Severe Skeletal Dysplasia Research Articles

Opsismodysplasia and Dilated Cardiomyopathy: a case report

Background: Opsismodysplasia (OPSMD) is an extremely rare and severe autosomal recessive skeletal dysplasia that is under the category of severe spondylodysplastic dysplasia. It is characterized by delayed bone maturation, and affected patients are identified by a peculiar craniofacioskeletal dysmorphism in the form of wide anterior fontanelle, depressed nasal bridge, anteverted nares, and short limbs and feet. Radiologically, they are characterized by severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. Case Presentation: We present the clinical and radiological features of a 14-month-old boy with a homozygous, likely pathogenic variant in INPPL1 gene c.2627dup (p.Pro977Thrfs*7) consistent with the diagnosis of OPSMD. He also has dilated cardiomyopathy. Conclusion: OPSMD is an uncommon form of skeletal dysplasia that should be suspected in the context of short stature with characteristic radiological features. Up to now, no definitive therapeutic measures are available, and hence preventive measures are essential in the management of families with affected members.

Thanatophoric Dysplasia

Objective: Report a case of thanatophoric dysplasiaMethod: Case report Result: Case of a 25-year-old woman, with a diagnosis of gravid preterm G4P2A1H2 31-32 weeks + polyhydramnios + fetal hydrops, a single intrauterine live fetus with thanatophoric dysplasia. On ultrasound examination found fetal biometry; BPD: 7.78 cm, FL: 3.58 cm, HL: 3.11 cm, AC: 30.90 cm, HC: 28.48 cm AFI: 33.27 cm, a frontal bossing (+) picture appears, claver leaf skull (+) and micromelia (proximal, distal, phalanges). The ultrasound examination suggested Severe skeletal dysplasia (thanatophoric dysplasia), polyhydramnios, + single intrauterine live fetus + SC 1x scars. Then an amnioinfusion is performed and results are obtained. Chromosome analysis is carried out using the G-banding technique. Chromosomes have been studied from 20 cells from 3 different cell culture preparations and obtained the number of chromosomes in each cell studied is 46, XY which means the number of chromosomes 46 pieces with fetal sex chromosome XY. Mosaic chromosome abnormalities generally occur due to non-disjuntion in the mitotic phase after conception. At 33-34 weeks gestation, an infant was born by SC with birth weight: 1900 g, baby’s length: 31 cm, A / S 2/3.Conclusion : Thanatophoric dysplasia is a "lethal" skeletal dysplasia. A careful prenatal examination is needed in the diagnosis and termination of pregnancy.Keywords: Thanatophoric dysplasia, prenatal diagnosis

A xenograft model to evaluate the bone forming effects of sclerostin antibody in human bone derived from pediatric osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI) is a rare and severe skeletal dysplasia marked by low bone mass and poor bone quality which is especially burdensome during childhood. Since clinical trials for pediatric OI are difficult, there is a widespread reliance on genetically modified murine models to understand the skeletal effects of emerging therapeutics. However a common model does not yet exist to understand how patient-specific genotype may influence treatment efficacy. Recently, sclerostin antibody (SclAb) has been introduced as a novel putative anabolic therapy for diseases of low bone mass, but effects in pediatric patients remain unexplored. In this study, we aim to establish a direct xenograft approach using OI patient-derived bone isolates which retain patient-specific genetic defects and cells residing in their intrinsic extracellular environment to evaluate the bone-forming effects of SclAb as a bridge to clinical trials. OI and age matched non-OI patient bone typically discarded as surgical waste during corrective orthopaedic procedures were collected, trimmed and implanted subcutaneously (s.c.) on the dorsal surface of 4-6-week athymic mice. A subset of implanted mice were evaluated at short (1 week), intermediate (4 week), and long-term (12 week) durations to assess bone cell survival and presence of donor bone cells in order to determine an appropriate treatment duration. Remaining implanted mice were randomly assigned to a two or four-week SclAb-treated (25mg/kg s.c. 2QW) or untreated control group. Immunohistochemistry determined osteocyte and osteoblast donor/host relationship, TRAP staining quantified osteoclast activity, and TUNEL assay was used to understand rates of bone cell apoptosis at each implantation timepoint. Longitudinal changes of in vivo μCT outcomes and dynamic histomorphometry were used to assess treatment response and ex vivo μCT and dynamic histomorphometry of host femora served as a positive internal control to confirm a bone forming response to SclAb. Human-derived osteocytes and lining cells were present up to 12 weeks post-implantation with nominal cell apoptosis in the implant. Sclerostin expression remained donor-derived throughout the study. Osterix expression was primarily donor-derived in treated implants and shifted in favor of the host when implants remained untreated. μCT measures of BMD, TMD, BV/TV and BV increased with treatment but response was variable and impacted by bone implant morphology (trabecular, cortical) which was corroborated by histomorphometry. There was no statistical difference between treated and untreated osteoclast number in the implants. Host femora confirmed a systemic bone forming effect of SclAb. Findings support use of the xenograft model using solid bone isolates to explore the effects of novel bone-targeted therapies. These findings will impact our understanding of SclAb therapy in pediatric OI tissue through establishing the efficacy of this treatment in human cells prior to extension to the clinic.

