/
/

Costello syndrome

This is part of Rare diseases.

Diagnosis: Costello syndrome

Synonyms: Faciocutaneoskeletal syndrome, FCS syndrome

Innehåll


Publication date: 2011-12-29
Version: 1.0

ICD 10 code

87.8W

The disease

Costello syndrome is characterised by short stature, distinctive facial features, soft skin with deep creases in the palms of the hand and soles of the feet, increased levels of skin pigmentation (hyperpigmentation) and developmental delay or intellectual disability. There is also an increased incidence of heart defects. Many other symptoms may present, and there are wide variations between individuals. The syndrome is also associated with an increased risk of developing tumours, both malignant and benign.

The syndrome is named after New Zealand paediatrician Jack Costello who, in 1977, described two children with similar symptoms, but from different families.

Costello syndrome belongs to a group of related disorders named the RASopathies, or the RAS/MAPK syndromes (Ras/mitogen-activated protein kinase). Each syndrome belonging to the group presents with some unique clinical features, but many syndromes also share one or more features. This creates problems in making clinical diagnoses. RASopathies may be caused by many different mutations in various genes. However, a single mutation in one and the same gene may also result in separate syndromes. This complicates the diagnosis of syndromes within this group. The closely related conditions in this group are also referred to as neuro-cardio-facio-cutaneous syndromes.

Other syndromes included in the RASopathies are Noonan syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1 and NF1-like (Legius) syndrome. Separate information on Noonan syndrome and cardiofaciocutaneous (CFC) syndrome can be found in the Rare Disease Database of the Swedish National Board of Health and Welfare.

Occurrence

Costello syndrome is very rare. Only a few people in Sweden have been diagnosed with the disease.

Cause

Costello syndrome and the other RASopathies are caused by mutations in the genes expressing (coding for) proteins in a signal transduction pathway named RAS-MAPK. This pathway is important in cell signalling, an essential process by which cells communicate with each other and respond to external stimuli, including growth factors. RASopathies are named after the signalling pathway (RAS-MAPK) which is affected. Costello syndrome is caused by a mutation in the HRAS gene, located on the short arm of chromosome 15 (11p15.5). Currently (2011), it is the only gene known to cause Costello syndrome.

HRAS is a key component in the activation and deactivation of RAS-MAPK signals. In Costello syndrome the mutation causes the signalling pathway to be permanently active (a gain-of-function mutation). Mutations in genes coding for proteins in RAS-MAPK can also be acquired (somatic mutations) and cause cancer. Such mutations have been found in cancers located in the bladder, kidney and thyroid.

 Figure: Diagram of RAS-MAPK signalling pathways.

Figure: Diagram of RAS-MAPK signalling pathways. Syndromes caused by mutations in genes controlling production of signalling proteins are indicated.

Heredity

In most people, Costello syndrome is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children. It is very uncommon for people with Costello syndrome to become parents.

In isolated cases, somatic mosaicism has been demonstrated in a parent, meaning that he or she can carry the mutation in his/her reproductive cells without being affected. In such cases, there is an increased risk of having more children with the syndrome.

Symptoms

In Costello syndrome the foetus is often surrounded by an excess of amniotic fluid (polyhydramnios). At birth the head is often larger, and the child heavier, than average. The increased weight is caused by swelling resulting from fluid accumulating in the tissues (oedema). This then disappears and the child loses weight. Low blood sugar (hypoglycemia) is common. It can be difficult to make a diagnosis in the neonatal period as many of the characteristic symptoms present later.

Children with Costello syndrome have severe feeding problems, including difficulties sucking and swallowing, which result in a failure to thrive. Vomiting in the neonatal period is common and is caused by a blockage in the pylorus, the opening from the stomach into the small intestine (pyloric stenosis). This means that children do not gain weight at the same rate as other children, although the feeding problem usually diminishes after the age of three. Constipation is common. The testicles of boys with the syndrome often remain in the abdominal cavity (cryptorchidism).

Many of these children have heart abnormalities, which may be congenital or present later. They include constriction of the pulmonary valves (pulmonary valve stenosis), atrial septal defect (ASD), occasional rapid heart rate (supraventricular or paroxysmal tachycardia), a thickening of the ventricle walls (hypertrophic cardiomyopathy) and a hole in wall that separates the right and left ventricles (VSD, ventricular septal defect). In certain instances, cardiomyopathy may be progressive.

It is important to be aware that anaesthesia for children with hypertrophic cardiomyopathy or abnormal heart rate, is associated with risk.

The syndrome is associated with characteristic facial features including low-positioned ears, a high, broad forehead, depressed nasal bridge, epicanthal fold (a skin fold of the upper eyelid, covering the inner corner of the eye), prominent lips and a broad mouth. Drooping eyelids (ptosis) are also common. Hair is often curly or sparse, and fine in texture.

