Identifying non-genetic factors associated with trigger finger.

BACKGROUND: The non-genetic factors predisposing to trigger finger (TF) have mostly been characterised in small studies from individual institutions. Here, we aimed to provide a more complete picture of TF and its associations. METHODOLOGY: This case-control study used cross-sectional data from the UK Biobank population-based cohort to identify and determine the strength of associations of phenotypic variables with TF. We performed multivariable logistic regression of a multitude of phenotypic factors associated with TF. RESULTS: We identified 2250 individuals with medical and surgical diagnostic codes for TF, and 398,495 controls. TF was found to be significantly associated with age (OR 1.04, 95% CI 1.03-1.04, P < 2.23×10-308), female sex (OR 1.22, 95% CI 1.08-1.39, P = 2.35×10-3), body mass index (OR 1.10, 95% CI 1.04-1.16, P = 5.52×10-4), carpal tunnel syndrome (OR 9.59, 95% CI 8.68-10.59, P < 2.23×10-308), Dupuytren's disease (OR 4.89, 95% CI 4.06-5.89, P < 2.23×10-308), diabetes mellitus without complications (OR 1.35, 95% CI 1.15-1.58, P = 2.03×10-4) and with complications (OR 2.46, 95% CI 1.90-3.17, P = 4.98×10-12), HbA1c (OR 1.01, 95% CI 1.01-1.02, P = 8.99×10-9), hypothyroidism (OR 1.24, 95% CI 1.07-1.43, P = 4.75×10-3) and rheumatoid arthritis (OR 1.33, 95% CI 1.06-1.68, P = 0.014). CONCLUSION: Our results provide evidence supporting the well-known risk factors such as diabetes mellitus, carpal tunnel syndrome, age and female sex. Furthermore, we can confirm putative associations such as hypothyroidism, obesity and rheumatoid arthritis, while providing evidence against others such as hypertension and hyperlipidaemia. A novel finding arising from this study is the strong association with Dupuytren's disease. Our study design allowed us to identify these associations as being independent from carpal tunnel syndrome, thereby indicating a shared pathophysiology between this disease and TF.

Higher densities of T-lymphocytes in the subsynovial connective tissue of people with carpal tunnel syndrome.

Symptoms in people with carpal tunnel syndrome (CTS) are traditionally attributed to neural tissue, but recent studies suggest that the subsynovial connective tissue (SSCT) may also play a role in CTS. The SSCT undergoes fibrotic thickening which is generally described as "non-inflammatory" based on basic histology. This study uses immunohistochemistry to determine the presence of macrophages and T-cells within SSCT and their relationship with symptoms in people with CTS. SSCT was collected from twenty people with CTS and eight controls undergoing wrist fracture surgery. Immunohistochemical quantification of CD3+ T-cells and CD68+ macrophage densities as well as CD4+/CD8+ T-cell subpopulations were compared between groups using independent t-tests. Spearman correlations were used to identify associations between immune cell densities and CTS symptom scores. The density of CD3+ T-cells was significantly higher in SSCT of people with CTS compared to controls (CTS mean 26.7 (SD 13.7); controls 6.78 (6.3), p = 0.0005) while the density of CD68+ macrophages was lower (CTS mean 9.5 (SD 6.0); controls 17.7 (8.2), p = 0.0058). Neither CD68+ nor CD3+ cell densities correlated with symptom scores. In contrast to previous assumptions, our data show that the SSCT in the carpal tunnel in both people with CTS and controls is not devoid of immune cells. Whereas the higher density of CD68+ macrophages in control participants may be associated with their early recruitment after acute fracture, CD3+ cells within the SSCT may play a role in chronic CTS.

Modifiable Risk Factors for Prevention in Dupuytren Disease: A UK Biobank Case-Control Study.

