Multidisciplinary Management of Costello Syndrome: Current Perspectives

Figures & data

Figure 1 HRAS domain structure and pathogenic variants of HRAS identified in patients with Costello syndrome. Upper panel shows missense mutations, and lower panel shows intragenic duplications. More than 90% of pathogenic variants are clustered in codons 12 and 13. It has been shown that mutations at these codons impair the intrinsic GTPase activity, resulting in constitutive activations of downstream effectors.^3,9,136 Reproduced from Aoki Y, Niihori T, Banjo T, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93(1):173–180. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.¹³⁷ The de novo 10-nucleotide-long deletion within the intron-D-exon (IDX) is not shown in the figure.

Table 1 Genotype-phenotype relationships in Costello syndrome with missense HRAS variants, duplications, and deletions

Missense Change	Clinical Description	References
p.Gly12Ser	Classic phenotype of CS; 80% of reported cases	[^Citation3,Citation13]
p.Gly12Ala	Classic phenotype of CS; increased risk of malignancy compared to p.Gly12Ser	[^Citation18]
p.Gly12Val	Severe lethal phenotype: HCM, PVS, conduction disturbances, fetal hydrops, hepatomegaly, excessive amount of neuromuscular spindles. Most patients died before 18 months of age	[^Citation3,Citation23^–^Citation25]
p.Gly12Glu	Severe neonatal phenotype with pleural/pericardial effusion, congenital lung and airway abnormalities, HCM, PVS, cardiomegaly, patent foramen ovale, and conduction disturbances	[^Citation15,Citation17,Citation19^–^Citation21]
p.Gly12Cys
p.Gly12Asp
p.Gly13Asp	Less coarse facial features, slow growing sparse hair, no malignant tumors reported to date	[^Citation3,Citation28,Citation29]
p.Gly13Cys	Less coarse facial features, absence of multifocal atrial tachycardia and ulnar deviation of the wrist, fewer neurological anomalies, no malignant tumors reported to date	[^Citation3,Citation27]
p.Glu22Lys	Unusually severe fatal manifestation of HCM and hyperinsulinemic hypoglycemia or mild HCM and excess of muscle spindles	[^Citation26,Citation36]
p.Gly60Val	Severe lethal phenotype	[^Citation35]
p.Thr58Ile	Milder/less evident phenotype	[^Citation30,Citation37]
p.Gly60Asp		[^Citation31]
p.Lys117Arg		[^Citation32]
p.Ala146Thr		[^Citation29,Citation33,Citation34]
p.Ala146Val
p.Ala146Pro
p.Ser89Cys	Two siblings had severe fetal hydrops, but benign clinical course; the variant was inherited from the asymptomatic father	[^Citation43]
Duplications	Clinical Description
p.Glu37dup	Mental retardation, short stature, sparse hair, mild musculoskeletal manifestations	[^Citation44]
p.Glu62_Arg68dup	Milder/attenuated phenotype	[^Citation45,Citation47]
p.Glu63_Asp69dup		[^Citation46^–^Citation48]
p.Ile55_Asp57dup		[^Citation47]
Deletions	Clinical Description
c.481_490delGGGACCCTCT, NM_176795.4; p.Leu163ProfsTer52, NP_789765.1	Developmental delay, intellectual disability, ASD features, distinctive coarse facies, reduced growth, ectodermal anomalies	[^Citation49]

Figure 2 Core and ancillary disciplines involved in the management of pediatric and adult patients with CS. The impact of medical issues in the daily lives of patients with CS requires careful management throughout life. A comprehensive multidisciplinary assessment to be performed by physicians and therapists is needed from infancy to adulthood to promptly treat and monitor comorbidities. The latter change according to patients’ age. In particular, the most concerning problem to manage in children is related to failure to thrive. The cardiorespiratory system needs to be accurately evaluated to exclude severe morphological or rhythmic cardiac anomalies. Visual and global neurological functions need to be assessed in order to plan a personalized protocol of habilitative therapies (A). In adults, orthopedic manifestations often require treatment; a comprehensive dermatological evaluation is important to improve skin findings, and a surveillance protocol for cancer risk needs to be followed (B).

