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Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH.

Fibroblast growth factor receptor 3 (FGFR3) is the only gene known to cause achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia types I and II (TD I and TD II). A second, as yet unidentified, gene also causes HCH. In this study, we used sequencing analysis to determine the frequency of FGFR3 mutations for each phenotype in 324 cases from the International Skeletal Dysplasia Registry (ISDR). Our data suggest that there is a considerable overlap of genotype and phenotype between ACH and HCH. Thus, it is important to test for mutations found in either disorder when ACH or HCH is suspected. Only two of 29 cases with HCH did not have an identified mutation in FGFR3, much less than previously reported. We recommend testing other mutations in FGFR3, instead of just the common HCH mutation, p.Asn540Lys. The mutation frequency for TD I and TD II in the largest series of cases to date are also reported. This study provides valuable information on FGFR3 mutation frequency of four skeletal dysplasias for clinical diagnostic laboratories and clinicians.

Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies.

To investigate human long bone development in vivo by analyzing distal femoral epimetaphyseal structures and bone morphometrics on magnetic resonance (MR) images of fetuses.An institutional review board approved this retrospective study, and informed consent was waived. Included were 272 MR imaging examinations (April 2004-July 2011) in 253 fetuses with a mean gestational age (GA) of 26 weeks 6 days (range, 19 weeks 2 days to 35 weeks 6 days) without known musculoskeletal abnormalities. Two independent readers qualitatively analyzed epiphyseal and metaphyseal shape, secondary ossification, and the perichondrium on 1.5-T echo-planar MR images and correlated the results with the GA that was derived from previous fetal ultrasonography (US). Diaphyseal and epiphyseal morphometric measurements were correlated with GA by means of the Pearson correlation and linear regression. MR imaging measurements of diaphyseal length and US normative values were compared graphically. Interreader agreement analysis was performed with weighted κ statistics and the intraclass correlation coefficient.With advancing GA, the epiphyseal shape changed from spherical (r(2) = 0.664) to hemispherical with a notch (r(2) = 0.804), and the metaphyseal shape changed from flat (r(2) = 0.766) to clearly undulated (r(2) = 0.669). Secondary ossification (r(2) = 0.777) was not observed until 25 weeks 3 days. The perichondrium decreased (r(2) = 0.684) from 20 weeks onward. Correlation coefficients were 0.897 for diaphyseal length, 0.738 for epiphyseal length, and 0.801 for epiphyseal width with respect to GA. The range of measurements of diaphyseal length was larger than that of the reported US normative values. Interreader agreement was good for bone morphometrics (intraclass correlation coefficient, 0.906-0.976), and moderate for bone characteristics (weighted κ, 0.448-0.848).Prenatal MR imaging allows visualization of human bone development in vivo by means of epimetaphyseal characteristics and bone morphometrics.http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13112441/-/DC1.

Arterial complications are common in vascular type Ehlers-Danlos syndrome (EDS), accounting for 66% of first complications. Several cases in the literature have documented acute compartment syndrome (ACS) following vascular rupture in vascular type EDS. Other disorders of connective tissue have also demonstrated vascular fragility, leading to arterial aneurysm and rupture, but there have been no documented cases of ACS. Here, we report on a female patient with a history of recurrent compartment syndrome who exhibits some clinical findings seen in hypermobile and vascular EDS; however she does not meet clinical and molecular diagnostic criteria for either of them. We further review the literature on ACS in heritable connective tissue disorders and suggest that compartment syndrome may rarely complicate other heritable disorders of connective tissue.

Bent Bone Dysplasia-FGFR2 type is a relatively recently described bent bone phenotype with diagnostic clinical, radiographic, and molecular characteristics. Here we report on 11 individuals, including the original four patients plus seven new individuals with three longer-term survivors. The prenatal phenotype included stillbirth, bending of the femora, and a high incidence of polyhydramnios, prematurity, and perinatal death in three of 11 patients in the series. The survivors presented with characteristic radiographic findings that were observed among those with lethality, including bent bones, distinctive (moustache-shaped) small clavicles, angel-shaped metacarpals and phalanges, poor mineralization of the calvarium, and craniosynostosis. Craniofacial abnormalities, hirsutism, hepatic abnormalities, and genitourinary abnormalities were noted as well. Longer-term survivors all needed ventilator support. Heterozygosity for mutations in the gene that encodes Fibroblast Growth Factor Receptor 2 (FGFR2) was identified in the nine individuals with available DNA. Description of these patients expands the prenatal and postnatal findings of Bent Bone Dysplasia-FGFR2 type and adds to the phenotypic spectrum among all FGFR2 disorders. © 2016 Wiley Periodicals, Inc.

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.

Ehlers–Danlos syndrome (EDS) type VIII (periodontitis type) is a distinct form of EDS characterized by periodontal disease leading to precocious dental loss and a spectrum of joint and skin manifestations. EDS type VIII is transmitted in an autosomal dominant pattern; however, the mutated gene has not been identified. There are insufficient data on the spectrum of clinical manifestations and natural history of the disorder, and only a limited number of patients and pedigrees with this condition have been reported. We present a four-generation EDS type VIII kindred and show that EDS VIII is clinically variable and although some cases lack the associated skin and joint manifestations, microscopic evidence of collagen disorganization is detectable. We further propose that the diagnosis of EDS type VIII should be considered in familial forms of periodontitis, even when the associated skin and joint manifestations are unconvincing for the diagnosis of a connective tissue disorder. This novel observation highlights the uncertainty of using connective tissue signs in clinical practice to diagnose EDS type VIII.

