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BMJ Case Reports Apr 2021Pfeiffer syndrome is a rare inherited craniofacial disorder. Upper airway obstruction is common among patients with Pfeiffer syndrome due to craniosynostosis. They may...
Pfeiffer syndrome is a rare inherited craniofacial disorder. Upper airway obstruction is common among patients with Pfeiffer syndrome due to craniosynostosis. They may also present with lower respiratory tract obstruction due to a rare congenital airway malformation called tracheal cartilaginous sleeve (TCS). We report the case of a patient with Pfeiffer syndrome who presented with recurrent bronchopneumonia, discovered incidentally to have TCS via direct visualisation during tracheostomy. Relevant literature for this rare clinical condition are reviewed and discussed. Clinicians should be aware of TCS when encountering patients with craniosynostosis who present with recurrent lower respiratory tract infections. Careful and meticulous investigations should be performed to look for TCS, especially in patients with craniosynostosis.
Topics: Acrocephalosyndactylia; Cartilage; Child; Child, Preschool; Craniosynostoses; Humans; Infant; Male; Trachea; Tracheostomy
PubMed: 33811090
DOI: 10.1136/bcr-2020-236888 -
Archivos Argentinos de Pediatria Apr 2021The Saethre-Chotzen syndrome is a craniofacial malformation syndrome characterized by synostosis of coronal sutures and limb anomalies. The estimated prevalence of this...
The Saethre-Chotzen syndrome is a craniofacial malformation syndrome characterized by synostosis of coronal sutures and limb anomalies. The estimated prevalence of this syndrome is 1 in 25 000-50 000 live births. We present a case report of a neonate, without relevant family history, who presented craniofacial alterations at birth. Given the phenotypic features, a cranial computed tomography scan was performed, showing partial fusion of the coronal suture, evidencing the presence Síndrome de Saethre-Chotzen: a propósito de un caso Saethre-Chotzen syndrome: a case report of wormian bones in the metopic and right lambdoid location. With the clinical suspicion of craniofacial malformation syndrome, an analysis of the directed exome was requested confirming that the patient is a heterozygous carrier of the pathogenic variant c.415C>A, which induces a change of proline to threonine at position 139 of the TWIST1 gene, responsible for Saethre-Chotzen syndrome. The presence of wormian bones, a finding not described so far in the literature, extends the well-known phenotypic variability of this syndrome.
Topics: Acrocephalosyndactylia; Cranial Sutures; Heterozygote; Humans; Infant, Newborn; Nuclear Proteins; Twist-Related Protein 1
PubMed: 33749202
DOI: 10.5546/aap.2021.e129 -
Stem Cell Research & Therapy Dec 2020During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or...
BACKGROUND
During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or craniosynostosis, leading to craniofacial and cognitive issues. Saethre-Chotzen syndrome (SCS) is a common form of craniosynostosis, caused by TWIST-1 gene mutations. Currently, the only treatment option for craniosynostosis involves multiple invasive cranial surgeries, which can lead to serious complications.
METHODS
The present study utilized Twist-1 haploinsufficient (Twist-1) mice as SCS mouse model to investigate the inhibition of Kdm6a and Kdm6b activity using the pharmacological inhibitor, GSK-J4, on calvarial cell osteogenic potential.
RESULTS
This study showed that the histone methyltransferase EZH2, an osteogenesis inhibitor, is downregulated in calvarial cells derived from Twist-1 mice, whereas the counter histone demethylases, Kdm6a and Kdm6b, known promoters of osteogenesis, were upregulated. In vitro studies confirmed that siRNA-mediated inhibition of Kdm6a and Kdm6b expression suppressed osteogenic differentiation of Twist-1 calvarial cells. Moreover, pharmacological targeting of Kdm6a and Kdm6b activity, with the inhibitor, GSK-J4, caused a dose-dependent suppression of osteogenic differentiation by Twist-1 calvarial cells in vitro and reduced mineralized bone formation in Twist-1 calvarial explant cultures. Chromatin immunoprecipitation and Western blot analyses found that GSK-J4 treatment elevated the levels of the Kdm6a and Kdm6b epigenetic target, the repressive mark of tri-methylated lysine 27 on histone 3, on osteogenic genes leading to repression of Runx2 and Alkaline Phosphatase expression. Pre-clinical in vivo studies showed that local administration of GSK-J4 to the calvaria of Twist-1 mice prevented premature suture fusion and kept the sutures open up to postnatal day 20.
