Handbook of Genetic Counseling/FG Syndrome

FG Syndrome

Introduction and Contracting

• Can you explain to me in your own words why you were referred to genetics?
• What questions if any do you have for us today
• What are your main concerns at this time
• Outline the session and what will occur
  • Medical and developmental history
  • Family history (pedigree)
  • Dr. will physically examine him
  • We will explain any conclusions if any that we have reached and discuss what we think might be the explanation for the concerns and problems

Pedigree

• Basic 3 generation pedigree unless specific findings come up and may need explore maternal side further due to X-linked pattern of FG syndrome
• birth defects
• pregnancy loss
• poor muscle tone
• chronic constipation
• hearing loss
• vision problems
  • kidney problems
  • problems with the digestive tract
  • other chronic health problems
  • mental retardation of learning difficulties
  • large head size
  • broad thumbs and toes
  • fingernails that grow over tips of fingers
  • behavioral problems

Overview of FG

• X-linked recessive condition
• First described 1974 by Drs. John M. Opitz and Elizabeth G. Kaveggia
• Named after initials of first patients described
• Multiple congenital anomaly/mental retardation syndrome
• Characterized by MR, macrocephaly, congenital hypotonia, macrocephaly, facial dysmorphism and anomalies of the digestive tract
• No features are pathognomonic

FG syndrome physical characteristics

• prenatal oligohydrammios
• High degree of variability of physical features
• Hypotonia with joint hyperlaxity evolves into spasticity with joint contractures later in life
• chronic constipation is a distinctive major finding in FG (usually resolves during mid-childhood)
• hearing loss
• vision problems
• genital abnormalities (cryporchidism)
• respiratory problems
• congenital heart defects uncommon but include hypoplastic left heart, small VSD; VSD and mitral and aortic valve defect (Opitz, 1988)
• agenesis of the corpus collosum
• anteriorly positioned or imperforate anus
• kidney problems
• large head
• broad thumbs and toes
• characteristic fingerprint patterns
• webbed fingers and toes
• skeletal defects (occasionally including craniosynostosis and scoliosis)
• sacral pit
• tethered cord and Chiari I malformations
• wide set eyes
• broad nasal bridge
• low set simple ears that are small, rounded, and protruding
• thin upper lip and fuller lower lip
• cowlicks and a widow's peak hairline

Developmental and behavioral features of FG syndrome

• delayed acquisition of speech and motor skills
• Individuals with FG Syndrome tend to be outgoing, talkative, and crave lots of attention
• May be easily frustrated and are prone to temper tantrums
• Hyperactivity and impulsivness have been reported
• Most function in mild to moderate range of MR other reports state it is usually severe MR
  • Some clinicians feel MR is universal finding in FG, but others feel there is a wide range of cognitive ability and some are in normal range
• Often language skills are underdeveloped
• "Autistic-like" behaviors have been discussed. This may be due to a common trait of the FG Syndrome--- sensory integrative dysfunction. However, they are not believed to be autistic
  • Frequent fascinations with mechanical objects and toys, tendency to self-absorption

Life expectancy

• Death during infancy as high as 1/3 of patients due to bronchopulmonary problems and/or heart defects
• "Once they survived infancy death is rare"

Genetics

• presumably due to mutations on the X chromosome
• presumed to cause disruption in the development of the fetus
  • X-linked recessive
  • Heterogeneous condition
  • mapped one gene (FGS1) to Xq13 (Briault et al.) in some families using linkage analysis
  • evidence for another gene locus (FGS2) at Xq28 or Xq11q12 based on fact these are breakpoints of an inversion that segregate with FG phenotype (Briault et al., 2000)
  • Dr. Opitz lists a potential third gene (FGS3) at Xp22.3 (Opitz, Sep, 2001)
  • 9 candidate genes excluded in three families (A Lossi, A Fatima, S Briault, C Moraine, C Schwartz, 2000)

Diagnosis

• Clinical diagnosis
• No molecular testing available (Opitz, 2001)
• Diagnosis based on clustering of symptoms with no symptom being pathognomonic
• Some believe it is not uncommon and may account for many cases of unexplained X-linked MR

Genetic Testing

• Linkage analysis is possible in large families with multiple affected family members
• Prenatal testing and carrier testing only possible through such linkage analysis described above

Differential Diagnosis

• Fragile X syndrome
  • shares feature of protruding ears and X-linked MR as well as behaviors that are sometimes described by people as "autistic like"
• ATR-X syndrome (X-linked alpha thalassemia, mental retardation)
  • have severe MR, congenital hypotonia, genital abmormalities and a small head
  • differs from FG because those with FG have macrocephaly, friendly personality and hyperactivity
• Williams syndrome
  • shares personality and behavioral features with FG
  • different in that there is presence of "salient anxiety and internalizing symptoms in WS"
• G/BBB syndrome (Opitz syndrome)
  • Considerable overlap in features of G/BBB and FG syndromes
  • Features that are shared with FG include: sensorineural dysfunction, behavioral problems, imperforate anus, hypoplasia or agenesis of the corpus callosum, kidney abnormalities, cryptorchidism, heart (cardiac) defects, and mental retardation.
  • One form of G/BBB syndrome is inherited in X-linked recessive fashion and is due to mutations in MID1 gene
  • Other symptoms of G/BBB include; dysphagia, cleft palate and or cleft lip (which are not usually seen in FG). Pulmonary agenesis or hypoplasia and tetralogy of Fallot have been seen only in the G/BBB syndrome so far.

References

• John Opitz, Antonio Richieri-da Costa, Jon M. Asse, and Paul J. Benke. FG Syndrome Update 1988: Note of 5 New Patients and Bibliography. American Journal of Medical Genetics. 30:309-328 (1988).
• S Ozonoff et al. Behavior Phenotype of FG syndrome: Cognition, Personality, and Behavior in Eleven Affected Boys. American Journal of Medical Genetics 97:112-118 (2000).
• S Briault, et al. Mapping of X Chromosome Inversion Breakpoints Associated with FG Syndrome. American Journal of Medical Genetics. 95:178-181 (2000).
• A Lossi, A Fatima, S Briault, C Moraine, C Schwartz Exclusion of Nine Candidate Genes for Their Involvement in X-linked FG Syndrome (FGS1) in Three Families. Letter to the Editor. American Journal of Medical Genetics 94:386-388. (2000).
• JM Grahm Jr. Clinical and Behavioral Characteristics in FG Syndrome. American Journal of Medical Genetics. 85:470-475 (1999).
• S Briault et al. A Gene for FG Syndrome Maps in the Sq12-q21.31 Region. American Journal of Medical Genetics. 73:87-90 (1997).

Web info

• http://www.gle.egsd.k12.co.us/opitz/opitznord.html -- (information about Opitz G/BBB syndrome)
• Opitz JM, FG syndrome. Orphanet encyclopedia, September 2001: http://orphanet.infobiogen.fr/data/patho/GB/uk-FG.html
• http://www.fg-syndrome.org (FG Syndrome Family Alliance web site)
• This site seems to be biased towards the opinions of Dr. Opitz which are not shared by all medical professionals.

Notes

The information in this outline was last updated in 2002.