Family study of inherited syndrome with multiple congenital deformities: symphalangism, carpal and tarsal fusion, brachydactyly, craniosynostosis, strabismus, hip osteochondritis.
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A syndrome of brachydactyly (absence of some middle or distal phalanges), aplastic or hypoplastic nails, symphalangism (ankylois of proximal interphalangeal joints), synostosis of some carpal and tarsal bones, craniosynostosis, and dysplastic hip joints is reported in five members of an Italian family. It may represent a previously undescribed autosomal dominant trait. (+info)
A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.
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We have identified a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation in four unrelated individuals with skeletal dysplasia that approaches the severity observed in thanatophoric dysplasia type I (TD1). However, three of the four individuals developed extensive areas of acanthosis nigricans beginning in early childhood, suffer from severe neurological impairments, and have survived past infancy without prolonged life-support measures. The FGFR3 mutation (A1949T: Lys650Met) occurs at the nucleotide adjacent to the TD type II (TD2) mutation (A1948G: Lys650Glu) and results in a different amino acid substitution at a highly conserved codon in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs show that the Lys650Met mutation causes a dramatic increase in constitutive receptor kinase activity, approximately three times greater than that observed with the Lys650Glu mutation. We refer to the phenotype caused by the Lys650Met mutation as "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) because it differs significantly from the phenotypes of other known FGFR3 mutations. (+info)
Non-invasive aortic blood flow measurement in infants during repair of craniosynostosis.
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We have assessed the potential clinical benefit of a new echo-Doppler device (Dynemo 3000) which provides a continuous measure of aortic blood flow (ABF) using an aortic flowmeter and a paediatric oesophageal probe, during repair of craniosynostosis in infants under general anaesthesia. The data recorded included: ABFi (i = indexed to body surface area), stroke volume (SVi), systemic vascular resistance (TSVRi), pre-ejection period (PEP), left ventricular ejection time (LVET), mean arterial pressure (MAP), heart rate (HR) and central venous pressure (CVP). Data were collected: before (T1) and 3 min after skin incision (T2), at the time of maximal haemorrhage (T3) and at the end of the procedure (T4). Twelve infants (aged 7.0 (range 6-12) months) were included. ABFi, MAP and CVP were significantly lower at T3 compared with T1 (2.0 (0.8) vs 3.0 (0.8) litre min-1 m-2, 46.1 (5.8) vs 65.2 (8.9) mm Hg and 2.8 (1.6) vs 5.2 (2.1) mm Hg; P < 0.05). PEP/LVET ratio was significantly lower at T2 compared with T1 (0.25 (0.05) vs 0.30 (0.06)) and increased at T4 (0.36 (0.04); P < 0.05). These preliminary results suggest that this non-invasive ABF echo-Doppler device may be useful for continuous haemodynamic monitoring during a surgical procedure associated with haemorrhage in infants. (+info)
Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders.
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Craniosynostoses are a heterogeneous group of disorders characterized by premature fusion of cranial sutures. Mutations in fibroblast growth factor receptors (FGFRs) have been associated with a number of such conditions. Nevertheless, the cellular mechanism(s) involved remain unknown. We analyzed cell proliferation and differentiation in osteoblasts obtained from patients with three genetically and clinically distinct craniosynostoses: Pfeiffer syndrome carrying the FGFR2 C342R substitution, Apert syndrome with FGFR2 P253R change, and a nonsyndromic craniosynostosis without FGFR canonic mutations, as compared with control osteoblasts. Osteoblasts from craniosynostotic patients exhibited a lower proliferation rate than control osteoblasts. P253R and nonsyndromic craniosynostosis osteoblasts showed a marked differentiated phenotype, characterized by high alkaline phosphatase activity, increased mineralization and expression of noncollagenous matrix proteins, associated with high expression and activation of protein kinase Calpha and protein kinase Cepsilon isoenzymes. By contrast, the low proliferation rate of C342R osteoblasts was not associated with a differentiated phenotype. Although they showed higher alkaline phosphatase activity than control, C342R osteoblasts failed to mineralize and expressed low levels of osteopontin and osteonectin and high protein kinase Czeta levels. Stimulation of proliferation and inhibition of differentiation were observed in all cultures on FGF2 treatment. Our results suggest that an anticipated proliferative/differentiative switch, associated with alterations of the FGFR transduction pathways, could be the causative common feature in craniosynostosis and that mutations in distinct FGFR2 domains are associated with an in vitro heterogeneous differentiative phenotype. (+info)
Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome.
