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At least 361 records · Page 20Linked to original sources
PubMed2001

Premature calvarial synostosis and epidermal hyperplasia (Beare-Stevenson syndrome-like anomalies) resulting from a P250R missense mutation in the gene encoding fibroblast growth factor receptor 3.

We report on a patient with a severe premature calvarial synostosis and epidermal hyperplasia. The phenotype was consistent with that of a mild presentation of Beare-Stevenson syndrome but molecular analysis of the IgIII-transmembrane linker region and the transmembrane domain of the gene encoding the FGFR2 receptor, revealed wild-type sequence only. Subsequently, molecular analysis of the FGFR3 receptor gene identified a heterozygous P250R missense mutation in both the proposita and her mildly affected father. This communication extends the clinical spectrum of the FGFR3 P250R mutation to encompass epidermal hyperplasia and documents the phenomenon of activated FGFR receptors stimulating common downstream developmental pathways, resulting in overlapping clinical outcomes.

Amino Acid Substitution↗
PubMed2001

Novel SNP at the common primer site of exon IIIa of FGFR2 gene causes error in molecular diagnosis of craniosynostosis syndrome.

Most mutations in Crouzon, Pfeiffer, and Apert syndromes are in the extracellular, third immunoglobulin-like domain and adjacent linker regions (exons IIIa and IIIc) of the fibroblast growth factor receptor 2 (FGFR2) gene. Using the published primers for PCR, a patient with Crouzon syndrome was found to be homozygous for a mutation that results in a Q289P amino acid substitution in FGFR2. Two additional patients; one with Apert syndrome and P253R mutation, the other with Pfeiffer syndrome and S267P mutation, also appeared to be homozygous. Using a new primer located 146 bp 5' of exon IIIa for PCR followed by sequencing revealed an A to G polymorphism at -62 [corrected] position of exon IIIa. All three patients were heterozygous for both the mutation and the polymorphism. These results indicate that the polymorphism and the mutation are not on the same chromosome. The single nucleotide polymorphism is located at the second to the last base of the 3' end of the published primer. This primer mismatch caused the failure of amplification of the normal chromosome and thus, the apparent homozygosity. The frequency of this novel polymorphism was determined to be 0.03 by studying 326 chromosomes from the general population. We propose that a new primer should be used for mutational analysis of exon IIIa of FGFR2 to avoid misdiagnosis caused by primer mismatch.

Base Sequence↗
PubMed2001

Semilobar holoprosencephaly, coronal craniosynostosis, and multiple congenital anomalies: a severe expression of the Genoa syndrome or a newly recognized syndrome?

We report on a female newborn with holoprosencephaly, craniosynostosis, and multiple congenital anomalies including cloverleaf skull, Dandy-Walker malformation, bilateral microphthalmia, cleft soft palate, congenital scoliosis, hypoplastic nails and coarctation of aorta. Some of these features are consistent with the diagnosis of the Genoa syndrome, (MIM 601370) a rare autosomal recessive disorder recently described. The findings of other serious and previously undescribed malformations, however, raises the possibility of a newly recognized disorder.

Abnormalities, Multiple↗
PubMed2003

Clinical and genetic aspects of trigonocephaly: a study of 25 cases.

We reviewed 25 patients ascertained through the finding of trigonocephaly/metopic synostosis as a prominent manifestation. In 16 patients, trigonocephaly/metopic synostosis was the only significant finding (64%); 2 patients had metopic/sagittal synostosis (8%) and in 7 patients the trigonocephaly was part of a syndrome (28%). Among the nonsyndromic cases, 12 were males and 6 were females and the sex ratio was 2 M:1 F. Only one patient with isolated trigonocephaly had an affected parent (5.6%). All nonsyndromic patients had normal psychomotor development. In 2 patients with isolated metopic/sagittal synostosis, FGFR2 and FGFR3 mutations were studied and none were detected. Among the syndromic cases, two had Jacobsen syndrome associated with deletion of chromosome 11q 23 (28.5%). Of the remaining five syndromic cases, different conditions were found including Say-Meyer syndrome, multiple congenital anomalies and bilateral retinoblastoma with no detectable deletion in chromosome 13q14.2 by G-banding chromosomal analysis and FISH, I-cell disease, a new acrocraniofacial dysostosis syndrome, and Opitz C trigonocephaly syndrome. The last two patients were studied for cryptic chromosomal rearrangements, with SKY and subtelomeric FISH probes. Also FGFR2 and FGFR3 mutations were studied in two syndromic cases, but none were found. This study demonstrates that the majority of cases with nonsyndromic trigonocephaly are sporadic and benign, apart from the associated cosmetic implications. Syndromic trigonocephaly cases are causally heterogeneous and associated with chromosomal as well as single gene disorders. An investigation to delineate the underlying cause of trigonocephaly is indicated because of its important implications on medical management for the patient and the reproductive plans for the family.

