Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.

The antiviral protein viperin regulates chondrogenic differentiation via CXCL10 protein secretion.

Viperin (also known as radical SAM domain-containing 2 (RSAD2)) is an interferon-inducible and evolutionary conserved protein that participates in the cell's innate immune response against a number of viruses. Viperin mRNA is a substrate for endoribonucleolytic cleavage by RNase mitochondrial RNA processing (MRP) and mutations in the RNase MRP small nucleolar RNA (snoRNA) subunit of the RNase MRP complex cause cartilage-hair hypoplasia (CHH), a human developmental condition characterized by metaphyseal chondrodysplasia and severe dwarfism. It is unknown how CHH-pathogenic mutations in RNase MRP snoRNA interfere with skeletal development, and aberrant processing of RNase MRP substrate RNAs is thought to be involved. We hypothesized that viperin plays a role in chondrogenic differentiation. Using immunohistochemistry, real-time quantitative PCR, immunoblotting, ELISA, siRNA-mediated gene silencing, plasmid-mediated gene overexpression, label-free MS proteomics, and promoter reporter bioluminescence assays, we discovered here that viperin is expressed in differentiating chondrocytic cells and regulates their protein secretion and the outcome of chondrogenic differentiation by influencing transforming growth factor ß (TGF-ß)/SMAD family 2/3 (SMAD2/3) activity via C-X-C motif chemokine ligand 10 (CXCL10). Of note, we observed disturbances in this viperin-CXCL10-TGF-ß/SMAD2/3 axis in CHH chondrocytic cells. Our results indicate that the antiviral protein viperin controls chondrogenic differentiation by influencing secretion of soluble proteins and identify a molecular route that may explain impaired chondrogenic differentiation of cells from individuals with CHH.

Molecular mechanism of CHRDL1-mediated X-linked megalocornea in humans and in Xenopus model.

Chordin-Like 1 (CHRDL1) mutations cause non-syndromic X-linked megalocornea (XMC) characterized by enlarged anterior eye segments. Mosaic corneal degeneration, presenile cataract and secondary glaucoma are associated with XMC. Beside that CHRDL1 encodes Ventroptin, a secreted bone morphogenetic protein (BMP) antagonist, the molecular mechanism of XMC is not well understood yet. In a family with broad phenotypic variability of XMC, we identified the novel CHRDL1 frameshift mutation c.807_808delTC [p.H270Wfs*22] presumably causing CHRDL1 loss of function. Using Xenopus laevis as model organism, we demonstrate that chrdl1 is specifically expressed in the ocular tissue at late developmental stages. The chrdl1 knockdown directly resembles the human XMC phenotype and confirms CHRDL1 deficiency to cause XMC. Interestingly, secondary to this bmp4 is down-regulated in the Xenopus eyes. Moreover, phospho-SMAD1/5 is altered and BMP receptor 1A is reduced in a XMC patient. Together, we classify these observations as negative-feedback regulation due to the deficient BMP antagonism in XMC. As CHRDL1 is preferentially expressed in the limbal stem cell niche of adult human cornea, we assume that CHRDL1 plays a key role in cornea homeostasis. In conclusion, we provide novel insights into the molecular mechanism of XMC as well as into the specific role of CHRDL1 during cornea organogenesis, among others by the establishment of the first XMC in vivo model. We show that unravelling monogenic cornea disorders like XMC-with presumably disturbed cornea growth and differentiation-contribute to the identification of potential limbal stem cell niche factors that are promising targets for regenerative therapies of corneal injuries.

Guiding Registry for Skeletal Dysplasia. Rational Approach in Classification.

The official nosology and classification of genetic skeletal disorders lists more than 500 recognized diagnostic entities and groups them by clinical, radiographic and - if available - molecular data. The list helps in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists. It can be the basis of a nosology-guided skeletal dysplasia registry and archive. An archive using a slightly modified classification system has been established in Magdeburg/Germany. Its benefits include: i. guidance of molecular testing, ii. disclosure of genetic heterogeneity, iii. delineation of new disorders, iv. disclosure of etiopathogenetic relationships, v. individual prognostication through follow-up. These items are illustrated with examples from classification subgroup 7, the spondylometaphyseal dysplasias. In contrast to usual, passive depositories we expect classifying registries to be living tools connecting researchers, students, patients and their relatives with each other and with self-help organisations.

FAM111A mutations result in hypoparathyroidism and impaired skeletal development.

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.

Mutations in WNT1 cause different forms of bone fragility.

We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated ß-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.

Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.

PURPOSE: Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited. METHODS: We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed. RESULTS: Eleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent. CONCLUSION: RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226-1234.

Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP.

We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints.

Mutations in the TGFß binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias.

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 TGFß-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFß signaling were consistent features in GD and AD fibroblasts. 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 TGFß 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.

Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene.

BACKGROUND: Intellectual disability (ID) is often associated with behavioral problems or disorders. Mutations in the GRIN2B gene (MRD6, MIM613970) have been identified as a common cause of ID (prevalence of 0.5 - 1% in individuals with ID) associated with EEG and behavioral problems. METHODS: We assessed five GRIN2B mutation carriers aged between 3 and 14 years clinically and via standardized questionnaires to delineate a detailed behavioral phenotype. Parents and teachers rated problem behavior of their affected children by completing the Developmental Behavior Checklist (DBC) and the Conners' Rating Scales Revised (CRS-R:L). RESULTS: All individuals had mild to severe ID and needed guidance in daily routine. They showed characteristic behavior problems with prominent hyperactivity, impulsivity, distractibility and a short attention span. Stereotypies, sleeping problems and a friendly but boundless social behavior were commonly reported. CONCLUSION: Our observations provide an initial delineation of the behavioral phenotype of GRIN2B mutation carriers.

Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias resulting in short-limbed dwarfism, joint pain, and stiffness. PSACH and the largest proportion of autosomal dominant MED (AD-MED) results from mutations in cartilage oligomeric matrix protein (COMP); however, AD-MED is genetically heterogenous and can also result from mutations in matrilin-3 (MATN3) and type IX collagen (COL9A1, COL9A2, and COL9A3). In contrast, autosomal recessive MED (rMED) appears to result exclusively from mutations in sulphate transporter solute carrier family 26 (SLC26A2). The diagnosis of PSACH and MED can be difficult for the nonexpert due to various complications and similarities with other related diseases and often mutation analysis is requested to either confirm or exclude the diagnosis. Since 2003, the European Skeletal Dysplasia Network (ESDN) has used an on-line review system to efficiently diagnose cases referred to the network prior to mutation analysis. In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED.

TRPV4-associated skeletal dysplasias.

Dominant mutations in the TRPV4 gene result in a bone dysplasia family and form a continuous phenotypic spectrum that includes, in decreasing severity, lethal, and nonlethal metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), and autosomal dominant brachyolmia. Several rare variant phenotypes that have some overlap but deviate in some ways from the general pattern have also been described. The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly. Interestingly, different TRPV4 mutations have been associated with dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Finally, a small number of patients have been identified in whom a TRPV4 mutation results in a phenotype combining skeletal dysplasia with peripheral neuropathy. The TRPV4 gene encodes a regulated calcium channel implicated in multiple and diverse cellular processes. Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotype-phenotype correlations in this group of disorders remains somewhat mysterious. Since the phenotypic expression of most mutations seems to be relatively constant, careful clinical and radiographic assessment is useful in directing molecular analysis.

The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals.

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti-inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis.

Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia.

The matrix metalloproteinases MMP9 and MMP13 catalyze the degradation of extracellular matrix (ECM) components in the growth plate and at the same time cleave and release biologically active molecules stored in the ECM, such as VEGFA. In mice, ablation of Mmp9, Mmp13, or both Mmp9 and Mmp13 causes severe distortion of the metaphyseal growth plate. We report that mutations in either MMP9 or MMP13 are responsible for the human disease metaphyseal anadysplasia (MAD), a heterogeneous group of disorders for which a milder recessive variant and a more severe dominant variant are known. We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13, whereas dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency.

TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: a report of three patients.

Heterozygous missense mutations of transient receptor potential vanilloid 4 channel (TRPV4) cause a spectrum of skeletal disorders, including brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, parastremmatic dysplasia, and spondyloepimetaphyseal dysplasia Maroteaux type. Similarly, heterozygous missense mutations of TRPV4 cause a spectrum of peripheral neuropathy, including hereditary motor and sensory neuropathy type IIC, congenital spinal muscular atrophy, and scapuloperoneal spinal muscular atrophy. There are no apparent differences in the amino acid positions affected or type of change predicted by the TRPV4 mutations responsible for the two disease spectrums; nevertheless, no fundamental phenotypic overlap has been shown between the two spectrums. Here, we report on three patients who had both skeletal dysplasia and peripheral neuropathy caused by heterozygous TRPV4 missense mutations. The skeletal and neurologic phenotypes of these patients covered the wide spectrum of reported TRPV4-pathies (disease caused by TRPV4 mutations). The molecular data are complementary, proving that "neuropathic" mutations can cause skeletal dysplasia but also the "skeletopathic" mutations can lead to neuropathies. Our findings suggest that pathogenic mechanisms of TRPV4-pathies in skeletal and nervous systems are not always mutually exclusive and provide further evidence that there is no clear genotype-phenotype correlation for either spectrum. Co-occurrence of skeletal dysplasia and degenerative neuropathy should be kept in mind in clinical practice including diagnostic testing, surgical evaluation, and genetic counseling.

