Download Costello Syndrome - South West Thames Regional Genetics Service

SW Thames Molecular Genetics Diagnostic Laboratory
Sheet code: DISINFCOS.01
Medical Genetics Unit,
St George's,
Cranmer Terrace,
London SW17 0RE
Tel: 020 8725 5964 / 1098
Fax: 020 8725 2138
Web: www.southwestthamesgenetics.nhs.uk
Email: [email protected]
SW Thames Molecular Genetics Diagnostic Laboratory
UKGTN member
Costello Syndrome
Introduction
Costello Syndrome (MIM#218040) also known as Faciocutaneoskeletal syndrome (FCS) is a multiple
congenital anomaly and mental retardation syndrome that overlaps phenotypically with Noonan Syndrome (NS)
and with Cardio-Facio-Cutaneous (CFC) Syndrome. It is associated in all cases with a characteristic coarse
facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive.
Other features include curly hair, thick and loose skin of the hands and feet, papillomata around the nose and
mouth, mental retardation, cardiomyopathy, and an increased risk of malignancy.
Most referrals are expected to be children but some adults may also be referred. The majority of cases are
sporadic in origin. Costello syndrome is very rare with an estimated 250 cases worldwide.
HRAS has four coding exons (exons 2, 3, 4 and 5) and Aoki et al. (Nature Genetics, 37:1038-1040, 2005) found
heterozygous, de novo mutations in the HRAS gene in 12 of 13 Costello Syndrome patients. The mutations
were all located in exon 2 in either codon 12 or 13 and mutations in exons 3 and 4 (common Lys117Arg
mutation) have also been observed.
Mutations in BRAF, KRAS , MEK1 and MEK2 have also been identified in ‘CS’ like patients
Referrals
?
Diagnostic testing - Individuals with a possible diagnosis of Costello or CFC syndrome. Samples
received from individuals with characteristic features of Costello syndrome will be appropriate for analysis. In
practice, due to the high degree of phenotypic overlap with other syndromes of the MAPK pathway particularly
CFC syndrome, it is difficult to restrict analysis by phenotype alone, so referrals for CFC will also be accepted
on occasion.
? Confirmation testing- individuals where a mutation has been identified in a research laboratory
? Familial testing Individuals with a familial mutation in the HRAS gene
? Prenatal cases in families with a known HRAS mutation both CVS and amniocytes can be analysed in non
de novo cases. Please contact the laboratory to discuss each case prior to sending prenatal samples to the
laboratory.
Service offered
Bi-directional sequencing of exons 2, 3, 4and 5 is predicted to be almost 100% sensitive and analysis of exons
2 and 4 are expected to detect 80-90% of cases. Mutations in exon 3 are rare. Exon 5 is included as it is
situation very close to exon 4 and is encompassed within the exon 4 amplicon.
Technical
Screening is carried out by ABI bi-directional sequencing of exons 2, 3, 4 and 5, patients are analysed when
and as they are received
Target reporting time
Diagnostic referrals 8 weeks within white paper reporting guidelines
Confirmation/familial samples within 4 weeks
Prenatals are carried out within 3 working days, please contact the laboratory.
Future development
Other genes for ‘CS’ like patients can be analysed by another laboratory
Samples required
4-8mls venous blood in plastic EDTA bottles (1ml from neonates)
Prenatals must be arranged in advance, through a Clinical Genetics department if possible.
Amniotic fluid or CV samples should be sent to Cytogenetics for dissecting and culturing, with instructions to forward the sample to the
Regional Molecular Genetics laboratory for analysis
A completed DNA request form should accompany all samples (available by on our website at
http://www.southwestthamesgenetics.nhs.uk/molecular_default.asp).
Patient details/GP name and address
To facilitate accurate testing and reporting please provide patient demographic details (full name, date of birth,
Address, postcode and ethnic origin), details of any relevant family history and full contact details for the referring clinician
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Date issued: 20/01/09
Authorised by: RT