BACKGROUND: Dupuytren disease is associated with significant comorbidity and mortality, and it has no existing prevention strategies. It is unclear which modifiable risk factors are most amenable for prevention. This study aimed to determine the strength of modifiable risk factors for Dupuytren disease, and to investigate associations with other diseases. METHODS: Using UK Biobank data, this case-control study analyzed the association between phenotypic variables and Dupuytren disease through multivariable logistic regression. Exposures assessed were age, sex, body mass index, waist-to-hip ratio, Townsend deprivation index, smoking status, alcohol intake, diabetes mellitus, hypertension, cancer, liver disease, respiratory disease, rheumatoid arthritis, epilepsy, psoriasis, and gout. RESULTS: There were 4148 cases and 397,425 controls. Male sex (OR, 3.23; 95% CI, 2.90 to 3.60; P = 1.07 × 10 -100 ), increasing age (OR, 1.08; 95% CI, 1.07 to 1.08; P = 6.78 × 10 -167 ), material deprivation (OR, 1.01; 95% CI, 1.00 to 1.02; P = 0.0305), high-density lipoprotein cholesterol (OR, 1.76; 95% CI, 1.58 to 1.96; P = 3.35 × 10 -24 ), smoking exposure, and alcohol intake were all associated with increased odds of Dupuytren disease. With increasing obesity class, there was approximately 25% decreased odds (OR, 0.774; 95% CI, 0.734 to 0.816; P = 4.71 × 10 -21 ). Diabetes with microvascular or end-organ complications was associated with more than 2.5 times increased odds of Dupuytren disease (OR, 2.59; 95% CI, 1.92 to 3.44; P = 1.92 × 10 -10 ). Within this group, increasing hemoglobin A1c values by 10 mmol/mol, or 0.9%, increased the odds by 31% (OR, 1.31; 95% CI, 1.13 to 1.51; P = 2.19 × 10 -4 ). CONCLUSION: Diabetes and poor glycemic control are major risk factors for Dupuytren disease, which present an opportunity for prevention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Genetic correlations between migraine and carpal tunnel syndrome.

BACKGROUND: Surgical deactivation of extracranial nerve trigger sites is now well-established as an effective treatment for migraine headache. Parallels have been drawn to median nerve decompression for carpal tunnel syndrome (CTS), and two previous studies have demonstrated an association between migraine and CTS. We sought to: (1) substantiate these findings in a considerably larger UK cohort, and; (2) investigate potential genetic associations between the two disorders. METHODS: Nested case-control studies were conducted in the UK Biobank cohort of 401,656 individuals. Odds ratios were calculated for the association between migraine and CTS in the overall cohort and sex-stratified subsets. Genetic correlation between migraine and CTS was interrogated by linkage disequilibrium score regression (LDSC), leveraging data from published genome-wide association studies. Regions of genetic overlap were identified by Multi-Trait Analysis of GWAS (MTAG) and Cross-Phenotype Association (CPASSOC). RESULTS: Migraine and CTS show a significant epidemiological association within UK Biobank (OR=1.14, 95% CI: 1.04-1.25, p=0.0058), which is specific to females (OR=1.15; 95% CI: 1.04-1.28, p=0.0057) and not males (OR=1.07; 95% CI: 0.82-1.40, p=0.61). Genetic analysis demonstrated a significant positive genetic correlation between the two disorders (rg=0.13, p=0.0039), and implicated the TRIM32 locus on chromosome 9 as a region of genetic overlap. CONCLUSIONS: This study replicates past reports of an epidemiological association between CTS and migraine, albeit in females only. This association is underpinned by a genetic correlation, with shared genetic susceptibility at the TRIM32 locus. Our data adds credibility to the notion that an element of entrapment neuropathy underlies migraine pathophysiology.

Dupuytren's disease is a work-related disorder: results of a population-based cohort study.

