Costello syndrome (patient information)

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Costello syndrome (patient information)
OMIM	218040
DiseasesDB	32846

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Costello syndrome is a genetic disorder that affects many parts of the body. This condition is characterized by delayed development and mental retardation, distinctive facial features, loose folds of extra skin (especially on the hands and feet), and unusually flexible joints. Heart abnormalities are common, including a very fast heartbeat (tachycardia), structural heart defects, and overgrowth of the heart muscle (hypertrophic cardiomyopathy). Infants with Costello syndrome may be large at birth, but have difficulty feeding and grow more slowly than other children. Later in life, people with this condition have relatively short stature and many lack growth hormone.

Beginning in early childhood, people with Costello syndrome have an increased risk of developing certain cancerous and noncancerous tumors. Small growths called papillomas are the most common noncancerous tumors seen with this condition. They usually develop around the nose and mouth or near the anus. The most frequent cancerous tumor associated with Costello syndrome is a soft tissue tumor called a rhabdomyosarcoma. Other cancers also have been reported in children and adolescents with this disorder, including a tumor that arises in developing nerve cells (neuroblastoma) and a form of bladder cancer (transitional cell carcinoma).

What are the symptoms of Costello syndrome?

At Birth

• An excess of amniotic fluid
• Increased birth weight
• Subsequent weight loss and a failure to thrive
• Difficulty feeding
• Short stature

Physical Appearance

• Oversized features, particularly the head and mouth
• Curly, thin hair
• Wide, short nose
• Deep, hoarse voice
• Loose, soft skin
• Increased pigmentation
• A large amount of warts on the face, may be absent during infancy and appear during early childhood
• Hair loss
• Splayed fingers
• Abnormal fingernails
• Abnormal feet positioning

Developmental

• Developmental delay, mental retardation
• Sociable personality

Musculoskeletal

• Tight Achilles tendons
• Abnormal curvature of the spine
• Assymetric rib cage

Cardiovascular

• Increased heart tissue
• Heart defects present since birth
• Arrhythmia, abnormal electrical activity of the heart, causing irregular heart beats, faster or slower than normal

Neurologic

• Hydrocephalus, an abnormal accumulation of cerebrospinal fluid in the brain
• Seizures

In addition, there is a 15% chance that children and young adults with Costello syndrome suffer from malignant, solid tumors most commonly found in connective tissue, developing nerve cells, and the bladder.

What are the causes of Costello syndrome?

Costello syndrome is inherited in an autosomal dominant manner, which means one copy of the altered gene is sufficient to cause the disorder. Almost all cases have resulted from new mutations, however, and occur in people with no history of the disorder in their family.

Geneticists believe that the symptoms associated with Costello syndrome are a result of a missense mutation in the HRAS gene. The HRAS gene provides instructions for making a protein that helps control cell growth and division. Mutations that cause Costello syndrome lead to the production of an HRAS protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This unchecked cell division may predispose to the development of benign and malignant tumors. It remains unclear how mutations in the HRAS gene cause the other features of Costello syndrome, but many of the signs and symptoms may result from cell overgrowth and abnormal cell division.

Who is at highest risk?

Because Costello syndrome typically occurs as the result of a new mutation, family members are, for the most part, not at increased risk. In some cases, however, depending on the genetic make-up of the parents, siblings of people with Costello syndrome may be at risk for the condition.

In addition, although people with Costello syndrome typically do not reproduce, if they were to reproduce, the chance of passing the condition to their offspring is 50%.

How to know you have Costello syndrome?

Diagnosis of Costello syndrome is based on the presence of multiple, characteristic symptoms and is confirmed by molecular genetic testing. Sequence analysis of HRAS, the only gene currently known to be associated with Costello syndrome, detects missense mutations in 80%-90% of individuals with the clinical diagnosis. The clinical diagnosis should be reconsidered if no HRAS mutation is identified, and other genetic syndromes should be considered as alternative diagnoses.

Where to find medical care for Costello syndrome?

Directions to Hospitals Treating Costello syndrome