APERT SYNDROM case report

Craniosynostosis may occur in conjunction with limb and visceral anomalies in more than 100 syndromes and may include anomalies of the elbow. Apert's, Pfeiffer's, Crouzon's, and Saethre-Chotzen syndrome have been linked with anomalies of the elbow, but the incidence and severity of such anomalies is unknown. A prospective radiographic study was undertaken to establish the types, incidence, and severity of elbow anomalies in patients with either Apert's, Pfeiffer's, Crouzon's, or Saethre-Chotzen syndrome attending the Craniofacial Centre at Great Ormond Street Hospital during a 12-month period. This study showed that elbow anomalies were very common in Apert's and Pfeiffer's syndrome, but less so in Crouzon's syndrome. The elbows in all patients with Saethre-Chotzen syndrome were normal. A range of anomalies was seen, with overlap between the syndromes. The severest anomaly seen in children with Crouzon's, Pfeiffer's, and Apert's syndrome was complete synostosis, which may require surgical intervention in due course. The results of this study suggest that the incidence of elbow anomalies in Apert's, Pfeiffer's, and Crouzon's syndrome is higher than the current literature suggests. Synostosis can be so severe that orthopedic review as part of the management of these children may be beneficial and may become increasingly important as more of these children survive into adulthood.

Dear Editor, It is with great interest that we read the paper entitled BMorphology of the foramen magnum in syndromic and non-syndromic brachycephaly^ by Assadsangabi et al.[1]. The authors studied the shape and size of the foramen magnum in syndromic craniosynostosis including Apert, Crouzon, and Pfeiffer syndromes. Using the same methodology we applied in a previous paper [2], that is (i) non-parametric comparison, (ii) transverse and anteroposterior diameter analysis, (iii) LOESS regression curve, the authors found that patients with Crouzon syndrome and Pfeiffer syndrome have a smaller area of the foramen magnum than control subjects. Conversely, patients with non-syndromic synostosis have a foramen magnum similar to controls. Unfortunately, it is not clear whether all the children included in their study were classified according to a genetic confirmation of the syndromes as the authors only mention that Bpatients with a clinical and/or genetic diagnosis of Crouzon, Pfeiffer, Apert and SaethreChotzen^ were studied. Including only patients with genetically confirmed syndromes is a strong argument for the homogeneity of the population and allows a comparison with published series [2–5]. This is of critical importance in the so-called non-syndromic cases in which a Pro250Arg mutation in FGFR3 or a TCF12 mutation could be missed clinically [6]. Indeed, in a previous study, we found that patients with bicoronal synostosis and FGFR3 mutation actually have a smaller foramen compared to controls [5]. Moreover, it is unfortunately not specified in the paper the percentage of hydrocephalic patients nor the number of patients who received a ventriculoperitoneal cerebrospinal fluid shunt or any other procedure for the management of CSF circulation disorders. It is well recognized in the medical literature that the placement of a ventriculoperitoneal shunt may induce a secondary craniosynostosis or aggravate a preexisting one [7–13]. Hydrocephalus is common in these children. In the literature, several studies have found hydrocephalus in 9 to 17 % of patients with Crouzon syndrome, 28 to 64 % of patients with Pfeiffer syndrome, and 4 to 7 % of patients with Apert syndrome [3, 14–21]. The presence of hydrocephalus is also important in regard to the size of the foramenmagnum [2, 3]. In a similar study in genetically confirmed FGFR2-related faciocraniosynostosis (31 children under 2 years of age before any surgical procedure, 14 with Crouzon syndrome, 11 with Apert syndrome, and 6 with Pfeiffer syndrome), we found in fact that hydrocephalus was statistically associated with a small foramen magnum area in Crouzon and Pfeiffer syndromes but not in Apert syndrome [3]. Finally, the disparity found in the ages of the children studied in the article also represents a limitation. The use of age groups would have overcome the bias related to the growth of the skull base found in the pediatric population [3]. It is nevertheless interesting that the results of this study corroborate those of the literature, thus adding some confirmation that the skull base growth is deeply altered in complex synostosis. * Guillaume Coll gcoll@chu-clermontferrand.fr

