Faciocutaneoskeletal Syndrome (Costello Syndrome)

Etiology

Costello syndrome is caused by germline heterozygous pathogenic variants in the HRAS gene on locus 11p15.5. Most cases of Costello syndrome are due to missense mutations, although some cases have been attributed to deletions and duplications involving the HRAS gene.[4] The most common variant is c.34G>A, which results in p.Gly12Ser substitution in the protein product and is seen in about 80% of Costello syndrome cases. In contrast, the second most common pathogenic variant results in a p.Gly12Ala substitution.[4][10] Certain pathogenic variants of Costello Syndrome have been associated with an increased rate of malignancy and severe cardiac and pulmonary involvement.[3][4] 

Epidemiology

Costello syndrome is autosomal dominant and has no predisposition to sex. Most cases noted have arisen de novo, and most pathogenic variants are on the paternal chromosome, suggesting a paternal parent of origin.[11] An increased incidence is also noted with advanced paternal age. Therefore, Costello syndrome is also labeled as one of the Paternal Age Effect disorders.[11][12] Costello syndrome is a rare RASopathy compared to neurofibromatosis and Noonan syndrome, with a prevalence in the United Kingdom of 1:380,000.[13] The frequency of Costello in Japan is much less than in the United Kingdom, occurring at 1:1,290,000.[14] 

According to Kratz and colleagues (2015), children with Costello syndrome face a significantly heightened cancer risk, being 42.4 times more likely to develop cancer compared to their peers. The most commonly reported solid tumors in childhood include neuroblastoma and rhabdomyosarcoma, whereas bladder carcinoma tends to appear in adolescence and adulthood.[15]

Pathophysiology

The HRAS gene is located on chromosome 11p15.5 and codes for HRAS. HRAS is a protein that regulates cell growth and replication in the RAS/MAPK pathway.[16] HRAS is inactive when bound to GDP and activated when bound to GTP. It has intrinsic GTPase activity, which is stimulated by the GTPase activating proteins (GAPs) to convert back to its inactive form.[17] Heterozygous pathogenic variants at codons 12 and 13 are gain-of-function variants that cause reduced GAP-induced GTPase activity. The glycine molecules at codons 12 and 13 are essential for binding GTP.[18] This leaves the Ras in an activated state, reducing the regulation of growth and replication.[7][16][19][20]

History and Physical

Similar to other RASopathies, Costello syndrome affects many systems, just like other RASopathies. Although no diagnostic clinical criterion has been established, the following clinical features raise suspicion for Costello syndrome outlined below:

