Pediatric whole-body magnetic resonance imaging: comparison of STIR and T2 Dixon sequences in the detection and grading of high signal bone marrow changes.

OBJECTIVES: To compare short time inversion recovery (STIR) and T2 Dixon in the detection and grading of high signal intensity areas in bone marrow on whole-body MRI in healthy children. METHODS: Prospective study, including whole-body 1.5-T MRIs from 77 healthy children. Two experienced radiologists in consensus identified and graded areas of high bone marrow signal on STIR and T2-weighted (T2W) turbo spin echo (TSE) Dixon images (presence, extension) in two different sessions at an interval of at least 3 weeks. In a third session, a third observer joined the two readers for an additional consensus reading with all sequences available (substitute gold standard). RESULTS: Four hundred ninety of 545 (89.9%) high signal areas were visible on both sequences, while 27 (5.0%) were visible on STIR only and 28 (5.1%) on T2W Dixon only. Twenty-four of 27 (89%) lesions seen on STIR only, and 25/28 (89%) seen on T2W Dixon only, were graded as mildly increased signal intensity. The proportion of true positive high signal lesions was higher for the T2W Dixon images as compared to STIR (74.2% vs. 68.2%) (p = 0.029), while the proportion of false negatives was lower (25.9% vs. 31.7% (p = 0.035) for T2W Dixon and STIR, respectively). There was a moderate agreement between the T2W Dixon and STIR-based extension scores on a 0-4 scale, with a kappa of 0.45 (95% CI = 0.34-0.56). CONCLUSIONS: Most high signal bone marrow changes identified on a 1.5-T whole-body MRI were seen on both STIR and water-only T2W Dixon, underscoring the importance of using identical protocols when following bone-marrow signal changes over time. KEY POINTS: • Whole-body MRI is increasingly being used to diagnose and monitor diseases in children, such as chronic non-bacterial osteomyelitis, malignant/metastatic disease, and histiocytosis. • Standardized and validated imaging protocols, as well as reference standards by age for the growing skeleton are lacking. • Prospective single-center study showed that 90% of high signal bone marrow areas identified on a 1.5-T whole-body MRI in healthy children is seen on both STIR and water-only T2W Dixon, while 5% is seen on STIR only and 5% on T2W Dixon only.

In children and adolescents with temporomandibular disorder assembled with juvenile idiopathic arthritis - no association were found between pain and TMJ deformities using CBCT.

BACKGROUND: Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer from temporomandibular disorder (TMD). Due to this, imaging diagnosis is crucial in JIA with non-symptomatic TM joint (TMJ) involvement. The aim of the study was to examine the association between clinical TMD signs/symptoms and cone-beam computed tomography (CBCT) findings of TMJ structural deformities in children and adolescents with JIA. METHODS: This cross-sectional study is part of a longitudinal prospective multi-centre study performed from 2015-2020, including 228 children and adolescents aged 4-16 years diagnosed with JIA, according to the International League of Associations for Rheumatology (ILAR). For this sub-study, we included the Bergen cohort of 72 patients (32 female, median age 13.1 years, median duration of JIA 4.5 years). Clinical TMD signs/symptoms were registered as pain on palpation, pain on jaw movement, and combined pain of those two. The severity of TMJ deformity was classified as sound (no deformity), mild, or moderate/severe according to the radiographic findings of CBCT. RESULTS: Of 72 patients, 21 (29.2%) had pain on palpation at and around the lateral pole, while 41 (56.9%) had TMJ pain upon jaw movement and 26 (36.1%) had pain from both. Of 141 TMJs, 18.4% had mild and 14.2% had moderate/severe structural deformities visible on CBCT. CBCT findings were not significantly associated with either the pain on palpation or the pain on jaw movement. A significant difference was found between structural deformities in CBCT and the combined pain outcome (pain at both palpation and movement) for both TMJs for the persistent oligoarticular subtype (p = 0.031). CONCLUSIONS: There was no association between painful TMD and CBCT imaging features of the TMJ in patients with JIA, but the oligoarticular subtype of JIA, there was a significant difference associated with TMJ pain and structural CBCT deformities.

Prevalence of temporomandibular disorder in children and adolescents with juvenile idiopathic arthritis - a Norwegian cross- sectional multicentre study.