Residents' journal review

BackgroundOculo-orbital disproportion in patients with craniosynostosis have similarities and dissimilarities between syndromic and nonsyndromic cases. We hypothesize these two conditions have specific individual influences as it relates to development of the orbital and periorbital skeletons.MethodA total of 133 preoperative CT scans (nonsyndromic bicoronal synostosis, n=38; Apert syndrome bicoronal synostosis subtype, n=33; Crouzon syndrome bicoronal synostosis subtype, n=10; controls, n=52) were included. Craniometric and volumetric analyses related to the orbit and periorbital anatomy were performed.ResultsThe orbital cavity volume is mildly restricted in nonsyndromic bicoronal synostosis (7%, p=0.147), but more so in Apert and Crouzon syndromes, 17% (p=0.002) and 21% (p=0.005), respectively. The sphenoid side angle in Apert syndrome is wider than when compared to Crouzon syndrome (p=0.043). The ethmoid side angle in Apert patients however is narrower (p=0.066) than that in Crouzon patients. Maxilla anteroposterior length is more restricted in Apert syndrome than Crouzon syndrome (21%, p=0.003) and nonsyndromic cases (26%, p<0.001). The posterior nasal spine position is retruded in Crouzon syndrome (39%, p<0.001), yet the anterior nasal spine position is similar in Apert and Crouzon syndromes.ConclusionOrbit and periorbital malformation in syndromic craniosynostosis is likely the combined influence of syndromic influences and premature suture fusion. Apert syndrome expands the anteriorly contoured lateral orbital wall associated with bicoronal synostosis, while Crouzon syndrome has more infraorbital rim retrusion, resulting in more severe exorbitism. Apert syndrome develops maxillary hypoplasia, in addition to the maxillary retrusion, observed in Crouzon syndrome and nonsyndromic bicoronal synostosis patients.

To evaluate patency of circummaxillary sutures in children with Apert, Crouzon, and Pfeiffer Syndromes and to compare it to a nonsyndromic matched control group. Case-control study. Tertiary care public hospital. Thirty-eight computed tomography (CT) scans of patients affected by syndromic craniofacial synostosis (13 patients with Apert syndrome, 20 patients with Crouzon syndrome, and 5 patients with Pfeiffer syndrome), average age 5 ± 2.8 years, range 1.9 to 12 years, were compared to age- and sex-matched control CTs of 38 nonsyndromic children. Computed tomography scans of the study group had to be performed prior to any midfacial surgery. Midpalatal suture, zygomaticomaxillary sutures, and pterigomaxillary sutures were evaluated and scored. The syndromic group showed a significant earlier ossification of all sutures compared to the nonsyndromic group. Significant differences were already present in early childhood and continued through adolescence. Based on the differences in terms of maxillary sutural ossification identified, midfacial hypoplasia does not seem to be only secondary to premature cranial base ossification, but also to primary synostosis of facial sutures, thus providing new insights into the pathogenesis of midface deficiency in children with craniofacial-synostosis. Care should be taken when planning any maxillary orthopedics, such as expansion or maxillary protraction, given the high frequency of early fusion of circummaxillary sutures.

