FG syndrome OPitz G/BBB relationship

FG Syndrome

FG Syndrome by Opitz JM, G syndrome. From Orphanet

For Original Article got to http://www.orpha.net/data/patho/GB/uk-FG.html

FG Syndrome

Author: Prof John M. Opitz
Scientific Editor : Prof Didier Lacombe

Creation date: September 2001

Disease name and synonyms

FG syndrome,
Opitz-Kaveggia syndrome, includes the neurofaciodigitorenal (NFDR) syndrome and probably some cases of the Neuhäuser megalocornea syndrome.
Syndrome FGS1
Megalocornea-Mental Retardation syndrome.

Excluded disorder

For the moment the Opitz (G/BBB) syndromes are excluded.
Opitz syndrome.

Diagnostic criteria, definition

FG syndrome may affect boys and girls with a syndrome of relative shortness of stature with disproportionately large head, a characteristic combination of minor anomalies including high, prominent forehead, cowlicks and abnormalities of hair whorls, apparent hypertelorism,
relatively thin vermilion of the upper lip with prominence of the lower lip, hypotonic mouth breathing facial changes, minor ear anomalies, the appearance of relatively large corneae, broad thumbs and halluces, short perineal body, deep pilonidal dimple and diastasis recti. Malformations include (partial) agenesis of corpus callosum, Chiari I malformation, vertebral malformation, intestinal/anal atresia, limb malformations (poly-, oligo-, syndactyly), genitourinary abnormalities, cryptorchidism, herniae and congenital heart defects.

Nosology

Primarily with the "Opitz" (G/BBB) syndromes which show extensive overlap with FG except that laryngeal cleft, pulmonary agenesis or hypoplasia and tetralogy of Fallot have so far been seen only in the G/BBB syndrome.

Prevalence

Possibly as common as 1/1000 in the population of the Utah valley, but apparently common elsewhere in the US and in Italy.

Clinical description

The first clinical features include prenatal oligohydrammios, ultrasonographic ventricular dilatation, reduced fetal movements, fetal distress with frequent delivery by caesarian section, neonatal respiratory distress syndrome, thrombocytopenia, transient jaundice, gastroesophageal reflux at times requiring fundoplication, constipation, frequent middle ear infections, delayed acquisition of speech and motor skills. Childhood is frequently dominated by severe behavior problems, in part in response to communication difficulties but to a larger part to delayed sensory integration with overreaction to sensory stimulation including touch, sound, light, crowds, emotional pressure, temperature variations, and oral aversion to food textures (with tendency to "bolt" food and risk of aspiration and asphyxiation); overreactions occur in the form of severe temper tantrums and withdrawal. Frequent fascinations with mechanical objects and toys, tendency to self-absorption. Frequently diagnosed as "autistic" or as having Asperger syndrome or "pervasive developmental disorder". Mental retardation is rare- most affected boys and girls function in the normal range. Seizures are rare; spastic diplegia more common.

Management

Correct diagnosis is mandatory. Symptomatic treatment for reflux, constipation, seizures, hyperactivity and attention deficit is the rule. Psychological and pediatric neurological care; rarely orthopedic care for consequences of lower limb spasticity are required. Helmet for plagiocephaly; neurosurgical care for symptomatic Chiari malformation with syrinx and craniosynostosis; cardiac evaluation (most patent ductus, atrial septal and ventricular septal defects close spontaneously) are needed. Correct school setting; may need to learn sign language or to use assisted communication devices; early introduction of educational computers are advised

Etiology

Presumed to be due to mutations on the X-chromosome. FGS1 is roughly mapped to Xq13, FGS2 (on the basis of an X paracentric inversion) to Xq11 or Xq28, and FGS3 to Xp22.3. Clinical overlap with the G/BBB syndromes suggests not just a pathogenetic but perhaps a causal relationship, since midin, a product of the X-linked G/BBB syndrome gene, is known to interact with that of the gene MIDIA1 at Xq13, a candidate gene for the FG syndrome. Many/most carriers show more or less subtle signs of the FG syndrome including high forehead, cowlick(s)/widow's peak, broad thumbs/halluces, at times constipation, migraines, depression, anxiety. The fact that FG signs are frequently found in all of the sibs in segregating
cases and in some of the fathers suggests a genetic abnormality (i.e. meiotic drive, segregation distortion) or gene/gene (i.e. FG/G/BBB)
interaction.

Diagnostic methods

Routine pediatric, neurologic, gastroenterological, cardiologic, child psychologic approaches, including MRI, EEG, echocardiography, and electromyography.

