7. DIAGNOSIS
Onset of Parents‘ Concern
12 MONTHs
Second Child with a Full Mutation
Before 1st Child was Diagnosed
25% Families
Diagnosis of FXS
35-37 MONTHs
9. Diagnosis
• Developmental Delay
• Borderline Intellectual Abilities or Intellectual Disability
• Diagnosis of Autism without a Specific Etiology
Physical and Behavioral
Characteristics of FXS
A Relative with Undiagnosed
Intellectual Disability
Child with Suspected FXS
10. Diagnosis
• Females with Primary Ovarian Insufficiency (POI)
• Patients over 50 y/o with Progressive Cerebellar Ataxia
and Intention Tremor
• Adults with Typical Features and Intellectual Disability
without a Specific Etiology
Genetic Testing should be Offered
Adult with Suspected FXS
11. FXS Suspected due to Family History
01 02 03 04
Intellectual Disability,
Developmental Delay,
Learning Disabilities,
Specific Problems
with Mathematics
Cognitive
Effects
Speech
Delay
Autism
Spectrum
ADHD
Unusual Speech
Pattern
Autism Spectrum
Disorder or Autistic-
Like Behaviors
Attention Deficit or
Attention Deficit
Hyperactivity Disorder
(ADHD)
12. FXS Suspected due to Family History
05 06 07 08
Macrocephaly, Large
Ears, Long Face,
Broad Forehead,
Prominent Jaw,
Strabismus, Large
Testicles
Dysmorphic
Features
Loose
Connective
Tissue
Neurologic
Symptoms
Mental
Illness
Hyperextensible
Joints, Flat Feet,
Hypotonia, Mitral
Valve Prolapse,
Hernias
Seizures, Late-Onset
Progressive Tremor,
Ataxia, Difficulty
Walking, Balance
Problems, Short-Term
Memory Loss, Loss of
Sensation in Limbs
Depression,
Schizophrenia,
Bipolar Disorder,
Obsessive
Compulsive Disorder,
Schizoaffective
Disorder, Schizoid
Personality
13. FXS Suspected due to Family History
09 11
Impulsiveness, Anger
Outbursts, Violent
Behavior, Solitary
Behavior, Counseling
or Medication for
Behavioral Difficulties
Behavioral
Problems
OBGYN
Issue
10 Conditions
Shyness, Social
Anxiety, Excessive
Worrying,
Counseling or
Medication for
Emotional Difficulties
Premature
Menopause, Fertility
Problems
14.
15. Diagnosis
• Several Features are Present ☞ Symptomatic Individual
• Several Features are Present ☞ Strong Family History
• Genetic Counseling / Testing ☞ At-Risk Family Members
of Patients with FXS, even if Asymptomatic
FMR1 DNA Analysis Diagnosis of FXS ☞ Detection of an
Alternation in Fragile X Mental
Retardation 1 (FMR1) Gene!
Molecular Testing is Warranted!
16. Diagnosis
• Standard Karyotype
• DNA Testing
FMR1 DNA Analysis Detect FMR1 Gene
Exact # of CGG Triplet Repeats
Molecular Testing is Warranted!
17. Diagnosis
Adult
Whole Blood 3 mL
Pre-Labor
Chorion 10mg
Amniotic Fluid 10 mL
Umbilical Cord Blood 2 mL
Molecular Testing is Warranted!