Abnormalities, Multiple↗
PubMed2003

Medial temporal lobe dysgenesis in Muenke syndrome and hypochondroplasia.

Hypochondroplasia (HCH) and Muenke syndrome (MS) are caused by mutations on FGFR3 gene. FGFR3 is known to play a role in controlling nervous system development. We describe the clinical and neuroradiological findings of the first two patients, to our knowledge, affected by HCH and MS, respectively, in whom bilateral dysgenesis of the medial temporal lobe structures has been observed. In both patients diagnosis was confirmed by molecular analysis. They were mentally normal and showed similarities in early-onset temporal lobe-related seizures. In both patients EEG recorded bilateral temporal region discharges. MRI detected temporal lobe anomalies with inadequate differentiation between white and gray matter, defective gyri, and abnormally shaped hippocampus.

Abnormalities, Multiple↗
PubMed2003

Craniosynostosis and congenital heart anomalies associated with a maternal deletion of 15q15-22.1.

We report an infant with multiple congenital anomalies, including craniosynostosis, tetralogy of Fallot variant, and limb anomalies associated with a maternal deletion of 15q15-22.1. Only two other patients have been reported with a similar deletion, but the deletion was paternal in both cases. We review our patient's findings and compare them to previously reported individuals with similar 15q abnormalities. Our patient allows an expansion of phenotype associated with mid-15q deletions to include severe craniosynostosis, congenital heart disease, and limb anomalies. This will assist in prenatal counseling and predicting postnatal outcome for other affected individuals. The specific breakpoints in our patient and the other patients with similar deletions may also assist in determining a critical region for suture formation.

Abnormalities, Multiple↗
PubMed2003

Beare-Stevenson syndrome: Two South American patients with FGFR2 analysis.

We report two patients with Beare-Stevenson syndrome. This syndrome presents craniosynostosis with or without clover-leaf skull, craniofacial anomalies, cutis gyrata, acanthosis nigricans, prominent umbilical stump, furrowed palms and soles, genital and anal anomalies. Both female newborn patients presented at birth with craniofacial anomalies, variable cutis gyrata in forehead and preauricular regions, prominent umbilical stump and anogenital anomalies. Furrowed palms and soles were also observed. The radiologic examination showed a cloverleaf-form craniosynostosis. Chromosomes were normal. They were born with respiratory distress and were connected to mechanical ventilation for ventilatory support. Both of them died in 50 days after birth due to secondary complications. The molecular analysis of these patients identified the mutation Tyr375Cys in the FGFR2 gene.

Abnormalities, Multiple↗
PubMed2003

Screening of patients with craniosynostosis: molecular strategy.

Craniosynostosis is the premature fusion of calvarial bones leading to an abnormal head shape. The craniosynostosis syndromes are clinically heterogeneous with overlapping features, which make an accurate diagnosis difficult at times. Although the clarification of a genetic lesion does not have a direct impact on patient management in many cases, there is a significant benefit in providing accurate prenatal diagnosis. Genetic counsellors are also able to offer better risk estimates of recurrences to non-manifesting carriers and their extended family members and for affected patients of reproductive age. Advances in gene discovery have shown that craniosynostosis syndromes delineated on clinical bases, with the possible exception of Apert syndrome, are genetically heterogeneous, and mutations have been found in fibroblast growth factor receptors (FGFR) 1, 2, 3 and TWIST. We surveyed 99 craniosynostosis patients at the molecular level and found mutations in 50 of them. Six novel point mutations were identified: three in FGFR2 and three in TWIST. Two Saethre-Chotzen patients with TWIST microdeletions at 7p21 were also found. The other mutations identified have been previously reported. In studying these 99 patients, we developed a diagnostic strategy for craniosynostosis testing, where sequential analysis of recurrent mutations was followed by selective sequencing. This algorithm makes testing of craniosynostosis disorders more efficient and cost-effective.