CONCLUSION
The inhibition of Kdm6a and Kdm6b activity by GSK-J4 could be used as a potential non-invasive therapeutic strategy for preventing craniosynostosis in children with SCS. Pharmacological targeting of Kdm6a/b activity can alleviate craniosynostosis in Saethre-Chotzen syndrome. Aberrant osteogenesis by Twist-1 mutant cranial suture mesenchymal progenitor cells occurs via deregulation of epigenetic modifiers Ezh2 and Kdm6a/Kdm6b. Suppression of Kdm6a- and Kdm6b-mediated osteogenesis with GSK-J4 inhibitor can prevent prefusion of cranial sutures.
Topics: Acrocephalosyndactylia; Animals; Histone Demethylases; Jumonji Domain-Containing Histone Demethylases; Mice; Molecular Targeted Therapy; Nuclear Proteins; Osteogenesis; Twist-Related Protein 1
PubMed: 33298158
DOI: 10.1186/s13287-020-02051-5 -
BMC Musculoskeletal Disorders Nov 2020Apert syndrome is characterised by the presence of craniosynostosis, midface retrusion and syndactyly of hands and feet, thus, synonymously referred to as... (Review)
Review
BACKGROUND
Apert syndrome is characterised by the presence of craniosynostosis, midface retrusion and syndactyly of hands and feet, thus, synonymously referred to as acrocephalosyndactyly type I. Considering these multidisciplinary issues, frequently requiring surgical interventions at an early age, deformities of the feet have often been neglected and seem to be underestimated in the management of Apert syndrome. Typical Apert foot features range from complete fusion of the toes and a central nail mass to syndactyly of the second to fifth toe with a medially deviated great toe; however, no clear treatment algorithms were presented so far. This article reviews the current existing literature regarding the treatment approach of foot deformities in Apert syndrome.
STATE-OF-THE-ART TOPIC REVIEW
Overall, the main focus in the literature seems to be on the surgical approach to syndactyly separation of the toes and the management of the great toe deformity (hallux varus). Although the functional benefit of syndactyly separation in the foot has yet to be determined, some authors perform syndactyly separation usually in a staged procedure. Realignment of the great toe and first ray can be performed by multiple means including but not limited to second ray deletion, resection of the proximal phalanx delta bone on one side, corrective open wedge osteotomy, osteotomy of the osseous fusion between metatarsals I and II, and metatarsal I lengthening using gradual osteodistraction. Tarsal fusions and other anatomical variants may be present and have to be corrected on an individual basis. Shoe fitting problems are frequently mentioned as indication for surgery while insole support may be helpful to alleviate abnormal plantar pressures.
CONCLUSION
There is a particular need for multicenter studies to better elaborate surgical indications and treatment plans for this rare entity. Plantar pressure measurements using pedobarography should be enforced in order to document the biomechanical foot development and abnormalities during growth, and to help with indication setting. Treatment options may include conservative means (i.e. insoles, orthopedic shoes) or surgery to improve biomechanics and normalize plantar pressures.
LEVEL OF EVIDENCE
Level V.
Topics: Acrocephalosyndactylia; Foot Deformities; Hand; Humans; Metatarsal Bones; Osteotomy
PubMed: 33248465
DOI: 10.1186/s12891-020-03812-2 -
Medicine Sep 2020Apert syndrome (AS) is an autosomal dominant inheritance pattern of the most severe craniosynostosis syndrome. AS is characterized by synostosis of cranial sutures and...