OBJECTIVES: Dupuytren's disease (DD) is a fibroproliferative disorder of the hands, characterised by the development of fibrous nodules and cords that may cause disabling contractures of the fingers. The role of manual work exposure in the aetiology of DD is controversial. We investigated whether current occupational exposure to manual work is associated with DD, and if there is a dose-response relationship. METHODS: In this population-based cohort analysis, we used data from the UK Biobank cohort. Our primary outcome was the presence of DD. The exposure of interest was manual work, measured for each participant in two different ways to allow two independent analyses to be undertaken: (1) the current manual work status of the occupation at the time of recruitment, and (2) a cumulative manual work exposure score, calculated based on the occupational history. We performed propensity score matching and applied a logistic regression model. RESULTS: We included 196 265 participants for the current manual work analysis, and 96 563 participants for the dose-response analysis. Participants whose current occupation usually/always involved manual work were more often affected with DD than participants whose occupation sometimes/never involved manual work (OR 1.29, 95% CI 1.12 to 1.49, p<0.001). There was a positive dose-response relationship between cumulative manual work exposure score and DD. Each increment in cumulative work exposure score increased the odds by 17% (OR 1.17, 95% CI 1.08 to 1.27, p<0.001). CONCLUSIONS: Manual work exposure is a risk factor for DD, with a clear dose-response relationship. Physicians treating patients should recognise DD as a work-related disorder and inform patients accordingly.

Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis.

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.

Genome-wide association analysis and replication in 810,625 individuals with varicose veins.

Varicose veins affect one-third of Western society, with a significant subset of patients developing venous ulceration, costing $14.9 billion annually in the USA. Current management consists of either compression stockings, or surgical ablation for more advanced disease. Most varicose veins patients report a positive family history, and heritability is ~17%. We describe the largest two-stage genome-wide association study of varicose veins in 401,656 individuals from UK Biobank, and replication in 408,969 individuals from 23andMe (total 135,514 cases and 675,111 controls). Forty-nine signals at 46 susceptibility loci were discovered. We map 237 genes to these loci, several of which are biologically plausible and tractable to therapeutic targeting. Pathway analysis identified enrichment in extracellular matrix biology, inflammation, (lymph)angiogenesis, vascular smooth muscle cell migration, and apoptosis. Using a polygenic risk score (PRS) derived in an independent cohort, we demonstrate its predictive utility and correlation with varicose veins surgery.

Systemic inflammatory markers in neuropathic pain, nerve injury, and recovery.

ABSTRACT: The role that inflammation plays in human nerve injury and neuropathic pain is incompletely understood. Previous studies highlight the role of inflammation in the generation and maintenance of neuropathic pain, but the emerging evidence from the preclinical literature for its role in the resolution of neuropathic pain remains to be explored in humans. Here, we use carpal tunnel syndrome (CTS) as a human model system of nerve injury and neuropathic pain to determine changes in serum cytokine protein levels and gene expression levels before (active stage of disease) and after carpal tunnel decompression surgery (recovery). Fifty-five patients with CTS were studied, and 21 healthy age-matched and gender-matched participants served as controls. In the active stage of the disease (CTS before surgery vs healthy controls), PTGES2 mRNA was decreased in patients (adjusted P = 0.013), while transforming growth factor-ß and C-C motif chemokine ligand 5 protein levels were increased (adjusted P = 0.016 and P = 0.047, respectively). In the resolution phase (CTS before surgery vs after surgery), IL-9 mRNA was increased after surgery (adjusted P = 0.014) and expression of IL-6 mRNA and IL-4 protein levels were increased before surgery (adjusted P = 0.034 and P = 0.002, respectively). IL-9 mRNA expression negatively correlated with several (neuropathic) pain scores. By contrast, protein levels of IL-4 positively correlated with pain scores. In conclusion, we demonstrate specific dysregulation of systemic cytokine expression in both the active and resolution phases of nerve injury and neuropathic pain. IL-9 represents an interesting candidate associated with resolution of nerve injury and neuropathic pain.

Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones.

