What is Costello syndrome?
Costello syndrome, also known as faciocutaneoskeletal syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by failure to thrive at infancy, short stature, distinctive facial features and delay of motor and cognitive development.
Costello syndrome is a genetic disorder that can be inherited in an autosomal dominant pattern. Autosomal dominant means, that in order for disease to be present, an abnormal gene is needed only from one parent (also see Cowden syndrome). In case of Costello syndrome, mutation is in the HRAS gene. This mutation results in abnormal production of protein that causes the symptoms.
This condition is caused by mutation in the HRAS gene. The HRAS gene is responsible for making the H-Ras protein. H-Ras takes part as a regulatory protein in the cell division process. Mutated gene can be inherited from either the mother or the father, or it can also be a new mutation in the early cell division process.
Since Costello syndrome is an autosomal dominant disorder, the risk of passing the mutation to the child is 50%. In some cases, the gene is inherited from one of the parents, even though they don´t have any symptoms. In these cases more than one child in the family has Costello syndrome. This occurrence is possible due to so called cell mosaicism- some of the parents’ reproductive cells contain the mutated gene, while other ones do not.
The HRAS gene belongs to a group of genes called oncogenes. These genes can potentially cause cancer, if they have been mutated. The mutated HRAS gene gives signals to produce overly active H-Ras protein. This overly active protein signals cells to grow and divide in abnormal speed. That leads to symptoms benign or malignant tumor development. HRAS gene is the only gene currently linked to Costello syndrome. The exact mechanism of how the H-Ras protein causes all other symptoms is not known.
Patients usually are born with birth weight which is more than the average newborns. After birth there are usually difficulties with feeding and subsequent weight loss. Some patients have increased blood sugar levels. Visual features depend on the severity of each patient’s condition. These include:
- Prominent and low set ears
- Uplifted nose tip, short nose
- Large mouth, full lips
- Loose skin
- Deep skin folds on extremities
- Epicanthal folds
During infancy, child can present with delayed development- motor and cognitive, curly, fine hair, loose joints, hip dysplasia. Patient can also present with symptoms due to various heart conditions like enlarged ventricles, pulmonary stenosis, arrhythmias, hypertrophic cardiomyopathy, aortic dilatation. Neurological system can also be involved. Patients with Costello syndrome suffer from:
- Epileptic seizures
- Arnold-Chiari malformation
- Tethered spinal cord
In later years patients can develop tightness of Achilles tendon, which influences the ability to walk. Other musculo-skeletal manifestations are kyphosis, scoliosis, deviation of wrists and fingers. Patients usually have delayed puberty and later they show signs of premature aging. Osteoporosis and osteopenia is a common sign at an untypically young age. Patients also have a higher risk to develop tumors. Voice can be very hoarse or whispery.
Diagnosis of Costello syndrome is made based on the clinical presentation and can be confirmed by molecular genetic testing. There are no diagnostic criteria, but diagnosis can be made by observing several typical features.
There are a variety of tests that can be done during pregnancy. Costello syndrome can be diagnosed before the baby has been born, if it is suspected, for example, if the gene has been diagnosed in a family member. There are also some unspecific signs in the ultrasound that can suggest Costello syndrome, like:
- Polyhydramnios- increased volume of amniotic fluid
- Increased weight of the baby (due to edema)
- Possible signs of heart, neurological or skeletal defects- short humerus, fetal tachicardia
There is a wide variety of symptoms and visual features associated with Costello syndrome:
- Craniofacial features: macrocephaly, full cheeks, lips, large mouth, very fine hair, skin fold in the corner of the eye, wide, short nose, deep voice.
- Skin: loose, soft, with elevated pigmentation, deep folds on palms and feet, skin growths know as papillomata can be present on the face.
- Musculoskeletal system- muscle hypotonia, loose joints, a typical posture of hands, inflexible Achilles tendons, foot deformity, vertical talus (anklebone), rib deformities, such as pectus carinatum and excavatum, hip dysplasia.
- Cardiovascular system- hypertrophy of the heart muscle that can cause cardiomyopathy, pulmonic valve stenosis, arrhythmias, dilatation of the aorta
- Development delay, mental retardation, characteristic personality- patients are very sociable and outgoing
- Growth of tumors- embrional rhabdomyosarcoma, neuroblastomas, bladder transitional cell carcinoma. Also see Li-Fraumeni syndrome for genetic causes of tumor growth.
All of these symptoms are diagnosed since the birth of the patient. To determine the extent of the condition several investigations have to be done:
- Surveillance of growth by measuring weight, height and body circumference
- Doppler echocardiography, Holter monitoring, exercise testing to determine heart conditions
- MRI to determine neurological anomalies
- Ophtalmologic examination
- Surveillance of motor and cognitive development
There are no specific blood tests except for molecular genetic studies to determine Costello syndrome.
There is no treatment for Costello syndrome, but the symptoms can be managed depending on their severity
Patients often require feeding through either nasogastric tube or gastrostomy. Patients who present with pyloric stenosis might require surgical treatment. Costello syndrome patients require a high calorie intake.
Treatment depends on the condition patient is presented with. It can include medications and cardiac stimulators to manage arrhythmias, or surgical treatment for heart malformations.
Usually patients require physical therapy and in later years occupational therapy. There are various braces to treat postural manifestations. Surgical Achilles tendon lengthening can be used.
Other treatment options
Depending on the symptoms, patients might need to use medications and surgical treatments. Patients also benefit from speech therapy, physiotherapy, and well planned education. Tumor treatment depends on the type of tumor, but it follows the standard protocols.
Differential diagnosis of Costello syndrome includes syndromes that have similar features:
- Noonan syndrome
- Cardiofaciocutaneous syndrome
- Beckwith-Wiedemann syndrome
- Sympson-Golabi-Behmel syndrome
- Williams syndrome
The prognosis for patients with Costello syndrome depends on the severity of symptoms and the affected organ systems. Malignant tumors, presence of seizures, failure to thrive can negatively affect the outcome. There have only been around 300 cases of Costello syndrome worldwide therefore there is no specific statistics of life expectancy.
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- Genetics of Costello syndrome https://ghr.nlm.nih.gov/condition/costello-syndrome#diagnosis
- Clinical features, diagnosis and treatment of Costello syndrome https://www.ncbi.nlm.nih.gov/books/NBK1507/
- Causes of Costello syndrome https://rarediseases.org/rare-diseases/costello-syndrome/
- More information on Costello syndrome http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=3071