• Prenatal and perinatal findings
  • Polyhydramnios
  • Increased nuchal translucency
  • Ulnar deviation of the wrists
  • Short long bones (humeri and ulnar)
  • Fetal arrhythmia
  • Increased birth head circumference
  • Increased birth weight
  • Neonatal hypoglycemia
• Craniofacial features
  • Relative macrocephaly
  • Low-set posteriorly rotated ears
  • Relatively high forehead
  • Full, thick eyebrows
  • Dolichocilia
  • Epicanthic folds
  • Down-slanted palpebral fissures
  • Wide nasal bridge
  • Short nose
  • Wide mouth
  • Full lips
  • Coarse facial features
• Neurological and behavioral features
  • Autism spectrum disorder
  • Sociable personality (in late childhood and adolescence)
  • Megalencephaly
  • Mild to moderate developmental delay/intellectual disability (sometimes severe)
  • Seizures
  • Chiari I malformation
  • Syringomyelia
  • Hydrocephalus
• Ocular features
  • Refractive errors (eg, myopia, hyperopia, or astigmatism)
  • Strabismus
  • Nystagmus
  • Optic nerve anomalies
  • Ptosis
  • Retinal dystrophy (rare)
  • Bilateral anterior chamber plaque (rare)
  • Anterior lenticular opacities (rare)
• Cardiovascular features
  • Hypertrophic cardiomyopathy
  • Chaotic atrial tachycardia (usually supraventricular tachycardia)
  • Valvular pulmonic stenosis
  • Aortic dilation
  • Mitral valve defects
• Respiratory features
  • Adenoid/tonsillar hypertrophy
  • Pharyngomalacia
  • Laryngomalacia
  • Tracheo-bronchiomalacia
  • Bronchopulmonary dysplasia
  • Bronchiectasis
  • Lung hypoplasia
  • Pulmonary vascular dysplasia
  • Obstructive sleep apnea
• Ectodermal features
  • Sparse or curly hair, or both
  • Papillomata (perinasal, perianal)
  • Premature ageing
  • Acanthosis nigricans
  • Loose and soft skin
  • Deep palmar and plantar creases
  • pachydermatoglyphia
  • Hyperkeratosis
  • Unusual body odor
• Musculoskeletal findings
  • Ulnar deviation of the wrists and fingers
  • Hypotonia
  • Joint laxity
  • Kyphoscoliosis
  • Six lumbar vertebrae
  • Pectus carinatum, pectus excavatum
  • Hip dysplasia
  • Tight Achilles tendons
  • Vertical talus
  • Pes planus
  • Decreased bone mineral density
• Gastrointestinal features
  • Pyloric stenosis
  • Feeding difficulties (suckling and swallowing) until 2 to 4 years of age
  • Gastro-oesophageal reflux
  • Preference for strong tastes at the initiation of oral feeds
• Endocrine features
  • Growth hormone deficiency (partial or complete)
  • Cortisol deficiency
  • Short stature
  • Delayed bone age
  • Delayed/dysregulated puberty
  • Neonatal hyperinsulinism
• Genito-urinary features
  • Echogenic kidneys
  • Ectopic kidney(s)
  • Dilated renal pelvis
  • Hydronephrosis
  • Bladder stones
  • Cryptorchidism
  • Hypoplastic or prominent labia minora
• Oncological features
  • Rhabdomyosarcoma
  • Neuroblastoma
  • Transition cell bladder carcinoma [3][7][4]

Evaluation

Molecular Testing

Costello syndrome can be diagnosed clinically. However, having molecular diagnostic confirmation to clarify the risks based on the documented genotype-phenotype correlations is essential.[3] Most pathogenic variants are missense mutations; therefore, sequencing of the HRAS gene yields a greater yield in detecting pathogenic variants than other genetic testing modalities. If no pathogenic variants are detected, clinicians should evaluate the differential diagnoses of Costello syndrome. 

Prenatal Evaluation

Key diagnostic indicators that may suggest Costello syndrome in utero include polyhydramnios, which is common in many pregnancies, supraventricular tachycardia, increased nuchal translucency, macrosomia, and macrocephaly (typically observed after 20 weeks gestation), and unusual fetal posture. Additionally, the reduced length of long bones has been noted. Fetal arrhythmias, though rare, usually respond well to treatment. While maternal diabetes is the most common cause of polyhydramnios associated with fetal macrosomia, other causes (eg, Costello syndrome) should be considered once diabetes is ruled out.[21]

A distinguishing feature for gynecologists in differential diagnosis is that fetuses with Costello syndrome tend to have increased head size and body weight, but their length remains within the normal range. This is likely because the macrosomia is primarily due to subcutaneous edema rather than true overgrowth.

 Additional Diagnostic Studies

Electrocardiographic (ECG) anomalies, such as arrhythmias—typically supraventricular tachycardia—can manifest both in fetal and postnatal life. While HCM is generally not present before birth, it develops later. Consequently, a thorough cardiac evaluation, including echocardiography, ECG, and cardiological assessment, should be routinely conducted from birth to monitor the development of HCM and any rhythmic abnormalities.[22]

Treatment / Management

Management of Costello syndrome requires an interprofessional approach because its effects on the body are multi-systemic. In children with Costello syndrome, the core disciplines involved in managing Costello syndrome include gastroenterology and endocrinology; neurologists and neurodevelopmental specialists; cardiology and pulmonology; and ophthalmology. The auxiliary disciplines that assist in the management of the pediatric population include orthopedics, dermatology, and oncology for tumor surveillance.[4] In adults with Costello syndrome, the core managing specialties are dermatology, orthopedics, and oncology (for tumor surveillance), while the auxiliary disciplines include gastroenterology, endocrinology, neurology, cardiology, pulmonology, and ophthalmology.(B3)

