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Objective: We present perinatal imaging findings of a fetus with Pfeiffer syndrome and a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in FGFR2 presenting a cloverleaf skull, craniosynostosis and short limbs on prenatal ultrasound mimicking thanatophoric dysplasia type II (TD2)., Case Report: A 37-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. However, craniofacial anomaly was found on prenatal ultrasound at 21 weeks of gestation, which showed a cloverleaf skull with severe craniosynostosis and relatively short straight long bones. Fetal magnetic resonance imaging (MRI) analysis at 22 weeks of gestation showed a cloverleaf skull, proptosis and relatively shallowing of the sylvian fissures. Prenatal ultrasound at 24 weeks of gestation showed a fetus with a cloverleaf skull with a biparietal diameter (BPD) of 6.16 cm (equivalent to 24 weeks), an abdominal circumference (AC) of 18.89 cm (equivalent to 24 weeks) and a femur length (FL) of 3.65 cm (equivalent to 21 weeks). A tentative diagnosis of TD2 was made. The pregnancy was subsequently terminated, and a 928-g malformed fetus was delivered with severe craniosynostosis, proptosis, midface retrusion, a cloverleaf skull, broad thumbs and broad big toes. The broad thumbs were medially deviated. Whole body X-ray showed a cloverleaf skull and straight long bones. However, molecular analysis of FGFR3 on the fetus revealed no mutation in the target regions. Subsequent whole exome sequencing (WES) on the DNA extracted from umbilical cord revealed a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in the FGFR2 gene., Conclusion: Fetuses with a Y340C mutation in FGFR2 may present a cloverleaf skull on prenatal ultrasound, and WES is useful for a rapid differential diagnosis of Pfeiffer syndrome from TD2 under such a circumstance., (Copyright © 2024. Published by Elsevier B.V.)

Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Unlabelled: Apert syndrome is a congenital disorder characterized by craniosynostosis and midface hypoplasia. This study looks to identify to what extent bipartition distraction corrects the morphological abnormalities of this condition. Preoperative and postoperative three-dimensional computed tomography (3DCT) scans of 10 patients with Apert syndrome (12-21 years) were identified from the Great Ormond Street Hospital database. To analyse preoperative and postoperative scans, 98 landmarks and 13 normal skulls were used. Principal component analysis (PCA) was used to analyse patterns in the datasets. Within each group, eigenvectors were identified that demonstrated the aspects of the skull where most variations were found. The analysis allowed both global shape measurement and local proportions. Postoperative and normal scans both showed the same first three principal components. Warping from preoperative to postoperative illustrates midface advancement and inward rotation of the orbits. Postoperative to normal warps demonstrate some remaining differences. The reliability of the used land marks varied between 77% and 95% for the highly reproducible landmarks between the two observers. 95% versus 100% were at least acceptable reproducible landmarks. This study allows us to understand the way bipartition distraction corrects the abnormalities of the Apert skull. Analysing the surgical outcome of facial bipartition with geometric morphometrics shows that some major Apert characteristics are corrected. Using the data and the output of further studies, surgical procedures can be adapted in order to achieve a postoperative result closer to the normal population., Level of Evidence: Therapeutic clinical question Level IV., (Copyright © 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Syndromic craniosynostosis is known to be associated with various obstructive respiratory disorders, including sleep apnoea. We performed early midfacial distraction in 11 syndromic craniosynostotic patients with obstructive respiratory apnoea and obtained good results. There were four patients with Crouzon syndrome, three patients with Pfeiffer syndrome and four patients with Apert syndrome. Their ages ranged from 7 months to 3 years, 9 months (mean: 2 years, 5 months). Midfacial distraction was performed using an internal or external device to improve obstructive respiratory disorders, such as sleep apnoea, and to avoid tracheostomy. Evaluation was performed by comparison of the pre- and postoperative polysomnograms (PSGs) and cephalograms. All patients had markedly improved respiratory disorders during sleep and avoided tracheostomy. Preoperative PSGs and cephalograms were compared with those from 1 year to 1 year, 6 months postoperatively. The postoperative PSGs and cephalograms showed marked improvements compared with preoperative PSGs and cephalograms. Syndromic craniosynostotic patients have facial bone hypoplasia, particularly of the maxilla. The tongue and parapharyngeal soft tissue become enlarged, and the enlarged tissues can cause airway obstruction. In this study, marked improvements were observed in physical evaluation using PSGs and morphological evaluation using cephalograms. Early midfacial distraction is thought to be a very useful method to reconstruct a large pharyngeal cavity, enlarge the airway, improve obstructive respiratory disorders and to avoid tracheostomy. It is important to select a device suitable for each case when surgery and distraction are performed., (Copyright © 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with variable expression. Here we report on a female infant with a de novo balanced translocation 46, XX, t(7;12)(p21.2;p12.3) and presenting at birth brachycephaly, antimongolic palpebral fissures, ocular hypertelorism, broad nose with low nasal bridge and low-set ears. This phenotype is suggestive of a subtle form of SCS, given the absence of limbs anomalies. Cloning of both breakpoints revealed that the translocation does not interrupt the TWIST1 coding region, on 7p21, known to be causative for SCS, but downregulates TWIST1 expression due to a position effect. On chromosome 12, the breakpoint translocates a shorter transcript of PTPRO gene, the osteoclastic protein-tyrosine phosphatase, PTP-oc, near to regulatory region of 7p leading to down-regulation of PTP-oc in the proband's fibroblasts. This is a confirmatory case report providing further evidence for TWIST1 haploinsufficiency in SCS, although a possible role of PTP-oc as genetic factor underlying or at least influencing the development of craniosynostosis could not be a priori excluded., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Apert syndrome is a rare disorder characterized by coronal craniosynostosis, syndactyly, brachycephaly, midfacial hypoplasia, and central nervous system anomalies, among other malformations. We present a case of Apert syndrome examined at 22 + 0 weeks' gestation. Three-dimensional maximum mode was decisive for the correct prenatal diagnosis by demonstrating the cranial deformities.