RATIONALE
Apert syndrome (AS) is an autosomal dominant inheritance pattern of the most severe craniosynostosis syndrome. AS is characterized by synostosis of cranial sutures and acrocephaly, including brachycephaly, midfacial hypoplasia, and syndactyly of the hands and feet. Patients with AS often present with craniosynostosis, severe syndactyly, and skin, skeletal, brain, and visceral abnormalities.
PATIENT CONCERNS
A pregnant Chinese woman presented with a fetus at 23 + 5 weeks of gestation with suspected AS in a prenatal ultrasound examination. Following ultrasound, the pregnancy underwent spontaneous abortion. Gene sequencing was performed on the back skin of the dead fetus.
DIAGNOSIS
The diagnosis of AS was confirmed on the basis of clinical manifestations of the fetus, and a de novo mutation in the fibroblast growth factor receptor 2 (FGFR2) gene was identified.
INTERVENTIONS
The couple finally chose to terminate the pregnancy based on the ultrasonic malformations and the risk of the parents having a neonate with AS in the future is small. However, any future pregnancy must be assessed by prenatal diagnosis.
OUTCOMES
The dead fetus presented with bilateral skull deformation. Additionally, there were bilateral changes to the temporal bone caused by inwards movement leading to concave morphology, a "clover" sign, and syndactyly from the index finger/second toe to the little finger/little toe. AS was diagnosed by genetic testing, which showed a p.S137W (c.410C>G, chr10:123279677) mutation in the FGFR2 gene.
LESSONS
Clinicians should be aware that there are a variety of ultrasound findings for AS. Therefore, genetic testing should be used when appropriate to confirm diagnosis of AS.
Topics: Abortion, Spontaneous; Acrocephalosyndactylia; Female; Humans; Prenatal Diagnosis; Receptor, Fibroblast Growth Factor, Type 2; Ultrasonography, Prenatal
PubMed: 32991447
DOI: 10.1097/MD.0000000000022340 -
Developmental Medicine and Child... Jan 2021To assess the long-term outcomes of our management protocol for Saethre-Chotzen syndrome, which includes one-stage fronto-orbital advancement.
AIM
To assess the long-term outcomes of our management protocol for Saethre-Chotzen syndrome, which includes one-stage fronto-orbital advancement.
METHOD
All patients born with Saethre-Chotzen syndrome between January 1992 and March 2017 were included. Evaluated parameters included occipital frontal head circumference (OFC), fundoscopy, neuroimaging (ventricular size, tonsillar position, and the presence of collaterals/an abnormal transverse sinus), polysomnography, and ophthalmological outcomes. The relationship between papilledema and its associated risk factors was evaluated with Fisher's exact test.
RESULTS
Thirty-two patients (21 females, 11 males) were included. Median (SD) age at first surgery was 9.6 months (3.1mo) for patients who were primarily referred to our center (range: 3.6-13.0mo), the median (SD) age at last follow-up was 13 years (5y 7mo; range: 3-25y). Seven patients had papilledema preoperatively, which recurred in two. Two patients had papilledema solely after first surgery. Second cranial vault expansion was indicated in 20%. Thirteen patients had an OFC deflection, indicating restricted skull growth, one patient had ventriculomegaly, and none developed hydrocephalus. Eleven patients had emissary veins, while the transverse sinus was aberrant unilaterally in 13 (hypoplastic n=10 and absent n=3). Four patients had mild tonsillar descent, one of which was a Chiari type I malformation. Four patients had obstructive sleep apnoea (two mild, one moderate, and one severe). An aberrant transverse sinus was associated with papilledema (p=0.01).
INTERPRETATION
Single one-stage fronto-orbital advancement was sufficient to prevent intracranial hypertension for 80% of our patients with Saethre-Chotzen syndrome. Follow-up should focus on OFC deflection and venous anomalies.