PURPOSE: Mutations in the fibroblast growth receptor 2 (FGFR2) gene have been identified in syndromic craniosynostosis syndromes such as Apert, Crouzon, and Pfeiffer syndrome. Patients have severe malformations of the skull and face requiring multiple complex reconstructive procedures. As described by Paul Tessier, surgical correction of such patients is performed for 3 main reasons: functional, morphologic, and psychological. The surgical treatment algorithm has evolved over time. Despite numerous articles describing treatment of syndromic craniosynostosis, there are few reports of long-term results. Long-term follow up of patients after midface surgeries is important for evaluating which techniques result in consistent favorable outcomes, and which should be improved. We present a retrospective review reporting surgical procedures performed by a single surgeon in patients with Apert, Crouzon, and Pfeiffer Syndrome over a period of 45 years, with the intent to delineate procedures that have been effective over time. We also present our surgical treatment algorithm for pediatric patients with FGFR2 mutation–related syndromic craniosynostosis based on the senior author’s experience. METHODS: A retrospective review was performed of all patients with FGFR2 mutation–related syndromic craniosynostosis that underwent reconstruction for craniofacial defects, as performed by the senior author between 1975 and 2020. Patients without syndromic craniosynostosis were excluded. Inclusion criteria was limited to Apert, Crouzon, and Pfeiffer syndromes. Surgical procedures and complications were recorded for patients at all stages of the reconstructive process. RESULTS: A total of 68 patients were identified who had complete records for evaluation, including 30 patients with Apert syndrome, 27 patients with Crouzon syndrome and 11 patients with Pfeiffer syndrome. The average patient age was 30±15.8 years, with a range of 3–77 years of age. Mean long-term follow-up after initial surgery was 10.5 ± 10.1 years. Primary procedures performed for correction of craniofacial deformities included posterior distraction or expansion (10.3%), frontal expansion (14.7%), fronto-orbital advancement (39.7%), facial bipartition (11.8%), Le Fort III (19.1%), and Le Fort I (23.5%). Mean ages at which procedures were performed were 1.5 ± 1.6 years for posterior distraction or expansion, 1.1 ± 1.2 years for fronto-orbital advancement, 6.2 ± 3.8 years for monobloc frontoacial advancement, 4.6 ± 1.8 years for monobloc frontofacial advancement with facial bipartition, 13.2 ± 8.2 years for Le Fort III, and 17.0 ± 3.8 years for Le Fort I. Additional procedures commonly used included nasal bone grafts (25.0%) and lateral canthopexies (19.1%). CONCLUSIONS: This study, with an extensive long-term follow-up period, presents a pediatric surgical treatment algorithm for patients with FGFR2 mutation–related syndromic craniosynostosis. Our treatment algorithm entails a posterior distraction or expansion and fronto-orbital advancement at 6 months, monobloc frontofacial advancement ± facial bipartition at age 6 or 7, or a Le Fort III if morphologically indicated, and in most cases, a Le Fort I at age 17 or 18. Although multiple reconstructive procedures are necessary, complications are rare. This treatment algorithm results in good results in adolescence, allowing patients to integrate into mainstream life. However, patients tend to prematurely age, a problem that is not addressed by the current pediatric surgical treatment algorithm. Future directions include defining aesthetic surgical management of adults.

Fibroblast growth factors and fibroblast growth factor receptors (FGFRs) play important roles in human axial and craniofacial skeletal development. FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. Many of these disorders are relatively common in the pediatric population, and diagnosis is often challenging. These skeletal disorders can be classified based on which FGFR is affected. Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia, and disorders caused by type 2 mutations include Crouzon syndrome (CS), Apert syndrome (AS), and PS. Disorders caused by type 3 mutations include achondroplasia, hypochondroplasia, thanatophoric dysplasia (TD), severe achondroplasia with developmental delay and acanthosis nigricans, Crouzonodermoskeletal syndrome, and Muenke syndrome. Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. Imaging plays a key role in the evaluation of these skeletal disorders. Knowledge of the characteristic imaging and clinical findings can help confirm the correct diagnosis and guide the appropriate molecular genetic tests. Some characteristics and clinical findings include premature fusion of cranial sutures and deviated broad thumbs and toes in PS; premature fusion of cranial sutures and syndactyly of the hands and feet in AS; craniosynostosis, ocular proptosis, and absence of hand and foot abnormalities in CS; rhizomelic limb shortening, caudal narrowing of the lumbar interpediculate distance, small and square iliac wings, and trident hands in achondroplasia; and micromelia, bowing of the femora, and platyspondyly in TD. ©RSNA, 2017.

