Clinical Guidance
HRAS-related Costello syndrome (Costello syndrome) affects multiple organ systems. The typical presentation is characterized by diffuse hypotonia and severe feeding difficulties in infancy; short stature; developmental delay or intellectual disability; characteristic facial features; curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement (including hypertrophic cardiomyopathy [HCM], congenital heart defects, and arrhythmia). Postnatal cerebellar overgrowth can result in Chiari I malformation with associated hydrocephalus or syringomyelia. There is an approximate 15% lifetime risk for malignant tumors in individuals with Costello syndrome including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. To date, more than 100 individuals have been identified with a pathogenic variant in HRAS [, , , , , , ]. The following description of the phenotypic features associated with this condition is based on these reports. Table 2. Costello Syndrome: Frequency of Select Features
Feature | % or # of Persons w/Feature | Comment |
|---|
Failure to thrive | 95% | Failure to thrive is typical in infancy. |
Short stature | 95% | Stature typically remains short, even w/GH treatment. Gastrointestinal/ feeding |
G-tube requirement | 65% | Inability to eat by mouth is common throughout infancy early childhood.; Weight gain remains slow, even w/feeding tube use high caloric intake. Pyloric stenosis |
Hypotonia | 70% | — |
Chiari I malformation | 50% | Chiari I malformation may develop over time. |
Seizures | 25% | Diagnosis of seizures should prompt investigation for hypoglycemia . Cardiac |
Arrhythmia | 55% | — |
HCM | 60% | — |
Pulmonic valve stenosis | 10% | — |
Aortic dilatation | 5%-10% | — |
Atrial septal defects | 5%-7% | — |
Developmental delay | 95% | — |
Intellectual disability | 80% | — |
Anxiety | 65% | Dermatologic |
Papillomata | 50%-60% | — |
Callouses | 65% | Musculoskeletal |
Hip dysplasia | 17%-45% | — |
Osteopenia | 45% | — |
Scoliosis/kyphosis | 17%-75% | Scoliosis kyphosis may increase w/age. |
Ulnar deviation of fingers | 82% | — |
Elbow contractures | 53% | — |
Obstructive sleep apnea | 7/10 | — |
GH deficiency | 45% | — |
Solid tumors (overall risk incl rhabdomyosarcoma, neuroblastoma, transitional cell carcinoma of bladder) | 15% | See . Vision issues |
Nystagmus | 40% | — |
Myopia | 60% | Genitourinary |
Cryptorchidism | 50% of males | — |
Renal anomalies | 50% | Based on , , , , , , , , , Growth. Increased birth weight and head circumference (often 50th centile) for gestational age can lead to the categorization of Costello syndrome as a macrosomia disorder, which is misleading. Increased birth weight is instead related to fetal hydrops. |
Source: GeneReviews — "HRAS-Related Costello Syndrome"