Objective Previous studies have shown a correlation between hypospadias and intrauterine growth restriction (IUGR), suggesting an association between placental insufficiency and abnormal genital development. This study sought to analyze the association of IUGR and genital abnormalities apparent on fetal magnetic resonance imaging (MRI). Methods This retrospective study included 22 MRI scans of 20 male fetuses between 20 and 35weeks of gestation presenting with IUGR. On MRI, penile length and testicular descent were evaluated. Student’s t-testing and analysis of covariance were used to compare MRI penile length measurements with published normative data obtained from fetal ultrasonography (US) and MRI. McNemar testing was used to evaluate testicular descent in IUGR, compared with reported fetal MRI normative data. Results The penile length in IUGR fetuses was shorter than in normal fetuses (p

Acrodysostosis is a dominantly-inherited, multisystem disorder characterized by skeletal, endocrine, and neurological abnormalities. To identify the molecular basis of acrodysostosis, we performed exome sequencing on five genetically independent cases. Three different missense mutations in PDE4D, which encodes cyclic AMP (cAMP)-specific phosphodiesterase 4D, were found to be heterozygous in three of the cases. Two of the mutations were demonstrated to have occurred de novo, providing strong genetic evidence of causation. Two additional cases were heterozygous for de novo missense mutations in PRKAR1A, which encodes the cAMP-dependent regulatory subunit of protein kinase A and which has been recently reported to be the cause of a form of acrodysostosis resistant to multiple hormones. These findings demonstrate that acrodysostosis is genetically heterogeneous and underscore the exquisite sensitivity of many tissues to alterations in cAMP homeostasis.

To the Editor: Ehlers-Danlos syndrome (EDS) type VIII (OMIM # 130080) is a distinct, largely unrecognized form of EDS characterized primarily by generalized periodontal disease causing progressive loss of the alveolar bone and subsequent dental loss. The associated clinical abnormalities include joint and skin manifestations and with much clinical overlap to other EDS subtypes, mainly the hypermobility and classic types [Stewart et al., 1977; Reinstein et al., 2011; Castori et al., 2010]. A few reported patients had facial characteristics like EDS type IV. The diagnosis of EDS type VIII is established in an individual presenting with dental and connective tissue findings and a typical pattern of inheritance. Previous studies suggest that EDS type VIII is due to dominantly transmitted heterozygous mutations in a yet to be identified gene that is most likely expressed in the periodontal ligament – the tooth supporting matrix – in addition to other connective tissues. Periodontal disease in EDS type VIII seems to be highly penetrant, and can affect young children, which rarely have periodontal disease, even in the presence of poor oral hygiene. Limited data are available on the spectrum of clinical manifestations and natural history of the disorder, resulting in part from the fact that periodontitis and joint hypermobility syndromes are common in the general population [Papapanou, 1999; Khalili, 2008; Biro et al., 1983; Seckin et al., 2005]. Thus, it is likely that individuals with milder clinical manifestations do not come to medical attention and thus go undetected. Musculoskeletal involvement is a frequent finding in hereditary disorders of connective tissue (HDCT). The range of skeletal abnormalities is broad and involves rather benign pectus deformity and pes planus to a more severe expression including progressive scoliosis, contractures, craniosynostosis, recurrent large joint dislocations, and chronic joint instability leading to an early onset degenerative joint disease. There is significant phenotypic variability in EDS type VIII, especially in regard to the skeletal phenotype. Several skeletal phenotypes are known in EDS type VIII, including large and small joint laxity (minimal or significant) and dislocations, Marfanoid habitus, arachnodactyly, chronic joint and limb pain, pectus excavatum, scoliosis, and pes planus [Karrer et al., 2000; Reinstein et al., 2011]. We aimed to explore the skeletal manifestations and complications in a proposita of a previously unreported three generation kindred with EDS type VIII. The patient is a 37-year-old woman who was referred for evaluation of connective tissue disorder. She always had problems with her teeth. Her deciduous teeth appeared at age 1 but soon after turned black and rotten, and all had to be removed before age 18 months. Her permanent teeth appeared at age 7. During her teenage years and in her 20's she underwent numerous dental treatments and extractions, eventually loosing most of her permanent teeth, except for her incisors, in her late 20's. Dental exam and imaging revealed multiple missing teeth and gingival inflammation was severe throughout the mouth. There was moderate periodontitis (class III; with IV being the most severe according to the American Dental Association classification) and radiographic widening of the periodontal ligament space on tooth 27 which was mobile. During the past year, the patient lost the residual incisors and currently wears dentures. She was told that the reason for her dental loss is “soft bone“. The patient reported being very flexible and double jointed from childhood but did not dislocate any joints. During adolescence she developed scoliosis diagnosed through routine exam in high school. She first experienced lower back, hip and knee joint pain in her early 20's; these symptoms have become chronic. At that time, rheumatology workup excluded autoimmune disorders and inflammatory arthritis and she was given pain medications without a specific diagnosis. At age 36 she was first seen by an orthopedist because of increasing left hip pain and imaging studies of the pelvis showed left proximal femur enchondroma which was excised. Since her generalized joint pain had not resolved following surgery, she was further referred for genetic evaluation. Other relevant medical history includes easy bruising with normal healing and normal scar formation. She has myopia and strabismus; a recent echocardiogram was unremarkable. The patient is now experiencing chronic pain in her back, knees, hips and most of her finger joints and is treated with high dose of opiate analgesics. She has a normal body habitus, and soft, doughy but not hyperextensible skin, mild joint laxity was noted although full evaluation for Beighton score was limited because of joint pain triggered by motion. Facial characteristics showed long and narrow nasal bridge with prominent tip; features that have been described before in patients with this type of EDS (Fig.1). Her mother and maternal grandmother have the same medical condition. Her mother, age 58, reports a very similar history with joint laxity for most of her life and dental problems. Currently joint laxity is less pronounced [Beighton score 3], and she is experiencing intermittent back and joint pains. She has osteoporosis diagnosed by bone density scan in her early 40's. She lost all her teeth by age 35 and has worn dentures since than. Facial features are similar to her daughter. The patient's maternal grandmother, currently 82, lost all her teeth by age 20. She has generalized joint pain but has not been under clinical supervision due to lack of insurance. Following establishment of clinical diagnosis of EDS type VIII in this family, radiological evaluation prompted by the proposita's complaints was completed. Figure 1 Facial and dental appearance of family with EDS type VIII. Skeletal survey at the age of 37 years demonstrated multiple abnormal findings in the axial and appendicular skeleton as detailed below. There was moderate scoliosis and radiographically decreased bone density; the latter was confirmed by a dual-emission X-ray absorptiometry (DEXA) study yielding a T score of −2.2 (Fig.2). The sacroiliac joints and hip joints demonstrated no obvious degeneration on conventional radiography. Furthermore, at the right hip, ossicular findings suggested tendinopathy of the gluteal musculature, and at the left hip, there were postsurgical changes of the femoral neck following osteosynthetic treatment of enchondroma (Fig.3). At the right shoulder there was acromio-clavicular joint degeneration, with osteophytic changes and abnormal joint space, also suggesting ligamentous disease. No abnormalities were identified at the left shoulder, the elbow and wrist joints. Radiography and subsequent MR imaging demonstrated distinct osteoarthritis of the right knee joint. Notably, there was marked thinning and damage of the retro-patellar cartilage, as well as in the medial and lateral knee compartments, associated with multiple subchondral cysts and osteophytic changes. At the left knee joint, mild thinning of the cartilaginous surfaces was observed but without further osseous degenerative changes. Joint effusion was present on both sides (Figs.4–5). There were no traumatic or degenerative changes of the collateral and cruciate ligaments of the patellar or quadriceps tendons. Based on an orthopedist evaluation, a joint replacement procedure was suggested to treat right knee joint degeneration. Figure 2 Anterior-posterior and lateral spine radiographs. Figure 3 Pelvic radiographs. Anterior-posterior radiograph of the pelvis. Figure 4 MR imaging of the knee joints. Figure 5 Coronal MR imaging of the right knee joint. We show here the radiological manifestations of early-onset osteoarthritis and reduced bone density that can be associated with EDS type VIII. Although prevalent in middle-age and older adults [affecting 10% of individuals over the age of 50 years and up to 70% of the population over the age of 65 years], osteoarthritis is not a common finding in younger individuals unless resulting from mechanical loading/overuse [Karachalios et al., 2004]. The natural history and skeletal complications associated with EDS VIII are understudied, mainly because of the complexity in patient diagnosis; recruitment and long term follow up. While chronic joint pain and scoliosis have been reported in a recent study of an EDS type VIII family, those manifestations have not been documented radiologically but were rather based on patients description [Reinstein et al., 2011]. Although considerable childhood joint hypermobility was reported by the family reported here, progressive joint stiffness made it less noticeable at the time of examination. These observations highlight the importance of screening for early skeletal manifestations in patients with EDS type VIII, as the symptoms and the radiological abnormalities can present years before the patient comes to medical attention and a correct diagnosis is made. A suggested clinical follow-up would consist of spinal surveillance for scoliosis, imaging studies for joint pain, and DEXA bone density scan followed by proper treatment when indicated. In conclusion, this report supports and extends previous research showing that EDS type VIII can be associated with early-onset degenerative joint disease and reduced bone density, as observed in some other EDS forms. Thus, it implies that clinical surveillance for those complications is warranted. Further detailed clinical studies in larger cohorts of EDS type VIII patients are needed to better delineate the skeletal phenotypic spectrum, and allow optimized clinical follow-up.