Purpose: To report on the use of fluorescence in situ hybridization (FISH) and dosage-sensitive Southern blot analysis in the molecular diagnosis of patients with Saethre-Chotzen syndrome., Methods: FISH and dosage-sensitive Southern blot analysis utilizing TWIST gene probes were performed on patients with Saethre-Chotzen syndrome but without an identifiable TWIST sequence variation., Results: Four unrelated patients with a deletion of the TWIST gene were identified by Southern blot; one of them had a complex chromosomal rearrangement involving 7p21 and no apparent deletion by FISH, suggesting a smaller deletion in the region including the TWIST gene. A fifth patient had an abnormal TWIST gene fragment on Southern blot analysis that segregated with the disease in the family; FISH was normal in this patient, suggesting a partial deletion or rearrangement in or near the gene., Conclusion: FISH and dosage-sensitive Southern blot analysis are useful diagnostic tools in Saethre-Chotzen syndrome without TWIST sequence variation.

Background: Mental retardation, considered as common in Apert syndrome could be in part due to associated brain abnormalities., Population and Methods: Sixty patients (32 males, 28 females) were included in the study. Patient age at the last examination was over 3 years (mean 10 years, range 3-28 years) in 38 patients. IQ was assessed from psychometric tests adapted for age. Brain anatomy was studied by MRI. Age at operation and quality of familial environment were also evaluated., Results: The IQ was over 70 in 12 patients (32%), over 90 in five (13%) and the mean IQ was 62 (10-114). Thirty percent of patients had abnormalities of the corpus callosum, 43% of the cerebral ventricles and 55% of the septum pellucidum. There was no anomaly in 28% of the patients. One or more operations were performed in 53 patients, before one year of age in 37. Ten children were institutionalized or in deleterious family situation. The main factor influencing the mental prognosis was the age at operation: the final IQ was over 70 in 50% of the children operated on before one year of age versus 8% in those operated on later (P = 0.01). Only the anomalies of the septum pellucidum seemed to play a role: 50% of the patients with normal septum had an IQ > 70 compared to 18% in those with septum anomalies (P < 0.04). The quality of the familial environment also influenced the mental development: 12.5% of the patients who were institutionalized or in difficult familial situation had an IQ > 70 compared to 39% of those who live in a normal family., Conclusions: Careful investigation including MRI is necessary for detecting associated brain abnormalities. The patients must be operated on early, if possible before the age of nine months. Attention has also to be paid to quality of the sociofamilial environment.