22. SUMMARY
Prevalence
01
Male: 1/7000 – 1/4000
Most Frequent
Inherited Intellectual
Disability
X-Linked
02
Fragile X Mental Retardation 1 (FMR1)
Gene ☛ FMRP
Loss of Function
Mutation
Clinical Features
03
Mutation State
Degree of Methylation
Sex
Tissue Variation
Depend on
Manifestations
04
Physical
Cognitive
Behavioral
Wide Range Features
23. SUMMARY
Clinical Suspicion
Cognitive / Developmental / Behavioral
Molecular Testing
Diagnosis
Autism Spectrum Disorder
ADHD
Other causes of Intellectual Disability
or Developmenal Delay
Differential Diagnosis
It is important to make the diagnosis of FXS as early as possible so that appropriate interventions (eg, speech and language therapy, special education support, genetic counseling) can be initiated. Surveys of parents of children diagnosed with FXS indicate a significant delay between the onset of their concerns (average age approximately 12 months) and the diagnosis of FXS (average age 35 to 37 months). Approximately one-fourth of families had a second child with a full mutation before the first child was diagnosed
發生率在台灣較歐美低,約為1/10,000。
檢體需求
成人: 全血 3 ml 產前:絨毛(10mg以上)、羊水(10ml)或臍帶血(2ml)
報告時程
1周
Autism spectrum disorder. Although children with FXS often have autistic behaviors and may have comorbid autism, absence of other clinical features of FXS suggests the isolated diagnosis of autism.
Attention deficit hyperactivity disorder (ADHD). FXS is unlikely in the child with ADHD and normal intelligence.
Other causes of intellectual disability or developmental delay, including
Fragile XE syndrome (FRAXE). FRAXE, which is extremely rare, is characterized by mild intellectual disability without consistent physical features. It has been described in boys with expanded cytosine-cytosine-guanine (CCG) repeats in fragile X mental retardation 2 (FMR2) gene, near the fragile X mental retardation 1 (FMR1) gene.
XXY (Klinefelter syndrome). Boys with Klinefelter syndrome may have specific learning disabilities, particularly in expressive language. In contrast to postpubertal boys with FXS, boys with XXY usually have small testes.
Cerebral gigantism (also known as Sotos syndrome). Characteristic features of cerebral gigantism include typical facial appearance (macrocephaly, frontal bossing, prominent chin, pointed chin, downslanting palpebral fissures), overgrowth, learning disability, behavioral problems, and congenital cardiac anomalies.
Prader-Willi syndrome (PWS). Some boys with FXS have a phenotype similar to that of PWS, but they do not have the genetic abnormalities associated with PWS.
● Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability, with a prevalence between 1 in 4000 and 1 in 7000 in males. The prevalence in females is approximately two-thirds to one-half of that in males.完全突變型(full mutation): 男性 1/4,000,女性 1/8,000潛在突變的女性帶因者(premutation carrier): 1.3%台灣地區男性完全突變型: 1/10,000, 男性潛在突變型: 1/1,674
● FXS is an X-linked disorder. It is caused by a loss of function mutation in the fragile X mental retardation 1 (FMR1) gene that leads to decreased or absent fragile X mental retardation protein (FMRP).
● The clinical features of FXS vary depending upon the mutation state (full mutation versus premutation), degree of methylation, sex, and tissue variation (table 1).
●All males with full mutation FXS have manifestations of FXS, but there are a wide range of physical, cognitive, and behavioral features.
•Classic physical features include long and narrow face with prominent forehead and chin, large ears, and testicular enlargement, but these features typically are not obvious until adolescence or adulthood (picture 1). Physical features in younger males may include macrocephaly, strabismus, midface hypoplasia, arched palate, mitral valve prolapse, hyperextensible joints, hypotonia, soft skin, and flexible flat feet.
•Intellectual disability is usually in the moderate range. Expressive language is more affected than receptive language.
•Behavioral features may include hyperactivity, inattention, gaze aversion, stereotypic movements (eg, hand flapping, hand biting), hyperarousal, social anxiety, and unusual speech.
●Girls with the full mutation usually have milder features than boys, and 50 percent have normal cognitive function. However, the full spectrum of cognitive, behavioral, and physical findings may occur. (See 'Full mutation in girls'above.)
●In the absence of a family history of FXS, diagnosis of FXS requires a low threshold for clinical suspicion based upon cognitive, developmental, or behavioral concerns, as described above. Diagnosis is confirmed by molecular testing.
●The differential diagnosis of FXS includes autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and other causes of intellectual disability or developmental delay.