Magnetic resonance imaging (MRI) appears to be increasingly used, in addition to standard ultrasonography for the diagnosis of abnormalities in utero. Previous studies have recently drawn attention to the technical refinement of MRI to visualize the fetal bones and muscles. Beyond commonly used T2-weighted MRI, echoplanar, thick-slab T2-weighted and dynamic sequences, and three-dimensional MRI techniques, are about to provide new imaging insights into the normal and the pathological musculoskeletal system of the fetus. This review emphasizes the potential significance of MRI in the visualization of the fetal musculoskeletal system. © 2012 John Wiley & Sons, Ltd.

Objective In view of the implementation of magnetic resonance imaging (MRI) as an adjunct to ultrasonography in prenatal diagnosis, this study sought to demonstrate normal penile growth on prenatal MRI. Methods This was a retrospective study of MRI of 194 male fetuses (18–34 weeks' gestation) with normal anatomy or minor abnormalities. On sagittal T2-weighted MRI sequences, we measured penile length from the glans tip to the scrotal edge (outer length) and from the glans tip to the symphyseal border (total length). Descriptive statistics, as well as correlation and regression analysis, were used to evaluate penile length in relation to gestation. T-tests were calculated to compare mean outer/total length on MRI with published ultrasound data. Results Mean length values, including 95% CIs and percentiles, were defined. Penile length as a function of gestational age was expressed by the following regression equations: outer mean length = − 5.514 + 0.622 × gestational age in weeks; total mean length = − 8.865 + 1.312× gestational age in weeks. The correlation coefficients, r = 0.532 and r = 0.751, respectively, were statistically significant (P < 0.001). Comparison of outer penile length on MRI with published ultrasound penile length data showed no significant differences, while total penile length on MRI was significantly greater than ultrasound penile length (P < 0.001). Conclusion Our MRI results provide a reference range of fetal penile length, which, in addition to ultrasonography, may be helpful in the identification of genital anomalies. Outer penile length on MRI is equivalent to penile length measured on ultrasound, whereas total length is significantly greater. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (lepto-SEMDJL, aka SEMDJL, Hall type), is an autosomal dominant skeletal disorder that, in spite of being relatively common among skeletal dysplasias, has eluded molecular elucidation so far. We used whole-exome sequencing of five unrelated individuals with lepto-SEMDJL to identify mutations in KIF22 as the cause of this skeletal condition. Missense mutations affecting one of two adjacent amino acids in the motor domain of KIF22 were present in 20 familial cases from eight families and in 12 other sporadic cases. The skeletal and connective tissue phenotype produced by these specific mutations point to functions of KIF22 beyond those previously ascribed functions involving chromosome segregation. Although we have found Kif22 to be strongly upregulated at the growth plate, the precise pathogenetic mechanisms remain to be elucidated.

