Search

RPL13-related disorder is a newly described skeletal dysplasia characterized as a form of spondyloepimetaphyseal dysplasia with normal birth length, early postnatal growth deficiency, severe short stature, and genu varum. We present a 9-year-old male with a history of lower leg pain and concern for an unspecified form of multiple epiphyseal dysplasia (MED). Exome sequencing revealed a de novo heterozygous RPL13 c.477+1G>A (IVS4+1G>A) pathogenic variant. This is the first identified case of an individual with an RPL13-related skeletal dysplasia, normal height, and radiographs consistent with a form of MED and Legg-Calve-Perthes-like disease. This case expands the phenotype of RPL13-related disorders.

Background Beyond its structural role in the skeleton, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skeletal disorders, yet the consequences of an abnormal ECM on cellular communication remains less well understood Methods Clinical and radiographic examinations defined the phenotype in this unappreciated bent bone skeletal disorder. Exome analysis identified the genetic alteration, confirmed by Sanger sequencing. Quantitative PCR, western blot analyses, immunohistochemistry, luciferase assay for WNT signaling were employed to determine RNA, proteins levels and localization, and dissect out the underlying cell signaling abnormalities. Migration and wound healing assays examined cell migration properties. Findings This bent bone dysplasia resulted from biallelic mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein. This finding uncovered a mechanism of disease driven by ECM-cell interactions between alpha-5-containing laminins, and integrin-mediated focal adhesion signaling, particularly in cartilage. Loss of LAMA5 altered β1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase, FYN. Loss of LAMA5 negatively impacted the actin cytoskeleton, vinculin localization, and WNT signaling. Interpretation This newly described mechanism revealed a LAMA5-β1 Integrin-PYK2-FYN focal adhesion complex that regulates skeletogenesis, impacted WNT signaling and, when dysregulated, produced a distinct skeletal disorder. Funding Supported by NIH awards R01 AR066124, R01 DE019567, R01 HD070394, and U54HG006493, and Czech Republic grants INTER-ACTION LTAUSA19030, V18-08-00567 and GA19-20123S.

The short-rib polydactyly syndromes (SRPS) are autosomal recessively inherited, genetically heterogeneous skeletal ciliopathies. SRPS phenotypes were historically categorized as types I-IV, with type I first delineated by Saldino and Noonan in 1972. Characteristic findings among all forms of SRP include short horizontal ribs, short limbs and polydactyly. The SRP type I phenotype is characterized by a very small thorax, extreme micromelia, very short, poorly mineralized long bones, and multiple organ system anomalies. To date, the molecular basis of this most severe type of SRP, also known as Saldino-Noonan syndrome, has not been determined. We identified three SRP cases that fit the original phenotypic description of SRP type I. In all three cases, exome sequence analysis revealed compound heterozygosity for mutations in DYNC2H1, which encodes the main component of the retrograde IFT A motor, cytoplasmic dynein 2 heavy chain 1. Thus SRP type I, II, III and asphyxiating thoracic dystrophy (ATD), which also result from DYNC2H1 mutations. Herein we describe the phenotypic features, radiographic findings, and molecular basis of SRP type I.

Although mucolipidosis type II has similar metabolic abnormalities to those found in all the mucopolysaccharidoses and mucolipidoses, there are distinctive diagnostic radiographic changes of mucolipidosis II in the perinatal/newborn/infant period.To describe the early characteristic radiographic changes of mucolipidosis II and to document when these changes manifest and resolve.We retrospectively reviewed radiographs and clinical records of 19 cases of mucolipidosis II from the International Skeletal Dysplasia Registry (1971-present; fetal age to 2½ years). A radiologist with special expertise in skeletal dysplasias evaluated the radiographs.The most common abnormalities were increased vertebral body height (80%, nonspecific), talocalcaneal stippling (86%), periosteal cloaking (74%) and vertebral body rounding (50%). Unreported findings included sacrococcygeal sclerosis (54%) and vertebral body sclerosis (13%). Rickets and hyperparathyroidism-like (pseudohyperparathyroidism) changes (rarely reported) were found in 33% of cases. These changes invariably started in the newborn period and resolved by 1 year of age. The conversion from these early infantile radiographic features to dysostosis multiplex changes occurred in 41% of cases, and within the first year after birth.Several findings strongly suggest the diagnosis of mucolipidosis II, including cloaking in combination with one or more of the following radiographic criteria: talocalcaneal stippling, sacrococcygeal or generalized vertebral body sclerosis, vertebral body rounding, or rickets/hyperparathyroidism-like changes in the perinatal/newborn/infancy period. These findings are not found in the other two forms of mucolipidosis nor in any of the mucopolysaccharidoses.