Developmental delay, or a mild to moderate intellectual disability, are also characteristic of the syndrome. On average a child with the syndrome can sit without support at the age of two, and walk independently when he or she is around five. The age at which the child learns to speak varies between two and nine. In the first years, the child is often irritable, sensitive to light and touch, has problems sleeping and is extremely shy of strangers. These symptoms usually become milder with age, but some individuals with the condition continue to experience anxiety and to be very sensitive to sound. Older children and adults often have sociable, outward-going personalities.

Some children have epilepsy.

The growth and maturity of the skeleton are delayed, which results in the child being shorter than others of the same age. Skeletal abnormalities include curvature of the spine (kyphoscoliosis) and the sternum (pigeon, or funnel chest). Loss of muscle tone (muscular hypotonus) and hypermobile joints often present. Some people with the disease have deformities of the joints of the hand and fingers (including ulnar deviation), foot deformities and short Achilles tendons. Fingernails are often thinner than normal.

Puberty is often delayed or abnormal. The average, final height of individuals with the disease at approximately twenty-one years of age is 130 cm for women and 142 cm for men.

Squinting is common and results in delayed visual development. Vision usually improves with age.

Soft, loose skin with deep creases in the palms of the hands and soles of the feet, is typical of the syndrome. Excessive sweating, as well as thickened skin on the palms and soles of the feet (hyperkeratosis), also manifest. Increased levels of skin pigmentation are also common. Benign, wart-like skin tumours (papillomatas) may present in late childhood. Tooth enamel may be defective.

Brittle bones (osteoporosis) is common in adolescents and adults with Costello syndrome.

Some adults develop gastroesophageal reflux, a condition in which the stomach contents leak into the lower part of the oesophagus. Structural abnormalities in the cerebellum (Arnold-Chiari malformation) have also been reported in adults with the syndrome.

Both benign and malignant tumours are common. There is an increased risk of people with the disease developing a malignant tumour at some stage in their lives. The most common malignantant tumours include those in the connective tissue (rabdomyo sarcoma), nerve tissue (neuroblastoma) and the bladder. Tumours can develop from childhood onwards. During the teens and adulthood, benign, wart-like tumours and breast tumours (fibroadenomas) may develop.

Diagnosis

The diagnosis Costello syndrome is based on a clinical examination and confirmed by DNA-based testing. In between 80 to 90 per cent of cases it is possible to prove mutations in the HRAS gene.

When it is not possible to establish a mutation in HRAS, the diagnosis should be re-evaluated. In such cases, other syndromes within the RAS-MAPK group of diseases should be considered as alternative diagnoses, for example cardiofaciocutaneous syndrome (CFC).

At the same time that the diagnosis is made the family should be offered genetic counselling.

Treatment/interventions

Currently, there is no cure for Costello syndrome although early intervention is important in alleviating symptoms and preventing complications. As many organ systems can be affected, treatment may require the coordinated efforts of a team of specialists. Treatment should be directed towards the specific needs of each individual and his or her family.

Parents of children who have feeding problems require early contact with a dietician and a speech therapist to establish good feeding routines. For very young children, a feeding tube through the nose may be essential for a period. Some children may need to be fed via a PEG (percutaneous endoscopic gastrostomy), in which a tube is passed into a patient’s stomach through the abdominal wall. Gastroesophageal reflux and blockages in the lower cardia sometimes require surgical intervention. Constipation can be eased by increasing the fibre content in the diet.

Congenital heart defects can be diagnosed by ultrasound examinations. The type and severity of the disorder determine the treatment. A severe constriction of the pulmonary valve (pulmonary stenosis) may require either an immediate balloon angioplasty procedure or an operation. In a balloon angioplasty a catheter is passed into the body through a blood vessel in the groin and is placed in the constricted valve. The balloon is then inflated so that the constricted area is widened. If the constriction is less severe this procedure can be carried out later in childhood. When the heart defect is caused by a thickening of the heart muscle, in some cases medication can be helpful, while in others an operation may be necessary. In rare cases a pacemaker is necessary.

Deformities of the fingers and joints of the hand require a brace and/or occupational and physical therapy. Limited extension in the larger joints should be addressed early through physical therapy, by practising stretching exercises and repeating wide-ranging movements. Shortened tendons, particularly Achilles tendons, may require surgery to lengthen them. Changes to the skeleton, including abnormal curvature of the spine, may sometimes also require surgical intervention. As young people with the syndrome often have brittle bones, measurements of bone density should be carried out and medication prescribed if required.

In cases of epileptic seizures the underlying cause should be investigated. Epilepsy can be treated with medication.

Boys whose testicles have not descended into the scrotum require early surgery.

Regular ultrasound examinations are important to detect malignant tumours at an early stage. Benign skin tumours can be unsightly and may easily be removed if they cause problems for the individual.

It is important that vision is checked regularly. Squints may be treated by covering the normal eye with a patch in order to train the affected eye. Some children require spectacles. Drooping eyelids (ptosis) can be corrected by surgery if caused by poor muscle function.

