

Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the 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. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Researchers indicate that Costello syndrome sometimes appears to be associated with advanced parental age, a finding that is consistent with sporadic autosomal dominant mutations.

There have been only a few reports of more than one affected sibling in a family (kindred). Investigators indicate that such familial cases may be consistent with "germline mosaicism" in an unaffected parent. In germline mosaicism, some of the parent's reproductive cells (germ cells) may carry the gene mutation whereas others contain a normal cell line ("mosaicism"). As a result, one or more of the parent's children may inherit the gene mutation, leading to manifestation of the autosomal dominant disorder, whereas the parent may have no apparent symptoms (asymptomatic carrier). Germline mosaicism may be suspected when unaffected parents have more than one child with the same genetic abnormality.

However, in certain rare familial cases, other investigators indicate that autosomal recessive inheritance cannot be ruled out, such as a few reported patients with parents who are closely related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Further research is necessary to learn more about the underlying genetic cause or causes and mode of transmission of syndrome.
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Costello syndrome is a rare genetic disorder that appears to affect males and females in relatively equal numbers. Since the disorder was originally described in 1977 in two unrelated children, more than 100 cases have been recorded in the medical literature. The disorder is named after the investigator (Costello JM) who originally reported the disease entity.
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Symptoms of the following disorders can be similar to those of Costello syndrome. Comparisons may be useful for a differential diagnosis:

Cardiofaciocutaneous 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). According to the medical literature, all reported cases of Cardiofaciocutaneous syndrome have occurred as isolated events (sporadically). (For more information on this disorder, choose Cardiofaciocutaneous as your search term in the Rare Disease Database.)

Cantu syndrome is an extremely rare inherited disorder characterized by mild mental retardation; short stature (dwarfism); excessive, loose skin (cutis laxa); wrinkled palms of the hands and soles of the feet; and/or abnormal flexibility of certain joints (joint hyperextensibility). Individuals with Cantu syndrome may also have abnormalities of the head and facial (craniofacial) area, skeletal malformations, and/or heart abnormalities. Characteristic facial features may include an abnormally large head (macrocephaly), prominent forehead (frontal bossing), and/or widely-spaced eyes (ocular hypertelorism). According to the medical literature, all cases of Cantu syndrome have appeared to occur randomly for no apparent reason (sporadically). Cantu syndrome has only been reported in one family and some researchers think it may be the same disorder as Costello syndrome.

De Barsy syndrome is an extremely rare inherited disorder characterized by loose, excessive skin (cutis laxa); abnormal clouding (opacity) of the front, clear portion of the eye through which light passes (cornea); short stature (dwarfism); slow involuntary purposeless movements of various muscles (athetosis); and/or mental retardation. Other findings associated with De Barsy syndrome may include small joints that are unusually flexible, an abnormally prominent forehead (frontal bossing), and/or dislocated thumbs and/or great toes. In many cases, De Barsy syndrome is thought to be inherited as an autosomal recessive trait. Other cases have appeared to occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose "De Barsy" as your search term in the Rare Disease Database.)

Noonan syndrome is a rare genetic disorder that is typically evident at birth (congenital). The disorder may be 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. Most cases of Noonan syndrome occur as isolated events (sporadically). However, some cases may be inherited as autosomal dominant trait. (For more information on this disorder, choose "Noonan" as your search term in the Rare Disease Database.)

Diagnosis
Certain features of Costello syndrome such as difficulty swallowing, poor sucking ability, and/or the presence of certain heart (cardiac) or craniofacial abnormalities may be apparent during infancy and may be the first signs suggesting a diagnosis of this disorder. Growth delays leading to short stature; excessive, loose skin (cutis laxa); development of benign growths (papillomata); and/or other characteristic facial abnormalities that may be necessary to differentiate Costello syndrome from other disorders may not become apparent until later in childhood. A diagnosis of Costello syndrome may be confirmed based upon the identification of such characteristic findings, thorough clinical evaluation, a detailed patient history, and specialized diagnostic tests. Experts indicate that any individuals with an established diagnosis of Costello syndrome should undergo thorough cardiac evaluation and ongoing follow-up to help ensure prompt detection and appropriate treatment of heart abnormalities potentially associated with the disorder. Such evaluation may include assessment of heart and lung sounds with a stethoscope, x-ray studies, electrocardiography (EKG), echocardiography, and/or other cardiac studies. An EKG, which records the electrical activities of heart muscle, may reveal abnormal electrical patterns (e.g., resulting in arrhythmias). During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion.

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.

In individuals with cardiac abnormalities, such as hypertrophic cardiomyopathy, treatment 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.

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 will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Researchers at the Alfred I. duPont Hospital for Children have established the Costello Program to address the multiple medical and developmental needs of individuals with Costello syndrome and their families. The program evaluates individuals for a possible diagnosis of Costello syndrome; and coordinates medical care; and collaborates with pediatric subspecialists who are aware of this rare disorder and its associated medical problems. For more information, contact:

Alfred I. dupont Hospital for Children
1600 Rockland Road
Wilmington, DE 19803
Office: (302) 651-5916
Appointments: (302) 651-5916
Fax: (302) 651-5033

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:218040; Last Update:8/27/03. Entry No:114620; Last Update: 4/9/94. Entry No: 219150; Last Update: 4/18/94. Entry No: 115150; Last Update:7/26/96.

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