The turricephaly index: A validated method for recording turricephaly and its natural history in Apert syndrome.

INTRODUCTION: We present the CT scan-derived turricephaly index (TI) as a quotient of the maximal occipito-frontal length of the skull to the distance from the centre of the sella to the highest point on the vertex as a validated tool for assessing turricephaly and evaluating surgical techniques aimed at reducing it. MATERIALS AND METHODS: Measurements taken from CTs of non-operated children with Apert syndrome and age-matched controls were analysed using Centricity PACS system (from the lateral scout image) and the thick-sliced Osirix tool. CTs from non-operated children with Apert syndrome were used to investigate the natural history of their turricephaly both as a group and individually. RESULTS: There was statistically significant agreement between measurements taken from the CT scout and Osirix for 42 control children (R2 = 0.97) and 42 children with Apert syndrome (R2 = 0.98) and between two separate observers. There was a statistically significant difference (p < 0.001) between CT scout-derived TI value between controls (1.73 ± 0.12, range 1.46-1.99) and Apert children (1.42 ± 0.15, range 1.13-1.73). Analysis of 113 CTs of 65 non-operated children with Apert syndrome showed a decrease in turricephaly with age (positive spearman correlation: r = 0.50, p < 0.001). Analysis of 37 CTs of those with multiple (>2) CT's showed a similar decrease in turricephaly in the individual child (p < 0.001). CONCLUSIONS: TI derived from the CT scout view provides a simple, objective and validated method for assessing turricephaly. We recommend it for monitoring and for the prospective evaluation of reconstructive techniques in children with complex/syndromic craniosynostosis.

[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.

Describing Crouzon and Pfeiffer syndrome based on principal component analysis.

UNLABELLED: Crouzon and Pfeiffer syndrome are syndromic craniosynostosis caused by specific mutations in the FGFR genes. Patients share the characteristics of a tall, flattened forehead, exorbitism, hypertelorism, maxillary hypoplasia and mandibular prognathism. Geometric morphometrics allows the identification of the global shape changes within and between the normal and syndromic population. METHODS: Data from 27 Crouzon-Pfeiffer and 33 normal subjects were landmarked in order to compare both populations. With principal component analysis the variation within both groups was visualized and the vector of change was calculated. This model normalized a Crouzon-Pfeiffer skull and was compared to age-matched normative control data. RESULTS: PCA defined a vector that described the shape changes between both populations. Movies showed how the normal skull transformed into a Crouzon-Pfeiffer phenotype and vice versa. Comparing these results to established age-matched normal control data confirmed that our model could normalize a Crouzon-Pfeiffer skull. CONCLUSIONS: PCA was able to describe deformities associated with Crouzon-Pfeiffer syndrome and is a promising method to analyse variability in syndromic craniosynostosis. The virtual normalization of a Crouzon-Pfeiffer skull is useful to delineate the phenotypic changes required for correction, can help surgeons plan reconstructive surgery and is a potentially promising surgical outcome measure.

Craniostenosis: a neurosurgeon's perspective.

In pediatric neurosurgery departments in India, craniosynostosis is being increasingly identified and dealt with during the past several years. The management of this problem is well established in units that have a strong pediatric bias, whereas it is still in infancy in certain departments. Some misconceptions exist regarding this condition with reference to clinical, genetic aspects and management-in particular, the surgical indications. The experience gained for more than 2 decades of treating this condition as well as the problems faced in the management of this condition will be discussed. Although the terms craniostenosis and craniosynostosis do not mean quite the same thing, the terms are used interchangeably and will be done so in this communication.

Pfeiffer syndrome: analysis of a clinical series and development of a classification system.