Children require enhanced preventive dental care and frequent visits to the dentist. In certain cases and to prevent possible problems, antibiotics can be given to people with heart defects prior to dental treatment which may cause bleeding. This is because bacteria in the oral cavity can sometimes cause infections affecting the heart (endocarditis).

Habilitation

The child and his/her family require early contact with a habilitation team made up of professionals with special expertise in how disability affects everyday life, health and development. Support and treatment take place within the medical, educational, psychological, social and technical fields. Habilitation also covers visual disabilities. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information on support offered by the local authority, and advice on adapting accommodation and other environments. The family may also need help in coordinating interventions.

Habilitation is planned and implemented in collaboration between the child, the parents and personnel from the preschool or school, and is adapted to the child’s abilities and limitations. The objective is that a young person or adult should be able to participate in the life of the community on his or her own terms.

It is important that the child is given opportunities to develop communication and language skills from an early age. For that reason language skills should be stimulated by AAC (augmentative and alternative communication, a collective term for non-verbal communication).

Physical exercise to stimulate motor skills and to prevent or slow the development of joint deformities is important.

The local authority can offer different forms of support to facilitate the family’s everyday life. Respite care can, for example, take the form of a contact family or short-term accommodation outside the home.

Adults

Adults with Costello syndrome may require continued individual medical treatment, habilitation and support in their daily lives. This may take the form of support and care in accommodation offering specialist services and daily activities.

Practical advice

--

National and regional resources in Sweden

Paediatric cardiac operations are carried out at The Queen Silvia Children’s Hospital in Gothenburg and at Skåne University Hospital in Lund. Units for paediatric cardiology are located in the paediatric clinics of Sweden’s regional hospitals.

There are paediatric neurology departments at Swedish county and regional hospitals.

Resource personnel

Professor Göran Annerén, Department of Clinical Genetics, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 59 42, fax: +46 18 611 55 25, email: goran.anneren@igp.uu.se.

Associate Professor Marie-Louise Bondeson, Department of Clinical Genetics, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 59 39, fax: +46 18 55 40 25, email: marielouise.bondeson@igp.uu.se.

Courses, exchanges of experience, recreation

--

Organizations for the disabled/patient associations

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Gävlegatan 18 C, Stockholm. Mailing address: Box 6436, SE-113 82 Stockholm, Sweden. Tel; +46 8 508 866 00, email: fub@fub.se, www.fub.se.

There is an international association, The Costello Syndrome Support Group: http://costellokids.com.

Courses, exchanges of experience for personnel

--

Research and development (R&D)

Research into Costello syndrome is taking place in Europe and the US. In Sweden, research into RASopathies is underway at the Department of Clinical Genetics at Uppsala University Hospital. Clinical trials are taking place to establish whether chemotherapy as used in cancer treatment can alleviate some of the symptoms of RASopathies.

Information material

An information leaflet on Costello syndrome summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2011-8-5). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

The website of the Costello Syndrome Support Group contains information in English: http://costellokids.com.

Literature

Aoki Y, Niihori T, Kawame H, Ohashi H, Tanaka Y, Filocamo M et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 2005; 37: 1038-1040.

Axelrad ME, Schwartz DD, Katzenstein JM, Hopkins E, Gripp K. Neurocognitive, adaptive, and behavioral functioning of individuals with Costello syndromes: a review. Am J Med Genet 2011; 157: 115-122.

Costello JM. A new syndrome: mental subnormality and nasal papillomata. Austr J Paediatr 1977; 13: 114-118.

Gripp KW. Tumour predisposition in Costello syndrome. Am J Med Genet 2005; 137: 72-77.

Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI, Doyle D et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet 2006; 140: 1-7.

Gripp KW, Innes AM, Axelrad ME, Gillan TL, Parbossingh JS, Davies C et al. Costello syndrome associated with novel germline mutations: an attenuated phenotype? Am J Med Genet 2008; 146: 683-690.

Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg, PS. Cancer in Noonan, Costello, Cardiofaciocuteneous and LEOPARD syndromes. Am J Med Genet 2011; 157: 83-89.

Rauen KA, Banerjee A, Bishop WR, Lauchle JO, McCormic F, McMahon M et al. Costello and Cardio-Facio-Cutaneous Syndromes: Moving toward clinical trials in RASopaties. Am J Med Genet 2011; 157: 136-146.

White SM, Graham JM, Kerr B, Gripp K, Weksberg R, Cytrynbaum C et al. The adult phenotype in Costello syndrome. Am J Med Genet 2005; 136: 128-135.

Database references

OMIM (Online Medelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: costello syndrome

GeneReviews (University of Washington)
www.genetests.org (click on GeneReviews, then Titles)
Search: costello syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Marie-Louise Bondeson, Uppsala University Hospital, Sweden.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2011-12-29
Version: 1.0
Publication date of the Swedish version: 2011-10-03

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.