BACKGROUND: Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer pain from temporomandibular disorder (TMD). Still, routines for the assessment of temporomandibular joint (TMJ) pain in health and dental care are lacking. The aims of this study were to examine the prevalence of TMD in children and adolescents with JIA compared to their healthy peers and to investigate potential associations between JIA and TMD. METHODS: This comparative cross-sectional study is part of a longitudinal multicentre study performed during 2015-2020, including 228 children and adolescents aged 4-16 years with a diagnosis of JIA according to the ILAR criteria. This particular substudy draws on a subset of data from the first study visit, including assessments of TMD as part of a broader oral health examination. Children and adolescents with JIA were matched with healthy controls according to gender, age, and centre site. Five calibrated examiners performed the clinical oral examinations according to a standardised protocol, including shortened versions of the diagnostic criteria for TMD (DC/TMD) and the TMJaw Recommendations for Clinical TMJ Assessment in Patients Diagnosed with JIA. Symptoms were recorded and followed by a clinical examination assessing the masticatory muscles and TMJs. RESULTS: In our cohort of 221 participants with JIA and 221 healthy controls, 88 (39.8%) participants with JIA and 25 (11.3%) healthy controls presented with TMD based on symptoms and clinical signs. Painful TMD during the last 30 days was reported in 59 (26.7%) participants with JIA vs. 10 (5.0%) of the healthy controls (p <  0.001). Vertical unassisted jaw movement was lower in participants with JIA than in controls, with means of 46.2 mm vs. 49.0 mm, respectively (p <  0.001). Among participants with JIA, a higher proportion of those using synthetic disease-modifying antirheumatic-drugs and biologic disease-modifying antirheumatic-drugs presented with painful masticatory muscles and TMJs at palpation. CONCLUSION: Symptoms and clinical signs of TMD were seen in approximately half of the JIA patients compared to about one fourth of their healthy peers. Painful palpation to masticatory muscles and decreased vertical unassisted jaw movement were more frequent in participants with JIA than among healthy controls and should be part of both medical and dental routine examinations in patients with JIA.

Juvenile idiopathic arthritis and the temporomandibular joint: A comprehensive review.

Juvenile idiopathic arthritis is the most common inflammatory rheumatic disease of childhood and represents a series of chronic inflammatory arthritides of unknown cause. Involvement of the temporomandibular joint has been reported in up to 87% of children with juvenile idiopathic arthritis when based on magnetic tomography imaging; it can be asymptomatic and may lead to severe long term complications. In this review a summary of the contemporary literature of imaging of the temporomandibular joint in children with juvenile idiopathic arthritis will be provided, including ultrasound which is a valuable method for guided joint injections, but does not necessarily allow detection of acute inflammation, cone beam computed tomography, which has emerged as a feasible and accurate low-dose alternative as compared to conventional computed tomography to detect destructive change, and magnetic resonance imaging which is considered the method of choice for assessing acute, inflammatory change, although the lack of normative standards remains a challenge in children.

The alpha angle in cam-type femoroacetabular impingement: new reference intervals based on 2038 healthy young adults.

We report on gender-specific reference intervals of the alpha angle and its association with other qualitative cam-type findings in femoroacetabular impingement at the hip, according to a population-based cohort of 2038 19-year-olds, 1186 of which were women (58%). The alpha angle was measured on standardised frog-leg lateral and anteroposterior (AP) views using digital measurement software, and qualitative cam-type findings were assessed subjectively on both views by independent observers. In all, 2005 participants (837 men, 1168 women, mean age 18.6 years (17.2 to 20.1) were included in the analysis. For the frog-leg view, the mean alpha angle (right hip) was 47° (26 to 79) in men and 42° (29 to 76) in women, with 97.5 percentiles of 68° and 56°, respectively. For the AP view, the mean values were 62° (40 to 105) and 52° (36 to 103) for men and women, respectively, with 97.5 percentiles of 93° and 94°. Associations between higher alpha angles and all qualitative cam-type findings were seen for both genders on both views. The reference intervals presented for the alpha angle in this cross-sectional study are wide, especially for the AP view, with higher mean values for men than women on both views.

Imaging in juvenile idiopathic arthritis (JIA): an update with particular emphasis on MRI.