Topics: Acrocephalosyndactylia; Adolescent; Adult; Child; Child, Preschool; Clinical Protocols; Computed Tomography Angiography; Female; Frontal Bone; Humans; Infant; Intracranial Hypertension; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuroimaging; Neurosurgical Procedures; Orbit; Outcome Assessment, Health Care; Tomography, Optical Coherence; Young Adult
PubMed: 32909287
DOI: 10.1111/dmcn.14670 -
The Laryngoscope Apr 2021To characterize tracheal cartilage morphology in mouse models of fibroblast growth factor receptor (Fgfr2)-related craniosynostosis syndromes. To establish relationships...
OBJECTIVES
To characterize tracheal cartilage morphology in mouse models of fibroblast growth factor receptor (Fgfr2)-related craniosynostosis syndromes. To establish relationships between specific Fgfr2 mutations and tracheal cartilaginous sleeve (TCS) phenotypes in these mouse models.
METHODS
Postnatal day 0 knock-in mouse lines with disease-specific genetic variations in the Fgfr2 gene (Fgfr2 , Fgfr2 , Fgfr2 , Fgfr2 , and Fgfr2 ) as well as line-specific controls were utilized. Tracheal cartilage morphology as measured by gross analyses, microcomputed tomography (μCT), and histopathology were compared using Chi-squared and single-factor analysis of variance statistical tests.
RESULTS
A greater proportion of rings per trachea were abnormal in Fgfr2 tracheas (63%) than Fgfr2 (17%), Fgfr2 (17%), Fgfr2 (12%), and controls (10%) (P < .001 for each vs. Fgfr2 ). TCS segments were found only in Fgfr2 (100%) and Fgfr2 (72%) tracheas. Cricoid and first-tracheal ring fusion was noted in all Fgfr2 and 94% of Fgfr2 samples. The Fgfr2 and Fgfr2 groups were found to have greater areas and volumes of cartilage than other lines on gross analysis and μCT. Histologic analyses confirmed TCS among the Fgfr2 and Fgfr2 groups, without appreciable differences in cartilage morphology, cell size, or density; no histologic differences were observed among other Fgfr2 lines compared to controls.
CONCLUSION
This study found TCS phenotypes only in the Fgfr2 mouse lines. These lines also had increased tracheal cartilage compared to other mutant lines and controls. These data support further study of the Fgfr2 mouse lines and the investigation of other Fgfr2 variants to better understand their role in tracheal development and TCS formation.
LEVEL OF EVIDENCE
NA Laryngoscope, 131:E1349-E1356, 2021.
Topics: Acanthosis Nigricans; Acrocephalosyndactylia; Animals; Cartilage; Craniofacial Dysostosis; Craniosynostoses; Disease Models, Animal; Ear; Genetic Association Studies; Humans; Mice; Mutation; Phenotype; Receptor, Fibroblast Growth Factor, Type 2; Scalp Dermatoses; Skin Abnormalities; Trachea; Tracheal Diseases; X-Ray Microtomography
PubMed: 32886384
DOI: 10.1002/lary.29060 -
International Journal of Pediatric... Nov 2020The tracheal cartilaginous sleeve (TCS) is a rare, difficult to diagnose airway malformation in which segmented tracheal rings are replaced by a solid sheath of...
The tracheal cartilaginous sleeve (TCS) is a rare, difficult to diagnose airway malformation in which segmented tracheal rings are replaced by a solid sheath of cartilage. TCS is a significant cause of morbidity and mortality in patients with syndromic craniosynostosis, and early diagnosis is essential. We report a case in which ultrasound (US) was used to diagnose TCS in a patient with Pfeiffer syndrome. This is the first case demonstrating the use of US as the initial tool to diagnose TCS. The case supports ongoing research investigating the use of US as a screening and diagnostic imaging modality for TCS.