Over a decade ago, the Atacama humanoid skeleton (Ata) was discovered in the Atacama region of Chile. The Ata specimen carried a strange phenotype—6-in stature, fewer than expected ribs, elongated cranium, and accelerated bone age—leading to speculation that this was a preserved nonhuman primate, human fetus harboring genetic mutations, or even an extraterrestrial. We previously reported that it was human by DNA analysis with an estimated bone age of about 6–8 yr at the time of demise. To determine the possible genetic drivers of the observed morphology, DNA from the specimen was subjected to whole-genome sequencing using the Illumina HiSeq platform with an average 11.5× coverage of 101-bp, paired-end reads. In total, 3,356,569 single nucleotide variations (SNVs) were found as compared to the human reference genome, 518,365 insertions and deletions (indels), and 1047 structural variations (SVs) were detected. Here, we present the detailed whole-genome analysis showing that Ata is a female of human origin, likely of Chilean descent, and its genome harbors mutations in genes (COL1A1, COL2A1, KMT2D, FLNB, ATR, TRIP11, PCNT) previously linked with diseases of small stature, rib anomalies, cranial malformations, premature joint fusion, and osteochondrodysplasia (also known as skeletal dysplasia). Together, these findings provide a molecular characterization of Ata's peculiar phenotype, which likely results from multiple known and novel putative gene mutations affecting bone development and ossification.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman–Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.

Shwachman-Bodian-Diamond syndrome (OMIM 260400) was identified in 1964 by pediatricians Harry Shwachman, a leader in cystic fibrosis, and Louis K. Diamond, a hematologist, along with pediatrician and morbid anatomist Martin Bodian. Initially the syndrome's clinical presentation included exocrine pancreatic insufficiency (lipomatous replacement of the pancreas) and neutropenia. In 1967 skeletal changes of metaphyseal chondrodysplasia were also described, completing the triad of findings; these abnormalities are present in all affected children and should be viewed as an integral feature of the syndrome, also called Shwachman-Diamond syndrome.

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

Background Skeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib polydactyly syndrome (SRPS), a recessively inherited perinatal lethal condition characterized by a long narrow chest, markedly shortened long bones, polydactyly and, often, multi-organ system involvement. SRPS shows extensive locus heterogeneity with mutations in genes encoding proteins that participate in cilia formation and/or function. Results Herein we describe mutations in IFT43, a satellite member of the retrograde IFT-A complex, that produce a form of SRPS with unusual bending of the ribs and appendicular bones. These newly described IFT43 mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that the IFT43 SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43. Conclusions This study defines a new IFT43-associated phenotype, identifying an additional locus for SRPS. The data demonstrate that IFT43 is essential for ciliogenesis and that the mutations disrupted the orderly proliferation and differentiation of growth plate chondrocytes, resulting in a severe effect on endochondral ossification and mineralization. Phenotypic similarities with SRPS cases resulting from mutations in the gene encoding the IFT43 direct interacting protein IFT121 suggests that similar mechanisms may be disrupted by defects in these two IFT-A satellite interactors. Electronic supplementary material The online version of this article (doi:10.1186/s13630-017-0051-y) contains supplementary material, which is available to authorized users.

Multiple Epiphyseal Dysplasia (MED) is a relatively mild skeletal dysplasia characterized by mild short stature, joint pain, and early-onset osteoarthropathy. Dominantly inherited mutations in COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2, account for the molecular basis of disease in about 80–85% of the cases. In two families with recurrent MED of an unknown molecular basis, we used exome sequencing and candidate gene analysis to identify homozygosity for recessively inherited missense mutations in CANT1, which encodes calcium-activated nucleotidase 1. The MED phenotype is thus allelic to the more severe Desbuquois dysplasia phenotype and the results identify CANT1 as a second locus for recessively inherited MED.

Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin. Cells transfected with the MYH3 missense mutations had reduced TGFβ signaling, revealing a regulatory role for embryonic myosin in the TGFβ signaling pathway. In wild-type mice, there was persistent postnatal expression of embryonic myosin in the small muscles joining the neural arches of the spine suggesting that loss of myosin function in these muscles contribute to the disease. Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions.