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Apert syndrome is characterized by craniosynostosis, midfacial hypoplasia and bilateral syndactyly. We document in detail the intrauterine natural history of Apert syndrome by serial sonographic examination. Ultrasound examination of a 19-week fetus revealed an abnormal appearance of the skull. The subsequent examination including transvaginal brain scanning demonstrated a deformed occipital part of the cerebrum and lateral ventricles, frontal bossing, a low nasal bridge and an abnormal appearance of the fetal hands and feet. The distortion of the fetal profile became progressively worse with advancing gestation. Towards the end of pregnancy, anterior prominence of the cerebrum, ventricles and corpus callosum was demonstrated and mild non-progressive ventriculomegaly was seen. The female 3152-g newborn with the typical facial appearance of Apert syndrome, bilateral syndactyly of the fingers and toes and isolated cleft palate was delivered at 37 weeks. Postnatal three-dimensional computed tomography scan demonstrated the fusion of the coronal suture and a wide mid-line calvarial defect, and cranial magnetic resonance imaging confirmed the prenatal sonographic findings. Although the karyotype was normal, genomic DNA analysis of the fibroblast growth factor receptor 2 revealed Ser252Trp, which is specified in the mutational basis of Apert syndrome. The time course of the prenatal findings in this case may help increase understanding of the intrauterine natural history of Apert syndrome. (+info)
Reduction of operating time and blood transfusion for craniosynostosis by simulated surgery using three-dimensional solid models.
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Preoperative planning of craniofacial synostosis can be achieved through the use of two- or three-dimensional (3D) computed tomography (CT) images and by 3D solid models. The advantage of using 3D models was evaluated by calculating the amount of blood transfused and the operating time for 36 craniosynostosis procedures, 21 planned with 3D models and 15 with CT images performed in the past 7 years. The use of 3D models reduced both blood loss and operating time for fronto-orbital advancement with reshaping, LeFort III advancement, and LeFort IV minus Glabellar advancement; blood loss for fronto-orbital advancement without reshaping; and operating time for total cranial reshaping. (+info)
Three-dimensional morphological analysis of isolated metopic synostosis.
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Morphological differences were quantified in three-dimensions among individuals with untreated isolated metopic synostosis and between those individuals and similar aged-matched normal dry skulls to test two hypotheses: first, that the dysmorphology is a self-correcting condition; and second, that a lack of vertical growth of the skull produces this dysmorphology. Three-dimensional (3D) coordinates were recorded for 22 craniofacial landmarks from CT scans of 15 metopic patients, ranging from 5- to 32-months-old, and of four normal dry skulls, ranging in age from 6- to 36-months-old. The patient population was diagnosed with isolated metopic synostosis at The Johns Hopkins Medical Institutions in Baltimore, Maryland or Children's Hospital in St. Louis, Missouri. Comparisons between the metopic age groups indicate that the trigonocephalic phenotype worsens through time. Between 5 and 14 months, the neurocranium displays an increase in vertical growth. This was followed by a lack of vertical growth between 14 and 32 months. The face displays a lack of vertical growth from 5 to 14 months and an increase in vertical growth after 14 months. Comparisons between the metopic age groups and the normal skulls indicate that the trigonocephalic head is taller superoinferiorly and longer anteroposteriorly. Relative to the normal phenotype, the inferior temporal region in the metopic phenotype is narrow. These findings enabled the rejection of both hypotheses and localized form differences between normal and metopic phenotypes. Based on these results, we suggest that the trigonocephalic phenotype worsens with age and the amount of vertical growth that produces the trigonocephalic phenotype varies throughout growth with respect to location within the skull and age. (+info)
Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?
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The Antley-Bixler syndrome has been thought to be caused by an autosomal recessive gene. However, patients with this phenotype have been reported with a new dominant mutation at the FGFR2 locus as well as in the offspring of mothers taking the antifungal agent fluconazole during early pregnancy. In addition to the craniosynostosis and joint ankylosis which are the clinical hallmarks of the condition, many patients, especially females, have genital abnormalities. We now report abnormalities of steroid biogenesis in seven of 16 patients with an Antley-Bixler phenotype. Additionally, we identify FGFR2 mutations in seven of these 16 patients, including one patient with abnormal steroidogenesis. These findings, suggesting that some cases of Antley-Bixler syndrome are the outcome of two distinct genetic events, allow a hypothesis to be formulated under which we may explain all the differing and seemingly contradictory circumstances in which the Antley-Bixler phenotype has been recognised. (+info)