Topics: Acrocephalosyndactylia; Cartilage; Child; Female; Humans; Infant, Newborn; Trachea; Tracheostomy; Ultrasonography
PubMed: 32877875
DOI: 10.1016/j.ijporl.2020.110321 -
The Application of Clinical Genetics 2020Pfeiffer syndrome (PS) is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor FGFR1 and FGFR2 genes, occurring in approximately...
BACKGROUND
Pfeiffer syndrome (PS) is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor FGFR1 and FGFR2 genes, occurring in approximately 1:100,000 live births. PS has a wide range of clinical expression and severity, so early prenatal diagnosis is difficult and genetic counseling is desirable. We describe a PS newborn with her ultrasound and molecular studies.
CASE REPORT
We describe a female term newborn with cloverleaf-shaped skull, facial hypoplasia, low ears, exophthalmos and wide, broad and deviated thumbs and hallux. The patient was diagnosed by ultrasound at 29 WGA and referred to a tertiary care hospital for her follow-up. Molecular test revealed a heterozygous pathogenic variant in intron 8 of the FGFR2 gene (FGFR2: c.940-1G>C). It was a de-novo mutation. At 17 days of life, craniosynostosis correction and a Lefort-III frontomaxillary advancement were performed.
CONCLUSION
Pfeiffer syndrome is a devastating genetic disorder. Prenatal diagnosis according PS morphological features in prenatal ultrasound allows timely genetic counseling, early referral to third-level centers, and close follow-up in the prenatal and postnatal stages.
PubMed: 32848441
DOI: 10.2147/TACG.S251581 -
Developmental Dynamics : An Official... Mar 2021Apert syndrome is an autosomal, dominant inherited disorder characterized by craniosynostosis and syndactyly caused by gain-of-function mutations in the fibroblast...
Aberrantly activated Wnt/β-catenin pathway co-receptors LRP5 and LRP6 regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome (Fgfr2 ) mouse model.
BACKGROUND
Apert syndrome is an autosomal, dominant inherited disorder characterized by craniosynostosis and syndactyly caused by gain-of-function mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Wnt/β-catenin signaling plays critical roles in regulating the skeletal development. Here, we analyzed the role of this pathway in the developing coronal sutures (CS) of a murine Apert syndrome model (Fgfr2 ).
RESULTS
We observed aberrantly increased mRNA expression of Lrp5 and Lrp6 in CS of Fgfr2 mice, whereas both wild type (WT) and Fgfr2 mice showed similar expression of other Wnt/β-catenin-related genes, such as Wnt3, Wnt3a, Fzd4, Fzd6, Axin2, and Dkk1 as evidenced by in situ hybridization. Significantly increased Lrp5 and Lrp6 mRNA expression was observed by quantitative PCR analysis of cultured cells isolated from CS of Fgfr2 mice. Phospho-LRP5, phospho-LRP6, and non-phospho-β-catenin were upregulated in Fgfr2 CS compared with that in WT CS. Short-interfering RNA targeting Lrp5 and Lrp6 significantly reduced runt-related transcription factor 2, collagen type 1 alpha 1, and osteocalcin mRNA expression, and alkaline phosphatase activity in cultured cells.
CONCLUSIONS
The Wnt/β-catenin pathway was activated in the CS of Fgfr2 mice during craniofacial development, suggesting the involvement of the Wnt/β-catenin pathway in the pathogenesis of CS synostosis in Fgfr2 mice.
Topics: Acrocephalosyndactylia; Amino Acid Substitution; Animals; Cell Differentiation; Cranial Sutures; Disease Models, Animal; Low Density Lipoprotein Receptor-Related Protein-5; Low Density Lipoprotein Receptor-Related Protein-6; Mice; Mice, Transgenic; Mutation, Missense; Osteoblasts; Receptor, Fibroblast Growth Factor, Type 2; Wnt Signaling Pathway; beta Catenin
PubMed: 32822074
DOI: 10.1002/dvdy.239