Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a mutation in the FGFR2 gene in affected members of a large family with inherited autosomal dominant craniosynostosis. The mutation is a G1044A transition at codon 344 of exon B of the gene and results in abnormal splicing of the FGFR2 transcript. The phenotypic effect of the mutation varies greatly. It ranges from minor anomalies such as slight hypertelorism and maxillary hypoplasia to severe manifestations such as brachycephaly and dolichocephaly. The severe cases required surgery because of increased intracranial pressure. The patients cannot be assigned clinically to one of the known craniosynostotic syndromes with mutations in FGFR2, e.g., Crouzon, Pfeiffer, or Jackson-Weiss. This study demonstrates that FGFR2 mutations can result in a spectrum of craniofacial abnormalities even within one family. The known eponymic syndromes of Crouzon, Pfeiffer, or Jackson-Weiss only describe phenotypic extremes of this spectrum. Therefore, the clinical classification should be abandoned and replaced by a molecular one such as "FGFR-associated craniosynostosis syndromes."
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PMID:FGFR2 mutation in clinically nonclassifiable autosomal dominant craniosynostosis with pronounced phenotypic variation. 895 19

Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST, FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269-270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition-such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes-support the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.
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PMID:Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. 958 83

The authors performed a prospective study evaluating molecular diagnosis in patients with bilateral coronal synostosis. The patients were divided into two groups: (1) those clinically classified as having Apert, Crouzon, or Pfeiffer syndrome and (2) those clinically unclassified and labeled as having brachycephaly. Blood samples were drawn for genomic DNA analysis from 57 patients from 1995 to 1997. Polymerase chain reactions were performed using primers flanking exons in FGFR 1, 2, and 3. Each exon was screened for mutations using single-strand confirmation polymorphism, and mutations were identified by DNA sequencing. Mutations in FGFR2 or FGFR3 were found in all patients (n = 38) assigned a phenotypic (eponymous) diagnosis. All Apert syndrome patients (n = 13) carried one of the two known point mutations in exon 7 of FGFR2 (Ser252Trp and Pro253Arg). Twenty-five patients were diagnosed as having either Crouzon or Pfeiffer syndrome. Five patients with Crouzon syndrome of variable severity had mutations in exon 7 of FGFR2. Fifteen patients (12 with Crouzon, 3 with Pfeiffer) had a mutation in exon 9 of FGFR2, many of which involved loss or gain of a cysteine residue. A wide phenotypic range was observed in patients with identical mutations, including those involving cysteine. Two patients labeled as having Crouzon syndrome had the Pro250Arg mutation in exon 7 of FGFR3. All three patients with the crouzonoid phenotype and acanthosis nigricans had the same mutation in exon 10 of FGFR3 (Ala391Glu). This is a distinct disorder, characterized by jugular foraminal stenosis, Chiari I anomaly, and intracranial venous hypertension. Mutations were found in 14 of 19 clinically unclassifiable patients. Three mutations were in exon 9, and one was in the donor splice site of intron 9 on FGFR2. The most common mutation discovered in this group was Pro250Arg in exon 7 of FGFR3. These patients (n = 10) had either bilateral or unilateral coronal synostosis, minimal midfacial hypoplasia with class I or class II occlusion, and minor brachysyndactyly. No mutations in FGFR 1, 2, or 3 were detected in five patients with nonspecific brachycephaly. In conclusion, a molecular diagnosis was possible in all patients (n = 38) given a phenotypic (eponymous) diagnosis. Different phenotypes observed with identical mutations probably resulted from modulation by their genetic background. A molecular diagnosis was made in 74 percent of the 19 unclassified patients in this series; all mutations were in FGFR2 or FGFR3. Our data and those of other investigators suggest that we should begin integrating molecular diagnosis with phenotypic diagnosis of craniosynostoses in studies of natural history and dysmorphology and in analyses of surgical results.
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PMID:Molecular diagnosis of bilateral coronal synostosis. 1054 Nov 59

Pfeiffer syndrome is clinically and genetically heterogeneous. Three clinical subtypes have been delineated based on the severity of acrocephalysyndactyly and associated manifestations. Severe cases are usually sporadic and caused by a number of different mutations in exons IIIa and IIIc of the fibroblast growth factor receptor 2 (FGFR2) gene. Mild cases are either sporadic or familial and are caused by mutations in FGFR2 or FGFR1, respectively. We report on two individuals with different novel de novo mutations in FGFR2. The first is a 17-year-old male who has a severe phenotype, within the spectrum of subtype 1 including severe ocular proptosis, elbow ankylosis, visceral anomalies, and normal intelligence. This patient was found to have a novel complex mutation at the 3' acceptor site of exon IIIc of FGFR2, denoted as C952-3 del10insACC. The other patient, a 2-year-old female, has a mild phenotype, typical of the classic subtype 1 including brachycephaly with coronal synostosis and hypertelorism. She was also found to have a mutation at the 3' acceptor site (the same splice site) of exon IIIc of FGFR2, a point mutation designated as 952-1G-->A. Speculation on the molecular mechanisms that cause severe and mild phenotypes is presented in relation to these two cases.
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PMID:Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2. 1212 45

