Table 4b.

Selected Single-Gene Disorders with Short Stature and Congenital Heart Disease in the Differential Diagnosis of Williams Syndrome

Gene(s)DisorderMOIClinical CharacteristicsComment
BRAF
KRAS
LZTR1
MAP2K1
MRAS
NRAS
PTPN11
RAF1
RASA2
RIT1
RRAS2
SOS1
SOS2 		Noonan syndrome (NS)AD
AR 1		Characteristic facies, short stature, DD of variable degree, & CHD (most commonly pulmonary valve stenosis, often w/dysplasia). Hypertrophic cardiomyopathy may be present at birth or develop in infancy or childhood.The facial features of NS & WS are similar in infancy but are more easily distinguished in older children & adults. CHD in WS is typically supravalvar or peripheral pulmonic stenosis & in NS is commonly valvar stenosis.
KDM6A
KMT2D 		Kabuki syndrome (KS)AD
XL 2		Typical facial features, minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate ID, & postnatal growth deficiency. ~70% of affected persons have CHD (most commonly left-sided obstructive lesions, esp coarctation of aorta).KS is assoc w/long palpebral fissures w/everted lower lid, leading to different facial gestalt than WS. The left-sided cardiac lesion in KS is typically aortic coarctation, while SVAS is most common CHD in WS.

AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart disease; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; SVAS = supravalvar aortic stenosis; WS = Williams syndrome; XL = X-linked

1.

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

2.

KMT2D-related Kabuki syndrome is inherited in an autosomal dominant manner; KDM6A-related Kabuki syndrome is inherited in an X-linked manner.

From: Williams Syndrome

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