Costello Syndrome: Signs, Diagnosis, Cancer Risk, Treatment
Rare RASopathy with distinctive facial features, loose skin, cardiac issues, and cancer risk—key insights into diagnosis and management.
Author: Dr. Amanda Oakley, Dermatologist, Hamilton, New Zealand. Reviewed: January 2026.
Introduction
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 classified as a RASopathy, resulting from a paternal-origin heterozygous germline mutation of the HRAS proto-oncogene on chromosome 11p15.5. Mutations at amino acid positions 12 and 13 of HRAS account for the vast majority of cases, leading to constitutive activation of the Ras/MAPK pathway.
The estimated birth prevalence is 1 in 300,000, though it may be underdiagnosed due to phenotypic overlap with other RASopathies like Noonan and cardiofaciocutaneous (CFC) syndromes.
Who gets Costello syndrome? (Epidemiology)
Costello syndrome affects males and females equally. Nearly all cases (about 99%) arise from de novo mutations, with rare familial inheritance reported, including male-to-male transmission in mosaic cases.
Diagnosis often occurs in infancy due to feeding difficulties and failure to thrive, but milder mosaic variants may present later, as in a reported 31-year-old woman with progressive skin changes.
Causes
Costello syndrome results from germline heterozygous mutations in the HRAS gene, predominantly c.34G>A (p.Gly12Ser) or c.37G>A (p.Gly13Asp).
These gain-of-function mutations cause hyperactivation of the Ras/MAPK signaling pathway, disrupting cellular processes including growth, differentiation, and survival. This pathway dysregulation explains the multisystem involvement, ectodermal defects, and cancer predisposition.
Mosaic HRAS variants can produce atypical features like streaky hyperpigmentation or unusually severe skin laxity.
Clinical features
Costello syndrome manifests across multiple systems, with core features including:
- Failure to thrive: Severe prenatal and postnatal growth retardation; birth weight often <2500g despite term delivery.
- Distinctive facies: Coarse features with full forehead, downslanting palpebral fissures, ptosis, epicanthal folds, low-set ears, depressed nasal bridge, wide mouth with full lips, and macroglossia.
- Neurological: Mild-to-moderate intellectual disability (IQ 20–60), hypotonia, motor delays, ataxia, and increased risk of seizures.
- Cardiac: Hypertrophic cardiomyopathy (60–75%), arrhythmias, mitral valve dysplasia, and pulmonary stenosis.
- Musculoskeletal: Joint laxity, tight Achilles tendons, scoliosis, foot deformities (e.g., hindfoot valgus), and osteopenia.
Dermatological manifestations
Ectodermal defects are prominent and often diagnostic, distinguishing Costello syndrome from other RASopathies.
Main skin features include:
- Loose anetodermic skin (cutis laxa): Velvety, redundant skin on neck, trunk, palms, soles, hands, and feet; deep palmar/plantar creases; improves slightly with age.
- Cutaneous papillomas: Occur in 72% (33/46 patients), onset infancy to 22 years; perinasal (most common), eyelids, ears, neck, fingers, perianal; more frequent than in CFC (72% vs 5%, p<0.001).
- Palmoplantar keratoderma: Hyperkeratotic, yellow-orange plaques on palms/soles (76%); pachydermatoglyphy (stippled fingertips, 31%).
- Acanthosis nigricans: Velvety hyperpigmented plaques in flexures (37%).
- Other: Hyperpigmentation (generalized or mottled along Blaschko lines), curly/sparse hair, low posterior hairline.
Nail defects: Slow-growing, dystrophic fingernails—toenails less affected; triangular lunulae, longitudinal ridging, hypoplasia.
Hair changes: Sparse, curly, slow-growing scalp hair; full thick eyebrows (unlike sparse in CFC); eyelashes normal or curly.
| Feature | Prevalence in CS | Comparison to CFC |
|---|---|---|
| Cutaneous papillomas | 71.7% | 4.9% (p<0.001) |
| Palmoplantar keratoderma | 76.1% | 36.1% (p<0.001) |
| Loose/redundant skin hands/feet | Common | Less prominent |
| Stippled dermatoglyphs | 31% | Rare |
| Acanthosis nigricans | 37% | Less frequent |
Diagnosis
Diagnosis combines clinical findings with genetic confirmation of HRAS mutation via sequencing of blood or saliva DNA.