Heterogeneous mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause a range of craniosynostosis syndromes. The specificity of the Apert syndrome-affected cranial phenotype reflects its narrow mutational range: 98% of cases of Apert syndrome result from an Ser252Trp or Pro253Arg mutation in the immunoglobulin-like (Ig)IIIa extracellular subdomain of FGFR2. In contrast, a broad range of mutations throughout the extracellular domain of FGFR2 causes the overlapping cranial phenotypes of Pfeiffer and Crouzon syndromes and related craniofacial dysostoses. In this paper the expression of FGFR1, the IgIIIa/c and IgIIIa/b isoforms of FGFR2, and FGFR3 is investigated in Apert syndrome (P253R mutation)- and Pfeiffer syndrome (C278F mutation)-affected fetal cranial tissue and is contrasted with healthy human control tissues. Both FGFR1 and FGFR3 are normally expressed in the differentiated osteoblasts of the periosteum and osteoid, in domains overlapped by that of FGFR2, which widely include preosseous cranial mesenchyme. Expression of FGFR2, however, is restricted to domains of advanced osseous differentiation in both Apert syndrome- and Pfeiffer syndrome-affected cranial skeletogenesis in the presence of fibroblast growth factor (FGF)2, but not in the presence of FGF4 or FGF7. Whereas expression of the FGFR2-IgIIIa/b (KGFR) isoform is restricted in normal human cranial osteogenesis, there is preliminary evidence that KGFR is ectopically expressed in Pfeiffer syndrome-affected cranial osteogenesis. Contraction of the FGFR2-IgIIIa/c (BEK) expression domain in cases of Apert syndrome- and Pfeiffer syndrome-affected fetal cranial ossification suggests that the mutant activation of this receptor, by ligand-dependent or ligand-independent means, results in negative autoregulation. This phenomenon, resulting from different mechanisms in the two syndromes, offers a model by which to explain differences in their cranial phenotypes.

Oculoorbital disproportion in patients with craniosynostosis has similarities and dissimilarities between syndromic and nonsyndromic cases. The authors hypothesized that these two conditions have specific individual influences as they relate to development of the orbital and periorbital skeletons. A total of 133 preoperative computed tomography scans (nonsyndromic bicoronal synostosis, n = 38; Apert syndrome bicoronal synostosis subtype, n = 33; Crouzon syndrome bicoronal synostosis subtype, n = 10; controls, n = 52) were included. Craniometric and volumetric analyses related to the orbit and periorbital anatomy were performed. Orbital cavity volume was mildly restricted in nonsyndromic bicoronal synostosis (7 percent, p = 0.147), but more so in Apert and Crouzon syndromes [17 percent (p = 0.002) and 21 percent (p = 0.005), respectively]. The sphenoid side angle in Apert syndrome was wider than when compared to Crouzon syndrome (p = 0.043). The ethmoid side angle in Apert patients, however, was narrower (p = 0.066) than that in Crouzon patients. Maxilla anteroposterior length was more restricted in Apert syndrome than Crouzon syndrome (21 percent, p = 0.003) and nonsyndromic cases (26 percent, p < 0.001). The posterior nasal spine position was retruded in Crouzon syndrome (39 percent, p < 0.001), yet the anterior nasal spine position was similar in Apert and Crouzon syndromes. Orbit and periorbital malformation in syndromic craniosynostosis is likely the combined influence of syndromic influences and premature suture fusion. Apert syndrome expanded the anteriorly contoured lateral orbital wall associated with bicoronal synostosis, whereas Crouzon syndrome had more infraorbital rim retrusion, resulting in more severe exorbitism. Apert syndrome developed maxillary hypoplasia, in addition to the maxillary retrusion, observed in Crouzon syndrome and nonsyndromic bicoronal synostosis patients. Risk, II.

