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Costello syndrome

Costello syndrome


Newborn feeding problems, poor growth, loose, wrinkled skin, and mental retardation are some of the recognizable features of Costello syndrome. Although the genetic basis is unknown, the unusual skin features have given an important clue as to the cause of the disorder.


The first sign of Costello syndrome may be seen even before birth. Many mothers carrying these babies have polyhydramnios (an excess of amniotic fluid in the womb). This may be due to the fact that the baby has poor swallowing ability, even in the womb. Many of these babies are large at birth, especially with respect to their weight. Their head size is usually larger too. Most significant, all of these babies begin life with severe feeding problems. They do not grow and thrive as most babies do. As this continues, they lose weight and become quite ill. Their height also tapers off. This poor growth continues until about two years of age. Then, for reasons unknown, their growth, especially weight gain, becomes more normal. However, these children continue to grow more slowly in height, and remain short throughout life. Most adults with Costello syndrome are approximately 4.5 ft (1.5 m) tall. X-ray studies done at different ages show that bone growth is delayed. The delay in normal bone growth leads to reduced height.

Some interesting features of the face and loose, soft skin add to the clinical picture. Even as babies, individuals with Costello syndrome have a slight downward slant of their eyes, full cheeks, and thick lips. The neck is short, and they have an upturned nose. The ears are low set (below the level of the nose) with large, fleshy ear lobes. These features seem to coarsen and become more noticeable over time. However, the signature feature of Costello syndrome is the soft, deeply wrinkled skin, especially on the hands and feet. This is evident at birth and becomes even more striking in the first few months of life. All individuals with Costello syndrome have these deep creases and looseness of the skin. Some physicians have described the distinct, deep creases in the skin as resembling "bath tub hands," i.e. similar to the puffiness seen after soaking one's hands in water for awhile.

Other features of Costello syndrome include skin markings, sparse, curly hair, and a hoarse voice. Individuals with Costello syndrome have unusual skin growths called papillomatous papules, which are skin-colored, raised bumps (not warts). These papules are found on the skin inside the nose and mouth, on the tongue, and around the anus. The papules form in late childhood or early teenage years. Most of these growths are benign (non-cancerous) and rarely become malignant (cancerous). Other skin markings may include dark colored moles on the palms of the hands and on the bottom of the feet; brownish colored skin marks (birthmarks) found almost anywhere on the body; and small, red marks which are broken blood vessels on the surface of their skin.

Most individuals with Costello syndrome also have sparse, curly hair. The hair turns gray in color at a much earlier age than expected (sometimes even in teenage years). Along with the loose, wrinkled skin, the graying of the hair makes them look much older than their age. The last feature of note is their voice, many times described as being low and hoarse. It has been suggested that the hoarse voice may possibly be due to weakness in the tissues or muscles of the larynx.

Cardiovascular problems are common in children with Costello sydrome. Among the congenital heart defects seen are atrial or ventricular septal defects, bicuspid aortic valve , patent ductus arteriosus , and mitral valve prolaspe. More than half of the reported cases of Costello sydrome included heart rhythm disturbances and abnormalities in the structure and functions of the heart muscle (hypertrophic cardiomyopathy).

Genetic profile

As of 2001, the genetic basis of Costello syndrome is unknown. There have been two instances where siblings (brother and sister) each had Costello syndrome. The sydrome has also occurred in a few families where the parents were said to be closely related (i.e., may have shared the same altered gene within the family). For these reasons, the possible involvement of an autosomal recessive gene in Costello syndrome was raised. An autosomal recessive condition is caused by a change in both genes of a pair.

As more individuals with Costello syndrome were described, the evidence began to suggest autosomal dominant inheritance . This means only one altered copy of a gene pair is needed to cause the disorder. The cases of Costello syndrome that occur for the first time in a family are probably due to a new, sporadic (non-inherited) gene mutation . To explain the two families with more than one child with Costello syndrome, the concept of germ line mosaicism was proposed.

Germ line mosaicism occurs when one parent carries an altered gene mutation that affects his or her germ line cells (either the egg or sperm cells) only. The gene mutation does not affect the somatic (body) cells. Therefore, the parent does not express the disease and DNA testing does not show that the parent carries an altered gene. However, parents with germ line mosaicism can have more than one child with a disorder (like Costello syndrome) since the syndrome occurs whenever an egg or sperm carrying the altered gene mutation is passed on. Germ line mosaicism occurs very rarely. However, it has been seen in other autosomal dominant conditions, such as osteogenesis imperfecta (brittle bone disease). Based on the available evidence, Costello syndrome is probably an autosomal dominant condition. In some families, germ line mosaicism explains the pattern of expression of the condition.