Bilateral coronal synostosis causes functional and morphological problems that require fronto-orbital advancement in infancy to correct the brachycephalic deformity and to prevent mental impairment caused by the intracranial hypertension. In this study, 99 children with isolated cases of brachycephaly were prospectively followed to study their preoperative and postoperative mental outcome, which was evaluated using developmental or intelligence quotients. Several factors were analyzed: age before treatment, age at the time of surgery, and the correlation between mental assessments before and after surgery. In a subgroup or patients tested for the FGFR3 P250R mutation (n = 48), mental and morphological assessments were analyzed. Before surgery, mental status was better in the patients tested before 1 year of age (p < 0.001). The preoperative mental assessment always correlated with the postoperative assessment (p < 0.0001). The postoperative mental outcome was better when surgery was performed before the patient reached 1 year of age (p < 0.02). Although both the morphological and functional outcomes were better in the subgroup of noncarriers of the mutation, the differences were not statistically significant. Prominent bulging of the temporal fossae was frequently responsible for poor morphological outcome in carriers of the mutation. This study confirms the need for early corrective surgery before 1 year of age in brachycephalic patients to prevent impairment of their mental development. Suboptimal morphological and mental outcomes can be expected in patients with nonsyndromic brachycephaly who carry the FGFR3 P250R mutation. Primary correction of the temporal bulging should be performed in conjunction with fronto-orbital advancement to improve the morphological outcome in patients with the mutation.
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PMID:Postoperative mental and morphological outcome for nonsyndromic brachycephaly. 1208 22

Mutations in genes known to be responsible for most of the recognizable syndromes associated with bilateral coronal synostosis can be detected by molecular testing. The genetic alterations that could cause unilateral coronal synostosis are more elusive. It is recognized that FGFR and TWIST mutations can give rise to either bilateral or unilateral coronal synostosis, even in the same family. The authors undertook a prospective study of patients presenting with synostotic frontal plagiocephaly (unilateral coronal synostosis) to Children's Hospital Boston during the period from 1997 to 2000. Mutational analysis was performed on all patients and on selected parents whenever familial transmission was suspected. Intraoperative anthropometry was used in an effort to differentiate those patients in whom a mutation was detected from those in whom it was not. The anthropometric measures included bilateral sagittal orbital-globe distance, inter medial canthal distance, and nasal angulation. Macrocephaly and palpebral angulation were also considered possible determinants. There was a 2:1 female preponderance in 47 patients with synostotic frontal plagiocephaly. Mutations were found in eight of 47 patients: two patients with different single-amino-acid changes in FGFR2, three patients with FGFR3 Pro250Arg, and three patients with TWIST mutations. Another patient had craniofrontonasal syndrome for which a causative locus has been mapped to chromosome X, although molecular testing is not yet available. Two features were strongly associated with a detectable mutation in patients with synostotic frontal plagiocephaly: asymmetrical brachycephaly (retrusion of both supraorbital rims) and orbital hypertelorism. Other abnormalities in the craniofacial region and extremities were clues to a particular mutation in FGFR2, FGFR3, TWIST, or the X-linked mutation. Neither macrocephaly nor degree of nasal angulation nor relative vertical position of the lateral canthi correlated with mutational detection. An additional four patients in this study had either unilateral or bilateral coronal synostosis in an immediate relative and had anthropometric findings that predicted a mutation, and yet no genetic alteration was found. This suggests either that the authors' screening methods were not sufficiently sensitive or that perhaps there are other unknown pathogenic loci. Nevertheless, molecular testing is recommended for infants who have unilateral coronal synostosis, particularly if there are the anthropometric findings highlighted in this study or an otherwise suspicious feature in the child or a parent. Infants with either an identified or a suspected mutation usually need bilateral asymmetric advancement of the bandeau and may be more likely to require frontal revision in childhood.
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PMID:Molecular analysis of patients with synostotic frontal plagiocephaly (unilateral coronal synostosis). 1525 76