Objective To visualize in utero male fetal testicular descent on magnetic resonance imaging (MRI) and to correlate it with gestational age. Methods This retrospective study included 202 MRI examination results of 199 male fetuses (17–39 gestational weeks) with normal anatomy or minor congenital abnormalities, following suspicion of anomalies on prenatal ultrasound examination. Using a 1.5-Tesla unit, multiplanar T2-weighted sequences were applied using a standard protocol to image and identify the scrotal content. The relative frequencies of unilateral and bilateral testicular descent were calculated and correlated with gestational age. Results Between 17 and 25 gestational weeks, neither unilateral nor bilateral testicular descent was visualized on MRI. Testicular descent was first observed at 25 + 4 weeks, in 7.7% of cases. 12.5% of 27-week fetuses showed unilateral descent and 50% showed bilateral descent. Bilateral descent was observed in 95.7% of cases, on average, from 30 to 39 weeks. Conclusions Our results chart the time course of testicular descent on prenatal MRI, which may be helpful in the identification of normal male sexual development and in the diagnosis of congenital abnormalities, including the early detection of cryptorchidism. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Objective In view of the increasing use of fetal magnetic resonance imaging (MRI) as an adjunct to prenatal ultrasonography, we sought to demonstrate the visualization of upper extremity abnormalities and associated defects on MRI, with regard to fetal outcomes and compared with ultrasound imaging. Methods This retrospective study included 29 fetuses with upper extremity abnormalities visualized with fetal MRI following suspicious ultrasound findings and confirmed by postnatal assessment or autopsy. On a 1.5-Tesla unit, dedicated sequences were applied to image the extremities. Central nervous system (CNS) and extra-CNS anomalies were assessed to define extremity abnormalities as isolated or as complex, with associated defects. Fetal outcome was identified from medical records. MRI and ultrasound findings, when available, were compared. Results Isolated upper extremity abnormalities were found in three (10.3%) fetuses. In 26 (89.7%) fetuses complex abnormalities, including postural extremity disorders (21/26) and structural extremity abnormalities (15/26), were demonstrated. Associated defects involved: face (15/26); musculoskeletal system (14/26); thorax and cardio/pulmonary system (12/26); lower extremities (12/26); brain and skull (10/26); and abdomen (8/26). Of the 29 cases, 18 (62.1%) pregnancies were delivered and 11 (37.9%) were terminated. MRI and US findings were compared in 27/29 cases: the diagnosis was concordant in 14 (51.9%) of these cases, and additional findings were made on MRI in 13/27 (48.1%) cases. Conclusions Visualization of upper extremity abnormalities on fetal MRI enables differentiation between isolated defects and complex ones, which may be related to poor fetal prognosis. MRI generally confirms the ultrasound diagnosis, and may provide additional findings in certain cases. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.

Diaphanospondylodysostosis (DSD) is a rare, recessively inherited, perinatal lethal skeletal disorder. The low frequency and perinatal lethality of DSD makes assembling a large set of families for traditional linkage-based genetic approaches challenging. By searching for evidence of unknown ancestral consanguinity, we identified two autozygous intervals, comprising 34 Mbps, unique to a single case of DSD. Empirically testing for ancestral consanguinity was effective in localizing the causative variant, thereby reducing the genomic space within which the mutation resides. High-throughput sequence analysis of exons captured from these intervals demonstrated that the affected individual was homozygous for a null mutation in BMPER, which encodes the bone morphogenetic protein-binding endothelial cell precursor-derived regulator. Mutations in BMPER were subsequently found in three additional DSD cases, confirming that defects in BMPER produce DSD. Phenotypic similarities between DSD and Bmper null mice indicate that BMPER-mediated signaling plays an essential role in vertebral segmentation early in human development.

The skeletal dysplasias (osteochondrodysplasias) are a heterogeneous group of more than 350 disorders frequently associated with orthopedic complications and varying degrees of dwarfism or short stature. These disorders are diagnosed based on radiographic, clinical, and molecular criteria. The molecular mechanisms have been elucidated in many of these disorders providing for improved clinical diagnosis and reproductive choices for affected individuals and their families. An increasing variety of medical and surgical treatment options can be offered to affected individuals to try to improve their quality of life and lifespan.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia due to mutations causing haploinsufficiency of RUNX2, an osteoblast transcription factor specific for bone and cartilage. The classic form of CCD is characterized by delayed closure of the fontanels, hypoplastic or aplastic clavicles and dental anomalies. Clinical reports suggest that a subset of patients with CCD have skeletal changes which mimic hypophosphatasia. Mutations in RUNX2 are detected in approximately 65% of cases of CCD, and microdeletions occur in 13%. We present clinical and radiological features in a 6-year-old child with severe CCD manifested by absence of the clavicles marked calvarial hypomineralization, osteoporosis and progressive kyphoscoliosis. Hypophosphatasia features included Bowdler spurs, severe osteopenia and low alkaline phosphatase. Following negative mutation analysis of RUNX2, comparative genomic hybridization (CGH) microarray was performed. The result revealed a microdeletion in RUNX2, disrupting the C-terminal part of the gene.

Treatment of patients with Hutchinson-Gilford progeria syndrome (HGPS) is based on the abnormalities of accelerated aging that affect the healing processes, combined with a fragile cardiovascular status. A classic HGPS case, of Korean ancestry, previously treated for severe coxa valga with bilateral varus osteotomies using blade plate fixation is presented. Complications over the blade plate area required removal of the hardware, after which the patient showed right-sided hypertonicity--determined to be a cerebrovascular accident. Subsequently, the patient returned almost completely to her presurgical neurologic status. Perioperative planning for HGPS patients should include risks that are typically considered in the planning for geriatric patient care.

The osteochondrodysplasias, or skeletal dysplasias are a genetically heterogeneous group of over 350 distinct disorders, and many of them can present in the prenatal period as demonstrated by ultrasound. Differentiating these disorders in the prenatal period can be challenging because they are rare and many of the ultrasound findings are not necessarily pathognomic for a specific disorder. However, differentiating known lethal disorders from nonlethal disorders, providing differential diagnoses before delivery, determining postdelivery management plans and ultimately determining accurate recurrences risks to the at-risk couples improves patient care. These guidelines provide an approach to a fetus suspected of manifesting a skeletal dysplasia.