Table 2 Timing of Clinical and Instrumental Follow-Up According to Literature and Our Experience

	Pediatric Age		Adult Age
	First Evaluation	Timing of Follow-Up Examinations*	Timing of Follow-Up Examinations*	References
Gastroenterological evaluation	At birth/diagnosis	Every 3–6 months	Every 12 months	[^Citation2,Citation29,Citation42,Citation54,Citation56,Citation57]
Clinical nutritionist evaluation	At birth/diagnosis	Every 3–6 months	According to patient’s needs	[^Citation56,Citation57]
Indirect calorimetry	12 months	Every 12 months	Every 12 months	[^Citation56,Citation60]
Auxological/endocrinological evaluation with growth velocity monitoring	At birth/diagnosis	Every 6–12 months	N/A	[^Citation29,Citation55,Citation58]
Comprehensive neurological assessment	At birth/diagnosis	Every 3–6 months in individuals <5 years old; every 6–12 months in individuals ≥5 years-old	According to patient’s characteristics	[^Citation70]
Evaluation of cognitive performance and adaptive behavior by using different scales according to age and level of intellectual disability	2 to 3 years	Every 12 months	According to patient’s characteristics	[^Citation71,Citation109^–^Citation114]
MRI	At birth/diagnosis	According to symptomatology (if the first one is negative, to be repeated after two to three years in absence of clinical symptoms)	According to symptomatology (if the first one is negative, to be repeated after three years in absence of clinical symptoms)	[^Citation29,Citation74,Citation75]
Comprehensive cardiological assessment, electrocardiogram, echocardiogram	At birth/diagnosis	Every 12 months	Every 12 months	[^Citation29,Citation76^–^Citation79,Citation82^–^Citation84]
ENT evaluation	At birth/diagnosis	According to symptomatology	According to symptomatology	[^Citation85]
Polysomnography	If symptoms for sleep disturbances or apneas are present	Every 12 months (if sleep disturbances or apneas are present)	Every 12 months (if sleep disturbances or apneas are present	[^Citation86]
Ophthalmologic evaluation with fundus oculi examination	At birth/diagnosis	Every 6 months in individuals <3 years old; every 12 months in individuals ≥3 years old	Every 12 months	[^Citation53,Citation87,Citation89,Citation90]
Orthopedic evaluation	At 12 months	Every 12 months	Every 12 months	[^Citation10,Citation29,Citation87,Citation91,Citation98^–^Citation101]
X-ray of spinal column	According to patient’s characteristics	According to patient’s characteristics	According to patient’s characteristics	[^Citation10,Citation29,Citation87,Citation91,Citation98^–^Citation101]
Hip X-ray	During infancy	To be repeated during adolescence	N/A	[^Citation10,Citation91,Citation99]
DEXA scan	From 5 years of age	Every 12–18 months	Every 12–18 months	[^Citation92,Citation100,Citation102]
Dosage of bone metabolism biomarkers	From 5 years of age	Every 24 months	Every 12–18 months	[^Citation92,Citation100,Citation102]
Complete dermatological evaluation with dermatoscopic examination	At diagnosis	Every 12 months	Every 12 months (closer follow-up schedules are suggested in case of risk factors)	[^Citation93,Citation94,Citation105,Citation106]
Abdominal US	At birth/diagnosis	Every 6–12 months	Every 6–12 months	[^Citation29,Citation95]
Routine clinical surveillance for RMS	At birth/diagnosis	Every 6–12 months	Every 6–12 months	[^Citation29,Citation95]
Screening for bladder cancer through physical-chemical urine exam, urine cytology, and cystoscopy	From 10 years of age	Every 12 months	Every 12 months	[^Citation96]

Note: *Timing of follow-up evaluations may vary according to patient’s symptomatology and characteristics.

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