The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis.

Collagen is the major structural component of cartilage, and mutations in the genes encoding type XI collagen are associated with severe skeletal dysplasias (fibrochondrogenesis and Stickler syndrome) and early-onset osteoarthritis (OA). The impact of the lack of type XI collagen on cell behaviour and mechanical performance during skeleton development is unknown. We studied a zebrafish mutant for col11a2 and evaluated cartilage, bone development and mechanical properties to address this. We show that in col11a2 mutants, type II collagen is made but is prematurely degraded in maturing cartilage and ectopically expressed in the joint. These changes are correlated with increased stiffness of both bone and cartilage; quantified using atomic force microscopy. In the mutants, the skeletal rudiment terminal region in the jaw joint is broader and the interzone smaller. These differences in shape and material properties impact on joint function and mechanical performance, which we modelled using finite element analyses. Finally, we show that col11a2 heterozygous carriers reach adulthood but show signs of severe early-onset OA. Taken together, our data demonstrate a key role for type XI collagen in maintaining the properties of cartilage matrix; which when lost leads to alterations to cell behaviour that give rise to joint pathologies.This article is part of the Theo Murphy meeting issue ‘Mechanics of development’.

Neurophysiology of hearing in patients with mucopolysaccharidosis type IV

BackgroundHearing impairment is a common problem in patients with mucopolysaccharidosis IV (MPS IV) throughout their life. Many of the adult patients with MPS IV exhibit permanent or severe hearing loss. However, there has been no systematic review of detailed audiological test results in MPS IV. Materials and methodsFourteen individuals with MPS IV (13 MPS IVA and 1 MPS IVB; aged between 12 and 38 years old) participated in the current study. We obtained auditory neurophysiological responses (auditory brainstem responses and otoacoustic emissions test) in addition to pure-tone audiometry and middle ear function tests (tympanometry and acoustic reflexes). ResultsThe results indicated various levels and types of hearing loss with abnormal neurophysiological responses even in those patients with MPS IVA with normal pure tone thresholds. We also found a strong relationship between height (short stature is an indicator of skeletal severity) and hearing sensitivity as well as a strong relationship between height and outer hair cell function in the inner ear (measured by otoacoustic emissions) among MPS IVA patients. ConclusionThe strong correlation between reduced height and hearing loss indicates that patients with severe skeletal dysplasia may be at higher risk of developing more severe hearing loss. More importantly, the spectrum of hearing disorders indicates that MPS IV patients should have annual neurophysiological hearing tests in addition to audiometric testing from an early age regardless of their skeletal severity to more carefully monitor disease progression.

Normative Values of Intracranial Translucency (IT) Thickness as an Ultrasonographic Marker for Neural Tube Defect (NTD) Screening in the Iranian Singleton Pregnancies

Background: Neural tube defects are the second most common congenital anomalies following congenital heart defects. Once NTD is detected prenatally, different options are available including pregnancy termination, and intrauterine fetal surgery. Considering these facts, prenatal screening for NTDs is becoming a part of routine fetal care. Several ultrasonographic markers have been suggested for detection of NTD during pregnancy. Intracranial translucency (IT) is a relatively new ultrasonographic marker for NTD screening during first-trimester. It actually represents the fourth cerebral ventricle, seen as an anechoic structure in the mid-sagittal plane of the fetal face posterior to the brainstem. Its absence or obliteration can be an indirect sign of open spina bifida, which is caused secondary to the caudal displacement of brain in these fetuses. In this study, we aimed to determine the normative values of this marker in the Iranian population. Objectives: To determine the normative values of intracranial translucency (IT) thickness in the Iranian singleton pregnancies. Methods: 230 consecutive singleton pregnancies between 11 weeks and 13 weeks+6 days of gestation were included in the study during 9 months (June 2015 to February 2016) prospectively in Mahdieh and Sarem womens hospital, Tehran, Iran. Crown-rump length (CRL), nuchal translucency (NT) thickness, fetal heart rate, and nasal bone status were evaluated by ultrasound as parts of the routine first-trimester screening for aneuploidies. Precise gestational age was determined by the fetal CRL as well. In addition, IT thickness was measured in the mid-sagittal view of the fetal head between two echogenic horizontal lines: posterior border of the brainstem anteriorly and anterior aspect of the fourth ventricle choroid plexus posteriorly (figure 1). All the measurements were performed by a radiologist with four years of experience in fetal imaging. Ethnicities other than Iranian, multiple gestation pregnancies, and pregnancies conceived by assisted reproductive technology (ART) were not included in the study initially. Other exclusion criteria were any obvious anatomic fetal anomaly in the ultrasound examination, abnormal genetic or maternal serum biomarker test result, increased NT, and presence of open NTD in the post-partum follow-up. Results: : Of the 230 included singleton pregnancies, all of them resulted in healthy live births, except for two pregnancies terminated at 19 and 17 weeks of gestation due to severe skeletal dysplasia and an abnormal genetic test result compatible with Down syndrome, respectively. None of born babies had open NTD on post-partum follow-up. Five pregnancies were excluded from the final analysis, including a fetus with increased NT, two pregnancies with abnormal maternal serum biomarker test result (one of which confirmed to be trisomy 21), poor visualization due to maternal severe obesity in one case, and skeletal dysplasia diagnosed at 19 weeks of gestation in one of pregnancies. The median maternal age was 29 (range, 16 - 49) years. Median gestational age was 12 weeks + 5 days (range, 11 weeks + 2 days-13 weeks + 6 days). There were 68 cases per gestational week between 11 and 11 + 6 weeks, 84 cases between 12 and 12 + 6 weeks, and 73 cases between 13 and 13 + 6 weeks. Mean IT thickness was 1.94 - 0.73 mm (95% CI, 1.84 - 2.04) in all included pregnancies. This measurement was 1.57 - 0.34 mm (95% CI, 1.49 - 1.65) for fetuses between 11 and 11 + 6 weeks, 1.86 - 0.29 mm (95% CI, 1.80 - 1.92) for fetuses between 12 and 12 + 6 weeks, and 2.12 - 0.41 mm (95% CI, 2.02 - 2.22) for fetuses between 13 and 13 + 6 weeks. Kolmogorov-Smirnov analysis demonstrated normality of IT thickness distribution in the included cases (P > 0.10). Linear regression analysis demonstrated that there was a statistically significant positive linear association between IT thickness and gestational age (rs = 0.92, P = 0.021). Conclusions: We determined the normative values of IT thickness for the Iranian fetuses in a pilot study, which may be considered for NTD screening during the first-trimester in the national and international guidelines. It is important to determine normal measurements of different ultrasonographic and biochemistry markers nationally, since there are significant differences among various ethnicities. One should expect that IT thickness increases in a linear manner during first-trimester, and in case of its obliteration or absence open NTDs should be strongly suspected.

