Further evidence that fibroblast growth factor receptor 2 mutations cause Antley‐Bixler syndrome

Tsai, Fuu‐Jen; Wu, Jer‐Yuarn; Yang, Chi Fan; Tsai, Chang Hai

doi:10.1111/j.1651-2227.2001.tb00811.x

Cited by 24 publications

(12 citation statements)

References 8 publications

(3 reference statements)

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“…Interestingly, another amino-acid substitution creating an unpaired cysteine residue, namely S351C, also results in severe forms of PS in most reported cases. 31 -33 Although confusion might exist between severe PS and the so-called 'Antley-Bixler-like' phenotype, 34,35 we consider that the heterozygous S351C FGFR2 mutation is a hallmark of severe forms of PS, given that typical forms of Antley-Bixler syndrome are caused by recessive mutations in the P450 oxido-reductase (POR) gene. 36 Altogether, these data indicate that the presence of craniosynostosis and multiple anomalies evocative of severe PS (type II or III) should be confirmed at the molecular level by analysing recurrent FGFR2 mutations (W290C, Y340C, C342R and S351C) first.…”

Section: Discussionmentioning

confidence: 99%

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

et al. 2006

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Crouzon Syndrome (CS), Pfeiffer syndrome (PS) and the phenotypically related Jackson-Weiss (JW) variant are three craniosynostotic conditions caused by heterozygous mutations in Fibroblast Growth Factor Receptor (FGFR) genes. Screening a large cohort of 84 patients with clinical features of CS, PS or JW by direct sequencing of genomic DNA, enabled FGFR1, 2 or 3 mutation detection in 79 cases. Mutations preferentially occurred in exons 8 and 10 of FGFR2 encoding the third Ig loop of the receptor. Among the 74 FGFR2 mutations that we identified, four were novel including three missense substitutions causing CS and a 2 bp deletion creating a premature stop codon and producing JW phenotype. Five FGFR2 mutations were found in one of the two tyrosine kinase subdomains and one in the Ig I loop. Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively. Our data provide conclusive evidence that the mutational spectrum of FGFR2 mutations in CS and PS is wider than originally thought. Genotype-phenotype analyses based on our cohort and previous studies further indicate that in spite of some overlap, PS and CS are preferentially accounted for by two distinct sets of FGFR2 mutations. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) is commonly associated with the most severe Pfeiffer phenotypes of poor prognosis.

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Section: Discussionmentioning

confidence: 99%

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

et al. 2006

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“…Due to prior reports [Chun et al, 1998;Reardon et al, 2000;Tsai et al, 2001] about FGFR2 involvement with ABS, DNA analysis of exons 8 (IIIa), 10 (IIIc), and 11 in FGFR2 revealed no mutations in this patient. As mutations in the gene encoding P450 (cytochrome) oxidoreductase, POR, have been shown to be associated with both an ABS phenotype and ambiguous genitalia, as seen in our patient, direct sequencing of POR was performed with primers previously reported .…”

Section: Biochemical and Genetic Analysis And Resultsmentioning

confidence: 81%

“…Mutations in the gene encoding for fibroblast growth factor receptor 2 (FGFR2) were previously suggested as a cause of ABS including autosomal dominant cases with an ABS-like phenotype. However, these cases represent a unique condition, not ABS [Chun et al, 1998;Gorlin, 1999;Gripp et al, 1999;Reardon et al, 2000;Tsai et al, 2001]. An important breakthrough in understanding the pathogenesis of ABS occurred when Reardon et al [2000] reported alteration of steroid biogenesis in 7 of 16 patients with the syndrome.…”

Section: Introductionmentioning

confidence: 97%

Linking Antley–Bixler syndrome and congenital adrenal hyperplasia: A novel case of P450 oxidoreductase deficiency

Williamson

Arlt

Shackleton³

et al. 2006

American J of Med Genetics Pt A

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The Antley-Bixler syndrome (ABS) is a multiple congenital malformation syndrome with craniosynostosis, radiohumeral synostosis, femoral bowing, choanal atresia or stenosis, joint contractures, urogenital abnormalities and, often, early death. Autosomal recessive and dominant inheritance have been postulated, as has fluconazole teratogenesis. Mutations in POR (P450 (cytochrome) oxidoreductase, an essential electron donor to enzymes participating in cholesterol biosynthesis), have been identified in some patients with the ABS phenotype. Recent evidence suggests that these mutations cause attenuated steroid hydroxylation, which in turn, causes congenital adrenal hyperplasia (CAH) with ambiguous genitalia in both sexes and glucocorticoid deficiency. Here, we report on a new patient with findings of both ABS and CAH that further illustrates how low maternal estriol at prenatal screening can serve as a marker steroid facilitating early diagnosis.

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“…Detailed phenotypic assessment has revealed that some of the patients also manifest disordered sex development (DSD), with either underdeveloped male external genitalia (46,XY DSD) or virilised external female genitalia (46,XX DSD). Several studies demonstrated fibroblast growth factor receptor 2 (FGFR2) mutations as disease-causing in affected patients [5,6]. However, Reardon et al were first to note that FGFR2 mutations were only found in patients with malformations as their only clinical manifestation.…”

mentioning

confidence: 97%

P450 oxidoreductase deficiency and Antley–Bixler syndrome

Arlt

2007

Rev Endocr Metab Disord

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Antley-Bixler syndrome is a congenital malformation syndrome that primarily manifests with craniofacial abnormalities but may include skeletal malformations. Some cases have been shown to be caused by fibroblast growth factor receptor 2 mutations and, recently, it was revealed that others are caused by mutations in the electron donor enzyme P450 oxidoreductase (POR). P450 oxidoreductase deficiency, however, is not only associated with the malformations but frequently presents with disordered sex development in affected patients of both sexes. Furthermore, biochemical work-up invariably reveals impairment of 17-hydroxylase and 21-hydroxylase activities, two steroidogenic enzymes dependent on electron transfer from POR. While we begin to gain insight into the pathogenesis of disease, detailed genotype-phenotype studies are still lacking and POR deficiency presents several challenges for research. Firstly, the exact pathogenesis of the skeletal malformations as a consequence of POR mutations is unclear, though impaired sterol biosynthesis has been implicated. Secondly, it needs to be explained, why the external genitalia in affected boys may appear undervirilized while affected girls can be severely virilized. Further evidence is required for the proposed alternative pathway in human androgen synthesis that might explain the apparently contradictory finding of low circulating androgens and severely virilised external genitalia in affected girls. Recent studies have provided evidence for a differential interaction of specific POR mutations with different electron-accepting P450 enzymes and this may provide the key for further understanding of the complex pathogenesis of this complex disease.

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Further evidence that fibroblast growth factor receptor 2 mutations cause Antley‐Bixler syndrome

Cited by 24 publications

References 8 publications

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

Linking Antley–Bixler syndrome and congenital adrenal hyperplasia: A novel case of P450 oxidoreductase deficiency

P450 oxidoreductase deficiency and Antley–Bixler syndrome

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