Muenke syndrome: An international multicenter natural history study.

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P = 0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x-rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss.

Executive Function and Adaptive Behavior in Muenke Syndrome.

OBJECTIVE: To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls. STUDY DESIGN: Participants in this cross-sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]). RESULTS: Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS-II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (<25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite. CONCLUSION: Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings.

The beginnings of Acta Neurochirurgica and the work of Fritz Loew, chief editor from 1958 - 1997. An historical vignette.

Acta Neurochirurgica was founded in 1950, in the difficult time after World War II, by Mario Milletti (Bologna) and Wolfram Sorgo (Innsbruck), and published by Springer press, Vienna. From the beginning the new journal was conceived as an international journal with an impressive list of outstanding neurosurgeons in the editorial board. Only a few years later the issues appeared at irregular intervals due to individual problems of both editors. Wilhelm Tönnis took the initiative to keep the journal alive, when he asked-in consent with Springer press-his staff member Fritz Loew to continue the editorial work and to assemble a new prestigious editorial board. Loew succeeded with both tasks and remained editor-in-chief for nearly 38 years. Initially, all papers were published in the native languages of the authors: English, French, German, Italian and Spanish. With ongoing time the journal accepted manuscripts in English only. The slow progress of this process exemplifies the slow integration of the European countries. In 1971, at the founding meeting of the European Association of Neurosurgical Societies (EANS) in Prague, Acta Neurochirurgica became the official organ of the EANS. Right from the beginning of Acta Neurochirurgica, Supplement volumes were added. Also, the book series Advances and Technical Standards in Neurosurgery is an offspring of Acta Neurochirurgica. Acta Neurochirurgica has become one of the most important neurosurgical journals worldwide. This historical sketch is based on an interview with Fritz Loew, now 91 years old, to which data from the available literature and the Archives of German Neurosurgery, as well as personal information by several colleagues were added.

[Georges Schaltenbrand (26. 11. 1897 24. 10. 1979)]. / Georges Schaltenbrand (26. 11. 1897 - 24. 10. 1979).

Georges Schaltenbrand was one of the most prodigious and internationally renowned neurologists in post war Germany. Trained by Max Nonne in Hamburg, he early gained international experience during stays in The Netherlands, the United States, and China. In 1935 quarrels with Nazi representatives forced him to go to Würzburg, where he built an own neurological service. This unit subsequently grew up to an internationally recognized center. Schaltenbrand scientifically contributed to the organization and diagnostics of the motor system, to the physiology and pathology of the cerebrospinal fluid system, and to multiple sclerosis. His textbook and atlas on stereotaxy, authored with his American friend Percival Bailey in 1959, remained a standard reference in stereotactic surgery until recent years. Only late after his death his unethical scientific activities during wartime came to common public knowledge. In an attempt to confirm his hypothesis of an infectious aetiology of multiple sclerosis, he had inoculated mentally handicapped and other severely ill patients with cerebrospinal fluid of apes putatively suffering from multiple sclerosis and also of patients with verified multiple sclerosis. He explicitly accepted the risk of causing some morbidity and even mortality in his study persons. He published his experiments in several articles and oral presentations since 1940, and, comprehensively, in a monograph 1943. Although commented as early as 1949, his dubious studies were widely ignored until a critical review appeared in an American journal in 1994. Since then, the studies are frequently cited as a typical example of Nazi medical science. However, with due regard to the historical background and the personality of Schaltenbrand his experiments should rather be brought into line with a worldwide practice at that time of using patients as study objects without asking for their consent. As a response to this practice several laws had been adopted, beginning in 1900, carried on in 1931 and culminating 1947 in the Nuremberg code. As a historical fact, not only before but also after World War II these legal acts were widely ignored and became only gradually accepted.

Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome.

The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.

Friedrich Weickmann (1913-1983): some reminiscences.

Friedrich Weickmann was one of the most distinguished neurosurgeons of the former German Democratic Republic and an eminent representative of the neurosurgical school established by Fedor Krause. For 25 years he was head of the neurosurgical department in Berlin-Buch, which he developed into an excellent nonuniversity center. Weickmann was the first German to publish a comprehensive text on pediatric neurosurgery. He deserves particular credit for defending the autonomy of the neurosurgical specialty and for promoting neuroradiology as a subspecialty of radiology.

Occipital plagiocephaly: unilateral lambdoid synostosis versus positional plagiocephaly.

OBJECTIVE: We defined parameters that could differentiate between positional and synostotic plagiocephaly and defined a diagnostic chart for decision making. DESIGN: Prospective study. SETTING: We examined 411 children with non-syndromic skull abnormalities between January 2011 and December 2012. PARTICIPANTS: A total of 8 infants under 1 year of age with proven unilateral non-syndromic lambdoid synostosis (LS) and 261 children with positional deformity were examined to outline the specific clinical features of both diagnoses. After clinical examination, an ultrasound revealed either a closed suture suggestive of LS or a patent lambdoid suture suggestive of positional deformity. For patients with synostosis, plain radiographs, MR imaging and follow-up examinations were performed. In cases of open sutures, only follow-ups were completed. MAIN OUTCOME MEASURE: Clinical, imaging, genesis and treatment differences between positional plagiocephaly and LS. RESULTS: In all 8 cases of unilateral LS and 258 cases of positional plagiocephaly, the diagnosis was established by clinical examination alone. In three cases of positional plagiocephaly, diagnosis was determined after an additional ultrasonography. MR imaging revealed a unilateral tonsillar herniation in five of the eight children with LS and hydrocephalus in one child. CONCLUSIONS: We have suggested a list of clinical features that specify the underlying cause of posterior plagiocephaly. An additional ultrasound scanning confirmed the diagnosis without any risks of ionising radiation or sedation as in a CT scan.

Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis.

We have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation; a family with pansynostosis with compound heterozygous missense mutations, p.Pro200Thr and p.Arg237Pro; and two further Turkish families with Crouzon-like syndrome carrying the homozygous nonsense mutations p.Tyr232* and p.Arg292*. Using transient coexpression in HEK293T and COS7 cells, we demonstrated dramatically reduced IL11-mediated STAT3 phosphorylation for all mutations. Immunofluorescence analysis of mouse Il11ra demonstrated specific protein expression in cranial mesenchyme which was localized around the coronal suture tips and in the lambdoidal suture. In situ hybridization analysis of adult zebrafish also detected zfil11ra expression in the coronal suture between the overlapping frontal and parietal plates. This study demonstrates that mutations in the IL11RA gene cause an autosomal recessive Crouzon-like craniosynostosis.

Historical perspective on neurosurgery in Germany after World War II.

AFTER THE COLLAPSE of the Third Reich, the specialty of neurosurgery in Germany, although well developed in the late 1930s, had to start anew, and for decades to come, had to deal with the physical and political consequences of World War II. Because of the division of the country, neurosurgery developed separately in the two independent states. In West Germany, the evolution was promoted by a few personalities who represented different schools according to their own training: these "surgical neurologists" emphasized the neurological basis of neurosurgery and were represented by Traugott Riechert and the students of Otfrid Foerster, such as Arist Stender and Hans Kuhlendahl. In contrast, the "neurological surgeons" stressed their origins in general surgery. Their main proponent was Wilhelm Tönnis, who gained particular merit for promoting neurosurgical teaching, the development of new neurosurgical units, and the recognition of neurosurgery as an autonomous specialty. In East Germany, progress was delayed by a weak economy and a repressive political system. Yet several excellent neurosurgeons won international recognition, predominantly Georg Merrem, who came from the school of Fedor Krause. Following a worldwide trend, the number of neurosurgical units in West Germany increased dramatically from 18 in 1950 to 85 in 1988. In 2006, in the unified nation, 1200 certified neurosurgeons in 138 hospital departments and 75 private practices served 82 million people. Since its founding in 1949, the German Neurosurgical Society has promoted the idea of reconciliation and has focused on international collaboration in both science and education. This idea, shared by other European nations, eventually gave rise to the European Association of Neurosurgical Societies. At present, escalating costs in the health sector pose a problem to neurosurgical services and have led to reconsiderations about their structure and financing.

The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation.

BACKGROUND: Saethre-Chotzen syndrome (SCS) and Muenke-type mutation (MTM) are complex syndromes with craniosynostosis and skeletal anomalies including syndactyly, carpal and tarsal fusions, and cervical spine abnormalities. OBJECTIVE: In this study, we analysed radiographs of the cervical spine, hands and feet of a large patient population with genetically proven SCS and MTM. The aim was to describe the pattern of skeletal anomalies and to determine whether specific features are present that could help differentiate between the two entities. MATERIALS AND METHODS: Radiographs of 43 patients (23 males, 20 females) with SCS (n=35) or MTM (n=8) were evaluated. The median age was 8 years (range 1 month-36 years). All radiographs were reviewed by two radiologists. RESULTS: In the hands and feet, a variety of anomalies such as brachyphalangy, clinodactyly, partial syndactyly, partial carpal or tarsal fusion, and cone-shaped epiphyses were noted. Duplicated distal phalanx of the hallux (n=12/35) and triangular deformity of the epiphysis of the distal phalanx of the hallux (n=10/35) were detected in SCS only; calcaneo-cuboid fusion (n=2/35) was detected in MTM only. In the cervical spine, fusion of vertebral bodies and/or the posterior elements occurred only in patients with SCS. CONCLUSIONS: Pathognomonic signs for SCS are the triangular shape of the epiphysis and duplicated distal phalanx of the hallux. Calcaneo-cuboid fusion was detected in MTM only. These signs may be helpful in the differentiation of SCS from MTM.

Standardized evaluation and documentation of findings in patients with craniosynostosis.

Surgical correction of craniosynostosis is usually performed according to standard procedures. However, a standard for clinical examination and report of findings for patients with craniosynostosis does not exist as yet. To compare findings from different hospitals, a documentation system was developed by a national craniosynostosis group. This system comprises a two-page document, clinical photographs, radiographs, CT scans, anthropometric measurements and molecular genetic findings. Data from craniosynostosis patients collected from participating hospitals are stored in a database, which facilitates online access.The documentation system was developed in cooperation with the group during 3 years since 1996. It was evaluated as being practicable and reliable and enables a comparability of findings reported in different hospitals. Molecular genetic analysis was found to support the investigation of patients with craniosynostosis and should therefore be integrated in the clinical evaluation. Copyright 2001 European Association for Cranio-Maxillofacial Surgery.