Complex Airway Management in Patients with Tracheal Cartilaginous Sleeves.

OBJECTIVES/HYPOTHESIS: A tracheal cartilaginous sleeve (TCS) is a rare anomaly characterized by anterior fusion of tracheal cartilages. TCS is associated with syndromic craniosynostoses including Apert, Crouzon and Pfeiffer syndromes and FGFR2, FGFR3, and TWIST1 variants. This study presents a 30-year review of patients with syndromic craniosynostosis and TCS and describes diagnostic methods, genetic variants, surgical interventions, and long-term outcomes. STUDY DESIGN: Retrospective, single-institution review. METHODS: This review included patients with syndromic craniosynostosis and TCS treated at Seattle Children's Hospital from 1990 to 2020. Tracheostomy, genetic variants, and additional surgery were primary measures. Fisher's exact test compared need for tracheostomy in patients with proposed high-risk (FGFR2 p.W290 or FGFR2 p.C342) versus low-risk genetic variants. RESULTS: Thirty patients with TCS were identified. Average age at diagnosis was 12 months (range 2-weeks to 7.9-years; standard deviation 19.8 months). Syndromes included Pfeiffer (37%), Apert (37%), and Crouzon (26%). Severe obstructive sleep apnea was present in 76% of patients. Tracheostomy was performed in 17 patients (57%); five were successfully decannulated. Additional interventions included adenotonsillectomy (57%), nasal (20%), laryngeal (17%), and craniofacial skeletal surgery (87%). All patients with Pfeiffer syndrome and FGFR2 p.W290C variants and 83% of patients with FGFR2 p.C342 variants required tracheostomy, differing from other variants (P = .02, odds ratio 33, 95% confidence interval 1.56-697.96). One patient (3%) died. CONCLUSION: TCS contributes to multilevel airway obstruction in patients with syndromic craniosynostosis. Genetic testing in patients with FGFR2-related syndromic craniosynostoses may identify those at risk of TCS and facilitate early intervention. A better understanding of this patient population may foster individualized airway management strategies and improve outcomes. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:215-221, 2022.

Novel GLI3 variant causes Greig cephalopolysyndactyly syndrome in three generations of a Lithuanian family.

BACKGROUND: Preaxial polydactyly type IV, also referred as polysyndactyly, has been described in a few syndromes. We present three generations of a family with preaxial polydactyly type IV and other clinical features of Greig cephalopolysyndactyly syndrome (GCPS). METHODS AND RESULTS: Sequencing analysis of the GLI3 coding region identified a novel donor splice site variant NC_000007.14(NM_000168.6):c.473+3A>T in the proband and the same pathogenic variant was subsequently identified in other affected family members. Functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) sample revealed that the splice site variant c.473+3A>T disrupts the original donor splice site, thus leading to exon 4 skipping. Based on further in silico analysis, this pathogenic splice site variant consequently results in a truncated protein NP_000159.3:p.(His123Argfs*57), which lacks almost all functionally important domains. Therefore, functional cDNA analysis confirmed that the haploinsufficiency of the GLI3 is the cause of GCPS in the affected family members. CONCLUSION: Despite the evidence provided, pathogenic variants in the GLI3 do not always definitely correlate with syndromic or nonsyndromic clinical phenotypes associated with this gene. For this reason, further transcriptomic and proteomic evaluation could be suggested.

Autistic symptoms in Greig cephalopolysyndactyly syndrome: a family case report.

BACKGROUND: Greig cephalopolysyndactyly syndrome is a rare multiple congenital anomaly syndrome characterized by the triad of polysyndactyly (preaxial or mixed preaxial and postaxial), macrocephaly, and ocular hypertelorism. Little is known about the neuropsychological phenotype and the developmental features of this syndrome. CASE PRESENTATION: We describe the clinical features of a 7-year-old Italian white boy affected by Greig cephalopolysyndactyly syndrome in comorbidity with autism spectrum disorder and the case of his 45-year-old white father, carrying the same point deletion (c.3677del) in the GLI3 gene and showing subclinical autistic symptoms. We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative, and behavioral skills of the child. Concurrently, the father underwent his first psychiatric evaluation of cognitive skills and autistic symptoms. CONCLUSIONS: We report the first clinical description of an association between autistic symptoms and Greig cephalopolysyndactyly syndrome in two members of the same family with the same genetic point deletion. Further research is required in order to draw an accurate conclusion regarding the association between Greig cephalopolysyndactyly syndrome and autism.