Juvenile idiopathic arthritis (JIA) is a heterogeneous condition encompassing all forms of chronic arthritis of unknown origin and with onset before 16 years of age. During the last decade new, potent therapeutic agents have become available, underscoring the need for accurate monitoring of therapeutic response on both disease activity and structural damage to the joint. However, so far, treatment efficacy is based on clinical ground only, although clinical parameters are poor markers for disease activity and progression of structural damage. Not so for rheumatoid arthritis patients where the inclusion of radiographic assessment has been required by FDA to test the disease-modifying potential of new anti-rheumatic drugs. In imaging of children with JIA there has been a shift from traditional radiography towards newer techniques such as ultrasound and MRI, however without proper evaluation of their accuracy and validity. We here summarize present knowledge and discuss future challenges in imaging children with JIA.

Radiological findings that may indicate a prior silent slipped capital femoral epiphysis in a cohort of 2072 young adults.

The reported prevalence of an asymptomatic slip of the contralateral hip in patients operated on for unilateral slipped capital femoral epiphysis (SCFE) is as high as 40%. Based on a population-based cohort of 2072 healthy adolescents (58% women) we report on radiological and clinical findings suggestive of a possible previous SCFE. Common threshold values for Southwick's lateral head-shaft angle (≥ 13°) and Murray's tilt index (≥ 1.35) were used. New reference intervals for these measurements at skeletal maturity are also presented. At follow-up the mean age of the patients was 18.6 years (17.2 to 20.1). All answered two questionnaires, had a clinical examination and two hip radiographs. There was an association between a high head-shaft angle and clinical findings associated with SCFE, such as reduced internal rotation and increased external rotation. Also, 6.6% of the cohort had Southwick's lateral head-shaft angle ≥ 13°, suggestive of a possible slip. Murray's tilt index ≥ 1.35 was demonstrated in 13.1% of the cohort, predominantly in men, in whom this finding was associated with other radiological findings such as pistol-grip deformity or focal prominence of the femoral neck, but no clinical findings suggestive of SCFE. This study indicates that 6.6% of young adults have radiological findings consistent with a prior SCFE, which seems to be more common than previously reported.

Prevalence of radiographic findings associated with hip dysplasia in a population-based cohort of 2081 19-year-old Norwegians.

In Norway total joint replacement after hip dysplasia is reported more commonly than in neighbouring countries, implying a higher prevalence of the condition. We report on the prevalence of radiological features associated with hip dysplasia in a population of 2081 19-year-old Norwegians. The radiological measurements used to define hip dysplasia were Wiberg's centre-edge (CE) angle at thresholds of < 20° and < 25°, femoral head extrusion index < 75%, Sharp's angle > 45°, an acetabular depth to width ratio < 250 and the sourcil shape assessed subjectively. The whole cohort underwent clinical examination of their range of hip movement, body mass index (BMI), and Beighton hypermobility score, and were asked to complete the EuroQol (EQ-5D) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The prevalence of hip dysplasia in the cohort varied from 1.7% to 20% depending on the radiological marker used. A Wiberg's CE angle < 20° was seen in 3.3% of the cohort: 4.3% in women and 2.4% in men. We found no association between subjects with multiple radiological signs indicative of dysplasia and BMI, Beighton score, EQ-5D or WOMAC. Although there appears to be a high prevalence of hip dysplasia among 19-year-old Norwegians, this is dependent on the radiological parameters applied.

Novel automated system for magnetic resonance imaging quantification of the inflamed synovial membrane volume in patients with juvenile idiopathic arthritis.

OBJECTIVE: To introduce a novel automated method for the quantification of the inflamed synovial membrane volume (SV) using magnetic resonance imaging (MRI), and to investigate its feasibility and validity in patients with juvenile idiopathic arthritis (JIA). METHODS: The tool was tested on 58 patients with JIA and wrist involvement. Thirty-six patients had a 1-year MRI followup. MRI of the clinically more affected wrist was performed using a 1.5T scanner and a Flex small coil. An algorithmic approach, based on supervised voxel classification for automatic estimation of SV in a 3-dimensional MRI, was developed. The SV was estimated as the number of positively classified voxels and then normalized by the patient's body surface (NSV). Validation procedures included the analysis of reliability, construct validity, responsiveness to change, discriminant validity, and the predictive value. RESULTS: The agreement between the automated estimation of NSV and the manual measurements was excellent (intraclass correlation coefficient 0.93, 95% confidence interval 0.79-0.98). The automatic NSV demonstrated good construct validity by yielding strong correlations with local signs of disease activity and a moderate correlation with global physician assessment of disease activity and with the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system synovitis score. NSV showed a strong responsiveness to clinical change (standardized response mean values >1) and satisfactory discriminant validity. High baseline NSV (>4.6) had high predictive value (100%) with respect to erosive progression. CONCLUSION: The proposed automated method allowed reliable quantification of NSV, which represents a promising imaging biomarker of disease activity in JIA. The automated system has the potential to improve the longitudinal assessment of JIA and to predict progressive joint destruction.