Analysis of a nuclear family with three affected offspring identified an autosomal-recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a unique constellation of radiographic findings. Homozygosity for a haplotype that was identical by descent between two of the affected individuals identified a locus for the disease gene within a 17.4 Mb interval on chromosome 15, a region containing 296 genes. These genes were assessed and ranked by cartilage selectivity with whole-genome microarray data, revealing only two genes, encoding aggrecan and chondroitin sulfate proteoglycan 4, that were selectively expressed in cartilage. Sequence analysis of aggrecan complementary DNA from an affected individual revealed homozygosity for a missense mutation (c.6799G → A) that predicts a p.D2267N amino acid substitution in the C-type lectin domain within the G3 domain of aggrecan. The D2267 residue is predicted to coordinate binding of a calcium ion, which influences the conformational binding loops of the C-type lectin domain that mediate interactions with tenascins and other extracellular-matrix proteins. Expression of the normal and mutant G3 domains in mammalian cells showed that the mutation created a functional N-glycosylation site but did not adversely affect protein trafficking and secretion. Surface-plasmon-resonance studies showed that the mutation influenced the binding and kinetics of the interactions between the aggrecan G3 domain and tenascin-C. These findings identify an autosomal-recessive skeletal dysplasia and a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height.

Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen alpha1(I) and type II collagen alpha1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and 16 with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, "popcorn" epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations.

The osteochondrodysplasias or skeletal dysplasias are a heterogenous group of over 350 distinct disorders of skeletogenesis. Many manifest in the prenatal period, making them amenable to ultrasound prenatal diagnosis. A retrospective analysis evaluated 1,500 cases referred to the International Skeletal Dysplasia Registry (ISDR) to determine the relative frequency of specific osteochondrodysplasias and correlation of ultrasound versus radiographic diagnoses for these disorders. Within the retrospective cohort of 1,500 cases, 85% of the referred cases represented well-defined skeletal dysplasias, and the other 15% of cases were a mixture of genetic syndromes and probable early-onset intrauterine growth restriction. The three most common prenatal-onset skeletal dysplasias were osteogenesis imperfecta type 2, thanatophoric dysplasia and achondrogenesis 2, accounting for almost 40% of the cases. In a prospective analysis of 500 cases using a standardized ultrasound approach to the evaluation of these disorders, the relative frequencies of osteogenesis imperfecta type 2, thanatophoric dysplasia and achondrogenesis 2 were similar to the retrospective analysis. This study details the relative frequencies of specific prenatal-onset osteochondrodysplasias, their heterogeneity of prenatal-onset skeletal disorders and provides a standardized prenatal ultrasound approach to these disorders which should aid in the prenatal diagnosis of fetuses suspected of manifesting skeletal dysplasias.

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature(1). Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis. ispartof: Nature Genetics vol:40 issue:8 pages:999-1003 ispartof: location:United States status: published

Proteoglycans are a family of extracellular macromolecules comprised of glycosaminoglycan chains of a repeated disaccharide linked to a central core protein1,2. Proteoglycans have critical roles in chondrogenesis and skeletal development. The glycosaminoglycan chains found in cartilage proteoglycans are primarily composed of chondroitin sulfate3. The integrity of chondroitin sulfate chains is important to cartilage proteoglycan function; however, chondroitin sulfate metabolism in mammals remains poorly understood. The solute carrier-35 D1 (SLC35D1) gene (SLC35D1) encodes an endoplasmic reticulum nucleotide-sugar transporter (NST) that might transport substrates needed for chondroitin sulfate biosynthesis4,5. Here we created Slc35d1-deficient mice that develop a lethal form of skeletal dysplasia with severe shortening of limbs and facial structures. Epiphyseal cartilage in homozygous mutant mice showed a decreased proliferating zone with round chondrocytes, scarce matrices and reduced proteoglycan aggregates. These mice had short, sparse chondroitin sulfate chains caused by a defect in chondroitin sulfate biosynthesis. We also identified that loss-of-function mutations in human SLC35D1 cause Schneckenbecken dysplasia, a severe skeletal dysplasia. Our findings highlight the crucial role of NSTs in proteoglycan function and cartilage metabolism, thus revealing a new paradigm for skeletal disease and glycobiology.

Pachydermoperiostosis (PDP) is a rare genodermatosis, characterized by pachydermia, digital clubbing, periostosis and an excess of affected males. Although an autosomal dominant model with incomplete penetrance and variable expression has been proved, both autosomal recessive and X-linked inheritance have been suggested. However, at present, genetic heterogeneity is not fully supported. The aim of this study is to review the clinical and pedigree data of 68 published PDP families, including 204 patients. This analysis has confirmed an autosomal dominant mutation in 37 families and suggested the existence of an autosomal recessive form in the remaining families. The two forms may differ in clinical severity, intrafamilial variability and prevalence of some features. Additionally, the marked skewed sex ratio could not be easily explained by an X-linked mutation, but alternative explanations (i.e. testosterone promoting proliferation) are discussed.

Medical genetics emerged from a basic science only one half century ago. Scientists and physicians housed in a variety of basic science and clinical departments have accomplished many of the major advances in the study of genetic diseases in children. A scientific approach to human genetics emerged in 1948 with the establishment of the American Society of Human Genetics. Even before the use of modern laboratory techniques, Pediatric departments spearheaded the clinical description of simple genetic disorders, syndromes, and major malformations. The burgeoning of medical genetics as a specialty and its tremendous growth in departments of pediatrics was stimulated by major technological advances, such as the ability to visualize human chromosomes, the development of methods to study biochemical variations in blood and urine, cell culture, somatic cell hybridization, and molecular technology, all of which allowed for the diagnosis, treatment, and prevention of genetic disorders in children. Many pediatricians sought training in genetics, and training programs in medical genetics flourished in departments of pediatrics. The explosion of knowledge concerning the metabolic and molecular causes of genetic disease and understanding of their pathogenesis has led to a variety of specific diagnostic, preventive, and therapeutic approaches for alleviating the symptoms or preventing the complications of many of these disorders. Medical genetics is now recognized as a distinct medical specialty with its own American Board of Medical Specialties approved board (American Board of Medical Genetics) and clinical specialty college (American College of Medical Genetics).