Mandibular Spatial Reorientation and Morphological Alteration of Crouzon and Apert Syndrome.

BACKGROUND: From infancy to adulthood, the mandible develops increased ramus height, prominence of the chin, and laterally widened gonial angles. In Crouzon and Apert syndromes, both relative retrognathia and prognathic jaws have been reported. Growth is influenced by a variety of factors, including the growth and relative position of the skull base, functional coordination, and the spatial influence of the laryngopharynx. Thus, this study aimed to explore in detail the evolution of the mandible in both syndromes and its relationship with the entire facial structure and skull base. METHODS: One hundred twenty-three preoperative computed tomographic scans (Crouzon, n = 36; Apert, n = 33; control, n = 54) were included and divided into 5 age subgroups. Computed tomographic scans were measured using Materialise software. Cephalometrics relating to the mandible, facial structures, and cranial base were collected. Statistical analyses were performed using t test and statistical power analysis. RESULTS: In Crouzon syndrome, the angle between the cranial base and gnathion was increased prior to 6 months of age by 10.29 degrees (P < 0.001) and by adulthood to 11.95 degrees (P = 0.003) compared with normal. After 6 months of age, the distance between bilateral mandibular condylions (COR-COL) was narrower by 15% (P < 0.001) in Crouzon syndrome compared with control subjects. Before 6 months of age, Apert COR-COL decreased 16% (P < 0.001) compared with control subjects and 13% (P = 0.006) narrower than Crouzon. During 2 to 6 years of age, Apert mandibular ramus height caught up to, and became longer than, Crouzon by 12% (P = 0.011). The nasion-sella-articulare angle of the Apert skull was 5.04 degrees (P < 0.001) less than Crouzon overall. CONCLUSIONS: In Crouzon syndrome, the changes of the spatial relationship of the mandible to the cranial base develop earlier than the mandibular shape deformity, whereas in Apert syndrome, the spatial and morphological changes are synchronous. The morphological changes of the mandible are disproportional in 3 directions, initially significant shortening of the mandibular width and length, and, subsequently, reduced height. Crouzon has more shortening in mandibular height compared with Apert, reflecting the more shortened posterior cranial base length. The narrowed angle between the mandible and the posterior cranial base in Apert skulls is consistent with the more limited nasopharyngeal and oropharyngeal airway space.

Clinical and genetic findings of two cases with Apert syndrome / Hallazgos clínicos y genéticos de dos casos con síndrome de Apert

Abstract Background: Craniosynostosis is described as the premature fusion of cranial sutures that belongs to a group of alterations which produce an abnormal phenotype. Case report: Two unrelated female patients with clinical findings of Apert syndrome-characterized by acrocephaly, prominent frontal region, flat occiput, ocular proptosis, hypertelorism, down-slanted palpebral fissures, midfacial hypoplasia, high-arched or cleft palate, short neck, cardiac anomalies and symmetrical syndactyly of the hands and feet-are present. In both patients, a heterozygous missense mutation (c.755C>G, p.Ser252Trp) in the FGFR2 gene was identified. Conclusions: Two cases of Apert syndrome are described. It is important to recognize this uncommon entity through clinical findings, highlight interdisciplinary medical evaluation, and provide timely genetic counseling for the family.

Resumen Introducción: Las craneosinostosis se describen como la fusión prematura de las suturas craneales y resultan un grupo de alteraciones que producen un fenotipo anormal. Caso clínico: En este informe de casos se presentan dos pacientes de sexo femenino no emparentadas con hallazgos clínicos del síndrome de Apert, caracterizado por acrocefalia, región frontal prominente, occipucio plano, proptosis ocular, hipertelorismo, fisuras palpebrales hacia abajo, hipoplasia mediofacial, paladar alto o hendido, cuello corto, cardiopatía congénita y sindactilia simétrica en manos y pies. En ambas pacientes se identificó una mutación cambio de sentido en heterocigosis (c.755C>G, p.Ser252Trp) en el gen FGFR2. Conclusiones: Se presentan dos casos de síndrome de Apert. Es importante reconocer a través de los hallazgos clínicos esta entidad infrecuente, resaltar la evaluación médica interdisciplinaria y proporcionar un oportuno asesoramiento genético a la familia.

