FG Syndrome Research Articles

FG syndrome: linkage analysis in two families supporting a new gene localization at Xp22.3 [FGS3

FG syndrome (OMIM 305450) is an X-linked condition comprising mental retardation, congenital hypotonia, constipation or anal malformations, and a distinctive appearance with disproportionately large head, tall and broad forehead, cowlicks and telecanthus. In a first linkage analysis carried out on 10 families, we demonstrated heterogeneity and assigned one gene [FGS1] to region Xq12-q21.31 [Briault et al., 1997: Am J Med Genet 73:87-90] corroborated by Graham et al. [1998: Am J Med Genet 80:145-156]. Heterogeneity was supported by the study of one family with apparent FG syndrome co-segregating with an inversion of X chromosome [inv(X)(q11q28)] ([FGS2], OMIM 300321) [Briault et al., 1999: Am J Med Genet 86:112-114 and Briault et al., 2000: Am J Med Genet 95:178-181]. We present the results of a new linkage analysis carried out on two families with FG syndrome. The two earlier known loci for FG syndrome, FGS1 and FGS2 (Xq11 or Xq28) were excluded by multipoint analysis of both families. Linkage was found, however, with locus DXS1060 suggesting that a third FG locus might be located at Xp22.3. In this region, two potential candidate genes, VCX-A and PRKX, were excluded by sequence analysis of the coding region in patients of the two reported FG families. The search for new candidate genes is in progress.

Developmental expression of alpha4 protein phosphatase regulatory subunit in tissues affected by Opitz syndrome.

Mutations in the Mid1 gene are responsible for X-linked Opitz syndrome, characterized by midline defects of the brain, face, heart, and trachea. The regulatory subunit alpha4 binds protein phosphatase 2A to Mid1 and promotes Mid1 dephosphorylation, in opposition to MAP kinase. To examine the relationship between alpha4 expression and human defects in Opitz syndrome, developmental expression of alpha4 in embryonic day (E) 8-E16 mouse embryos was mapped by immunohistochemistry. At E10, alpha4 was first detected only in the heart. At E11, alpha4 was expressed in epithelium of the mandibular and maxillary arches and in specific subsets of mesenchymal cells within the arches. The fetal heart and brain also highly expressed alpha4. At E16, alpha4 expression broadened to include the heart, brain, skeletal muscle, and tracheal and esophageal epithelium but not smooth muscle. Consistent with immunolocalization in embryos, Western immunoblotting of adult rabbit tissues demonstrated high levels of alpha4 expression in brain, heart, lung, liver, and skeletal muscle with low expression in kidney, uterus, and intestine. Expression in slow type I skeletal muscle was much higher than in fast type II muscle. By using double immunohistochemical staining, alpha4 was coexpressed in mouse skeletal muscle cells containing slow type myosin. Expression of alpha4 overlaps with the tissue defects in Opitz syndrome. The alpha4 gene lies in the linkage interval for FG syndrome, characterized by skeletal muscle and brain defects that coincide closely to the expression pattern of alpha4.

MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, Alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders

BackgroundPatients with Opitz GBBB syndrome present with a variable array of developmental defects including craniofacial, cardiac, and genital anomalies. Mutations in the X-linked MID1 gene, which encodes a microtubule-binding protein, have been found in ~50% of Opitz GBBB syndrome patients consistent with the genetically heterogeneous nature of the disorder. A protein highly related to MID1, called MID2, has also been described that similarly associates with microtubules.ResultsTo identify protein partners of MID1 and MID2 we undertook two separate yeast two-hybrid screens. Using this system we identified Alpha 4, a regulatory subunit of PP2-type phosphatases and a key component of the rapamycin-sensitive signaling pathway, as a strong interactor of both proteins. Analysis of domain-specific deletions has shown that the B-boxes of both MID1 and MID2 mediate the interaction with Alpha 4, the first demonstration in an RBCC protein of a specific role for the B-box region. In addition, we show that the MID1/2 coiled-coil motifs mediate both homo- and hetero-dimerisation, and that dimerisation is a prerequisite for association of the MID-Alpha 4 complex with microtubules.ConclusionsOur findings not only implicate Alpha 4 in the pathogenesis of Opitz GBBB syndrome but also support our earlier hypothesis that MID2 is a modifier of the X-linked phenotype. Of further note is the observation that Alpha 4 maps to Xq13 within the region showing linkage to FG (Opitz-Kaveggia) syndrome. Overlap in the clinical features of FG and Opitz GBBB syndromes warrants investigation of Alpha 4 as a candidate for causing FG syndrome.