Among the craniosynostosis syndromes, Pfeiffer syndrome is notable because of high mortality and the need for multiple surgical interventions. However, it is variable in severity. We propose a new classification of Pfeiffer Syndrome to define pathology and function. A retrospective review was conducted of 42 patients with Pfeiffer syndrome treated from 1975 to 2010, the largest series reported to date. The classification was based on a functional assessment of patients in terms of respiratory, ocular, otological, and neurological status. This classification was tested by scoring and stratifying patients as follows: type A (mild problems), B (moderate problems), or C (severe problems). Patients were scored both at the time of presentation and after all surgical interventions to assess change in functional outcome. The functional classification system was compared to another previously reported. Type A patients did not have any change in postoperative functional outcomes (mean preoperative score 1.6, mean postoperative score 1.6); type B patients showed functional improvement (mean preoperative score 4.1, mean postoperative score 3.4) but type C patients (mean preoperative score 7.7, mean postoperative score 4.8) demonstrated the greatest improvement in functional scores after surgical intervention. Suture pathology did not indicate the clinical severity of phenotype, a variance from a previously published classification. The proposed classification is useful to assess severity of phenotype: respiratory, ocular, otologic, and neurologic problems are key indicators of the need for treatment. The classification can provide a helpful guide in multidisciplinary treatment planning, in reporting outcomes, and in the sharing of data among craniofacial anomalies centers.

Intestinal malrotation in a patient with Pfeiffer syndrome type 2.

Pfeiffer syndrome is a pleiotropic disorder characterized by multiple suture craniosynostosis, broad and medially deviated thumbs and great toes, and variable cutaneous syndactyly. We present the case of a 16-month-old boy with Pfeiffer syndrome type 2 who presented with intestinal malrotation for which the diagnosis was delayed. This is a rare complication of Pfeiffer syndrome, with few reported cases in the literature. This case illustrates the importance of recognizing gastrointestinal malrotation as a possible cause of feeding intolerance and persistent vomiting in patients with the severe forms of Pfeiffer syndrome.

[The Apert's syndrome hand: therapeutic management]. / La main du syndrome d'Apert: stratégie thérapeutique.

Apert's syndrome is the most common among acrocephalosyndactylies with complex malformations of the hands. Treatment of the Apert hand is complex and numerous procedures are required. The aim of this study is to propose a strategy for hand management. Sixteen Apert syndrome hands were submitted to early surgery which included opening of the first web, separation of the fingers, realignment of the thumb and correction of the clinodactylies. We performed an average of six operations per child. Treatment of the first web depended on the classification of Upton: for the severe stages, we used a dorsal hand flap. Radical clinodactyly was treated by osteotomy of the delta phalanx and Z-plasty. We treated nine hands with four fingers and seven hands with five fingers. There was always bilateral opposition and symphalangism, excluding the fifth finger. All of the children have a rudimentary but functional pinch grip. Revision of the webs was necessary in 16% of the cases. The Apert hand requires early and specialised treatment that aims to provide a functional hand before two or three years, with the least surgical complications. The functional prognosis is darkened by symphalangism.

Clinical features of syndromic craniosynostosis.

Disruption of normal suture development and function can result in premature suture fusion, craniosynostosis. This review focuses on syndromic forms of craniosynostosis. More than 100 syndromes in which craniosynostosis is a feature have been documented and here the most common conditions including Apert and Crouzon syndromes are described as well as other conditions with a particularly interesting molecular etiology, such as Saethre- Chotzen and craniofrontonasal syndrome.

Further evidence of association between mutations in FGFR2 and syndromic craniosynostosis with sacrococcygeal eversion.

BACKGROUND: Pfeiffer syndrome (PS; OMIM #101600) is an autosomal dominant disorder characterized by craniosynostosis, midface hypoplasia, broad thumbs, brachydactyly, broad great toes, and variable syndactyly. CASE: We report a case of PS (type 3) with tracheal and visceral involvement and sacrococcygeal eversion. The patient shows facial dysmorphism with macrocephaly, dolichocephaly, and trigonocephaly, and an asymmetric skull, bilateral and severe exophthalmia with shallow orbits and ocular hypertelorism, downslanting palpebral fissures, constant strabismus, short anterior cranial base, and midface hypoplasia. CONCLUSIONS: Molecular analysis of the FGFR2 gene in this patient revealed a point mutation (c.890G>C NM_000141). This mutation leads to the substitution of the residue tryptophan at position 290 to cysteine in the protein (p.Try290Cys). These data reinforce the hypothesis that the p.Trp290Cys mutation is more often associated with a severe and poor prognosis of PS. Furthermore they suggest that the presence of sacrococcygeal defects is not associated with any specific FGFR2 mutation.

Pfeiffer syndrome.