Long-Term Functional Upper-Extremity Outcomes in Adults with Apert Syndrome.

BACKGROUND: The goal of this study was to determine upper-extremity function and health-related quality of life in a cohort of adults with Apert syndrome. METHODS: Twenty-two adults with Apert syndrome completed the Disabilities of the Arm, Shoulder, and Hand survey; the 36-Item Short-Form Health Survey; and a semistructured interview. One surgeon administered the Jebsen Hand Function Test and measured sensation, joint motion, and strength. RESULTS: Median Disabilities of the Arm, Shoulder, and Hand score was 16.9, which indicated slightly greater disability than the population norm of 10.1. Median 36-Item Short-Form Health Survey scores were 54.5 for mental health and 57.0 for physical health-both more favorable than population norms. Total Jebsen Hand Function Test scores for dominant hand were 69.2 seconds for men and 64.7 seconds for women versus 37.8 seconds for population norms of both sexes. More complex syndactyly resulted in worse metacarpophalangeal joint motion but no significant difference in Disabilities of the Arm, Shoulder, and Hand; 36-Item Short-Form Health Survey; or other functional results. There was no difference in self-reported outcomes between patients with four (n = 8) versus five digits (n = 14) in each hand. CONCLUSIONS: In this cohort of adults with Apert syndrome, self-reported assessment of disability was more favorable than measured functional data would suggest. Despite significant functional deficits, the participants in this study had adapted remarkably well.

Clinical and genetic findings of two cases with Apert syndrome.

Background: Craniosynostosis is described as the premature fusion of cranial sutures that belongs to a group of alterations which produce an abnormal phenotype. Case report: Two unrelated female patients with clinical findings of Apert syndrome-characterized by acrocephaly, prominent frontal region, flat occiput, ocular proptosis, hypertelorism, down-slanted palpebral fissures, midfacial hypoplasia, high-arched or cleft palate, short neck, cardiac anomalies and symmetrical syndactyly of the hands and feet-are present. In both patients, a heterozygous missense mutation (c.755C>G, p.Ser252Trp) in the FGFR2 gene was identified. Conclusions: Two cases of Apert syndrome are described. It is important to recognize this uncommon entity through clinical findings, highlight interdisciplinary medical evaluation, and provide timely genetic counseling for the family.

Introducción: Las craneosinostosis se describen como la fusión prematura de las suturas craneales y resultan un grupo de alteraciones que producen un fenotipo anormal. Caso clínico: En este informe de casos se presentan dos pacientes de sexo femenino no emparentadas con hallazgos clínicos del síndrome de Apert, caracterizado por acrocefalia, región frontal prominente, occipucio plano, proptosis ocular, hipertelorismo, fisuras palpebrales hacia abajo, hipoplasia mediofacial, paladar alto o hendido, cuello corto, cardiopatía congénita y sindactilia simétrica en manos y pies. En ambas pacientes se identificó una mutación cambio de sentido en heterocigosis (c.755C>G, p.Ser252Trp) en el gen FGFR2. Conclusiones: Se presentan dos casos de síndrome de Apert. Es importante reconocer a través de los hallazgos clínicos esta entidad infrecuente, resaltar la evaluación médica interdisciplinaria y proporcionar un oportuno asesoramiento genético a la familia.

PIN1 is a new therapeutic target of craniosynostosis.

Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.

Syndromic craniosynostosis: neuropsycholinguistic abilities and imaging analysis of the central nervous system.

OBJECTIVE: To characterize patients with syndromic craniosynostosis with respect to their neuropsycholinguistic abilities and to present these findings together with the brain abnormalities. METHODS: Eighteen patients with a diagnosis of syndromic craniosynostosis were studied. Eight patients had Apert syndrome and 10 had Crouzon syndrome. They were submitted to phonological evaluation, neuropsychological evaluation and magnetic resonance imaging of the brain. The phonological evaluation was done by behavioral observation of the language, the Peabody test, Token test and a school achievement test. The neuropsychological evaluation included the WISC III and WAIS tests. RESULTS: Abnormalities in language abilities were observed and the school achievement test showed abnormalities in 66.67% of the patients. A normal intelligence quotient was observed in 39.3% of the patients, and congenital abnormalities of the central nervous system were observed in 46.4% of the patients. CONCLUSION: Abnormalities of language abilities were observed in the majority of patients with syndromic craniosynostosis, and low cognitive performance was also observed.