Cardiologists should be part of the interprofessional team from birth to determine appropriate timing and follow-up strategies, considering the progression of a cardiac phenotype marked by HCM and arrhythmias. Cardiology visits are essential for monitoring cardiac function using electrocardiography, echocardiography, and Holter monitoring, especially in the first 2 years of life. The cardiologist monitors the progression or regression of chaotic atrial tachycardia, HCM, left ventricular outlet tract (LVOT) obstruction, pulmonic valve stenosis, and other cardiovascular diseases noted on the cardiac workup. Treatment for cardiac abnormalities should follow established guidelines. Additionally, pulmonological assessments are recommended starting at pediatric age to rule out obstructive sleep apnea or other pulmonary issues, particularly in cases involving rare variants with more severe phenotypes.

HCM can vary in progression, with cases showing reversal, resolution, or worsening. Pharmacological treatment is usually the first-line therapy for progressive HCM, but in some instances, it may not be sufficient to halt its progression. Surgical treatment (eg, septal myectomy) is indicated in progressive hypertrophic cardiomyopathy and pulmonary valvuloplasty. Newer therapeutic options (eg, Trametinib) are promising in various case series of hypertrophic cardiomyopathy in Costello syndrome.[23][24]

Patients with Costello syndrome need neurological evaluation at birth and regularly in childhood. Cognitive performance and adaptive behavior for age will need to be assessed annually during the pediatric period. Imaging the brain and spine for structural abnormalities is according to the patient's symptoms. Other healthcare specialists involved in the management of Costello syndrome include gastroenterological and nutritional specialists, especially because patients with Costello syndrome have feeding difficulties in the first 2 to 4 years of life and may need to be fed with a gastrostomy tube or a nasal gastric tube after which they start to tolerate oral feeds with a preference for intense flavors (eg, ketchup). Therefore, a pediatric follow-up is needed every 3 to 6 months and annually in adulthood. Endocrinology visits are required to assess the growth failure as well as the endocrinological complications of Costello syndrome.

Differential Diagnosis

Several conditions have features that overlap with Costello syndrome, including:

• Noonan syndrome
• Cardiofaciocutaneous syndrome
• Noonan syndrome with multiple lentigines
• Lysosomal storage disorders

Some of the clinical features that distinguish Costello syndrome from other RASopathies or occur more in Costello Syndrome than other RASopathies include coarser facial features, increased incidence of feeding difficulties, facial and perianal papillomata, increased incidence of multifocal atrial tachycardia, ulnar deviation of the wrists, tight Achilles tendons, and increased incidence of malignant solid tumors (eg, rhabdomyosarcoma, neuroblastoma, and transition cell bladder carcinoma).[6][7]

Prognosis

People living with classic Costello syndrome can grow into adulthood and generally have a good quality of life with a few impediments, which include lack of independence, social relationships, male sex, and major medical issues.[25] The major medical issues documented include cardiovascular pathologies (eg, arrhythmias and hypertrophic cardiomyopathy), gastroesophageal reflux disease with or without Chiari malformation, concerns with vision, low bone density, anxiety, and the development of tumors, particularly transitional cell carcinoma of the bladder.[3][26] Although the life expectancy of people living with Costello syndrome has not been documented or properly studied, several studies have shown that they can live until their 40s. The oldest person known to have Costello syndrome died suddenly at the age of 47; unfortunately, no autopsy was performed.[3][27]

Complications

Several complications of Costello syndrome need to be prevented with regular follow-up, and these include:

• Failure to thrive
• Heart failure if the cardiac manifestations are progressive and not well-controlled
• Malnutrition, especially in infancy and early childhood
• Seizures or epilepsy
• Development of malignant tumors (eg, rhabdomyosarcoma, neuroblastoma, and transition cell bladder carcinoma)
• Psychiatric illnesses (eg, anxiety and depression)