Clinical criteria (supportive): Characteristic facies + ≥3 of: failure to thrive, loose skin, heart defects, papillomas/keratoderma, developmental delay.
Echocardiogram, skeletal survey, brain MRI, and tumor screening recommended at diagnosis.
Differential diagnoses
Phenotypic overlap with other RASopathies requires genetic testing to differentiate:
- Noonan syndrome: PTPN11/SOS1 mutations; milder skin laxity, no papillomas, pulmonary stenosis common.
- Cardiofaciocutaneous (CFC) syndrome: BRAF mutations; sparse eyebrows/lashes, keratosis pilaris, sparse curly hair; fewer papillomas.
- Cutis laxa syndromes: Gerodermia osteodysplastica (wrinkly skin, osteoporosis); arterial tortuosity syndrome.
- Mosaic disorders: Linear nevus sebaceous syndrome (NS), pigmentary mosaicism (Blaschko lines).
Risk of cancer
Increased malignancy risk (15–20%): rhabdomyosarcoma (most common, esp. embryonal), neuroblastoma, bladder/urothelial carcinoma.
Benign tumors: papillomas (72%), skin tags. Ras hyperactivation mimics paraneoplastic syndromes (e.g., tripe palms, acanthosis).
Screening: Abdominal/chest MRI q6–12mo until age 5, then annually; echocardiogram, urinalysis, blood pressure monitoring.
Treatment
Multidisciplinary: genetics, cardiology, dermatology, endocrinology, oncology, developmental pediatrics.
- Skin: Emollients for xerosis; salicylic acid/urea for keratoderma; cryotherapy/electrocautery for papillomas (recur).
- Growth: Gastrostomy tube if feeding issues; growth hormone trialed (monitor cancer risk).
- Cardiac: Beta-blockers, pacing for cardiomyopathy.
- Orthopedic: PT/OT for joint contractures; surgery for scoliosis.
- Cancer surveillance: As above; sirolimus (mTOR inhibitor) investigated for Ras pathway modulation.
Investigations
To confirm diagnosis and guide management:
- Genetic testing: HRAS sequencing (blood).
- Echocardiogram: Baseline and serial for cardiomyopathy.
- Abdominal ultrasound/MRI: Tumor screening.
- Brain MRI: If seizures/hydrocephalus.
- Dual-energy X-ray absorptiometry (DEXA): Osteopenia.
Prognosis
Life expectancy reduced due to cardiac complications and cancer; many survive to adulthood with support. Mosaic cases may have milder course.
Frequently asked questions
What is Costello syndrome?
A rare RASopathy from HRAS mutations causing coarse facies, loose skin, heart defects, delays, and tumors.
Is Costello syndrome inherited?
Usually de novo (sporadic); rare autosomal dominant inheritance, sometimes mosaic.
Do papillomas in Costello syndrome become cancerous?
Benign but indicate Ras dysregulation; monitor for rhabdomyosarcoma/neuroblastoma.
How is Costello syndrome diagnosed?
Clinical features + HRAS genetic testing; differentiate from Noonan/CFC.
What is the cancer risk in Costello syndrome?
15–20%; screen regularly for rhabdomyosarcoma, neuroblastoma, bladder cancer.
References
- Dermatological Phenotype in Costello Syndrome — Siegel et al., NIH/PMC. 2014-05-15. https://pmc.ncbi.nlm.nih.gov/articles/PMC4063554/
- Costello syndrome with special cutaneous manifestations — Zhang et al., NIH/PMC. 2021-06-15. https://pmc.ncbi.nlm.nih.gov/articles/PMC8222857/
- Costello syndrome — DermNet NZ. 2023-01-01. https://dermnetnz.org/topics/costello-syndrome
- Costello Syndrome — National Organization for Rare Disorders (NORD). 2024-01-01. https://rarediseases.org/rare-diseases/costello-syndrome/
- Costello Syndrome: Symptoms, Causes, Diagnosis & Treatment — Cleveland Clinic. 2025-01-01. https://my.clevelandclinic.org/health/diseases/costello-syndrome
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