BACKGROUND: Calcium kidney stones are common and recurrences are often not preventable by available empiric remedies. Their etiology is multifactorial and polygenic, and an increasing number of genes are implicated. Their identification will enable improved management. METHODS: DNA from three stone-formers in a Southampton family (UK) and two from an Italian family were analyzed independently by whole exome sequencing and selected variants were genotyped across all available members of both pedigrees. A disease variant of SLC25A25 (OMIM 608745), encoding the mitochondrial ATP-Mg/Pi carrier 3 (APC3) was identified, and analyzed structurally and functionally with respect to its calcium-regulated transport activity. RESULTS: All five patients had a heterozygous dominant SLC25A25 variant (rs140777921; GRCh37.p13: chr 9 130868670 G>C; p.Gln349His; Reference Sequence NM_001006641.3). Non-stone formers also carried the variant indicating incomplete penetrance. Modeling suggests that the variant lacks a conserved polar interaction, which may cause structural instability. Calcium-regulated ATP transport was reduced to ~20% of the wild type, showing a large reduction in function. CONCLUSION: The transporter is important in regulating mitochondrial ATP production. This rare variant may increase urine lithogenicity through impaired provision of ATP for solute transport processes in the kidney, and/or for purinergic signaling. Variants found in other genes may compound this abnormality.

An Integrated Approach to the Management of Meningoencephalocoeles.

ABSTRACT: Meningoencephalocoeles are congenital herniations of meningeal and cerebral tissues through a cranial defect. They occur most commonly in South-East Asia, and are relatively rare amongst European ancestry populations, with an estimated prevalence of 1/40,000 live births. The treatment of congenital meningoencephalocoeles is primarily surgical and are best managed by dedicated multi-disciplinary craniofacial teams. The authors performed a retrospective case review of all primary meningoencephalocoeles managed in the Oxford University Hospitals NHS Foundation Trust between 1986 and 2012. Twenty-nine cases (13 frontal, 9 occipital, 2 parietal, and 5 basal) were included in this study. The median age at presentation was 11 months (range 0-60 years). Twenty-five cases presented with an external mass; 3 with recurrent meningitis and 1 with otorrhoea. Twenty-six cases underwent surgery, and 17 of these were managed by an integrated approach between 2 or more surgical specialties. Twenty out of 26 operations were performed via a transcranial approach. The authors describe a particularly complex case in order to highlight the challenges associated with management of meningoencephalocoeles, the surgical technique employed, and the importance of a multidisciplinary surgical approach. This is the largest reported case series of meningoencephalocoeles managed in a single hospital in the United Kingdom. Designated craniofacial units with access to multidisciplinary surgical specialties provide a safe and optimal setting for the management of meningoencephalocoeles.

A common SNP risk variant MT1-MMP causative for Dupuytren's disease has a specific defect in collagenolytic activity.

Dupuytren's Disease (DD) is a common fibroproliferative disease of the palmar fascia. We previously identified a causal association with a non-synonymous variant (rs1042704, p.D273N) in MMP14 (encoding MT1-MMP). In this study, we investigated the functional consequences of this variant, and demonstrated that the variant MT1-MMP (MT1-N273) exhibits only 17% of cell surface collagenolytic activity compared to the ancestral enzyme (MT1-D273). Cells expressing both MT1-D273 and MT1-N273 in a 1:1 ratio, mimicking the heterozygous state, possess 38% of the collagenolytic activity compared to the cells expressing MT1-D273, suggesting that MT1-N273 acts in a dominant negative manner. Consistent with the above observation, patient-derived DD myofibroblasts with the alternate allele demonstrated around 30% of full collagenolytic activity detected in ancestral G/G genotype cells, regardless of the heterozygous (G/A) or homozygous (A/A) state. Small angle X-ray scattering analysis of purified soluble Fc-fusion enzymes allowed us to construct a 3D-molecular envelope of MT1-D273 and MT1-N273, and demonstrate altered flexibility and conformation of the ectodomains due to D273 to N substitution. Taking together, rs1042704 significantly reduces collagen catabolism in tissue, which tips the balance of homeostasis of collagen in tissue, contributing to the fibrotic phenotype of DD. Since around 30% of the worldwide population have at least one copy of the low collagenolytic alternate allele, further investigation of rs1042704 across multiple pathologies is needed.