Craniosynostosis is a congenital developmental disorder involving premature fusion of cranial sutures, which results in an abnormal shape of the skull. Significant progress in understanding the molecular basis of this phenotype has been made for a small number of syndromic craniosynostosis forms. Nevertheless, in the majority of the approximately 100 craniosynostosis syndromes and in non-syndromic craniosynostosis the underlying gene defects and pathomechanisms are unknown. Here we report on a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. Three dimensional cranial computer tomography showed fusion of the lambdoid sutures and distal part of the sagittal suture with a gaping anterior fontanelle. Mutations in the genes for FGFR2 and FGFR3 were excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes. SOX6 mutation screening of another 104 craniosynostosis patients revealed one missense mutation leading to the exchange of a highly conserved amino acid (p.D68N) in a single patient and his reportedly healthy mother. The breakpoint on chromosome 9 is located in a region without any known or predicted genes but, interestingly, disrupts patches of evolutionarily highly conserved non-genic sequences and may thus led to dysregulation of flanking genes on chromosome 9 or 11 involved in skull vault development. The present case is one of the very rare reports of an apparently balanced translocation in a patient with syndromic craniosynostosis, and reveals novel candidate genes for craniosynostoses and cranial suture formation.
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PMID:Balanced translocation in a patient with craniosynostosis disrupts the SOX6 gene and an evolutionarily conserved non-transcribed region. 1625 6

The aim of this study was to perform a morphometric analysis of untreated adult skulls displaying syndromic and nonsyndromic craniosynostosis. We analyzed, in detail, 42 adult craniosynostoses (18 scaphocephaly, 11 anterior plagiocephaly, 2 trigonocephaly, 9 oxycephaly, and 2 brachycephaly) from archeological (three skulls) and pathoanatomical samples (39 skulls). The univariate and bivariate measurements from the pathological skulls were compared with 40 anatomical skulls with normal cranial vault morphology. Bony signs of chronic elevated intracranial pressure (ICP) are (1) diffuse beaten copper pattern, (2) dorsum sellae erosion, (3) suture diastasis, and (4) abnormalities of venous drainage that particularly affect the sigmoid-jugular sinus complex. The mean cranial length was significantly greater in scaphocephaly than in anatomical skulls (20.3 vs 18.0 cm), and the sagittal suture was also longer (14.3 vs 11.8 cm). There were three types of suture course in the bregma region in scaphocephaly: anterior spur (28%), normal configuration (61%), and posterior spur (11%). The plagiocephaly measurements showed nonsignificant differences, and there was no correlation between the length of the anterior and middle skull base (ipsilateral anterior-posterior shortening of the skull) and incomplete or complete suture synostosis. Bony signs of chronic elevated ICP were found in 82% of cases of oxycephaly and brachycephaly. In three such cases of oxycephaly, we found a marked (1.8-2.1 cm) elevation of bregma region. One skull (Saethre-Chotzen syndrome) yielded human DNA sufficient for polymerase chain reaction (PCR)-based amplification procedures. Mutation analyses in the FGFR3 gene revealed nucleotide alterations located in the mutational hot spot at amino acid residue 250 (g.C749). The mean cranial length in adult scaphocephaly was 12% greater than anatomical skulls. A unilateral complete or incomplete coronal synostosis can be found with or without plagiocephalic deformation. Elevation of the bregma region is a bony sign of chronic elevated ICP. These data on adult craniosynostosis could be of interest for physicians dealing with craniosynostotic children.
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PMID:Morphometric analysis of untreated adult skulls in syndromic and nonsyndromic craniosynostosis. 1799 50

Antley-Bixler syndrome (ABS) is a skeletal malformation syndrome primarily affecting the skull and limbs. Although causal mutations in the FGFR2 gene have been found in some patients, mutations in the electron donor enzyme P450 oxidoreductase gene (POR) have recently been found to cause ABS in other patients. In addition to skeletal malformations, POR deficiency also causes glucocorticoid deficiency and congenital adrenal hyperplasia with ambiguous genitalia in both sexes. Here, we report on a 7-month-old Korean girl with ABS and ambiguous genitalia who was confirmed by POR gene analysis. Our patient showed typical skeletal findings with brachycephaly, mid-face hypoplasia, and radiohumeral synostosis. She also had partial labial fusion and a single urogenital orifice, as well as increased 17alpha-hydroxyprogesterone levels, suggesting a 21-hydroxylase deficiency. Cortisol and DHEA-sulfate response to rapid adrenocorticotropic hormone (ACTH) stimulation was inadequate. Direct sequencing of the POR gene revealed compound heterozygous mutations (I444fsX449 and R457H). This is the first report of a Korean patient with ABS caused by POR gene mutations.
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PMID:A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene. 1885 85

Pfeiffer syndrome is a rare autosomal dominant disorder characterized by coronal craniosynostosis, brachycephaly, mid-facial hypoplasia, and broad and deviated thumbs and great toes. Pfeiffer syndrome occurs in approximately 1:100,000 live births. Clinical manifestations and molecular genetic testing are important to confirm the diagnosis. Mutations of the fibroblast growth factor receptor 1 (FGFR1) gene or FGFR2 gene can cause Pfeiffer syndrome. Here, we describe a case of Pfeiffer syndrome with a novel c833_834GC>TG mutation (encoding Cys278Leu) in the FGFR2 gene associated with a coccygeal anomaly, which is rare in Pfeiffer syndrome.
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PMID:A case of Pfeiffer syndrome with c833_834GC>TG (Cys278Leu) mutation in the FGFR2 gene. 2118 55


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