Viperin mRNA is a novel target for the human RNase MRP/RNase P endoribonuclease.

RNase MRP is a conserved endoribonuclease, in humans consisting of a 267-nucleotide RNA associated with 7-10 proteins. Mutations in its RNA component lead to several autosomal recessive skeletal dysplasias, including cartilage-hair hypoplasia (CHH). Because the known substrates of mammalian RNase MRP, pre-ribosomal RNA, and RNA involved in mitochondrial DNA replication are not likely involved in CHH, we analyzed the effects of RNase MRP (and the structurally related RNase P) depletion on mRNAs using DNA microarrays. We confirmed the upregulation of the interferon-inducible viperin mRNA by RNAi experiments and this appeared to be independent of the interferon response. We detected two cleavage sites for RNase MRP/RNase P in the coding sequence of viperin mRNA. This is the first study providing direct evidence for the cleavage of a mRNA by RNase MRP/RNase P in human cells. Implications for the involvement in the pathophysiology of CHH are discussed.

TBX15 mutations cause craniofacial dysmorphism, hypoplasia of scapula and pelvis, and short stature in Cousin syndrome.

Members of the evolutionarily conserved T-box family of transcription factors are important players in developmental processes that include mesoderm formation and patterning and organogenesis both in vertebrates and invertebrates. The importance of T-box genes for human development is illustrated by the association between mutations in several of the 17 human family members and congenital errors of morphogenesis that include cardiac, craniofacial, and limb malformations. We identified two unrelated individuals with a complex cranial, cervical, auricular, and skeletal malformation syndrome with scapular and pelvic hypoplasia (Cousin syndrome) that recapitulates the dysmorphic phenotype seen in the Tbx15-deficient mice, droopy ear. Both affected individuals were homozygous for genomic TBX15 mutations that resulted in truncation of the protein and addition of a stretch of missense amino acids. Although the mutant proteins had an intact T-box and were able to bind to their target DNA sequence in vitro, the missense amino acid sequence directed them to early degradation, and cellular levels were markedly reduced. We conclude that Cousin syndrome is caused by TBX15 insufficiency and is thus the human counterpart of the droopy ear mouse.

Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis.

Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6-sulfotransferase) has been reported in a single kindred so far and in association with a phenotype of severe chondrodysplasia with progressive spinal involvement. We report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations. These patients had been given a diagnosis of either Larsen syndrome (three individuals) or humero-spinal dysostosis (three individuals), and their clinical features included congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfoot, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming functional impairment of CHST3 and distinguishing them from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells. These observations provide a molecular basis for recessive Larsen syndrome and indicate that recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type form a phenotypic spectrum.

Fetal akinesia in metatropic dysplasia: The combined phenotype of chondrodysplasia and neuropathy?

Dominant mutations in the receptor calcium channel gene TRPV4 have been associated with a family of skeletal dysplasias (metatropic dysplasia, pseudo-Morquio type 2, spondylometaphyseal dysplasia, Kozlowski type, brachyolmia, and familial digital arthropathy) as well as with dominantly inherited neuropathies (hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy). While there is phenotypic overlap between the various members of each group, the two groups were considered to be totally separate with the former being strictly a structural skeletal condition and the latter group being confined to the peripheral nervous system. We report here on fetal akinesia as the presenting feature of severe metatropic dysplasia, suggesting that certain TRPV4 mutations can cause both a skeletal and a neuropathic phenotype. Three cases were detected on prenatal ultrasound because of absent movements in the second trimester. Case 4 presented with multiple joint contractures and absent limb movements at birth and was diagnosed with "fetal akinesia syndrome". Post-interruption and post-natal X-rays showed typical features of metatropic dysplasia in all four. Sequencing of the TRPV4 gene confirmed the presence of de novo heterozygous mutations predicting G78W (Case 1), T740I (Cases 2 and 3), and K276E (Case 4). Although some degree of restriction of movements is not uncommon in fetuses with skeletal dysplasia, akinesia as leading sign is unusual and suggests that certain TRPV4 mutations produce both chondrodysplasia and a peripheral neuropathy resulting in a severe "overlap" phenotype.

Nosology and classification of genetic skeletal disorders: 2010 revision.

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.