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.

Serpentine fibula polycystic kidney syndrome (SFPKS; OMIM600330) is a rare skeletal dysplasia with a characteristic phenotype that includes polycystic kidneys, S-shaped fibulas, and abnormal craniofacial features. SFPKS shares features with Alagille (AGS; OMIM) and Hajdu–Cheney (HCS; OMIM10250) syndromes. All three syndromes result from mutations in the gene that encodes NOTCH2, one of the receptors involved in Notch signaling. Notch signaling is a major developmental signaling pathway, as well as a key regulator of numerous cellular processes. In this report, we present the prenatal ultrasound and postnatal findings in a 23-week fetus with severe manifestations of SPKS and heterozygosity for a de novo mutation in exon 34 of NOTCH2. These findings expand the phenotypic spectrum of NOTCH2 mutations and demonstrate the findings in the prenatal period. © 2014 Wiley Periodicals, Inc.

Opsismodysplasia (OMIM258480) is a rare, autosomal recessive skeletal dysplasia with delayed bone maturation. It was first described in 1977 by Zonana et al. and named opsismodysplasia by Maroteaux et al. in 1984 [Maroteaux et al., 1982; Maroteaux et al., 1984]. The clinical features include micromelia with extremely short hands and feet, as well as facial dysmorphism including prominent eyebrows, large open fontanels, depressed nasal bridge, short anteverted nose and relatively long philtrum. Some patients were also reported as having severe renal phosphate wasting [Below et al., 2013]. The characteristic radiographic features include severe platyspondyly, shortened long bones with dramatically delayed epiphyseal ossification, and characteristic hands with markedly delayed carpal ossification, short squared metacarpals and phalanges, and metaphyseal cupping [Beemer and Kozlowski 1994; Cormier-Daire et al., 2003; Maroteaux et al., 1984; Santos and Saraiva 1995; Tyler et al., 1999; Zonana et al., 1977]. The mortality is highly variable, ranging from death secondary to respiratory failure during the first few years of life to survival into adulthood.

Objective Mucopolysaccharidosis IVA (MPS IVA, or Morquio A syndrome) and VI (MPS VI, or Maroteaux–Lamy syndrome) are autosomal recessive lysosomal storage disorders. Skeletal abnormalities are common initial presenting symptoms and, when recognized early, may facilitate timely diagnosis and intervention, leading to improved patient outcomes. Patients with slowly progressing disease and nonclassic phenotypes can be particularly challenging to diagnose. The objective was to describe the radiographic features of patients with a delayed diagnosis of MPS IVA or VI. Materials and Methods This was a retrospective study. The records of 5 MPS IVA and 3 MPS VI patients with delayed diagnosis were reviewed. Radiographs were evaluated by a radiologist with special expertise in skeletal dysplasias. Results An important common theme in these cases was the appearance of multiple epiphyseal dysplasia (MED) with epiphyseal changes seemingly confined to the capital (proximal) femoral epiphyses. Very few patients had the skeletal features of classical dysostosis multiplex. Conclusions Radiologists should appreciate the wide phenotypic variability of MPS IVA and VI. The cases presented here illustrate the importance of considering MPS in the differential diagnosis of certain skeletal dysplasias/disorders, including MED, some forms of spondylo-epiphyseal dysplasia (SED), and bilateral Perthes-like disease. It is important to combine radiographic findings with clinical information to facilitate early testing and accurate diagnosis.

Congenital Disorder of Glycosylation type Ig (ALG12-CDG) is part of a group of autosomal recessive conditions caused by deficiency of proteins involved in the assembly of dolichol-oligosaccharides used for protein N-glycosylation. In ALG12-CDG, the enzyme affected is encoded by the ALG12 gene. Affected individuals present clinically with neurodevelopmental delay, growth retardation, immune deficiency, male genital hypoplasia, and cardiomyopathy. A total of six individuals have been reported in the literature. Here, we present an infant with rhizomelic short stature, talipes equinovarus, platyspondyly, and joint dislocations. The infant had marked under-ossification of the pubic bones. Exome sequencing was performed and two deletions, each resulting in a frameshift, were found in ALG12. A review of the literature revealed two infants with ALG12-CDG and a severe skeletal dysplasia, including under-ossification of cervical vertebrae, pubic bones, and knees; in addition to talipes equinovarus and rhizomelic short stature. The phenotype of the individual we describe resembles pseudodiastrophic dysplasia and we discuss similarities and differences between ALG12-CDG and pseudodiastrophic dysplasia. The differential diagnosis in selected undiagnosed skeletal dysplasias should include CDGs.

