Differential Diagnosis
Developmental delay/ intellectual disability (DD/ID). The signs of fragile X syndrome (FXS) in early childhood are nonspecific, with DD being an almost universal manifestation among affected individuals. Any child (male or female) with delay of speech, language, or motor development of unknown etiology should be considered for fragile X testing, especially in the presence of a family history of ID and a consistent physical and behavioral phenotype, and the absence of structural abnormalities of the brain or other birth defects . When fragile X molecular genetic testing is used regularly in this large and loosely defined group of unselected males with ID, the yield of positive test results is relatively low (~3%-6%) . In a more recent study, found the yield to be 1.2%. Because chromosome abnormalities and copy number variants have been identified as frequently or more frequently than FMR1 pathogenic variants in individuals with DD or ID who are referred for fragile X testing, microarray testing should be performed as a part of the laboratory evaluation . Conditions to be considered in the differential diagnosis of FXS include those summarized in . Table 5. Disorders to Consider in the Differential Diagnosis of Fragile X Syndrome
Disorder | Gene /Genetic Mechanism | MOI | Clinical Features of Differential Diagnosis Disorder |
|---|
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 PWS3; DD cognitive impairment; Temper tantrums, stubbornness, manipulative behavior, obsessive-compulsive traits |
Short stature Autismspectrumdisorder | See footnote 4. | ARADXLMu | Autistic-like behavior |
ADHD | See footnote 5. | ADMu | Hyperactivity |
Fragile XE syndrome (FRAXE) (OMIM 309548) | AFF26(FMR2) | XL | Mild ID (not as severe as is typically seen in FXS) |
Source: GeneReviews — "FMR1 Disorders"