Syndromic craniosynostosis: neuropsycholinguistic abilities and imaging analysis of the central nervous system / Craniossinostoses sindrômicas: habilidades neuropsicolinguísticas e análise por imagem do sistema nervoso central

ABSTRACT Objective: To characterize patients with syndromic craniosynostosis with respect to their neuropsycholinguistic abilities and to present these findings together with the brain abnormalities. Methods: Eighteen patients with a diagnosis of syndromic craniosynostosis were studied. Eight patients had Apert syndrome and 10 had Crouzon syndrome. They were submitted to phonological evaluation, neuropsychological evaluation and magnetic resonance imaging of the brain. The phonological evaluation was done by behavioral observation of the language, the Peabody test, Token test and a school achievement test. The neuropsychological evaluation included the WISC III and WAIS tests. Results: Abnormalities in language abilities were observed and the school achievement test showed abnormalities in 66.67% of the patients. A normal intelligence quotient was observed in 39.3% of the patients, and congenital abnormalities of the central nervous system were observed in 46.4% of the patients. Conclusion: Abnormalities of language abilities were observed in the majority of patients with syndromic craniosynostosis, and low cognitive performance was also observed.

RESUMO Objetivo: Caracterizar as habilidades neuropsicolinguísticas de indivíduos com craniossinostoses sindrômicas e apresentar esses achados com as anomalias do sistema nervoso central. Métodos: Participaram do estudo 18 sujeitos com diagnóstico clínico de craniossinostose sindrômica, 44,4% com a síndrome de Apert e 55,6% síndrome de Crouzon. Todos os sujeitos foram submetidos a avaliação fonoaudiológica, psicológica e exames de ressonância magnética do encéfalo. A avaliação fonoaudiológica foi contemplada pela Observação Comportamental da Linguagem, Teste Peabody (TVIP), Teste Token e Teste de Desempenho Escolar (TDE); enquanto a psicológica utilizou a WISC-III e a WAIS. Resultados: Observou-se alteração nas habilidades de linguagem em todos os protocolos utilizados, sendo o TDE o que apresentou maior porcentagem de alteração (66,67%).A avaliação cognitiva evidenciou quociente de inteligência dentro da média em 39,3% dos sujeitos, enquanto que 46,4% apresentaram malformações congênitas do sistema nervoso central. Conclusão: Constatou-se alterações nas habilidades de linguagem na maioria dos sujeitos com craniossinostoses sindrômicas, bem como o baixo desempenho cognitivo.

The Quality of Life in Adult Patients With Syndromic Craniosynostosis From Their Perspective.

INTRODUCTION: Clinical intuition may perceive those adults with syndromic craniosynostosis to have a lower quality of life (QOL) compared with the normative population. Classification of facial difference; standardization of cognitive capacity and selection of an appropriate QOL measurement tool provides a less intuitive and more evidence-based method of assessing QOL in this particular group of patients. METHODS: Adults with syndromic craniosynostosis treated by the same surgeons underwent Whittaker Classification for facial difference by an independent observer. Neuropsychology screening ensured cognitive ability in patients for independent answering of a World Health Organization QOL postal questionnaire. Data analysis using descriptive and z test statistics allowed comparison to nonsyndromic adult United Kingdom data provided by the World Health Organization. RESULTS: Forty adult patients met authors' inclusion criteria. Whittaker Classification of facial difference ranged from I (31 patients) to II (8 patients) and III (1 patient). Quality of life showed no correlation to facial difference. Quality of life was better in the physical, psychological, and environmental domains compared with the normative adult UK population. However, no statistical difference was found in the social domain. Female Apert syndrome patients had a worse QOL than males in the social domain. CONCLUSIONS: The counterintuitive findings show that adult syndromic patients with similar cognitive capacity perceive their quality of life as being above that experienced in a normative UK nonsyndromic population with no correlation to the degree of facial difference.

[Correction of the Thumb in Apert Syndrome - Modified Dome Osteotomy and Bilobed Flap]. / Daumenkorrektur bei Apert-Syndrom durch modifizierte Dom-Osteotomie und bilobed flap.