The story of Ellis-van Creveld syndrome is one of serendipity. By chance, Simon van Creveld and Richard Ellis purportedly met on a train and combined their independently encountered patients with short stature, dental anomalies and polydactyly into one landmark publication in 1940. They included a patient used in work published previously by Rustin McIntosh without naming McIntosh as a coauthor. This patient was followed radiologically by Caffey for nearly two decades. In 1964, Victor McKusick felt compelled to investigate a brief report in an obscure pharmaceutical journal on an unusual geographic cluster of short-statured Amish patients in Pennsylvania. This review highlights the lives of the individuals involved in the discovery of Ellis-van Creveld syndrome in their historic context.

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.

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.

Dominant mutations in TRPV4, which encodes the Transient Receptor Potential Cation Channel Subfamily V Member 4 calcium channel, result in a series of musculoskeletal disorders that include a set of peripheral neuropathies and a broad phenotypic spectrum of skeletal dysplasias. The skeletal phenotypes range from brachyolmia, in which there is scoliosis with mild short stature, through perinatal lethal metatropic dysplasia. We describe a case with phenotypic findings consistent with metatropic dysplasia, but in whom no TRPV4 mutation was detected by Sanger sequence analysis. Exome sequence analysis identified a known lethal metatropic dysplasia mutation, TRPV4L618P , which was present at lower frequency than would be expected for a heterozygous change. The affected individual was shown to be a somatic mosaic for the mutation, providing an explanation for the milder than expected phenotype. The data illustrate that high-throughput sequencing of genomic DNA can facilitate detection of mosaicism with higher sensitivity than Sanger sequence analysis and identify a new genetic mechanism for metatropic dysplasia. © 2016 Wiley Periodicals, Inc.

The short-rib polydactyly syndromes (SRPS) encompass a radiographically and genetically heterogeneous group of skeletal ciliopathies that are characterized by a long narrow chest, short extremities, and variable occurrence of polydactyly. Radiographic abnormalities include undermineralization of the calvarium, shortened and bowed appendicular bones, trident shaped acetabula and polydactyly. In a case of SRPS we identified compound heterozygosity for mutations in IFT52, which encodes a component of the anterograde intraflagellar transport complex. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. These data demonstrate that IFT52 is essential for anterograde complex integrity and for the biosynthesis and maintenance of cilia. The data identify a new locus for SRPS and show that IFT52 mutations result in a ciliopathy with primary effects on the skeleton.

We report on a male infant born at 38 weeks of gestation with hydrocephalus, right anophthalmia, left microphthalmia, cleft palate, midline cleft of lip, and microphallus. Autopsy showed pulmonary bronchial lymphangiectasia, hepatic periportal fibrosis, adrenal agenesis, ventricular septal defect, aortic stenosis, and undescended testes. The radiographic findings include short limbs and mild shortness of ribs. Karyotype with high-resolution banding was normal (46,XY). The combination of anomalies in this case could suggest a ciliopathy and may represent a new entity similar to that described by Cideciyan et al. [1].

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.

This historical report focuses on the first clinical description of pseudoachondroplasia and its radiographic findings. Only half a century ago, pseudoachondroplasia was recognized as a genetic disorder with a distinct but variable phenotype of short stature, normal facial features, and progressive joint problems starting in adolescence. Radiologically, the disease is particularly intriguing because the patients appear normal at birth. The patients develop the typical gait disturbances when they begin to walk. Radiographs show the characteristic anterior tongue-shaped lumbar vertebral body changes that develop after the first year of life. This account presents the most well-known group of individuals affected by pseudoachondroplasia, the Ovitz family, who narrowly escaped death in the concentration camp of Auschwitz in 1944 because of SS physician Dr. Josef Mengele's fascination with dwarfs. It was not until 1995 that the underlying genetic defect in the COMP gene was identified on chromosome 19.

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.

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 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.