Objective Recognition of prenatal-onset skeletal dysplasias has improved with advances in ultrasound imaging. Skeletal abnormalities can be recognized by two-dimensional (2D) ultrasound, but generating a precise diagnosis can be challenging. We aimed to determine whether three-dimensional (3D) imaging conferred any advantages over 2D imaging in these cases. Methods We studied five women with fetuses of 16–28 gestational weeks referred for abnormal ultrasound skeletal findings. First 2D and then 3D sonography was performed and the results compared. Results The pregnancies resulted in the following skeletal dysplasias: thanatophoric dysplasia, achondrogenesis II/hypochondrogenesis, achondroplasia, chondrodysplasia punctata (rhizomelic form) and Apert's syndrome. For all five fetuses, the correct diagnosis was made in the prenatal period by analysis of the 2D images. In each case the 3D images confirmed the preliminary diagnosis and for many findings it improved the visualization of the abnormalities. Conclusion The 3D imaging had advantages over the 2D imaging when it came to evaluation of facial dysmorphism, relative proportion of the appendicular skeletal elements and the hands and feet. Most importantly, the patient and referring physician appreciated the 3D images of the abnormal findings more readily which aided in counseling and management of the pregnancy. Copyright © 2003 ISUOG. Published by John Wiley & Sons, Ltd.

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and a short trunk with a barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. We performed a genomewide scan in a consanguineous family from Guam and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined two-point LOD score of 3.04 at a recombination fraction of 0 for the marker at locus D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in two affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the defective gene. Analysis of three small, unrelated families with Dyggve-Melchior-Clausen syndrome, a radiographically identical disorder with the additional clinical finding of mental retardation, provided evidence of linkage to the same region, a result consistent with the hypothesis that the two disorders are allelic.

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2–7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G→A, 157–158delAT, 191–192delTG, and 271–275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.

Ellis-van Creveld syndrome (EVC) is a relatively rare, usually non-lethal, autosomal recessive skeletal dysplasia characterized by short stature, polydactyly, cardiac and renal anomalies. Linkage analysis has localized the disease gene to chromosome 4p16, with the markers at loci D4S827 and D4S3135 defining the centromeric and telomeric limits of the linked interval, respectively. There has been long-term speculation that asphyxiating thoracic dystrophy (ATD) and the short-rib polydactyly syndromes (SRP) represent the severe end of the EVC disease spectrum. We performed linkage analysis using markers from the EVC region in seven families manifesting either ATD or SRP type III. In two of the families, one segregating ATD and one SRP kindred, linkage of the phenotype to the EVC region was excluded. In the other five families linkage of the phenotype to the EVC region could not be excluded, but the families were too small for linkage to the region to be established. The exclusion of the EVC region in ATD and SRP III families suggests that locus heterogeneity exists within the short-rib dysplasia (with and without polydactyly) group of disorders.

Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia. All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing of the index patients' genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.

SummaryMultiple synostoses syndrome is an autosomal dominant disorder characterized by premature onset of joint fusions, which initially affect the interphalangeal joints, by characteristic facies, and by deafness. We performed linkage analysis on a large Hawaiian family with multiple synostoses syndrome. Because another autosomal dominant disorder, proximal symphalangism, shares some clinical symptoms with multiple synostoses syndrome and has been linked to markers at loci at chromosome 17q21-22, we tested the hypothesis that multiple synostoses syndrome is linked to the same chromosomal region. Using polymorphic markers from the proximal symphalangism interval, we conducted linkage analysis and showed that the multiple synostoses–syndrome phenotype is linked to the same chromosomal region. A maximum LOD score of 3.98 at recombination fraction of .00 was achieved for the marker at locus D17S787. Further genetic analysis identified individuals with recombinant genotypes, allowing localization of the disease gene within the interval D17S931–D17S792, a 16-cM region. These data provide evidence that multiple synostoses syndrome and proximal symphalangism may be allelic disorders.

Type II collagen mutations have been identified in a phenotypic continuum of chondrodysplasias that range widely in clinical severity. They include achondrogenesis type II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia, Kniest dysplasia, and Stickler syndrome. We report here results that define the underlying genetic defect and consequent altered structure of assembled type II collagen in a neonatal lethal form of Kniest dysplasia. Electrophoresis of a cyanogen bromide (CNBr) (CB) digest of sternal cartilage revealed an alpha1(II)CB11 peptide doublet and a slightly retarded mobility for all major CB peptides, which implied post-translational overmodification. Further peptide mapping and sequence analysis of CB11 revealed equal amounts of a normal alpha1(II) sequence and a chain lacking the 18 residues (361-378 of the triple helical domain) corresponding to exon 24. Sequence analysis of an amplified genomic DNA fragment identified a G to A transition in the +5 position of the splice donor consensus sequence of intron 24 in one allele. Cartilage matrix analysis showed that the short alpha1(II) chain was present in collagen molecules that had become cross-linked into fibrils. Trypsin digestion of the pepsin-extracted native type II collagen selectively cleaved the normal length alpha1(II) chains within the exon 24 domain. These findings support a hypothesis that normal and short alpha-chains had combined to form heterotrimeric molecules in which the chains were in register in both directions from the deletion site, accommodated effectively by a loop out of the normal chain exon 24 domain. Such an accommodation, with potential overall shortening of the helical domain and hence misalignment of intermolecular relationships within fibrils, offers a common molecular mechanism by which a group of different mutations might act to produce the Kniest phenotype.

