Abstract
CLINICAL CHARACTERISTICS
While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.
DIAGNOSIS/TESTING
The diagnosis of Costello syndrome is established in a proband with suggestive clinical findings and a heterozygous HRAS pathogenic variant identified by molecular genetic testing.
MANAGEMENT
Treatment of manifestations: Failure to thrive is the most common and challenging clinical problem; most infants require nasogastric or gastrostomy feeding; many require Nissen fundoplication. Treatment of cardiac manifestations and malignancy is routine. Ulnar deviation of the wrists and fingers often requires early bracing and occupational and/or physical therapy; tight Achilles tendons may require surgical tendon lengthening. Developmental disability requires early-intervention programs and individualized education strategies. Recurrent facial papillomata may require routine removal with dry ice. Hemodynamically significant valvar stenoses require antibiotic prophylaxis for subacute bacterial endocarditis; anesthesia may pose a risk to those with hypertrophic cardiomyopathy or those predisposed to some types of atrial tachycardia. Surveillance: Monitoring for neonatal hypoglycemia; echocardiography with electrocardiogram at diagnosis with subsequent follow up by a cardiologist who is aware of the spectrum of cardiac disease and its natural history; abdominal and pelvic ultrasound examinations to screen for rhabdomyosarcoma and neuroblastoma every three to six months until age eight to ten years may be considered; annual urinalysis for evidence of hematuria to screen for bladder cancer beginning at age ten years.
GENETIC COUNSELING
Costello syndrome is inherited in an autosomal dominant manner. To date, most probands with Costello syndrome have the disorder as the result of a de novo pathogenic variant; although parents of probands are not affected, vertical transmission has been reported in two families with the rare, attenuated phenotype. Because Costello syndrome is typically caused by a de novo pathogenic variant, the risk to the sibs of a proband is presumed to be small; however, recurrence in sibs has been reported and is suspected to be the result of germline mosaicism in a parent. Individuals with Costello syndrome typically do not reproduce. Once an HRAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
TY - CHAP
T1 - Costello Syndrome
BT - GeneReviews®
A1 - Gripp,Karen W,
AU - Rauen,Katherine A,
Y1 - 1993///
PY - 2019/8/29/pubmed
PY - 2019/8/29/medline
PY - 2010/3/20/entrez
KW - GTPase HRas
KW - HRAS
KW - Costello Syndrome
N2 - CLINICAL CHARACTERISTICS: While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. DIAGNOSIS/TESTING: The diagnosis of Costello syndrome is established in a proband with suggestive clinical findings and a heterozygous HRAS pathogenic variant identified by molecular genetic testing. MANAGEMENT: Treatment of manifestations: Failure to thrive is the most common and challenging clinical problem; most infants require nasogastric or gastrostomy feeding; many require Nissen fundoplication. Treatment of cardiac manifestations and malignancy is routine. Ulnar deviation of the wrists and fingers often requires early bracing and occupational and/or physical therapy; tight Achilles tendons may require surgical tendon lengthening. Developmental disability requires early-intervention programs and individualized education strategies. Recurrent facial papillomata may require routine removal with dry ice. Hemodynamically significant valvar stenoses require antibiotic prophylaxis for subacute bacterial endocarditis; anesthesia may pose a risk to those with hypertrophic cardiomyopathy or those predisposed to some types of atrial tachycardia. Surveillance: Monitoring for neonatal hypoglycemia; echocardiography with electrocardiogram at diagnosis with subsequent follow up by a cardiologist who is aware of the spectrum of cardiac disease and its natural history; abdominal and pelvic ultrasound examinations to screen for rhabdomyosarcoma and neuroblastoma every three to six months until age eight to ten years may be considered; annual urinalysis for evidence of hematuria to screen for bladder cancer beginning at age ten years. GENETIC COUNSELING: Costello syndrome is inherited in an autosomal dominant manner. To date, most probands with Costello syndrome have the disorder as the result of a de novo pathogenic variant; although parents of probands are not affected, vertical transmission has been reported in two families with the rare, attenuated phenotype. Because Costello syndrome is typically caused by a de novo pathogenic variant, the risk to the sibs of a proband is presumed to be small; however, recurrence in sibs has been reported and is suspected to be the result of germline mosaicism in a parent. Individuals with Costello syndrome typically do not reproduce. Once an HRAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
PB - University of Washington, Seattle
CY - Seattle (WA)
UR - https://www.unboundmedicine.com/prime/citation/20301680/GeneReviews®:_Costello_Syndrome
L2 - https://www.ncbi.nlm.nih.gov/books/NBK1507
DB - PRIME
DP - Unbound Medicine
ER -