Most individuals with Costello syndrome have undergone extensive testing to look for a cause for their growth and developmental problems. For the most part these tests have been normal. The underlying problem appears to be complex. However, some researchers had the idea to look more closely at the makeup of the skin cells for clues to the disorder.

Stretchable tissues like the skin require not only strength but also the ability, once stretched, to return to their original form. Human skin is made up of a network of fibers that give the skin its flexibility. The fibers themselves are made out of different proteins. One such protein is called elastin. Elastin acts like a rubber band in the skin. It can be stretched and then returns to its original form. Within our skin cells, the elastin protein is randomly twisted and tied to form elastin fibers. A study of the skin cells of individuals with Costello syndrome shows that the elastin fibers do not appear to be formed in the normal way. The skin cells seem to stretch but do not have the ability to snap back, as do normal skin cells. Thus, the skin has a loose and wrinkled appearance. Specifically, a protein called the elastin binding protein seems to play a role in forming the elastin fibers. In Costello syndrome, this protein is abnormal causing the elastin fibers themselves to become loose and disrupted.

The defect in the elastin building pathway explains many of the clinical features of Costello syndrome, especially the loose and wrinkled skin. Elastin fibers make up tissues of the heart, the larynx, even the developing skeleton. Therefore, the heart disease, the hoarse voice, even the short height may be explained by abnormal formation of the elastin fibers.


In 1971, and later in 1977, Dr. J. Costello first described a syndrome of mental and growth delays, and distinct features of the face and skin that bear his name. After the initial description, there were no further reports of individuals with Costello syndrome until 1991. It was then that the term Costello syndrome was used to describe the features seen in a Canadian child. Further cases from several countries have since been reported. In all, at least 40 individuals with Costello syndrome have been described in medical literature. The condition may be more common than previously thought, and may be under diagnosed. It affects both males and females equally, and most likely occurs in every racial and ethnic group.

Signs and symptoms

All individuals with Costello syndrome have fairly significant mental retardation. This impairment leads to early delays in walking and talking. They are usually a few years behind other children their age. These learning problems continue as they get older, and require a special education environment. IQ testing in some individuals with Costello syndrome has shown a range from mild to moderate retardation (IQ from 30 to 68). Although they have special needs, their outgoing and friendly personality is an asset, and helps them make the most of their abilities.


The pattern of overgrowth in the womb, poor growth after birth, and short height is typical of individuals with Costello syndrome. Other clinical features, especially the loose, wrinkled skin and graying, curly hair give them an aged appearance that is quite distinct. The skin papules found in the nose, mouth, and on the anus add to the picture. Taking these features together, the diagnosis can be made.

Treatment and management

Heart disease is seen in almost half of the individuals with Costello syndrome. The heart problems are sometimes found at birth. The heart problems include holes in the muscle wall of the heart; abnormal thickening of the walls of the heart; and an abnormal heart beat or arrhythmia. An echocardiogram (ultrasound of the heart) is usually done early in life to assess heart function. Heart function is also closely monitored as these individuals get older.

At least eight individuals (of the 40 or so now described) with Costello syndrome have developed rare types of cancer . The cancers have occurred early in life, and a few cases have occurred in infancy. The tumors seen include two cases of ganglioneuroblastoma, a tumor of the nerve fibers; three cases of rhabdomyosarcoma, a tumor of the skeletal muscle; and two cases of bladder cancer in teenagers, a cancer usually seen in the elderly.


The severe problems with feeding and growth that characterize Costello syndrome can be life-threatening. Most of these infants need to be fed with a feeding tube in order to survive. Complications of heart disease are another cause for concern, even early in life. For most individuals, however, the heart problems are not severe, and usually can be successfully treated without heart surgery. Unfortunately, some individuals with Costello syndrome experienced heart failure and sudden death. Lastly, there may be an increased risk for developing cancer. Since some of these individuals have died from complications of their cancer, increased screening may be important to detect cancer at an early stage.



Costello, J. "A New Syndrome: Mental Submormality and Nasal Papillomata." Australian Pediatric Journal (July 1977): 114-118.

Hinek, Aleksander. "Decreased Elastin Deposition and High Proliferation of Fibroblasts from Costello Syndrome Are Related to Funtional Deficiancy in the 67-kD Elastin-Binding Protein." American Journal of Human Genetics (March 2000): 859-872.

Johnson, John. "Costello Syndrome: Phenotype, Natural History, Differential Diagnosis, and Possible Causes." The Journal of Pediatrics (September 1998): 441-448.

Lurie, I. "Genetics of the Costello Syndrome." American Journal of Medical Genetics (September 1994): 358-359.

Van Eeghen, A. "Costello Syndrome: Report and Review." American Journal of Medical Genetics (January 1999): 187-193.


"Costello Syndrome." Online Mendelian Inheritance in Man.<>

Kevin M. Sweet, MS, CGC

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