Digital radiography: optimization of image quality and dose using multi-frequency software.

BACKGROUND: New developments in processing of digital radiographs (DR), including multi-frequency processing (MFP), allow optimization of image quality and radiation dose. This is particularly promising in children as they are believed to be more sensitive to ionizing radiation than adults. OBJECTIVE: To examine whether the use of MFP software reduces the radiation dose without compromising quality at DR of the femur in 5-year-old-equivalent anthropomorphic and technical phantoms. MATERIALS AND METHODS: A total of 110 images of an anthropomorphic phantom were imaged on a DR system (Canon DR with CXDI-50 C detector and MLT[S] software) and analyzed by three pediatric radiologists using Visual Grading Analysis. In addition, 3,500 images taken of a technical contrast-detail phantom (CDRAD 2.0) provide an objective image-quality assessment. RESULTS: Optimal image-quality was maintained at a dose reduction of 61% with MLT(S) optimized images. Even for images of diagnostic quality, MLT(S) provided a dose reduction of 88% as compared to the reference image. Software impact on image quality was found significant for dose (mAs), dynamic range dark region and frequency band. CONCLUSION: By optimizing image processing parameters, a significant dose reduction is possible without significant loss of image quality.

Trajectories of weight disturbances during adolescence in relation to gender in a Swedish cohort.

AIM: To explore developmental trajectories among adolescents of thinness and overweight in relation to gender. METHODS: A group-based procedure was used to determine patterns of weight disturbances in a school-based sample of 3020 Swedish adolescents followed from age 11 to 18. A sensitivity analysis was performed to compensate for an increasing number of missing height and weight data after grade 8. RESULTS: Six trajectories represented the best description of developmental weight disturbances with the exception of thinness among boys, which was best described by four trajectories. Concerning thinness, 5.9% of girls and 4.2% of boys developed this condition during the study period, while 1.9% of girls and 3.0% of boys recovered from their initial thinness. For overweight, (including obesity) 1.5% of girls and 3.1% of boys developed this weight disturbance during the study period, while 10.1% of girls and 9.3% of boys recovered from overweight/obesity. Non-reporting of height and weight was biased towards an underestimation of the true prevalence of overweight and obesity in girls and of thinness in boys. CONCLUSIONS: Developmental trajectories provide a novel method to describe the dynamics of weight disturbances during adolescence. Similar patterns were found for overweight and thinness in boys and girls but group sizes varied between genders. Non-reporting of height and weight was found in a gender-specific pattern.

Low physical activity is a predictor of thinness and low self-rated health: gender differences in a Swedish cohort.

PURPOSE: To examine the relationship between leisure time physical activity in 15-year-old students, and weight status and self-rated health 3 years later. METHODS: Data were used from two follow-up waves, one in 2002 (grade 9, age 15 years) and one in 2005 (grade 12, age 18 years) of a cohort of approximately 2,500 adolescents. Adolescents reported height and weight, health behaviors, and self-rated health by a questionnaire at both occasions. Age and gender-specific body mass index cut-off points for thinness, overweight, and obesity were used to assess weight status. Logistic regression analyses were performed with weight status and self-rated health as the outcomes and level of leisure time physical activity as the independent variable. Adjustments were made for parental years of education, student's current smoking habits, and baseline body mass index. RESULTS: As compared with students who were active for more than 4 hours per week during leisure time, being active 2-4 hours (odds ratio [OR]: 4.15, confidence interval [CI]: 1.62-10.60) and <2 hours (OR: 3.92, CI: 1.30-11.78) predicted thinness in boys. In girls, the risk was smaller and became significant at <2 hours per week (OR: 2.57, CI: 1.38-4.77). Overweight or obesity was not significantly predicted by physical activity. A significant risk of low self-rated health was found at follow-up in boys active for <4 hours per week compared with those active for >4 hours per week. CONCLUSION: Physical activity is important to maintain a healthy body weight and for future self-rated health in boys.

Selectively reduced posterior corpus callosum size in a population-based sample of young adults born with low birth weight.