To investigate the effect of recombinant hGH treatment on the growth rate and proportion of individuals with achondroplasia and hypochondroplasia, we studied 15 individuals with these common skeletal dysplasias. The study lasted 24 months and included 6 months of observation, 12 months of hGH therapy (0.04 mg/kg.day), and 6 months of posttreatment growth rate determination. In achondroplasia, the mean growth rate during the hGH treatment (5.3 +/- 1.6 cm) was significantly increased compared with that during the pretreatment (4.0 +/- 1.0 cm.yr, P < 0.01)) and posttreatment periods (3.1 +/- 1.3 cm; P < 0.001). In the 4 children with hypochondroplasia, the growth rate during hGH treatment was 7.0 +/- 2.4 cm/yr and 4.9 +/- 1.5 cm/yr during the pre- and posttreatment periods, respectively. In achondroplasia, there was a significant increase in growth rate of only the lower segment (from 1.1 +/- 1.6 cm/yr to 3 +/- 1.2 cm/yr, P < 0.02). There was no significant acceleration in the growth of the upper segment and of the scanogram measurements of the long bones. No untoward effects were noted. Recombinant hGH increases short-term growth velocity in children with achondroplasia/hypochondroplasia. Unexpectedly, this treatment does not seem to have a lesser effect on limbs than on trunk growth rate and, therefore, during 1 yr of treatment, does not increase body disproportion.

The spondylometaphyseal dysplasias (SMDs) is a large heterogeneous group of skeletal dysplasias characterized radiologically by vertebral abnormalities and metaphyseal changes in the tubular bones (Maroteaux and Spranger 1991; Taybi and Lachman 2007; Warman et al. 2011; Rimoin et al. 2007; Marik et al. 2012). There are five well-described distinct entities; these include SMD-Kozlowski (SMD-K), SMD-corner fracture type (SMD-CF), SMD-Sedaghatian, and a recently delineated SMD associated with cone–rod dystrophy (SMD-CRD; Kitoh et al. 2011). The International Skeletal Dysplasia Society Nosology Group recently included a type of SMD termed SMD with retinal degeneration, axial type. A few other forms of SMD consist mostly of single case reports. A classification of the SMDs was attempted in the early 1990s (primarily based on severity and sites of metaphyseal changes), but it has seemed to have added little to the specific delineation of these disorders. Unless there are other clinical clues, even the concept of separating the SMDs into common, uncommon, and rare is not that helpful. Clinically, most types present in early childhood with short stature and gait problems, leading to clinical and radiological evaluation. Here, we present the clinical and radiographic features of a patient with SMD axial type with retinal degeneration and discuss the key recognizable characteristics of this condition that should aid the clinician with a diagnosis.

We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers–Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities.

Gastrointestinal complications are common in patients with Ehlers-Danlos syndrome, affecting up to 50% of individuals depending on the subtype. The spectrum of gastrointestinal manifestations is broad and ranges from life threatening spontaneous perforation of the visceral organs to a more benign functional symptoms. Here we describe the clinical and radiographic manifestations of visceroptosis of the bowel, a rare complication of Ehlers-Danlos syndrome that is characterized by prolapse of abdominal organs below their natural position. We further review the literature on gastrointestinal complications in the different forms of Ehlers-Danlos syndrome.

We have identified a large family with a dominantly inherited chondrodysplasia characterized by a waddling gait, short limbs, and early onset osteoarthritis. The radiographic presentation resembles pseudoachondroplasia in childhood and multiple epiphyseal dysplasia in adults. Electron microscopic examination of cartilage reveals accumulation of material within the rough endoplasmic reticulum similar to that seen in pseudoachondroplasia and the Fairbank type of multiple epiphyseal dysplasia. By linkage analysis, we have excluded the genes for aggrecan, decorin, hexabrachion (tenascin), type II procollagen, the alpha 1 chain of type XI procollagen, the alpha 1 chain of type IX procollagen, and link protein, candidate genes that encode structural components of the cartilage extracellular matrix, as the disease locus for this disorder.

Objectives To characterize the normal development of the female external genitalia on fetal magnetic resonance imaging (MRI). Methods This retrospective study included MRI examinations of 191 female fetuses (20–36 gestational weeks) with normal anatomy or minor abnormalities, following suspicion of anomalies on prenatal ultrasound examination. Using a 1.5-Tesla unit, the bilabial diameter was measured on T2-weighted sequences. Statistical description, as well as correlation and regression analyses, was used to evaluate bilabial diameter in relation to gestational age. MRI measurements were compared with published ultrasound data. The morphological appearance and signal intensities of the external genitalia were also assessed. Results Mean bilabial diameters, with 95% CIs and percentiles, were defined. The bilabial diameter as a function of gestational age was expressed by the regression equation: bilabial diameter =− 11.336 + 0.836 × (gestational age in weeks). The correlation coefficient, r = 0.782, was statistically significant (P < 0.001). Bilabial diameter on MRI was not significantly different from that on ultrasound (P < 0.001). In addition, on MRI we observed changes in morphology of the external genitalia and in signal intensities with increasing gestational age. Conclusions We have provided a reference range of fetal bilabial diameter on MRI, which, in addition to ultrasound findings, may be helpful in the identification of genital anomalies. Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.

International audience; Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFb-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFb signaling were consistent features in GD and AD fibro-blasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFb signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.

Pseudoachondroplasia (PSACH) is a dominantly inherited form of short-limb dwarfism characterized by dysplastic changes in the spine, epiphyses, and metaphyses and early onset osteoarthropathy. Chondrocytes from affected individuals accumulate an unusual appearing material in the rough endoplasmic reticulum, which has led to the hypothesis that a structural abnormality in a cartilage-specific protein produces the phenotype. We recently identified a large family with a mild form of pseudoachondroplasia. By genetic linkage to a dinucleotide repeat polymorphic marker (D19S199), we have localized the disease gene to chromosome 19 (maximum lod score of 7.09 at a recombination fraction of 0.03). Analysis of additional markers and recombinants between the linked markers and the phenotype suggests that the disease gene resides within a 6.3-cM interval in the immediate pericentromeric region of the chromosome.