Das FG-Syndrom - Ein definiertes Fehlbildungssyndrom

The FG syndrome is a distinctive genetic disorder which is characterized by mental retardation, hypotonia, anal stenosis and/or obstipation, macrocephaly and characteristic facial anomalies. The first description by J.M. Opitz and E.G. Kaveggia of the syndrome was in 1974. The inheritance is X-linked. The pathogenesis is not clear to date. FG are the initials of the first published family. FG syndrome is described here as a case report, a review of the literature is given.

Esophageal dysmotility in brothers with an FG-like syndrome

We present 4 brothers with developmental delay, minor anomalies, and symptoms due to gastrointestinal dysmotility. There was some resemblance with FG syndrome, although none of the brothers had sufficient findings to make this diagnosis. The index case presented with at age 1 month with screaming episodes, mild gastro-esophageal reflux (GER), and severe constipation. Esophageal manometry studies were consistent with the diagnosis of "nutcracker esophagus." Symptomatic and manometric improvement followed treatment with oral calcium channel blockers. Two older and less severely affected brothers had similar manometric findings but did not require treatment. A fourth brother with symptoms in infancy now has normal esophageal manometry findings. These boys in all likelihood have an X-linked syndrome with manifestations of FG syndrome, in which treatment with calcium channel blockers, produces clinical and manometric improvement. The FG syndrome is an X-linked syndrome of multiple congenital anomalies/mental retardation with facultative manifestations of gastrointestinal dysmotility, including gastro-esophageal reflux, severe feeding difficulties, and constipation. Esophageal dysmotility, in particular "nutcracker esophagus," should be suspected in infants with the FG syndrome and screaming attacks.

Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: A second FG locus [FGS2

FG syndrome is an X-linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints.

Behavior phenotype of FG syndrome: cognition, personality, and behavior in eleven affected boys.

In this study we examined several behavioral, personality, and cognitive characteristics of boys with FG syndrome. We confirmed high rates of attention and activity level problems, which were described previously. Nine of the 11 patients met criteria for attention deficit/hyperactivity disorder. The boys did not manifest autistic behavior, and none met criteria for an autism spectrum disorder, though their parents reported substantial repetitive behavior. The personalities of the participants often were described as friendly, good-natured, and cheerful, but they did not differ empirically on a standardized measure of personality structure from typically developing comparison children, even after controlling for the effects of IQ. Specifically, higher rates of agreeableness and extraversion were not confirmed, though these constructs do not correspond perfectly with the traits of affability and gregariousness described in earlier published case studies of FG syndrome. In terms of neuropsychological assessment, the boys had relatively less developed language, fine motor, and executive function skills, and visual-spatial abilities were a relative strength. Limitations and suggestions for future research are discussed.

Clinical and behavioral characteristics in FG syndrome

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974. Based on over 50 reported cases, FG syndrome is associated with agenesis of the corpus callosum, minor facial anomalies (high, broad forehead with frontal cowlick, ocular hypertelorism, down-slanted palpebral fissures, and small cupped auricles), relative macrocephaly, broad thumbs and halluces, and prominent fetal fingertip pads. Affected individuals manifest neonatal hypotonia and severe constipation, which usually resolves during mid-childhood. The hypotonia with joint hyperlaxity evolves into spasticity with joint contractures in later life. Affability, hyperactivity, and excessive talkativeness are noted frequently in patients with FG syndrome. Recently, we described three additional families (six additional patients) with FG syndrome who support the localization of a gene for the FG syndrome in chromosome region Xq12-q21 [Graham JM Jr, Tackels D, Dibbern K, Superneau D, Rodgers C, Corning K, Schwartz CE. 1998. Am J Med Genet 80:145-156.]. Using these same families and one additional sporadic case of FG syndrome, we compared behavioral and personality characteristics of 6 FG boys with other boys with syndromic and nonsyndromic mental retardation: eight with Down syndrome, seven with Prader-Willi syndrome, eight with nonspecific mental retardation, and 13 with Williams syndrome. Using the Vineland Adaptive Behavior Scales, the Reiss Personality Profiles, and the Achenbach Child Behavior Checklist, parents were asked to characterize the behavior and personality of their boys from ages 4 to 10 years. When compared with Williams syndrome, the FG boys had fewer internalizing behaviors and were significantly less anxious and withdrawn but had similar socially oriented, attention-seeking behaviors. On the Reiss Profile, FG boys were also quite similar to Williams syndrome boys. On the Vineland Scales, FG boys demonstrated significant relative strengths in their socialization skills, consistent with their personality, tending to confirm previous descriptions of their personalities.