Children with Apert syndrome have extensive malformations of the extremities and the head. The thumb in Apert syndrome is always short with radial deviation and the first web space is narrowed and flattened. These thumbs can be corrected in a simple manner by modified dome osteotomy of the proximal phalanx combined with soft tissue coverage using a bilobed flap with simultaneous widening of the first web space. A preoperative multi-slice computed tomography (MSCT) angiography scan helps in planning the surgical procedures. This article describes the surgical technique and the results in 6 hands of 3 children. The aim is to illustrate the correction of the axis and length of the thumb.

Correction of Brachymetatarsia and Medial Angulation of the Great Toe of Apert Foot By Distraction Osteogenesis: A Review of 7 Years of Experience.

BACKGROUND: Apert foot anomalies may cause severe problems such as pain and development of callus formation related to weight redistribution, problems with footwear, and gait disturbances that may limit their daily activities. The main purpose of this study was to review our experience with distraction osteogenesis for the correction of brachymetatarsia and the great toe angulation of the patients with Apert syndrome. METHODS: This study retrospectively reviewed 7 patients (14 extremities) followed up for Apert syndrome who underwent distraction for the correction of bilateral congenital brachymetatarsia and angulation of the great toe between 2004 and 2008. Correction of the metatarsal inclination angle, the medial angulation of the great toe, the percentage of lengthening, and lengthening rates of distracted bones were evaluated. RESULTS: Patients ranged in age from 4 to 8 years at the distraction operation, with a mean age of 5.4±1.3 years, and the average length of follow-up was 86.6±21.0 months. The length of the first metatarsal bone increased significantly from the average length of 32.6±5.7 mm to an average of 46.7±6.5 mm (P<0.001). The mean lengthening rate and lengthening percentages of distracted bones were 0.4%±0.1%/month and 30.2%±6.4%/month, respectively. Preoperative and postoperative metatarsal inclination angles were at a mean of 43.8±5.12 and 32.6±3.8, respectively, and the correction of metatarsal inclination was considered as statistically significant (P<0.001). The mean angulation of the great toe reduced significantly from 49.8±11.76 to 13.2±8.5 degrees after distraction (P<0.001). Minor complications such as pin loosening, pin-tract infection, and early union that required reoperation were observed in 5 extremities (35.7%). CONCLUSIONS: Anatomic features of Apert foot may lead to complaints that may limit patients' daily activities and require as much attention as associated hand and craniofacial anomalies. Distraction appears to be an effective and safe approach for the simultaneous correction of the shortness of the first ray and medial angulation of the great toe. LEVEL OF EVIDENCE: Level IV.

Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome.

INTRODUCTION: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. METHODS: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. RESULTS: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function.

INTRODUCCIÓN: El síndrome Apert (SA) es un síndrome que cursa con craneosinostosis el cual es ocasionado por mutaciones en el gen del Receptor 2 del Factor de Crecimiento de Fibroblastos (FGFR2). Se caracteriza clínicamente por presentar sindactilias cutáneas y óseas en manos y pies de forma simétrica, cursa además con manifestaciones variables esqueléticas, cerebrales, en piel y otros órganos internos. MÉTODOS: Miembros de dos familias con caso índice de Síndrome Apert fueron evaluados con el objetivo de describir las características clínicas relevantes y el análisis molecular (secuenciación y amplificación) de los exones 8, 9 y 10 del gen FGFR2. RESULTADOS: La familia 1 está constituida por la madre, el caso índice y un medio hermano que presenta labio y paladar hendido. En esta familia solo se encontró la mutación S252W en la secuencia del exón 8 del gen FGFR2 del caso índice. A pesar no encontrarse mutaciones dentro del estudio realizado al paciente afectado con labio y paladar hendido, se conoce que estas patologías comparten vías de señalización, lo que permite sospechar alteraciones en genes compartidos. En la familia 2, el resultado molecular del caso índice reportó la variante T78.501A en la secuencia del intrón 8, la cual se sitúa cercana al sitio de splicing, pudiendo alterar este proceso con una consecuente alteración de la función de la proteína.

Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome / Análisis molecular de los exones 8, 9 y 10 del gen del factor de crecimiento de fibroblastos (FGFR2) en dos familias con casos índice de síndrome de Apert

Introduction: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. Methods: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. Results: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function.

