Table 5.

Disorders to Consider in the Differential Diagnosis of Fragile X Syndrome

DisorderGene /
Genetic Mechanism		MOIClinical Features of Differential Diagnosis Disorder
Overlapping w/FXSDistinguishing from FXS
Sotos syndrome NSD1 AD
  • Typical facial appearance
  • Mild-to-severe learning disability
  • Behavior problems
  • Seizures
  • Overgrowth
  • Congenital cardiac anomalies
  • Neonatal jaundice
  • Renal anomalies
  • Scoliosis
Prader-Willi syndrome (PWS)See footnote 1.See footnote 2.
  • A small subset of those w/FXS have the hyperphagia & obesity characteristic of PWS 3
  • DD & cognitive impairment
  • Temper tantrums, stubbornness, manipulative behavior, & obsessive-compulsive traits
  • Hypogonadism (genital hypoplasia, incomplete puberty &, in most, infertility)
  • Characteristic PWS facial appearance
  • Short stature
Autism
spectrum
disorder		See footnote 4.AR
AD
XL
Mu		Autistic-like behaviorAbsence of cognitive & physical features of FXS
ADHDSee footnote 5.AD
Mu		HyperactivityAbsence of cognitive & physical features of FXS
Fragile XE syndrome (FRAXE) (OMIM 309548)AFF2 6
(FMR2)		XLMild ID (not as severe as is typically seen in FXS)Absence of physical features characteristic of FXS

AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; AR = autosomal recessive; DD = developmental delay; FXS = fragile X syndrome; MOI = mode of inheritance; Mu = multifactorial; XL = X-linked

1.

PWS is caused by an absence of expression of imprinted genes in the paternally derived PWS/Angelman syndrome (AS) region (i.e., 15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect).

2.

The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.

3.

PWS is characterized by severe infantile hypotonia and feeding difficulties, followed by early-childhood onset of excessive eating and development of morbid obesity unless controlled.

4.

See OMIM PS209850 for a list of genes associated with this phenotype in OMIM.

5.

See OMIM 143465 for discussion of multiple loci associated with susceptibility to ADHD.

6.

FRAXA and FRAXE are distinct fragile sites, albeit in close proximity on the X chromosome. The genes spanning the two fragile sites are designated FMR1 (FRAXA) and AFF2 (FRAXE). However, the genes do not have any detectable similarity at the DNA level and the associated clinical entities are discrete.

From: FMR1 Disorders

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