Unique mutations in three human fibroblast growth factor receptors (FGFRI, FGFR2, and FGFR3) have been identified as causing various skeletal disorders that affect the skull (craniosynostosis syndromes) and the growth of the long bones (dwarfism syndromes). Craniosynostosis is the premature fusion of one or more cranial sutures. It is relatively common, with an estimated birth prevalence of 340 per million. More than 90 syndromes are associated with craniosynostosis, and the majority are inherited in an autosomal dominant manner. The best known of these include Crouzon, Jackson-Weiss, Pfeiffer, Apert, and Saethre-Chotzen syndromes. These syndromes have in common premature synostosis of the coronal sutures of the skull, underdevelopment of the midface, some cases having variable abnormalities of the extremities and other organ systems. All are inherited as autosomal dominant traits, most with complete penetrance and variable expressivity. Although viewed clinically as distinct entities, Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes have now been shown to be allelic, with alterations in the same gene (FGFR2). Other craniosynostosis syndromes also shown to be caused by FGFR mutations include Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome with acanthosis nigricans, and a craniosynostosis syndrome associated with a unique FGFR3 point mutation. Interestingly, the two former conditions have dermatologic findings, but the first disorder is associated with FGFR2 mutations, whereas the second is secondary to a FGFR3 mutation. In contrast, there are two craniosynostotic conditions with mutations in transcription factors. Craniosynostosis, Boston type, is a result of a mutation in a homeobox gene, MSX2, and Saethre-Chotzen syndrome has been linked to mutations in the TWIST gene, a basic helix-loophelix transcription factor. It has been suggested that the FGFRs are part of the same signaling pathway as TWIST.KeywordsAcanthosis NigricansApert SyndromeCrouzon SyndromeThanatophoric DysplasiaFGFR2 MutationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The main characteristics of craniosynostosis were premature fusion of cranial sutures with specific skull shapes. There are divided into nonsyndromic and syndromic craniosynostosis. Syndromic craniosynostosis (SCS) was an inherited congenital craniofacial disorder and approximately 15% of craniosynostosis had associated anomalies in the face and limbs. Crouzon syndrome, Apert syndrome, Pfeiffer syndrome and Jackson-Weiss syndrome were the examples of SCS. Increased intracranial pressure (IICP), decrease intracranial volume, corneal exposure, decrease upper airway space, compression of optic nerve and midface hypoplaisa were the indications of surgical intervention. Current treatment modalities such as traditional surgical methods, including monobloc and LeFort III osteotomies as well as craniofacial distraction osteogenesis were reviewed and discussed.

Comparative three-dimensional analysis of CT-scans of the calvaria and cranial base in Apert and Crouzon syndromes

Cerebellar tonsillar herniation (TH) occurs frequently in syndromic craniosynostosis; however, the exact pathogenesis is unknown. This study evaluates the association between skull base deformities and TH in syndromic craniosynostosis. Retrospective study MRI study comparing syndromic craniosynostosis to controls. Measured parameters included clivus length, skull base angle, Boogard's angle, foramen magnum area, and cerebellar tonsillar position (TP). The association between skull base parameters and TP was evaluated with linear mixed models, correcting for age and risk factors for TH in craniosynostosis (hydrocephalus, intracranial hypertension, craniocerebral disproportion, and lambdoid synostosis). Two hundred and eighty-two scans in 145 patients were included, and 146 scans in 146 controls. The clivus was smaller at birth, and its growth was retarded in all syndromes. The skull base angle was smaller at birth in Apert and Crouzon syndromes, and the evolution through time was normal. Boogard's angle was smaller at birth in Apert syndrome, and its evolution was disturbed in Apert and Saethre-Chotzen syndromes. The foramen magnum was smaller at birth in Crouzon and Saethre-Chotzen syndromes, and its growth was disturbed in Apert, Crouzon, and Saethre-Chotzen syndromes. TP was higher at birth in Apert syndrome, but lowered faster. In Crouzon syndrome, TP was lower at birth and throughout life. A smaller clivus and larger foramen magnum were associated with a lower TP in controls (p<0.001, p=0.007), and in Crouzon syndrome, this applied to only foramen magnum size (p=0.004). The skull base and its growth are significantly different in syndromic craniosynostosis compared to controls. However, only foramen magnum area is associated with TP in Crouzon syndrome.