The existence of dwarfism is amply documented in ancient Egypt due to the rich biological and artistic legacies. In previous articles published in this journal, I discussed the roles of people with skeletal dysplasia in ancient Egyptian civilization. In this article I, along with my Egyptian and American colleagues, describe two skeletons of dwarfs that date to 2700–2184 BCE and were unearthed from a funerary complex near the Great Pyramids in Giza. The first skeleton belongs to a high official, Per-ni-ankh-w, who died between 45 and 50 years of age. His statue is on display in the Egyptian Museum of Cairo. The second skeleton belongs to a pregnant female worker found with a fetus in situ. Her estimated age at death was 25–30 years. She most likely died during childbirth due to a small pelvic outlet as supported by her narrow sacrum. The fetal bones appear normal. Radiological examination of both skeletons confirmed the clinical diagnosis of achondroplasia. Ancient Egyptians concerned themselves with the search for spiritual fulfillment through the tradition of moral teachings. Amenemope, a wise man who lived during the reign of Amenhotep III (1391–1354 BCE), advocated respect toward individuals with disabilities: Do not jeer at a blind man nor tease a dwarf, Neither interfere with the condition of a cripple. Do not taunt a man who is in the hand of God, Nor scowl at him if he errs. In summary, artistic, biological, and written resources indicate that dwarfs were well integrated in ancient Egyptian society. © 2011 Wiley-Liss, Inc.

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.

Heterozygous sequence variants of the COL2A1 gene cause a phenotypic spectrum collectively called type II collagenopathies. Here, we describe a COL2A1 sequence variant, c.2957C>T, p.Pro986Leu in the triple helical domain, which is a Y-position substitution in exon 41 of the repeating triplet sequence Gly-X-Y of the proα1(II) chain. This sequence variant was associated with a mild spondyloepiphyseal dysplasia phenotype in three individuals in a three-generation family. On clinical examination at the age of 19 months, the proband had a flat face, bifid uvula, and a protruding abdomen. Radiographically, he had rhizomelia, mesomelia, and ovoid-shaped vertebrae. He also had absent mineralization of the epiphyses, the os pubis, tali, and calcanei. His mother had myopia, mild lumbar lordosis, and mild coxa vara. She had a detached retina repaired at age 24 years. The maternal grandmother had cataracts but has had no kyphoscoliosis or lordosis. All three had disproportionate short stature. None had arthritis or hearing loss. The sequence variant in this family is the only reported Y-position proline substitution in the triple helical domain (Gly-X-Y) of the proα1(II) coded by the COL2A1 gene.

The mucopolysaccharidoses (MPS) represent a group of inheritable, clinically heterogeneous lysosomal storage disorders, in which progressive accumulation of glycosaminoglycans (GAGs) can affect organs and tissues all over the body. The current paper discusses the skeletal X-ray and neuroimaging findings in MPS patients, and the imaging techniques that can be used for diagnosing and monitoring abnormalities in the skeleton and central nervous system. Most MPS types show a typical radiologic expression, called dysostosis multiplex, which manifests as malformations of the skeletal system involving bones in the skull, thorax, spine, pelvis, long bones, and hands. Abnormalities of the spine and GAG deposits in the meninges surrounding the spinal cord can result in spinal cord compression, which, if untreated, can lead to compressive myelopathy. Magnetic resonance imaging (MRI) is the most powerful imaging technique for detecting spinal cord compression, but also radiography and computed tomography are useful. GAG deposits in the brain and surrounding tissues can result in brain anomalies, i.e. white matter lesions, brain atrophy, and hydrocephalus, which can be detected using MRI. Skeletal X-ray and neuroimaging findings can play an important role in diagnosis, follow-up, surgical or medical planning, and assessment of treatment response in MPS patients. There is a need for standardized procedures in evaluating and monitoring neurologic complications in these patients.

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.

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.

Here we report on a patient with an interstitial deletion on the long(q) arm of chromosome 1 who presents with a unique constellation of anomalies including brachydactyly type E, Müllerian agenesis, growth hormone deficiency, as well as other abnormalities. We present the clinical details of this patient's presentation, the skeletal findings, and provide characterization of the deletion at the molecular level. We postulate that these skeletal anomalies are distinctive to 1q deletions involving the 1q24q25 region.

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.

