Clinical and radiographic delineation of Bent Bone Dysplasia-FGFR2 type or Bent Bone Dysplasia with Distinctive Clavicles and Angel-shaped Phalanges.

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.

Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism.

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

Echocardiographic findings in patients with spontaneous CSF leak.

The presence of cardiovascular abnormalities in patients with spontaneous cerebrospinal fluid (CSF) leaks are not well-documented in the literature, as cardiovascular evaluation is not generally pursued if a patient does not exhibit additional clinical features suggesting an inherited connective tissue disorder. We aimed to assess this association, enrolling a consecutive group of 50 patients referred for spinal CSF leak consultation. Through echocardiographic evaluation and detailed medical history, we estimate that up to 20% of patients presenting with a spontaneous CSF leak may have some type of cardiovascular abnormality. Further, the increase in prevalence of aortic dilatation in our cohort was statistically significant in comparison to the estimated population prevalence. This supports a clinical basis for echocardiographic screening of these individuals for cardiovascular manifestations that may have otherwise gone unnoticed or evolved into a more severe manifestation.

Dynamic cervicomedullary cord compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia: review of an 11-year surgical case series.

OBJECT: Achondroplasia may be associated with compression at the cervicomedullary junction. Determining which patients are at greatest risk for neurological complications of cervicomedullary compression can be difficult. In the current study the authors reviewed their records to determine the incidence and clinical significance of dynamic cervicomedullary stenosis and obstruction of CSF flow along with surgical outcomes following posterior fossa decompression. METHODS: The authors reviewed 34 consecutive cases involving symptomatic children with achondroplasia undergoing cervicomedullary decompression performed by a single surgeon over 11 years. Of these patients, 29 had undergone preoperative dynamic MRI of the cervicomedullary junction with cine (cinema) CSF flow studies; 13 of these patients underwent postoperative dynamic MRI studies. Clinical outcomes included changes in polysomnography, head circumference percentile, and fontanel characteristics. Radiographic outcomes included changes in dynamic spinal cord diameter, improvement in CSF flow at the foramen magnum, and change in the Evans ratio. RESULTS: Patients were predominantly female, with a mean age at presentation of 6.6 years and mean follow-up of 3.7 years (range 1-10 years). All patients had moderate to excellent improvement in postoperative polysomnography, slight decrease in average head circumference percentile (from 46.9th percentile to 45.7th percentile), and no subjective worsening of fontanel characteristics. The Evans ratio decreased by 2%, spinal cord diameter increased an average of 3.1 mm, 5.2 mm, and 0.2 mm in the neutral, flexed, and extended positions, respectively, and CSF flow improved qualitatively in all 3 positions. There were no postoperative infections, CSF leaks, or other major complications. None of the patients undergoing initial foramen magnum decompression performed at our medical center required reoperation. CONCLUSIONS: Patients with achondroplasia and symptomatic cervicomedullary compression have increased risk of dynamic stenosis at the foramen magnum evident upon dynamic cine MRI. Operative decompression may be offered with low risk of complications or need for reoperation.

Patient-derived skeletal dysplasia induced pluripotent stem cells display abnormal chondrogenic marker expression and regulation by BMP2 and TGFß1.

Skeletal dysplasias (SDs) are caused by abnormal chondrogenesis during cartilage growth plate differentiation. To study early stages of aberrant cartilage formation in vitro, we generated the first induced pluripotent stem cells (iPSCs) from fibroblasts of an SD patient with a lethal form of metatropic dysplasia, caused by a dominant mutation (I604M) in the calcium channel gene TRPV4. When micromasses were grown in chondrogenic differentiation conditions and compared with control iPSCs, mutant TRPV4-iPSCs showed significantly (P<0.05) decreased expression by quantitative real-time polymerase chain reaction of COL2A1 (IIA and IIB forms), SOX9, Aggrecan, COL10A1, and RUNX2, all of which are cartilage growth plate markers. We found that stimulation with BMP2, but not TGFß1, up-regulated COL2A1 (IIA and IIB) and SOX9 gene expression, only in control iPSCs. COL2A1 (Collagen II) expression data were confirmed at the protein level by western blot and immunofluorescence microscopy. TRPV4-iPSCs showed only focal areas of Alcian blue stain for proteoglycans, while in control iPSCs the stain was seen throughout the micromass sample. Similar staining patterns were found in neonatal cartilage from control and patient samples. We also found that COL1A1 (Collagen I), a marker of osteogenic differentiation, was significantly (P<0.05) up-regulated at the mRNA level in TRPV4-iPSCs when compared with the control, and confirmed at the protein level. Collagen I expression in the TRPV4 model also may correlate with abnormal staining patterns seen in patient tissues. This study demonstrates that an iPSC model can recapitulate normal chondrogenesis and that mutant TRPV4-iPSCs reflect molecular evidence of aberrant chondrogenic developmental processes, which could be used to design therapeutic approaches for disorders of cartilage.

FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry.

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.

WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia.

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

Recurrent compartment syndrome in a patient with clinical features of a connective tissue disorder.

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

Human long bone development in vivo: analysis of the distal femoral epimetaphysis on MR images of fetuses.