Pfeiffer syndrome is a rare autosomal dominantly inherited disorder that associates craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly on hands and feet. Hydrocephaly may be found occasionally, along with severe ocular proptosis, ankylosed elbows, abnormal viscera, and slow development. Based on the severity of the phenotype, Pfeiffer syndrome is divided into three clinical subtypes. Type 1 "classic" Pfeiffer syndrome involves individuals with mild manifestations including brachycephaly, midface hypoplasia and finger and toe abnormalities; it is associated with normal intelligence and generally good outcome. Type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, developmental delay and neurological complications. Type 3 is similar to type 2 but without a cloverleaf skull. Clinical overlap between the three types may occur. Pfeiffer syndrome affects about 1 in 100,000 individuals. The disorder can be caused by mutations in the fibroblast growth factor receptor genes FGFR-1 or FGFR-2. Pfeiffer syndrome can be diagnosed prenatally by sonography showing craniosynostosis, hypertelorism with proptosis, and broad thumb, or molecularly if it concerns a recurrence and the causative mutation was found. Molecular genetic testing is important to confirm the diagnosis. Management includes multiple-staged surgery of craniosynostosis. Midfacial surgery is performed to reduce the exophthalmos and the midfacial hypoplasia.

Algorithm for treatment of apert hand.

The hand in Apert syndrome is one of the most complex examples of congenital deformity of the upper limb. The management is difficult, and mny different approaches have been published. The hands demonstrate many disturbances of soft tissue and bony structures. These include a short thumb with radial clinodactyly, complex syndactyly with a bony fusion involving the index, long and ring fingers, and symphalangism and simple syndactyly of the fourth web space. The soft tissue anomalies involve the intrinsic muscles, the extrinsic tendon insertions, and the neurovascular bundles. Correction of the appearance of the operated hand is readily apparent, but the complexity of the disorders in the bones and soft tissues explains the difficulty of the surgical management. The aim of this study is to propose a better surgical management: on the basis of the experience of our multidisciplinary team (188 procedures in 53 patients) in the light of recent publications and a better comprehension of the syndrome, we attempt to reduce the number of procedures and to select the best possible procedures for each patient. When possible, we perform a 3-step procedure (the first is bilateral, the others are unilateral) between 9 months and 2 years of age. Separation of the fingers improves function even though we must expect an inevitable stiffness in extension of the interphalangeal joints.

Surgical management of the hand in Apert syndrome.

In patients with Apert syndrome, the hands demonstrate many disturbances of soft tissue and bony structures. These include a short thumb with radial clinodactyly, complex syndactyly with a bony fusion involving the index, long and ring fingers, symphalangism and simple syndactyly of the fourth web space. The soft tissue anomalies involve the intrinsic muscles, the extrinsic tendon insertions and the neurovascular bundles. We have reviewed 52 patients who underwent surgical reconstruction of their hands. The aim of this study is to propose a better surgical management in the light of recent publications and to improve our understanding of the syndrome, attempting to reduce the number of procedures and to select the best possible procedures for each patient.

A case of acrocephalosyndactyly with low imperforate anus.

The authors report a case of a female acrocephalosyndactyly with imperforate anus without fistula, which is rare in girls. Acrocephalosyndactyly is characterized by premature closure of the sutures (craniosynostosis) and fusion or webbing of hands and feet (syndactyly). The most general types of the syndrome are the Apert syndrome and the Pfeiffer syndrome. They usually have some fibroblast growth factor receptor (FGFR) gene mutations, so that acrocephalosyndactyly is thought to be involved in "FGFR-related craniosynostosis." To the authors' knowledge, only 4 cases of anorectal anomaly in acrocephalosyndactyly have been reported in the world. The relationship between anorectal anomaly and the FGFR gene is not clear now, but might be clarified in the future.

Oral findings in Carpenter syndrome.

