Table 3.

Disorders of Interest in the Differential Diagnosis of Costello Syndrome

Gene(s) / Genetic MechanismDisorderMOIClinical Features of Disorder
Overlapping w/Costello SyndromeDistinguishing from Costello Syndrome
BRAF
KRAS
MAP2K1
MAP2K2 		Cardiofaciocutaneous (CFC) syndrome AD
  • Resembles CS in infants & young children
  • Hypotonia
  • Nystagmus
  • Mild-to-moderate ID
  • Postnatal growth deficiency
  • Feeding difficulties (may be less severe than in CS)
  • Dolichocephaly, high forehead, & slightly coarse facial features
  • Pulmonic valve stenosis & ASD
  • HCM 1
  • Lips not as thick & prominent
  • Hair more consistently sparse or curly
  • Eyebrows typically sparse or absent
  • Skin abnormalities incl severe atopic dermatitis, keratosis pilaris, & ichthyosis; absence of papillomata
  • Malignant tumors rarely reported
BRAF
KRAS
LZTR1
MAP2K1
MRAS
NRAS
PPP1CB
PTPN11
RAF1
RASA2
RIT1
RRAS2
SHOC2
SOS1
SOS2 		Noonan syndrome AD
AR 2
  • Resembles CS in infants & young children
  • Short stature
  • DD of variable degree & mild ID
  • Congenital heart defects incl pulmonary valve stenosis often w/dysplasia; HMC (may be present at birth or appear in infancy or childhood); ASD & VSD; branch pulmonary artery stenosis; tetralogy of Fallot
  • Cryptorchidism
  • Distinctive combination of pectus carinatum & pectus excavatum
  • Broad or webbed neck
  • Characteristic facies
  • Varied coagulation defects & lymphatic dysplasia
  • Birth length usually normal
  • Final adult height near lower limit of normal
Epigenetic/genomic alteration leading to abnormal methylation at 11p15.5; CNV at 11p15.5; or CDKN1C pathogenic variant Beckwith-Wiedemann syndrome Depends on genetic mechanism
  • In newborns: apparent "overgrowth" (more accurately: ↑ birth weight due to edema); protruding tongue; coarse facial features; hypoglycemia; HCM
  • Embryonal tumors
  • Macrosomia
  • Macroglossia
  • Visceromegaly
  • Omphalocele
  • Ear creases/pits
  • Adrenocortical cytomegaly
  • Renal abnormalities
Deletion of WBSCR at 7q11.23 Williams syndrome AD
  • Soft skin
  • Ligamentous laxity of small joints
  • Full lips
  • Friendly personality w/anxious demeanor in adolescence
  • ID
  • Specific cognitive profile
  • Unique personality characteristics
  • Distinctive facial features
  • Cardiovascular disease (elastin arteriopathy)
  • Range of connective tissue abnormalities
  • Hypercalcemia

AD = autosomal dominant; AR = autosomal recessive; ASD = atrial septal defect; CS = Costello syndrome; CNV = copy number variant; DD = developmental delay; HCM = hypertrophic cardiomyopathy; ID = intellectual disability; MOI = mode of inheritance; VSD = ventricular septal defects; WBSCR = Williams-Beuren syndrome critical region

1.

The ~40% incidence of hypertrophic cardiomyopathy in individuals with a molecular diagnosis of CFC is similar to that observed in Costello syndrome [Niihori et al 2006, Rodriguez-Viciana et al 2006, Gripp et al 2007]. Although atrial tachycardia has been reported in a small number of individuals with CFC, it has not been called chaotic atrial rhythm [Niihori et al 2006]. Non-reentrant atrial tachycardia has been described in individuals with Noonan and CFC syndrome, but is much more common in Costello syndrome [Levin et al 2018].

2.

Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.

From: HRAS-Related Costello Syndrome

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