Introducción: El síndrome Apert (SA) es un síndrome que cursa con craneosinostosis el cual es ocasionado por mutaciones en el gen del Receptor 2 del Factor de Crecimiento de Fibroblastos (FGFR2). Se caracteriza clínicamente por presentar sindactilias cutáneas y óseas en manos y pies de forma simétrica, cursa además con manifestaciones variables esqueléticas, cerebrales, en piel y otros órganos internos. Métodos: Miembros de dos familias con caso índice de Síndrome Apert fueron evaluados con el objetivo de describir las características clínicas relevantes y el análisis molecular (secuenciación y amplificación) de los exones 8, 9 y 10 del gen FGFR2. Resultados: La familia 1 está constituida por la madre, el caso índice y un medio hermano que presenta labio y paladar hendido. En esta familia solo se encontró la mutación S252W en la secuencia del exón 8 del gen FGFR2 del caso índice. A pesar no encontrarse mutaciones dentro del estudio realizado al paciente afectado con labio y paladar hendido, se conoce que estas patologías comparten vías de señalización, lo que permite sospechar alteraciones en genes compartidos. En la familia 2, el resultado molecular del caso índice reportó la variante T78.501A en la secuencia del intrón 8, la cual se sitúa cercana al sitio de splicing, pudiendo alterar este proceso con una consecuente alteración de la función de la proteína.

Aberrant facial flushing following monobloc fronto-facial distraction.

BACKGROUND: Patients with syndromic forms of craniosynostosis may experience functional problems such as raised intracranial pressure, proptosis, obstructive sleep apnoea and failure to thrive. The monobloc fronto-facial advancement with osteogenic distraction is increasingly used to correct these functional problems in one procedure as well as improve appearance. The authors report the phenomenon of post operative aberrant facial flushing - an unusual and previously unreported complication of the procedure. METHODS: The case notes of 80 consecutive patients undergoing fronto-facial advancement by distraction using the rigid external distraction device (RED) were reviewed for features of aberrant facial flushing. RESULTS: Four out of eighty individuals developed facial flushing after monobloc fronto-facial distraction using the rigid external distractor (RED) frame. All were female with Crouzon or Pfeiffer syndromes causing the severe functional problems for which they underwent the surgery. They were aged 6-8 years. Following removal of the frame, they developed intermittent but severe facial flushing. The flushing spontaneously settled in three patients after up to four years but persists in the other child seven years after her surgery. CONCLUSION: Aberrant facial flushing is a rare but significant complication of monobloc fronto-facial surgery. It occurred in 4 of our 80 (5%) patients. The skull base osteotomies essential for the procedure are made anterior to the pterygopalatine ganglion and it is our contention that damage from these was responsible for a neuropraxia of its efferent nerve branches. A review of the autonomic control of the facial vascular system suggests that the phenomenon is due to an unequal process of recovery that leaves the cutaneous vasodilating parasympathetic or beta-adrenergic innervation relatively unopposed - a situation that persists until with time a normal balance of autonomic input is achieved.

Venous hypertension in syndromic and complex craniosynostosis: the abnormal anatomy of the jugular foramen and collaterals.

UNLABELLED: Why craniosynostosis patients develop elevated intracranial pressure (ICP) is still a mystery. Our aim was to investigate jugular foramen size and its relation to venous hypertension and elevated ICP. Secondly, we evaluated whether occipital collateral veins develop as a compensatory mechanism for elevated ICP. We conducted a prospective study in 41 children with craniosynostosis who underwent a 3D-CT-angiography. We evaluated the anatomical course of the jugular vein, the diameter of the jugular foramen and the relation to the presence of papilledema. Additionally, we studied the anatomical variations of the cerebral venous drainage system. The diameter of the jugular foramen was significantly smaller in our patients. Abnormal venous collaterals were most often observed in patients with Apert, Crouzon-Pfeiffer and Saethre-Chotzen syndrome, even in children under two years of age. There was no significant difference in the number of collateral veins in patients with or without papilledema. Collaterals appear to reflect an inborn abnormality of the venous system, rather than a compensating mechanism for elevated ICP. This study confirms the presence of jugular foraminal narrowing in craniosynostosis patients and an abnormal venous system, which may predispose to elevated ICP. LEVEL OF EVIDENCE: Diagnostic II.