Genetic Counseling

Only after careful examination of parents and all sibs. Truly sporadic cases (i.e. presumed new mutations) are extremely rare; the FG syndrome is not as strikingly an iceberg mutation as the G/BBB syndrome with uncommon recurrence of cases as severe as that of the propositus. Rather, in the FG syndrome recurrence as severe as in propositi is common and may affect sibs, first cousins, nephews and other maternal relatives. It is hoped that molecular methods will soon aid diagnosis, carrier detection, prenatal diagnosis and more reliable genetic counseling.

Antenatal diagnosis

Prenatally frequently symptomatic on the basis of reduced fetal movements, oligohydramios, asymmetric intrauterine growth retardation with increased biparietal diameter and dilated ventricles and abnormal fetal responses indicating fetal distress. No specific molecular diagnosis as yet.

Unresolved questions

Causal or pathogenetic relationship with G/BBB syndromes, segregation ratio, paternal influence, gene mapping, cloning, sequencing and mutation analysis.

Keywords

FG syndrome, Opitz-Kaveggia syndrome, multiple congenital anomalies, congenital hypotonia, megalencephaly, developmental/speech delay, autism, Asperger syndrome, pervasive developmental disorder, constipation, gastroesophageal reflux, delayed sensory integration, genital abnormalities.

References.

Briault S, Hill R, Shrimpton A, Zhu D, Till M, Ronce N, Margaritte-Jeannin P, Baraitser M, Middleton-Price H, Malcolm S, Thompson E, Hoo J, Wilson G, Romano C, Guichet A, Pembrey M, Fontes M, Poustka A, Moraine C. 1997. A gene for FG syndrome maps in the Xq12-q21.31 region. Am J Med Genet 73:87-90.

Briault S, Villard L, Rogner U, Coy J, Odent S, Lucas J, Passarge E, Zhu D, Shrimpton A, Pembrey M, Till M, Guichet A, Dessay S, Fontes M, Poustka A, Moraine C. 2000. Mapping of X chromosome inversion breakpoints [inv
(X)(q11q28)] associated with FG syndrome: A second FG locus [FGS2]? Am J Med Genet 95:178-181.

Dessay S, Moizard MP, Gilardi JL, Opitz JM, Middleton-Price H, Pembrey M, Moraine C, Briault S. 2001. FG syndrome: Linkage analysis in two families supporting a new gene localization at Xp22.3 [FGS3]. Am J Med Genet, submitted.

Freire-Maia N, Pinheiro M, Opitz JM. 1982. The neurofaciodigitorenal (NFDR)
syndrome. Am J Med Genet 11:329-336 (Not a new syndrome but
rather the FG syndrome).

Meroni G, Cainarca S, Berti C, Messali S, Ballabio A. 2000. Identification and
characterization of proteins that interact with midin, the Opitz
syndrome gene product. Am Soc Hum Genet Program and Abstract, Abstract 959, p.
183.

Neri G, Blumberg B, Miles PV, Opitz JM. 1984. Sensorineural deafness in the FG
syndrome: report on four new cases. Am J Med Genet
19:369-377.

Neuhäuser G, Kaveggia EG, France TD, Opitz JM. 1975. Syndrome of mental
retardation, seizures, hypotonic cerebral palsy and megalocorneae,
recessively inherited. Z Kinderheilkd 120:1-18 (the familial cases 1-3 may very
well be examples of the FG syndrome).

Opitz JM, Kaveggia EG. 1974. Studies of malformation syndromes of man XXXIII:
the FG syndrome. An X-linked recessive syndrome of multiple
congenital anomalies and mental retardation. Z Kinderheilk 117:1-18.

Opitz JM, Kaveggia EG, Adkins WNJ Jr, Gilbert EF, Viseskul C, Pettersen JC,
Blumberg B. 1982. Studies of malformation syndromes of humans
XXXIIIC: the FG syndrome- further studies on three affected individuals from the
FG family. Am J Med Genet 12:147-154.

Opitz JM, Richieri-da Costa A, Aase JM, Benke PJ. 1988. FG syndrome update 1988:
Note of 5 new patients and bibliography. Am J Med Genet
30:309-328.

Riccardi VM, Haessler E, Lubinsky MS. 1977. The FG syndrome: further
characterization, report of a third family, and of a sporadic case. Am J Med
Genet 1:47-58.