A multilayered patella is a characteristic radiographic finding of recessive multiple epiphyseal dysplasia (rMED) caused by DTDST mutations. However it has been recently reported in a dominant MED case with a COL9A2 mutation. We report on a new radiographic patellar finding in a patient with pseudoachondroplasia and a heterozygous COMP mutation. It is similar to the radiographic appearance of fusing multilayered patellae in rMED cases. This led us to search the International Skeletal Dysplasia Registry for similar abnormalities. We did not observe this finding in other skeletal dysplasias or other pseudoachondroplasia cases. However we found an accessory ossification center of the patella in another pseudoachondroplasia case. Thus, we hypothesize that variable defects of cartilage extracellular matrix can result in similar abnormal patellar ossifications, and emphasize the importance of a lateral knee radiograph in patients with the pseudoachondroplasia-MED bone dysplasia group of disorders.

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

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia associated with cranial, clavicular, and dental anomalies. It is caused by mutations in the RUNX2 gene, which encodes an osteoblast-specific transcription factor and maps to chromosome 6p21. We report clinical and molecular cytogenetic studies in a patient with clinical features of CCD including wormian bones, delayed fontanel closure, hypoplastic clavicles and pubic rami, and supernumerary dentition. Additional abnormalities of bone growth and connective tissue, including easy bruisability, scarring, bleeding, joint hypermobility, and developmental delay were also observed. Molecular cytogenetic studies identified a de novo apparently balanced three-way translocation 46,XY,t(4;6;21)(p16;p21.1;q21). Further mapping revealed the breakpoint on 6p21 to be approximately 50 kb upstream of exon 1 of the RUNX2 gene, with RUNX2 being intact on the derivative chromosome 6. We hypothesize that the proband's CCD has arisen from disruption of the developmentally regulated gene RUNX2 at the 6p21 breakpoint, due to a position effect mutation which may have altered the expression of the gene. Further studies might unravel a new regulatory element for RUNX2.

Angulated or bent femur (isolated or associated with other long bone bowing) in the fetus or newborn is relatively common when evaluating patients with skeletal dysplasias. To determine the extent and heterogeneity of disorders associated with angulated or bent femurs, we analyzed cases in the radiographic database (1998-2006) of the International Skeletal Dysplasia Registry (ISDR) and determined which established skeletal dysplasias and genetic syndromes are associated with this finding. The results show that more than 40 distinct disorders with varying frequency (very rare to more commonly occurring disorders) can be associated with bowed/bent/angulated femurs. Sixty-six percent of the cases with angulated femurs belonged to three well described groups of disorders; campomelic disorders (24.4%), thanatophoric dysplasia (23.9%) and osteogenesis imperfecta (OI) (18.1%). With specific emphasis on these, this cross-sectional cohort provides discussion of data on other rare disorders associated with angulated femurs and the importance of the finding relative to its occurrence within a diagnostic group. This study aims to provide differential diagnosis of entities to be considered when a fetus or newborn is found to have congenital bowing/angulation of the femur.

The purpose of the nosology is to serve as a "master" list of the genetic disorders of the skeleton to facilitate diagnosis and to help delineate variant or newly recognized conditions. This is the 9th edition of the nosology and in comparison with its predecessor there are fewer conditions but many new genes. In previous editions, diagnoses that were phenotypically indistinguishable but genetically heterogenous were listed separately but we felt this was an unnecessary distinction. Thus the overall number of disorders has decreased from 456 to 436 but the number of groups has increased to 42 and the number of genes to 364. The nosology may become increasingly important today and tomorrow in the era of big data when the question for the geneticist is often whether a mutation identified by next generation sequencing technology in a particular gene can explain the clinical and radiological phenotype of their patient. This can be particularly difficult to answer conclusively in the prenatal setting. Personalized medicine emphasizes the importance of tailoring diagnosis and therapy to the individual but for our patients with rare skeletal disorders, the importance of tapping into a resource where genetic data can be centralized and made available should not be forgotten or underestimated. The nosology can also serve as a reference for the creation of locus-specific databases that are expected to help in delineating genotype-phenotype correlations and to harbor the information that will be gained by combining clinical observations and next generation sequencing results. (C) 2015 Wiley Periodicals, Inc.

The filamins are a family of cytoplasmic proteins that bind to and organize actin filaments, link membrane proteins to the cytoskeleton, and provide a scaffold for signaling molecules. Mutations in the gene encoding filamin B (FLNB) cause a spectrum of osteochondrodysplasias, including atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII). AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations. Previous studies have shown that heterozygosity for missense mutations that alter the CH2 domain and repeat 6 region of filamin B produce AOI and AOIII. In this study, 14 novel missense mutations in FLNB were found in 15 unrelated patients with AOI and AOIII. The majority of the mutations resided in exon 2 and exon 3, which encode the CH2 domain of the actin,binding region of filamin B. The remaining mutations were found in exon 28 and exon 29, which encode repeats 14 and 15 of filamin B. These results show that clustering of mutations in two regions of FLNB produce AOI/AOIII, and highlight the important role of this cytoskeletal protein in normal skeletogenesis. Hum Mutat 27(7), 705-710,2006. Published 2006 Wiley,Liss, Inc.(dagger).