Craniosynostoses↗
PubMed2004

Treacher Collins syndrome with craniosynostosis, choanal atresia, and esophageal regurgitation caused by a novel nonsense mutation in TCOF1.

Treacher Collins syndrome (TCS) is caused by mutations in TCOF1 of the nonsense, small deletion, and small insertion types, which most likely result in haploinsufficiency. We report a novel de novo nonsense mutation 2731C --> T, resulting in Arg911Stop, which truncates the protein. Our patient had the classic findings of TCS, but with documented craniosynostosis, choanal atresia, and esophageal regurgitation.

Arginine↗
PubMed2004

Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome.

Antley-Bixler syndrome (ABS) is characterized by skeletal defects including craniosynostosis and radiohumeral synostosis. Although mutations in the FGFR2 gene have been found in some patients called ABS, genetic heterogeneity of this syndrome has been proposed. We have previously reported three ABS patients with unique abnormalities in steroidogenesis (apparent decreased activity of 17alpha-hydroxylase, 17,20-lyase, and 21-hydroxylase). Decreased activity of lanosterol 14alpha-demethylase has also been described in an ABS patient. Since all these enzymes require cytochrome P450 oxidoreductase (encoded by POR) as an electron donor, we studied POR in two unrelated ABS patients with abnormal steroidogenesis. Direct sequencing of POR revealed that both patients had compound heterozygous mutations (1329insC and R454H in a male patient, 1698insC and R454H in a female patient). The two insertional mutations were assumed to generate truncated and unstable mRNAs. The R454H mutation was assumed to be deleterious because the R454 resides in the FAD-binding domain and is highly conserved among diverse species. Our results demonstrate that mutations in POR cause the ABS phenotype with autosomal recessive inheritance and with characteristic abnormalities in steroidogenesis.

Abnormalities, Multiple↗
PubMed2004

Undetectable maternal serum uE3 and postnatal abnormal sterol and steroid metabolism in Antley-Bixler syndrome.

Antley-Bixler syndrome (ABS) is a rare condition characterized by radiohumeral synostosis, craniosynostosis, midface hypoplasia, bowing of the femora, multiple joint contractures, and urogenital defects. Several reports have implicated errors of steroid or sterol metabolism in the pathogenesis of ABS. Evidence for this has included association with maternal luteomas, fetal 21-hydroxylase deficiency, early pregnancy exposure to high-dose fluconazole, lanosterol 14-alpha-demethylase deficiency, and a unique urinary steroid profile consistent with apparent pregnene hydroxylation deficiency (APHD). We report two sibs with classic ABS. During both pregnancies, mid-trimester maternal serum screening demonstrated undetectable levels of uncongugated estriol (uE3). The brother had ambiguous genitalia and increased serum levels of progesterone and 17-alpha-hydroxyprogesterone. Postnatal tests performed on the sister demonstrated both the unique urinary steroid profile that defines APHD and evidence of impaired lanosterol 14-alpha-demethylase activity. Our results suggest that in at least some patients with ABS, the skeletal findings and altered steroidogenesis are not associated with genes specific to individual sterol or steroid pathways but rather are related to an element, such as NADPH cytochrome P450 reductase (CPR) or cytochrome b5 (CYb5), that is common to all of these pathways.

17-alpha-Hydroxyprogesterone↗
PubMed2005

Gracile bones, periostal appositions, hypomineralization of the cranial vault, and mental retardation in brothers: milder variant of osteocraniostenosis or new syndrome?

We report on two brothers with ossification anomalies of membranous and cranial bones, remodeling defect of long bones leading to dense, overtubulated, narrow diaphyses, metaphyseal flare, periostal hyperosotosis that increased during the first months of life, thoracic dystrophy and severe hypotonia. One boy had hypospadias and cleft palate. Follow-up of the surviving boy documented progressive osteopenia, slow healing of the periostal anomalies, liver angiomatosis, mental and motor delay, thoracic deformity, delay in tooth eruption, and progressive microcephaly with enlargement of the cerebral ventricles. This disorder shares some traits with osteocraniostenosis, but lacks the cranial deformity and acromelic micromelia of the latter, in which periostal anomalies are not described. The syndrome reported here may represent a milder form of osteocraniostenosis, or a new entity belonging to the same "family." Genealogical data are consistent with AR or XLR inheritance. No mutations were found in the coding sequence of filamin A.

Abnormalities, Multiple↗