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

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 disorders

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

Diagnostic criteria and 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 been seen only in the G/BBB syndrome so far.

Prevalence

The disease is possibly as common as 1:1,000 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. Patients should be placed in a correct school setting and may need to learn sign language or to use assisted communication devices. Early introduction of educational computers is advised.

Etiology

This syndrome is 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 only 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, neurological, gastroenterological, cardiologic, child psychological 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 help 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.

Key words

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.

De la Casa-Esperon E, Loredo-Osti JC, Pardo-Manuel de Villena F, Briscoe T, Malette JM, Vaughan JE, Morgan K, Sapienza C. 2002. X chromosome effect on maternal recombination and meitoic drive in the mouse. Genetics 161:1651-1659.

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).

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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.

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Raynand M, Dessay S, Ronce N, Opitz J, Pembrey M, Romano C, Moraine C, Briault S. 2003. Skewed X chromosome inactivation in carriers is not a constant finding in FG syndrome.

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.