BACKGROUND AND PURPOSE: Several studies suggest that VLBW is associated with a reduced CC size later in life. We aimed to clarify this in a prospective, controlled study of 19-year-olds, hypothesizing that those with LBWs had smaller subregions of CC than the age-matched controls, even after correcting for brain volume. MATERIALS AND METHODS: One hundred thirteen survivors of LBW (BW <2000 grams) without major handicaps and 100 controls underwent a 3T MR examination of the brain. The cross-sectional area of the CC (total callosal area, and the callosal subregions of the genu, truncus, and posterior third) was measured. Callosal areas were adjusted for head size. RESULTS: The posterior third subregion of the CC was significantly smaller in individuals born with a LBW compared with controls, even after adjusting for size of the forebrain. Individuals who were born with a LBW had a smaller CC (mean area, 553.4 mm(2)) than the controls (mean area, 584.1 mm(2)). Differences in total area, however, did not remain statistically significant after adjusting for FBV. CONCLUSIONS: The uncorrected callosal size in 19-years-olds born with LBW was smaller than that of normal controls. However, after adjusting for FBV, the group difference was restricted to the posterior third. The clinical impact of a smaller posterior part needs further investigation.

The paediatric wrist revisited: redefining MR findings in healthy children.

OBJECTIVES: During a multicentre study on juvenile idiopathic arthritis, wide variations were observed in bone shape, signal intensity and volume of joint fluid as shown by MRI which in part appeared to be unrelated to disease activity. A study was undertaken to examine these features in a cohort of healthy children. METHODS: 88 children of mean age 9.8 years (range 5-15) underwent MRI imaging (T1-weighted Spin Echo and Spectral Selection Attenuated Inversion Recovery (SPAIR)) of the left wrist. The number of bony depressions, distribution and amount of joint fluid and the presence of bone marrow changes were assessed. RESULTS: Bony depressions were present in all children, increasing with age from a mean of 4.0 in children aged 4-6 years to 9.2 in those aged 12-15 years (p<0.001)). 45 of 84 children (53.6%) had a high signal on SPAIR with a corresponding low signal on T1 in at least one bone. No associations were seen between bone marrow change (present or not) and sex (p=0.827) or sports club membership (p=0.616). All children had visible joint fluid in at least one of the joints assessed. No associations were seen between the presence of joint fluid and age group, except for the radius/scaphoid and capitate-scaphoid joints and a recess lateral to the hamate. CONCLUSIONS: It is important to be aware of the high prevalence of bony depressions, signal changes suggestive of bone marrow oedema and the volume of joint fluid seen in normal children. Such findings must be interpreted with care in children with suspected disease such as juvenile arthritis.

Antenatal ultrasound and postnatal autopsy findings in terminations after 12 weeks' gestation due to fetal abnormality: population-based study in Western Norway, 1988-2002.

BACKGROUND: Ultrasound screening has been part of antenatal care for several decades, and warrants high expertise to meet the criteria for a worthwhile screening program. In particular, the rate of false positives should be low. PURPOSE: To examine time trends of pregnancy terminations for fetal abnormality after 12 weeks' gestation, and to assess the agreement between antenatal ultrasound and post-termination autopsy findings for the main pathologies leading to termination. MATERIAL AND METHODS: During the period 1988 to 2002, 198 pregnancies were terminated for fetal abnormality after 12 weeks' gestation. We reviewed the case notes for those 151 who were autopsied (male/female/undetermined ;= ;91/56/4). Annual rates of live births and stillbirths were retrieved from the Medical Birth Registry of Norway. RESULTS: Antenatal ultrasound provided a correct diagnosis of the major abnormality in 149/151 cases (99%), based on post-termination autopsy findings. The annual rate of terminations after 12 weeks' gestation varied between 0.6 and 3.4 (mean 1.8) per 1000 live births, with a trend toward higher rates over the study period (P=0.001, chi-square test for linear-by-linear association). CONCLUSION: The specificity of antenatal ultrasound for major abnormalities was high, as compared to postnatal autopsy findings. The mean annual rates of termination after 12 weeks' gestation tended to increase over the 14-year study period.

Neonatal bronchopulmonary dysplasia predicts abnormal pulmonary HRCT scans in long-term survivors of extreme preterm birth.