The relationship between body mass index and the risk of development of Dupuytren's disease: a Mendelian randomization study.

We performed Mendelian randomization analyses of body mass index and waist-hip ratio adjusted for body mass index in Dupuytren's disease using summary statistics from genome-wide association study meta-analyses. We found that adiposity is causally protective against Dupuytren's disease, with the inverse-variance weighted Mendelian randomization analysis estimating that a 1 standard deviation increase in body mass index (equivalent to 4.8 kg/m2) leads to 28% (95% confidence interval: 18-37%) lower relative odds of developing Dupuytren's disease, and a 1 standard deviation increase in waist-hip ratio adjusted for body mass index (equivalent to a waist-hip ratio of 0.09) leads to 26% (95% confidence interval: 6-42%) lower relative odds of developing Dupuytren's disease. We conclude from this study that regardless of the well-established negative health effects of obesity, the raised body mass index is associated with a lower risk of Dupuytren's disease and may be causally protective for the development of the disease.

The Pathophysiological Significance of Fibulin-3.

Fibulin-3 (also known as EGF-containing fibulin extracellular matrix protein 1 (EFEMP1)) is a secreted extracellular matrix glycoprotein, encoded by the EFEMP1 gene that belongs to the eight-membered fibulin protein family. It has emerged as a functionally unique member of this family, with a diverse array of pathophysiological associations predominantly centered on its role as a modulator of extracellular matrix (ECM) biology. Fibulin-3 is widely expressed in the human body, especially in elastic-fibre-rich tissues and ocular structures, and interacts with enzymatic ECM regulators, including tissue inhibitor of metalloproteinase-3 (TIMP-3). A point mutation in EFEMP1 causes an inherited early-onset form of macular degeneration called Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). EFEMP1 genetic variants have also been associated in genome-wide association studies with numerous complex inherited phenotypes, both physiological (namely, developmental anthropometric traits) and pathological (many of which involve abnormalities of connective tissue function). Furthermore, EFEMP1 expression changes are implicated in the progression of numerous types of cancer, an area in which fibulin-3 has putative significance as a therapeutic target. Here we discuss the potential mechanistic roles of fibulin-3 in these pathologies and highlight how it may contribute to the development, structural integrity, and emergent functionality of the ECM and connective tissues across a range of anatomical locations. Its myriad of aetiological roles positions fibulin-3 as a molecule of interest across numerous research fields and may inform our future understanding and therapeutic approach to many human diseases in clinical settings.

Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth.

We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P < 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P < 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P < 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 µm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration.

Lessons learned in posterior cranial vault distraction.

INTRODUCTION: Posterior distraction (PD) is rapidly emerging as an important technique to increase the intracranial volume and correct calvarial morphology in patients with severe brachycephaly or turribrachycephaly. METHODS: A retrospective review was performed of all 31 patients who underwent PD at the Oxford Craniofacial Unit between 2007 and 2012. RESULTS: Twenty-three patients (74.2%) underwent PD as a primary procedure at a median age of 8 months. Eight patients (25.8%) had PD as a secondary transcranial procedure at a median age of 48 months. Full distraction to 20 mm was achieved in 28 patients (90.3%). Of these, all but 1 demonstrated a significant improvement in morphology, with a resolution of the symptoms and signs of raised intracranial pressure in all proven to have it preoperatively. Unanticipated events occurred in 61.3% of patients, with 19.4% undergoing one or more unplanned procedures. Wound infection (29.0%) and tissue necrosis (22.6%) were the commonest. Cerebrospinal fluid leaks were rarer (6.5%) but prevented full distraction. Nine patients (29.0%) had a consolidation period of less than 30 days without experiencing relapse. In 11 patients who had a later fronto-orbital advancement and remodeling, wound closure was tight, resulting in dehiscence in 3 cases (27.3%). CONCLUSIONS: Posterior distraction is an effective procedure in the management of severe brachycephaly or turribrachycephaly but has associated risks. Our protocol has evolved with experience to favor a reduced latency period and consolidation phase and the use of 2 distractor devices.