Clinical and behavioral characteristics in FG syndrome

Clinical and behavioral characteristics in FG syndrome

Reluctance to accept FG syndrome diagnosis

American Journal of Medical GeneticsVolume 83, Issue 5 p. 430-430 Letter to the Editor Reluctance to accept FG syndrome diagnosis K. Chrzanowska, Corresponding Author K. Chrzanowska chrzanowska@czd.waw.pl Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-736 Warsaw, PolandSearch for more papers by this authorK. Kozlowski, K. Kozlowski Department of Radiology, Royal Alexandra Hospital for Children, Sydney, AustraliaSearch for more papers by this author K. Chrzanowska, Corresponding Author K. Chrzanowska chrzanowska@czd.waw.pl Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-736 Warsaw, PolandSearch for more papers by this authorK. Kozlowski, K. Kozlowski Department of Radiology, Royal Alexandra Hospital for Children, Sydney, AustraliaSearch for more papers by this author First published: 05 April 1999 https://doi.org/10.1002/(SICI)1096-8628(19990423)83:5<430::AID-AJMG19>3.0.CO;2-YAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume83, Issue523 April 1999Pages 430-430 RelatedInformation

Reluctance to accept FG syndrome diagnosis

Reluctance to accept FG syndrome diagnosis

FG syndrome: Report of three new families with linkage to xq12-q22.1

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974 in five related males with mental retardation, disproportionately large heads, imperforate anus, and congenital hypotonia. Partial agenesis of the corpus callosum was noted in at least one of the initial cases and has been seen in a number of subsequently-reported cases. The associated congenital hypotonia with joint hyperlaxity tends to progress to contractures with spasticity and unsteady gait in later life. The presence of subtle facial abnormalities and the characteristic behavior in midchildhood facilitate diagnosis at this age, particularly when there are other affected male relatives in the maternal family. Recently, Briault et al. [1997] mapped a gene for FG syndrome to the Xq12-q21.31 region. We describe three additional families (six additional patients) with FG syndrome on whom we have conducted linkage analysis. Our findings support the localization of a gene for the FG syndrome in Xq12-q21. In addition, we have noted skewed X-inactivation in carrier females, as well as new associated findings in affected males of sagittal craniosynostosis and split hand malformation.

FG syndrome: Report of three new families with linkage to xq12‐q22.1

FG syndrome: Report of three new families with linkage to xq12‐q22.1

Syndromal foramina parietalia permagna: ”new” or FG syndrome? Comments on the paper by Chrzanowska et al. [1998

