Author: V.N.Hiromel de Silva, Dermatology Registrar, Waikato Hospital, Hamilton, New Zealand, 2008. Updated by Dr Arun Gangakhedkar, Paediatrician, Waitemata District Board, Auckland. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. November 2018.
Costello syndrome is a rare genetic condition in which affected individuals have a distinct facial appearance, curly hair, loose skin, cardiac abnormalities, and cognitive delay.
Costello syndrome is also known as faciocutaneoskeletal syndrome. It is one of the rasopathies.
Normal individuals have 23 pairs of chromosomes in every cell with several genes present in specific positions on each chromosome. Each chromosome from the chromosomal pair has a copy of the gene, one copy inherited from each parent. The genes determine the synthesis of specific proteins that control the structure and function of each cell in the body. An abnormal change in the gene structure is called a mutation.
Costello syndrome is a rasopathy. it results from a paternal-origin heterozygous germline mutation of the HRAS gene present on chromosome 11p15.5. The mutations are restricted to a narrow spectrum on the p.Gly12Ser residue of the HRAS gene. HRAS gene normally controls cellular differentiation and function.
Costello syndrome typically results from a de novo mutation so there is no family history of the disorder. Affected individuals do not go on to have children, but there would be a 50% chance of having affected progeny if they were to reproduce. Men and women are affected equally [1–8].
The symptoms of Costello syndrome evolve over a period of time and developmental delay is common. The key clinical features are:
Perinatal features may include:
Hyperpigmentation of skin with deep creases and loose skin on the hands and feet should raise the clinical suspicion of Costello syndrome during infancy. Other features that can occur throughout the patient's life can include:
*Image courtesy Genetics 4 Medics
Ectodermal defects involving skin, hair, nails, and mucosal changes are common and often discriminating.
The main dermatological manifestations of Costello syndrome can include:
Slow growing, triangular, and brittle dystrophic fingernails with longitudinal striations.
Alopecia may be seen but this is a more common feature in cardio-facio-cutaneous syndrome. Hair loss with skin changes gives a prematurely aged appearance in adults.
Generalised hyperpigmentation of skin is seen in a third of the affected individuals; acanthosis nigricans is reported in a third with velvety plaques of on the neck and flexural areas and sometimes on posterior earlobes, these can be verrucous in older individuals.
Oral examination for gingival hypertrophy and mucocutaneous lip papules is important, as these are distinct features of Costello syndrome.
Over half of individuals with Costello syndrome do not like sun exposure or were extremely photosensitive, and three-quarters of affected individuals report heat intolerance.
Prenatal diagnosis is suspected from the perinatal phenotypic features; antenatal confirmative HRAS gene mutation testing has been reported.
Postnatal diagnosis is confirmed by identifying the HRAS mutations. Over 80% of affected individuals have mutations affecting the p.Gly12Ser residue, less commonly p.Gly12A. Rare mutations associated with either a mild or severe phenotype have been described.
Routine chromosomal microarray and karyotype may be non-diagnostic [1–13].
Overgrowth syndromes such as Beckwith-Weideman syndrome and Simpson-Golabi-Behmel syndrome with macrosomia and hypoglycemia may be confused with Costello syndrome in the neonatal period.
Congenital myopathy syndromes with hypotonia may also be mistaken for Costello syndrome.
Like Costello syndrome, other rasopathy syndromes such as Noonan syndrome, cardio-facio-cutaneous syndrome, and Noonan syndrome-like disorder with loose anagen hair syndrome, may also manifest with neonatal macrosomia, coarse facial features, pigmented skin changes, hair abnormalities, failure to thrive, and developmental delay.
Some somatic mutations in the HRAS gene predispose individuals with Costello syndrome to an increased risk of neoplasms, with a 15% lifetime risk of developing malignant tumours. There is a high risk of developing rhabdomyosarcoma, neuroblastoma, or transitional cell carcinoma of the bladder during childhood and adolescence [1–13].
There is no cure for Costello syndrome. There are recommended general supportive measures for managing the syndrome.
Surveillance and routine skin care should be undertaken to ensure timely recognition, diagnostic evaluation, and prompt therapy.
Genetic counselling should be offered to all the families with affected children so that they may understand the risk of Costello syndrome in future pregnancies. The risks of neoplasm and surveillance should be discussed. The implications to progeny of the affected individuals in the childbearing age should be discussed [1–13].
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