# 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 impulsiveness 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.