Acrocephalopolysyndactyly Type II (Carpenter Syndrome) is determined by autosomal recessive inheritance. Only some 40 cases have been described. Variable clinical signs have been described including prolonged retention of primary teeth and hypodontia. This paper describes the oral and dental findings in a family containing two affected brothers. The family pedigree is informative, as the mother has had children by three partners. The two affected individuals are full brothers. The first affected brother has delayed dental development, severe hypodontia and small tooth crown size. Mesio-distal and bucco-lingual dimensions were measured on the study models and compared with population data. The younger brother also has delayed dental development but only mild hypodontia. Their half sister has severe hypodontia but no signs of Carpenter Syndrome. This family study demonstrates two affected individuals with typical clinical features and a pedigree compatible with autosomal recessive inheritance. Small tooth crown size has been shown by standardized measurement and evidence advanced that hypodontia is not part of the syndrome but a coincidental finding which segregates independently. We have also shown that the marked delay in emergence of teeth is associated more with problems of tooth eruption, possibly related to the bony abnormalities, than to a generalized delay in dental development.

Apert syndrome variant with overlapping features of Crouzon syndrome.

A rare variant of Apert syndrome having overlapping features of Crouzon syndrome is described. The salient features of the two syndromes are briefly discussed and overlapping features are highlighted. A possible genetic explanation for the same is mentioned.

A variant of Reinhardt-Pfeiffer mesomelic skeletal dysplasia.

Mesomelic bone dysplasias are characterised by disproportionate shortness of the middle segment of the extremities and short stature. Various patterns of this dysplasia have been described in the literature. The type involving mainly the ulna and fibula was described by Reinhardt and Pfeiffer as the ulno-fibular mesomelic dysplasia affecting the distal ulna and proximal fibula. Involvement of the distal fibula in mesomelic dysplasia has not been described to our knowledge. We report here a case of mesomelic dysplasia affecting mainly the distal fibula and distal ulna, with severe ankle deformity requiring surgical correction.

Favorable prognosis for children with Pfeiffer syndrome types 2 and 3: implications for classification.

Pfeiffer syndrome (PS) is an autosomal dominant condition comprising bilateral coronal craniosynostosis, midface hypoplasia with a beaked nasal tip, and broad and medially deviated thumbs and great toes. It is a clinically variable disorder and has been divided into three subtypes [Cohen, 1993: Am J Med Genet 45:300-307]. Type 1 represents the less severe cases, while types 2 and 3 are the more severe cases. These latter types tend to have a higher risk for neurodevelopmental problems and a reduced life expectancy. Here we review the clinical course of seven children with PS type 3. All of these children had severe manifestations of PS; however, development was essentially normal in three, mild delay was noted in two, and moderate delay in one. Favorable outcomes in children with types 2 and 3 PS were also documented by Moore et al. [1995: Cleft Pal-Craniofac J 32:62-70]. These cases illustrate that while children with PS types 2 and 3 have an increased risk for neurodevelopmental difficulties, a favorable outcome can be achieved in some cases with aggressive medical and surgical management. Finally, although such management should be the rule for PS types 2 and 3, it needs to be remembered that normal outcome is not the rule. The prognosis for favorable neurodevelopmental outcome and/or life expectancy remains guarded in most cases.

Pfeiffer syndrome type 2: further delineation and review of the literature.

We present 5 unrelated patients, 3 boys and 2 girls, with Pfeiffer syndrome (PS) type 2. They all had cloverleaf skull, severe proptosis, ankylosis of the elbows, broad thumbs and/or broad halluces and variable accompanying anomalies. We review the literature on all subtypes of PS. Most patients with PS type 2 died shortly after birth. Causes of death include pulmonary problems, brain abnormalities, prematurity and post-operative complications. DNA studies were performed in 3 of the 5 patients. Two of them showed a 1036T --> C mutation in the fibroblast growth factor receptor 2 (FGFR2) gene, that was earlier reported in PS and in Crouzon syndrome. Probably most, if not all, PS type 2 cases are caused by a de novo mutation in the FGFR2 gene or in another, yet unidentified gene. To date all type 2 cases have been non-familial. A low recurrence risk for parents can be advised.

[Syndromes 2. Pfeiffer syndrome]. / Syndromen 2. Syndroom van Pfeiffer.

Acrocephalosyndactylias are syndromes characterized by abnormalities of the head (craniosynostosis), the face (hypertelorism, retromaxillism), hands and feet (cutaneous or bony syndactyly). Inheritance is autosomal dominant, but spontaneous cases are described also. The group is divided into several syndromes with varying penetrance and expressivity. As an example of an acrocephalosyndactylia is the Pfeiffer syndrome presented.