BACKGROUND: There is an increasing understanding that extreme preterm birth carries a risk of long-term pulmonary sequelae. A study was undertaken to investigate if, and in what way, neonatal factors were associated with subsequent abnormalities on pulmonary high-resolution CT (HRCT) scanning and if pulmonary function was related to these abnormalities. METHODS: HRCT scanning and pulmonary function tests were performed less than 2 weeks apart in 74/86 eligible subjects (86%) born at a gestational age of < or =28 weeks or with a birth weight of < or =1000 g within a defined area in Western Norway in 1982-5 (n = 42) or 1991-2 (n = 32). Mean age at examination was 18 and 10 years, respectively. HRCT scans were interpreted by a paediatric radiologist blinded to the clinical data using a structured system allowing scores from 0 to 50. RESULTS: Lung parenchymal abnormalities were found in 64 subjects (86%), the median (interquartile range) score being 3.0 (1.75-5.0) points. Prolonged neonatal requirement for oxygen treatment predicted poor outcome, and an increase of 100 days increased the average HRCT score by 3.8 points (p<0.001). There was also a positive association of the severity of pulmonary function abnormalities with the extent of HRCT abnormalities, exemplified by the relation between forced expiratory volume in 1 s and total HRCT score (beta = -0.090; p<0.001). CONCLUSIONS: In area-based cohorts of long-term survivors of extremely preterm birth, prolonged neonatal requirements for oxygen treatment predicted subsequent structural abnormalities on HRCT scans and in pulmonary function, and these two outcome measures were interrelated.

Trajectories of smokeless tobacco use and of cigarette smoking in a cohort of Swedish adolescents: differences and implications.

Developmental trajectories of cigarette smoking have often been described, but there are no such analyses dealing with smokeless tobacco use. A semi-parametric group-based mixture modeling procedure was used to determine the development of smokeless tobacco (snus) use, as well as of cigarette smoking, over time in a cohort of 2,175 Swedish adolescents who were never-users of tobacco at the time of recruitment. An indicator of snus and of cigarette consumption in the previous year was used to model the development of the behavior between 11 and 18 years of age. For snus use three trajectories best described the cohort's experience, while four trajectories provided the best description of cigarette smoking in the cohort. For both tobacco types there were two escalation patterns and one sustained trial trajectory, while an extinction pattern was apparent for cigarette smoking only. Marked sex differences were found, since rapid escalation for snus use was found only among males while high consumption of cigarettes was observed only among females. Dual users (54.9% of all users) showed a trajectory of steeper and more prolonged increase of tobacco consumption than exclusive users of either snus or cigarettes. Several risk factors for tobacco use measured at baseline influenced individual probabilities of belonging to a particular trajectory. The developmental patterns of snus use and cigarette smoking showed high similarity, but they evolved differently in the two sexes. Dual users emerged as a high-risk group for tobacco dependence and tobacco-related harms.

A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2.

BACKGROUND: Brachydactyly type A2 (OMIM 112600) is characterised by hypoplasia/aplasia of the second middle phalanx of the index finger and sometimes the little finger. BDA2 was first described by Mohr and Wriedt in a large Danish/Norwegian kindred and mutations in BMPR1B were recently demonstrated in two affected families. METHODS: We found and reviewed Mohr and Wriedt's original unpublished annotations, updated the family pedigree, and examined 37 family members clinically, and radiologically by constructing the metacarpo-phalangeal profile (MCPP) pattern in nine affected subjects. Molecular analyses included sequencing of BMPR1B, linkage analysis for STS markers flanking GDF5, sequencing of GDF5, confirmation of the mutation by a restriction enzyme assay, and localisation of the mutation inferred from the very recently reported GDF5 crystal structure, and by superimposing the GDF5 protein sequence onto the crystal structure of BMP2 bound to Bmpr1a. RESULTS: A short middle phalanx of the index finger was found in all affected individuals, but other fingers were occasionally involved. The fourth finger was characteristically spared. This distinguishes Mohr-Wriedt type BDA2 from BDA2 caused by mutations in BMPR1B. An MCPP analysis most efficiently detected mutation carrier status. We identified a missense mutation, c.1322T>C, causing substitution of a leucine with a proline at amino acid residue 441 within the active signalling domain of GDF5. The mutation was predicted to reside in the binding site for BMP type 1 receptors. CONCLUSION: GDF5 is a novel BDA2 causing gene. It is suggested that impaired activity of BMPR1B is the molecular mechanism responsible for the BDA2 phenotype.