Sandler L, Hiraizumi Y. 1961. Meiotic drive in natural populations of Drosophila
melanogaster. II A heritable aging effect on the phenomienon of
segregation distortion. Canad J Genet Cytol 3:34-

Sandler L, Novitski E. 1957. Meiotic drive as an evolutionary force. Amer
Natural 91:105-

Thompson EM, Baraitser M, Lindenbaum RH, Zaidi ZH, Kroll JS. 1985. The FG
syndrome: 7 new cases. Clin Genet 27:582-594.

Trockenbacher A, Schweiger S, Suckow V, Kraup S, Ropers H-H, Schneider R. 2000.
The Opitz syndrome gene product, MID1, interacts with the
gene product of an X-chromosomal gene mapping to the linkage interval of FG
syndrome. Program and abstracts Ann Mtg Austrian Soc Biochem
(ÖBG), Innsbruck, Sept 2000, abstract 37, pg. 34.

This paper should be referenced as such :
Opitz JM, G syndrome. Orphanet encyclopedia, September 2001:
http://orphanet.infobiogen.fr/data/patho/GB/uk-FG.html

Address for correspondence:
John M. Opitz, MD
University of Utah
Division of Medical Genetics
50 North Medical Drive
Salt Lake City
UT 84132, USA

Clinical signs of FG Syndrome

* Broad forehead
* High forehead
* Hypotonia
* Low hair line (front)
* Mental retardation(degree not assessed)
* Posterior angulation of ears
* X-linked recessive inheritance
* Broad/bifid great toe
* Broad/bifid thumb
* Clinodactyly of fifth finger
* Congenital cardiac anomaly
* Difficulties for feeding in infancy
* Epicanthic folds
* Expressionless face
* Fine hair
* High vaulted/narrow palate
* Hypertelorism
* Imperforate anus/anal stenosis
* Macrocephaly
* Malplaced anus
* Micrognatia/retrognatia
* Protruding lips
* Restricted joint mobility
* Sparse/absent scalp hair(generalized)
* Squint/paresis of ocular muscles
* Undescended/ectopic testes
* Abnormal gastrointestinal tract
* Camptodactyly
* Pyloric stenosis
* Stillbirth/neonatal death
* Syndactyly of fingers

Return to OpitzNet homepage

		FG Syndrome
		FG Syndrome
		FG Syndrome by Opitz JM, G syndrome. From Orphanet
		For Original Article got to http://www.orpha.net/data/patho/GB/uk-FG.html
		FG Syndrome
		Author: Prof John M. Opitz Scientific Editor : Prof Didier Lacombe
		Creation date: September 2001

		Disease name and synonyms
		FG syndrome, Opitz-Kaveggia syndrome, includes the neurofaciodigitorenal (NFDR) syndrome and probably some cases of the Neuhäuser megalocornea syndrome. Syndrome FGS1 Megalocornea-Mental Retardation syndrome.

		Excluded disorder
		For the moment the Opitz (G/BBB) syndromes are excluded. Opitz syndrome.

		Diagnostic criteria, definition
		FG syndrome may affect boys and girls with a syndrome of relative shortness of stature with disproportionately large head, a characteristic combination of minor anomalies including high, prominent forehead, cowlicks and abnormalities of hair whorls, apparent hypertelorism, relatively thin vermilion of the upper lip with prominence of the lower lip, hypotonic mouth breathing facial changes, minor ear anomalies, the appearance of relatively large corneae, broad thumbs and halluces, short perineal body, deep pilonidal dimple and diastasis recti. Malformations include (partial) agenesis of corpus callosum, Chiari I malformation, vertebral malformation, intestinal/anal atresia, limb malformations (poly-, oligo-, syndactyly), genitourinary abnormalities, cryptorchidism, herniae and congenital heart defects.



		Nosology
		Primarily with the "Opitz" (G/BBB) syndromes which show extensive overlap with FG except that laryngeal cleft, pulmonary agenesis or hypoplasia and tetralogy of Fallot have so far been seen only in the G/BBB syndrome.

		Prevalence
		Possibly as common as 1/1000 in the population of the Utah valley, but apparently common elsewhere in the US and in Italy.

		Clinical description
		The first clinical features include prenatal oligohydrammios, ultrasonographic ventricular dilatation, reduced fetal movements, fetal distress with frequent delivery by caesarian section, neonatal respiratory distress syndrome, thrombocytopenia, transient jaundice, gastroesophageal reflux at times requiring fundoplication, constipation, frequent middle ear infections, delayed acquisition of speech and motor skills. Childhood is frequently dominated by severe behavior problems, in part in response to communication difficulties but to a larger part to delayed sensory integration with overreaction to sensory stimulation including touch, sound, light, crowds, emotional pressure, temperature variations, and oral aversion to food textures (with tendency to "bolt" food and risk of aspiration and asphyxiation); overreactions occur in the form of severe temper tantrums and withdrawal. Frequent fascinations with mechanical objects and toys, tendency to self-absorption. Frequently diagnosed as "autistic" or as having Asperger syndrome or "pervasive developmental disorder". Mental retardation is rare- most affected boys and girls function in the normal range. Seizures are rare; spastic diplegia more common.