Purpose: Israeli investigators have identified several relatively frequent disorders due to founder point mutations in Persian (Iranian) Jews, who, for nearly three centuries up to the Islamic Revolution of 1979, were completely isolated reproductively. Methods: Using a community-based model previously employed with Tay-Sachs disease prevention, we developed a pilot program for the Persian Jewish community of greater Los Angeles. We screened for mutations responsible for four relatively frequent autosomal recessive conditions in Persian Jews in which effective interventions are available for each: Pseudocholinesterase deficiency (butyryl cholinesterase deficiency); Congenital hypoaldosteronism (corticosterone methyl oxidase II); Autoimmune polyendocrinopathy (autoimmune regulatory element); and Hereditary Inclusion Body myopathy. Results: One thousand individuals volunteered. Mutations were assessed in saliva-derived DNA and were positive for 121/1000 butyryl cholinesterase deficiency; 92/1000 Hereditary Inclusion Body myopathy; 38/1000 corticosterone methyl oxidase II; and 37/1000 autoimmune regulatory element. Ten homozygous individuals (9 butyryl cholinesterase deficiency and 1 Hereditary Inclusion Body myopathy) and 10 “at-risk” couples (seven for butyryl cholinesterase deficiency and one each for the other three disorders) were identified. These frequencies are comparable with those in Israel and indicate an extraordinary level of inbreeding, as anticipated. Conclusions: A carefully planned effort can be delivered to an “increased risk” community if detailed attention is given to planning and organization. However, availability of an effective intervention for those found to be “at-risk” or possibly affected, is essential before embarking.

The spondylometaphyseal dysplasias (SMDs) are a group of short-stature disorders distinguished by abnormalities in the ver-tebrae and the metaphyses of the tubular bones. SMD Kozlowski type (SMDK) is a well-defined autosomal-dominant SMD characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles similar to autosomal-dominant brachyolmia, which can result from heterozygosity for activating mutations in the gene encoding TRPV4, a calcium-permeable Ion channel. Mutation analysis in six out of six patients with SMDK demonstrated heterozygosity for missense mutations in TRPV4, and one mutation, predicting a R594H substitution, was recurrent in four patients. Similar to autosomal-dominant brachyolmia, the mutations altered basal calcium channel activity in vitro. Metatropic dysplasia is another SMD that has been proposed to have both clinical and genetic heterogeneity. Patients with the nonlethal form of metatropic dysplasia present with a progressive scoliosis, widespread metaphyseal involvement of the appendicular skeleton, and carpal ossification delay. Because of some similar radiographic features between SMDK and metatropic dysplasia, 'FRPV4 was tested as a disease gene for nonlethal metatropic dysplasia. In two sporadic cases, heterozygosity for de novo missense mutations in TRPV4 was found. The findings demonstrate that mutations in TRPV4 produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal-dominant brachyolmia to SMDK to autosomal-dominant metatropic dysplasia, suggesting that these disorders should be grouped into a new bone dysplasia family. ispartof: American Journal of Human Genetics vol:84 issue:3 pages:307-315 ispartof: location:United States status: published

We report a child with a 785 kb deletion of the 3p14.1p13 region including the genes FOXP1 , EIF4E3 , PROK2 , GPR27 resulting in speech delay, contractures, hypertonia and blepharophimosis. FOXP1 and FOXP2 are transcription factors containing a polyglutamine tract and a forkhead DNA binding domain. They both play a role in the developing human foregut and brain [W. Shu, M.M. Lu, Y. Zhang, P. Tucker, D. Zhou, E.E. Morrisey, Foxp2 and Foxp1 cooperatively regulate lung and esophagus development, Development 134 (2007) 1991–2000, E. Spiteri, G. Konopka, G. Coppola, J. Bomar, M. Oldham, J. Ou, et al. Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain, Am. J. Hum. Genet. 81 (2007) 1144–1157, S. Tamura, Y. Morikawa, H. Iwanishi, T. Hisaoka, E. Senba. Expression pattern of the winged-helix/forkhead transcription factor Foxp1 in the developing central nervous system, Gene Expr. Patterns. 3 (2003) 193–197.]. Mutations in FOXP2 are known to cause severe speech and language abnormalities [C.S.L. Lai, S.E. Fisher, J.A. Hurst, F. Vargha-Khadem, A.P. Monaco, A forkhead-domain gene is mutated in a severe speech and language disorder, Nature 413 (2001) 519–523.] in humans and animals. It has been suggested that overlap of FOXP1 and FOXP2 expression in the songbird and human brain may indicate that mutations in FOXP1 would also result in speech and language abnormalities. The roles of EIF4E3, PROK2 and GPR27 are also evaluated.

Background: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied.Methods: Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated.Results and discussion: The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G -> A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

Background: The majority of COL2A1 missense mutations are substitutions of obligatory glycine residues in the triple helical domain. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate. Objective: To investigate in more detail the phenotype resulting from arginine to cysteine mutations in the COL2A1 gene. Methods: The clinical and radiographic phenotype of all patients in whom an arginine to cysteine mutation in the COL2A1 gene was identified in our laboratory, was studied and correlated with the abnormal genotype. The COL2A1 genotyping involved DHPLC analysis with subsequent sequencing of the abnormal fragments. Results: Six different mutations (R75C, R365C, R519C, R704C, R789C, R1076C) were found in 11 unrelated probands. Each mutation resulted in a rather constant and site-specific phenotype, but a perinatally lethal disorder was never observed. Spondyloarthropathy with normal stature and no ocular involvement were features of patients with the R75C, R519C, or R1076C mutation. Short third and/or fourth toes was a distinguishing feature of the R75C mutation and brachydactyly with enlarged finger joints a key feature of the R1076C substitution. Stickler dysplasia with brachydactyly was observed in patients with the R704C mutation. The R365C and R789C mutations resulted in classic Stickler dysplasia and spondyloepiphyseal dysplasia congenita (SEDC), respectively. Conclusions: Arginine to cysteine mutations are rather infrequent COL2A1 mutations which cause a spectrum of phenotypes including classic SEDC and Stickler dysplasia, but also some unusual entities that have not yet been recognised and described as type II collagenopathies.