PURPOSE: To investigate human long bone development in vivo by analyzing distal femoral epimetaphyseal structures and bone morphometrics on magnetic resonance (MR) images of fetuses. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: Prenatal MR imaging allows visualization of human bone development in vivo by means of epimetaphyseal characteristics and bone morphometrics. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13112441/-/DC1.

Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study.

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

Ehlers-Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features.

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

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A.

Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.

Human Variome Project country nodes: documenting genetic information within a country.

The Human Variome Project (http://www.humanvariomeproject.org) is an international effort aiming to systematically collect and share information on all human genetic variation. The two main pillars of this effort are gene/disease-specific databases and a network of Human Variome Project Country Nodes. The latter are nationwide efforts to document the genomic variation reported within a specific population. The development and successful operation of the Human Variome Project Country Nodes are of utmost importance to the success of Human Variome Project's aims and goals because they not only allow the genetic burden of disease to be quantified in different countries, but also provide diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research, respectively. Here, we report the discussions and recommendations that resulted from the inaugural meeting of the International Confederation of Countries Advisory Council, held on 12th December 2011, during the 2011 Human Variome Project Beijing Meeting. We discuss the steps necessary to maximize the impact of the Country Node effort for developing regional and country-specific clinical genetics resources and summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects.

Visceroptosis of the bowel in the hypermobility type of Ehlers-Danlos syndrome: presentation of a rare manifestation and review of the literature.

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

Filamin A mutation associated with normal reading skills and dyslexia in a family with periventricular heterotopia.

Periventricular heterotopia (PH) is a disorder of neuronal migration during fetal development that is characterized by morphologically normal neurons being located in an anatomically abnormal position in the mature brain. PH is usually diagnosed in patients presenting with a seizure disorder, when neuroimaging demonstrates the ectopically placed nodules of neurons. PH is a genetically and phenotypically heterogeneous disorder. The most commonly identified genetic cause is the X-linked dominant inheritance of mutations in the Filamin A (FLNA) gene. Multiple lines of evidence support the contribution of genetic factors in dyslexia. As dyslexia does not show a single-gene pattern of inheritance, it is classified as a complex genetic disorder. We have recently identified a specific reading fluency deficit in a variable group of patients with PH, in the context of normal intelligence. Here, we present a study of a mother-daughter pair who share bilateral widespread gray matter heterotopia caused by a novel mutation in FLNA and the same pattern of X-chromosome inactivation but who exhibit divergent reading and cognitive profiles. This novel observation highlights the uncertainty of using heterotopia anatomy in clinical practice to predict behavioral outcome.

Clubfeet and associated abnormalities on fetal magnetic resonance imaging.

OBJECTIVE: Clubfoot, or talipes equinovarus (TEV), is commonly diagnosed on prenatal ultrasound. This study sought to visualize TEV and associated abnormalities on fetal magnetic resonance imaging (MRI) compared with ultrasound. METHODS: This retrospective study included the MRI scans of 44 fetuses with TEV using postnatal assessment and autopsy as standard of reference. Isolated TEV was differentiated from complex TEV with associated abnormalities. MRI findings and previous ultrasound diagnoses were compared. RESULTS: Isolated TEV was found in 19/44 (43.2%) fetuses and complex TEV in 25/44 (56.8%). Associated abnormalities consisted of the following: central nervous system/spinal abnormalities in 13/25 (52.0%) fetuses; musculoskeletal abnormalities in 7/25 (28.0%); thoracic abnormalities in 3/25 (12.0%); a tumor in one case; and hydrops fetalis in one. Of the 44 cases, 35 (79.5%) pregnancies were delivered, and nine (20.5%) pregnancies, which were terminated, all had complex TEV. Of the 42 available ultrasound reports, additional MRI findings were made in 8/42 (19.0%) cases. MRI did not add findings in isolated TEV on ultrasound. In 4/44 (9.1%) cases, autopsy revealed additional findings compared with prenatal imaging. CONCLUSION: Fetal MRI enables differentiation between isolated and complex TEV. Isolated TEV on ultrasound may not be an MRI indication, whereas MRI may be useful in cases of complex TEV.

Male genital abnormalities in intrauterine growth restriction.

OBJECTIVE: Previous studies have shown a correlation between hypospadias and intrauterine growth restriction (IUGR), suggesting an association between placental insufficiency and abnormal genital development. This study sought to analyze the association of IUGR and genital abnormalities apparent on fetal magnetic resonance imaging (MRI). METHODS: This retrospective study included 22 MRI scans of 20 male fetuses between 20 and 35 weeks of gestation presenting with IUGR. On MRI, penile length and testicular descent were evaluated. Student's t-testing and analysis of covariance were used to compare MRI penile length measurements with published normative data obtained from fetal ultrasonography (US) and MRI. McNemar testing was used to evaluate testicular descent in IUGR, compared with reported fetal MRI normative data. RESULTS: The penile length in IUGR fetuses was shorter than in normal fetuses (p<0.001). Furthermore, six of 20 fetuses presented with a micropenis (2.5 SD below the mean value for age). Undescended testes were significantly more frequent in IUGR fetuses than in normal fetuses (p=0.004). CONCLUSION: Our data confirm that abnormal fetal growth may be associated with penile shortening and, potentially, also undescended testes.

Exome sequencing identifies PDE4D mutations in acrodysostosis.

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.