American Journal of Medical GeneticsVolume 78, Issue 5 p. 406-407 Editorial Comment Syndromal foramina parietalia permagna: ”new” or FG syndrome? Comments on the paper by Chrzanowska et al. [1998] Anita Rauch, Anita Rauch Institut für Humangenetik, Friedrich-Alexander-Universität Erlangen, Nürnberg, GermanySearch for more papers by this authorJohn M. Opitz, Corresponding Author John M. Opitz ajmg@hsc.utah.edu Departments of Pediatrics, Human Genetics, and Obstetrics and Gynecology, University of Utah, Salt Lake City, UtahUniversity of Utah and Primary Children's Medical Center, 100 North Medical Drive, Suite 2100, Salt Lake City, UT 84113Search for more papers by this authorDiane Walker, Diane Walker Pleasant Grove, UtahSearch for more papers by this author Anita Rauch, Anita Rauch Institut für Humangenetik, Friedrich-Alexander-Universität Erlangen, Nürnberg, GermanySearch for more papers by this authorJohn M. Opitz, Corresponding Author John M. Opitz ajmg@hsc.utah.edu Departments of Pediatrics, Human Genetics, and Obstetrics and Gynecology, University of Utah, Salt Lake City, UtahUniversity of Utah and Primary Children's Medical Center, 100 North Medical Drive, Suite 2100, Salt Lake City, UT 84113Search for more papers by this authorDiane Walker, Diane Walker Pleasant Grove, UtahSearch for more papers by this author First published: 06 December 1998 https://doi.org/10.1002/(SICI)1096-8628(19980806)78:5<406::AID-AJMG2>3.0.CO;2-JCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume78, Issue56 August 1998Pages 406-407 RelatedInformation

Syndromal foramina parietalia permagna: ?new? or FG syndrome? Comments on the paper by Chrzanowska et al. [1998

Syndromal foramina parietalia permagna: ?new? or FG syndrome? Comments on the paper by Chrzanowska et al. [1998

Successful outcome with day 4 embryo transfer after preimplantation diagnosis for genetically transmitted diseases.

Preimplantation genetic diagnosis was performed in 61 day 3 embryos obtained by in-vitro fertilization from seven patient carriers of haemophilia, Marfan's syndrome, Bloch-Sulzemberg syndrome (incontinentia pigmentosa) or X chromosome-linked immune deficiency, retinitis pigmentosa, and FG syndrome, which is characterized by mental retardation and hypotonia. After multiplex polymerase chain reaction, 16 embryos were diagnosed as being unaffected, and these were transferred to the uterus on the following day (day 4). Of these embryos, six (37.5%) implanted, resulting in the delivery of a singleton and a twin pregnancy, a late second trimester miscarriage (twins at week 20) and a first trimester miscarriage at week 8. All the diagnoses were confirmed by amniocentesis. We report for the first time a late day 4 transfer of biopsied human embryos undergoing preimplantation genetic diagnosis. This transfer schedule allows an extra day to perform genetic analyses on single blastomeres and to monitor any adverse effect of the biopsy procedure.

A gene for FG syndrome maps in the Xq12-q21.31 region

FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.

A gene for FG syndrome maps in the Xq12‐q21.31 region

A gene for FG syndrome maps in the Xq12‐q21.31 region

Fragile X mutation and FG syndrome‐like phenotype

We present data on 4 mentally retarded brothers, 2 of whom were dizygotic twins with congenital hypotonia, constipation, head size disproportionately large for length or height, and a combination of minor anomalies suggestive of FG syndrome. These brothers have a mentally retarded full sister with similar minor anomalies and an older half-brother with the Martin-Bell syndrome. The mother is mentally retarded; 4 of 7 individuals are positive for fragile X, but all have a CGG expansion ranging from 0.2–2 to 4 kb. Although the phenotype is not completely typical of the FG syndrome and the coincidence of the FMR1 mutation and segregation of the MCA/MR phenotype are highly unlikely, the FMR1 mutation may affect morphogenesis more extensively and differently than the Martin-Bell syndrome does to effect an FG syndromelike phenotype in certain families. This phenotype does not appear to be a contiguous gene syndrome, but an effect of the FMR1 mutation on an adjacent gene must be considered. © 1996 Wiley-Liss, Inc.

A clinical follow-up of British patients with FG syndrome

The FG syndrome is an X-linked recessive mental retardation syndrome. Ten patients are reviewed with special emphasis on the natural history of the intellectual development, constipation, and the prognosis for growth and behaviour. Six out of 10 patients are still macrocephalic, and there is no evidence for a specific growth pattern with respect to height. The degree of mental retardation is is usually severe. The behaviour is characteristically friendly, sociable and over-talkative, with periodic aggression. Six patients have seizures. A characteristic progression seems to occur from congenital hypotonia with joint hyperlaxity at birth, to joint contractures with apparent spasticity and unsteady gait later in life. The constipation was a temporary problem in five cases. The cowlick and the fetal pads persist and are important, but not specific, for the diagnosis.