		Management
		Correct diagnosis is mandatory. Symptomatic treatment for reflux, constipation, seizures, hyperactivity and attention deficit is the rule. Psychological and pediatric neurological care; rarely orthopedic care for consequences of lower limb spasticity are required. Helmet for plagiocephaly; neurosurgical care for symptomatic Chiari malformation with syrinx and craniosynostosis; cardiac evaluation (most patent ductus, atrial septal and ventricular septal defects close spontaneously) are needed. Correct school setting; may need to learn sign language or to use assisted communication devices; early introduction of educational computers are advised



		Etiology
		Presumed to be due to mutations on the X-chromosome. FGS1 is roughly mapped to Xq13, FGS2 (on the basis of an X paracentric inversion) to Xq11 or Xq28, and FGS3 to Xp22.3. Clinical overlap with the G/BBB syndromes suggests not just a pathogenetic but perhaps a causal relationship, since midin, a product of the X-linked G/BBB syndrome gene, is known to interact with that of the gene MIDIA1 at Xq13, a candidate gene for the FG syndrome. Many/most carriers show more or less subtle signs of the FG syndrome including high forehead, cowlick(s)/widow's peak, broad thumbs/halluces, at times constipation, migraines, depression, anxiety. The fact that FG signs are frequently found in all of the sibs in segregating cases and in some of the fathers suggests a genetic abnormality (i.e. meiotic drive, segregation distortion) or gene/gene (i.e. FG/G/BBB) interaction.

		Diagnostic methods
		Routine pediatric, neurologic, gastroenterological, cardiologic, child psychologic approaches, including MRI, EEG, echocardiography, and electromyography.

		Genetic Counseling
		Only after careful examination of parents and all sibs. Truly sporadic cases (i.e. presumed new mutations) are extremely rare; the FG syndrome is not as strikingly an iceberg mutation as the G/BBB syndrome with uncommon recurrence of cases as severe as that of the propositus. Rather, in the FG syndrome recurrence as severe as in propositi is common and may affect sibs, first cousins, nephews and other maternal relatives. It is hoped that molecular methods will soon aid diagnosis, carrier detection, prenatal diagnosis and more reliable genetic counseling.

		Antenatal diagnosis
		Prenatally frequently symptomatic on the basis of reduced fetal movements, oligohydramios, asymmetric intrauterine growth retardation with increased biparietal diameter and dilated ventricles and abnormal fetal responses indicating fetal distress. No specific molecular diagnosis as yet.

		Unresolved questions
		Causal or pathogenetic relationship with G/BBB syndromes, segregation ratio, paternal influence, gene mapping, cloning, sequencing and mutation analysis.

		Keywords
		FG syndrome, Opitz-Kaveggia syndrome, multiple congenital anomalies, congenital hypotonia, megalencephaly, developmental/speech delay, autism, Asperger syndrome, pervasive developmental disorder, constipation, gastroesophageal reflux, delayed sensory integration, genital abnormalities.

		References.
		Briault S, Hill R, Shrimpton A, Zhu D, Till M, Ronce N, Margaritte-Jeannin P, Baraitser M, Middleton-Price H, Malcolm S, Thompson E, Hoo J, Wilson G, Romano C, Guichet A, Pembrey M, Fontes M, Poustka A, Moraine C. 1997. A gene for FG syndrome maps in the Xq12-q21.31 region. Am J Med Genet 73:87-90.

		Briault S, Villard L, Rogner U, Coy J, Odent S, Lucas J, Passarge E, Zhu D, Shrimpton A, Pembrey M, Till M, Guichet A, Dessay S, Fontes M, Poustka A, Moraine C. 2000. Mapping of X chromosome inversion breakpoints [inv (X)(q11q28)] associated with FG syndrome: A second FG locus [FGS2]? Am J Med Genet 95:178-181.
		Dessay S, Moizard MP, Gilardi JL, Opitz JM, Middleton-Price H, Pembrey M, Moraine C, Briault S. 2001. FG syndrome: Linkage analysis in two families supporting a new gene localization at Xp22.3 [FGS3]. Am J Med Genet, submitted.