Table 3.

Differential Diagnosis of SETD2-NDD with Macrocephaly/Overgrowth

Gene(s)DiffDx DisorderMOIClinical Features of DiffDx Disorder
Overlapping
w/SETD2-NDD
w/macrocephaly/
overgrowth		Distinguishing
from SETD2-NDD
w/macrocephaly/
overgrowth
FMR1 Fragile X syndrome (See FMR1 Disorders.)XLMacrocephaly, IDMacroorchidism, joint laxity
NSD1
NFIX 		Sotos syndrome (1 and 2)ADMacrocephaly, overgrowth, IDPointed chin, small mouth, everted lower lip
Mutation or deletion of imprinted genes w/in chromosome 11p15.5 region:
ICR1
KCNQ1OT1
CDKN1C		 Beckwith-Wiedemann syndrome AD 1Generalized overgrowth, DDMacroglossia, hypoglycemia, coarse facies, hepatomegaly, ear lobe creases
RNF125 Tenorio syndrome (OMIM 616260)ADMacrocephaly, overgrowth, IDMacroglossia, hypoglycemia
DICER1 GLOW syndrome (See DICER1 Tumor Predisposition.)ADMacrocephaly, overgrowth, IDLung cysts, Wilms tumor
HERC1 MDFPMR (OMIM 617011)ARMacrocephaly, overgrowth, IDLarge ears, asthenic adult habitus
PIK3CA Megalencephaly-capillary malformation-polymicrogyria syndrome (See PIK3CA-Related Overgrowth Spectrum.)SomaticMacrocephaly, overgrowth, IDCapillary malformations, polymicrogyria, hemihyperplasia
PTEN PTEN hamartoma tumor syndrome ADMacrocephaly, autismHamartomata, tumors
TET3 Beck-Fahrner syndrome AD
AR		Macrocephaly, overgrowth, IDElongated myopathic facies; short stature & microcephaly in some
FIBP Thauvin-Robinet-Faivre syndrome (OMIM 617107)ARMacrocephaly, overgrowth, IDMacroglossia, large hands & feet, kidney & urinary tract malformations
SUZ12 Imagawa-Matsumoto syndrome (OMIM 618786)ADMacrocephaly, overgrowth, IDSkeletal abnormalities
HRAS Costello syndrome ADMacrocephaly, IDFetal overgrowth w/postnatal short stature, coarse facial features, loose redundant skin
EED Cohen-Gibson syndrome (See EED-Related Overgrowth.)ADMacrocephaly, overgrowth, IDLarge long ears, skeletal abnormalities
GPC3 Simpson-Golabi-Behmel syndrome XLMacrocephaly, overgrowth, IDCoarse facies; hearing loss; large liver, spleen, & kidneys; skeletal anomalies
SHANK3 or
deletion of
22q13.33		 Phelan-McDermid syndrome ADMacrocephaly, overgrowth, IDLarge fleshy hands, ptosis
EZH2 Weaver syndrome (See EZH2-Related Overgrowth.)ADMacrocephaly, overgrowth, IDLarge bifrontal diameter, flat occiput, skeletal anomalies

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MDFPMR = macrocephaly, dysmorphic facies, and psychomotor retardation; NDD = neurodevelopmental disorder; XL = X-linked

1.

Most instances of Beckwith-Wiedemann syndrome are due to methylation abnormalities that are not heritable. A subset of affected persons have a pathogenic variant that is heritable, most commonly in an autosomal dominant manner.

From: SETD2 Neurodevelopmental Disorders

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