Larsen syndrome is an autosomal-dominant disorder characterized by multiple joint dislocations, vertebral anomalies and dysmorphic facies. Both autosomal-dominant and autosomal-recessive forms of the disorder have been proposed. Individuals with autosomal-dominant Larsen syndrome have characteristic "cylindrical-shape" thumbs caused by broad, shortened phalanges. Autosomal-dominant Larsen syndrome results from heterozygosity for mutations in filamin B, a cytoskeletal protein involved in multicellular processes. We report here a patient with a duplicated or accessory distal thumb phalanx and multiple large joint dislocations who was shown to be heterozygous for a filamin B mutation predicting the amino acid substitution G1691S. This adds a new radiographic finding, duplicated or accessory distal phalanx, to the radiographic abnormalities seen in this rare dominant disorder.

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.

We describe two Hispanic brothers born to unrelated parents with van den Ende-Gupta syndrome (VDEGS), a distinctive combination of characteristic dysmorphic features, skeletal abnormalities, and cerebellar hyperplasia. This syndrome was previously delineated by van den Ende et al. [1992: Am J Med Genet 42:467-469] and Gupta et al. [1995: J Med Genet 32:809-812], with additional reports by Phadke et al. [1998: Am J Med Genet 77:16-18] and Bistritzer et al. [1993: Clin Genet 44:15-19]. This is the fifth report of VDEGS, which is characterized by blepharophimosis, narrow nose with hypoplastic alae nasi, hypoplastic maxilla, everted lower lip, slender and elongated hands and feet, arachnodactyly, self-limiting joint contractures, and distinctive skeletal findings. This report of affected siblings, and a previous report of double second cousins born to consanguineous parents [Bistritzer et al. [1993: Clin Genet 44:15-19]], suggests autosomal recessive inheritance. This brings to eight, the total number of reported cases, derived from six families, three of which are consanguineous. It is important to distinguish VDEGS from Marden-Walker syndrome (MWS) since both syndromes include blepharophimosis, arachnodactyly, and congenital contractures. Both syndromes are inherited in an autosomal recessive fashion, but VDEGS lacks severe mental retardation, serious brain malformations, microcephaly, failure to thrive, and severe joint limitation, which are consistently present in MWS. Of particular importance, MWS may be associated with cerebellar malformations such as Dandy-Walker malformation, while the brothers reported herein with VDEGS both demonstrated distinctive cerebellar enlargement, a new finding for this disorder. While, congenital contractures with arachnodactyly are features commonly seen in several other delineated syndromes, such as congenital contractural arachnodactyly (CCA) syndrome, characteristic facial features (blepharophimosis, narrow nose with ocular hypertelorism, prominent ears, and everted lower lip), distinguish VDEGS from other syndromes associated with CCA, including CCA.

Desbuquois dysplasia is a rare chondrodysplasia characterized by short stature, joint laxity, and specific radiographic findings. We report the natural history of four patients (three boys and one girl) with Desbuquois dysplasia ages 16-22 years. The mean height in adulthood was 114 cm (-8.5 SD) with progressive deceleration of the growth curve from birth (-4 SD) to adulthood. Obesity was noted consistently and facial abnormalities were still present but less obvious than in childhood. Three of four patients had mental retardation of varying degree. Hyperlaxity was persistent but limited motion of various joints was also noted. Orthopedic complications included coxa vara or valga (3/4), scoliosis (3/4), marked lordosis (3/4), and ambulatory difficulties (3/4). Surgical treatment was necessary for all four patients, involving large joints, spine and hands. Other complications included acute open-angle glaucoma secondary to a congenital malformation of the angle in one case. In addition to consistent radiological findings, elevated greater trochanter, generalized osteoporosis especially of the spine, scoliosis and/or lordosis, wide metaphyses, flat epiphyses, and coxa vara or valga were part of the natural history of the disorder. Our study emphasizes the care of older patients with Desbuquois dysplasia.