Guiding the osteogenic fate of mouse and human mesenchymal stem cells through feedback system control.

Stem cell-based disease modeling presents unique opportunities for mechanistic elucidation and therapeutic targeting. The stable induction of fate-specific differentiation is an essential prerequisite for stem cell-based strategy. Bone morphogenetic protein 2 (BMP-2) initiates receptor-regulated Smad phosphorylation, leading to the osteogenic differentiation of mesenchymal stromal/stem cells (MSC) in vitro; however, it requires supra-physiological concentrations, presenting a bottleneck problem for large-scale drug screening. Here, we report the use of a double-objective feedback system control (FSC) with a differential evolution (DE) algorithm to identify osteogenic cocktails of extrinsic factors. Cocktails containing significantly reduced doses of BMP-2 in combination with physiologically relevant doses of dexamethasone, ascorbic acid, beta-glycerophosphate, heparin, retinoic acid and vitamin D achieved accelerated in vitro mineralization of mouse and human MSC. These results provide insight into constructive approaches of FSC to determine the applicable functional and physiological environment for MSC in disease modeling, drug screening and tissue engineering.

The fibroblast growth factor receptor 2 p.Ala172Phe mutation in Pfeiffer syndrome--history repeating itself.

Pfeiffer syndrome is an autosomal dominant condition classically combining craniosynostosis with digital anomalies of the hands and feet. The majority of cases are caused by heterozygous mutations in the third immunoglobulin-like domain (IgIII) of FGFR2, whilst a small number of cases can be attributed to mutations outside this region of the protein. A mild form of Pfeiffer syndrome can rarely be caused by a specific mutation in FGFR1. We report on the clinical and genetic findings in a three generation British family with Pfeiffer syndrome caused by a heterozygous missense mutation, p.Ala172Phe, located in the IgII domain of FGFR2. This is the first reported case of this particular mutation since Pfeiffer's index case, originally described in a German family in 1964, on which basis the syndrome was eponymously named. Genetic analysis demonstrated the two families to be unrelated. Similarities in phenotypes between the two families are discussed. Independent genetic origins, but phenotypic similarities in the two families add to the evidence supporting the theory of selfish spermatogonial selective advantage for this rare gain-of-function FGFR2 mutation.

Posterior calvarial distraction in craniosynostosis - an evolving technique.

BACKGROUND: Posterior advancement of the occiput is an established surgical option for the treatment of raised intracranial pressure (ICP) secondary to craniocerebral disproportion in syndromic craniosynostoses. Distraction osteogenesis has gained popularity in a variety of craniofacial procedures to achieve greater advancement in the anterior craniofacial skeleton, but has only relatively recently been used in the posterior calvarium. We report the Oxford Craniofacial Unit's experience of using distraction techniques to expand the occiput. METHODS: We preformed a retrospective casenote review of all patients with syndromic craniosynostoses who underwent posterior distraction at our centre from 2007 to 2010, as identified by the Oxford Craniofacial Database. RESULTS: Ten syndromic patients underwent posterior distraction (mean age of 18.1 months). Successful calvarial expansion (mean advancement of 19.7 mm) was achieved in all patients clinically and radiologically. There were 6 minor and 1 major complications. CONCLUSIONS: Posterior distraction was successfully performed in 10 patients including babies as young as 3 months of age. It achieved a reduction in turricephaly, an improvement in the cephalic index, and a resolution of raised ICP. We have customised our surgical technique to address individual patient needs. The use of distraction techniques in the occiput appears to increase the reliability of expansion in this region.