The authors performed a prospective study evaluating molecular diagnosis in patients with bilateral coronal synostosis. The patients were divided into two groups: (1) those clinically classified as having Apert, Crouzon, or Pfeiffer syndrome and (2) those clinically unclassified and labeled as having brachycephaly. Blood samples were drawn for genomic DNA analysis from 57 patients from 1995 to 1997. Polymerase chain reactions were performed using primers flanking exons in FGFR 1, 2, and 3. Each exon was screened for mutations using single-strand confirmation polymorphism, and mutations were identified by DNA sequencing. Mutations in FGFR2 or FGFR3 were found in all patients (n = 38) assigned a phenotypic (eponymous) diagnosis. All Apert syndrome patients (n = 13) carried one of the two known point mutations in exon 7 of FGFR2 (Ser252Trp and Pro253Arg). Twenty-five patients were diagnosed as having either Crouzon or Pfeiffer syndrome. Five patients with Crouzon syndrome of variable severity had mutations in exon 7 of FGFR2. Fifteen patients (12 with Crouzon, 3 with Pfeiffer) had a mutation in exon 9 of FGFR2, many of which involved loss or gain of a cysteine residue. A wide phenotypic range was observed in patients with identical mutations, including those involving cysteine. Two patients labeled as having Crouzon syndrome had the Pro250Arg mutation in exon 7 of FGFR3. All three patients with the crouzonoid phenotype and acanthosis nigricans had the same mutation in exon 10 of FGFR3 (Ala391Glu). This is a distinct disorder, characterized by jugular foraminal stenosis, Chiari I anomaly, and intracranial venous hypertension. Mutations were found in 14 of 19 clinically unclassifiable patients. Three mutations were in exon 9, and one was in the donor splice site of intron 9 on FGFR2. The most common mutation discovered in this group was Pro250Arg in exon 7 of FGFR3. These patients (n = 10) had either bilateral or unilateral coronal synostosis, minimal midfacial hypoplasia with class I or class II occlusion, and minor brachysyndactyly. No mutations in FGFR 1, 2, or 3 were detected in five patients with nonspecific brachycephaly. In conclusion, a molecular diagnosis was possible in all patients (n = 38) given a phenotypic (eponymous) diagnosis. Different phenotypes observed with identical mutations probably resulted from modulation by their genetic background. A molecular diagnosis was made in 74 percent of the 19 unclassified patients in this series; all mutations were in FGFR2 or FGFR3. Our data and those of other investigators suggest that we should begin integrating molecular diagnosis with phenotypic diagnosis of craniosynostoses in studies of natural history and dysmorphology and in analyses of surgical results.

Apert syndrome is a clinically distinctive condition characterized by craniosynostosis, mid-face hypoplasia, and severe symmetrical syndactyly of the hands and feet. Recently, mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been associated with several craniosynostosis conditions including Apert, Crouzon, Jackson-Weiss, and Pfeiffer syndromes. Mutations detected in Crouzon, Jackson-Weiss, and Pfeiffer syndromes are located at several sites in the FGFR2 gene. However, the mutational spectrum in Apert syndrome is remarkably narrow. Mutations detected thus far in Caucasian patients with this syndrome are exclusively transversions from cytosine to guanine at either nucleotide position 934 (C934G) or 937 (C937G) in the FGFR2 gene. To examine the possibility that the narrow mutational spectrum in Apert syndrome was a result of racial or environmental predilection, we studied three Apert syndrome patients from two unrelated Japanese families for C934G and C937G mutations. The C934G mutation was found in all three patients. This is the first demonstration of FGFR2 gene mutations in Japanese patients. Our evidence that the C934G mutation identified in Caucasian patients also occurs among Japanese patients excludes the possibility of racial or environmental predilection for this mutation. Nucleotide position 934 is a mutational hotspot of the FGFR2 gene in Japanese patients as well, although the mechanism by which the mutation occurs remains to be clarified. Whether C937G is a mutational hotspot in Japanese patients as well remains to be determined.