Skeletal Dysplasias: Growing Therapy for Growing Bones.

Skeletal dysplasias represent a large and diverse group of rare conditions affecting collagen and bone. They can be clinically classified based on radiographic and physical features, and many can be further defined at a molecular level (Bonafe et al., 2015). Early diagnosis is critical to proper medical management including pharmacologic treatment when available. Patients with severe skeletal dysplasias often have small chests with respiratory insufficiency or airway obstruction and require immediate intubation after birth. Thereafter a variety of orthopedic, neurosurgical, pulmonary, otolaryngology interventions may be needed. In terms of definitive treatment for skeletal dysplasias, there are few pharmacotherapeutic options available for the majority of these conditions. We sought to describe therapies that are currently available or under investigation for skeletal dysplasias.

Broadening the phenotypic spectrum of POP1‐skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia

Processing of Precursor 1 (POP1) is a large protein common to the ribonuclease-mitochondrial RNA processing (RNase-MRP) and RNase-P (RMRP) endoribonucleoprotein complexes. Although its precise function is unknown, it appears to participate in the assembly or stability of both complexes. Numerous RMRP mutations have been reported in individuals with cartilage-hair hypoplasia (CHH) but, to date, only three POP1 mutations have been described in two families with features similar to anauxetic dysplasia (AD). We present two further individuals, one with severe short stature and a relatively mild skeletal dysplasia and another in whom AD was suspected. Biallelic POP1 mutations were identified in both. A missense mutation and a novel single base deletion were detected in proband 1, p.[Pro582Ser]:[Glu870fs*5]. Markedly reduced abundance of RMRP and elevated levels of pre5.8s rRNA was observed. In proband 2, a homozygous novel POP1 mutation was identified, p.[(Asp511Tyr)];[(Asp511Tyr)]. These two individuals show the phenotypic extremes in the clinical presentation of POP1-dysplasias. Although CHH and other skeletal dysplasias caused by mutations in RMRP or POP1 are commonly cited as ribosomal biogenesis disorders, recent studies question this assumption. We discuss the past and present knowledge about the function of the RMRP complex in skeletal development.

EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.

We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.

Assessment of Mutation Genetics in FAM20A and FAM20C Genes Induction Syndrome Raine with New Mutation c.977-1T>A

Syndrome Raine, a severe skeletal dysplasia is usually caused the deaths of patients aged newborn. There are reports that patients with a milder form of the disease to live longer and have reached the age of a child. Radiological surveys show an increase in bone density generalized sclerosis and osteoarthritis. Raine syndrome is a very rare hereditary lethal skeletal dysplasia. There are few reports of milder phenotypes in which patients survived until late childhood. Radiologic investigations show increased bone density and osteosclerosis. The increased density of bones in the head and face causes a characteristic dysmorphic feature that include a prominent and narrow forehead, proptosis, a small hypoplastic nose with depressed nasal bridge, mid-face hypoplasia, a triangular mouth, coanal atresia, and intracranial cerebral classification. Osteosclerosis is severe enough and could be mistaken with osteopetrosis. Raine syndrome is a hereditary autosomal recessive disease. Its cause is a homozygous or compound heterozygous mutation in the FAM20C and FAM20A gene. The gene encodes a phosphorylase-kinase which is responsible for biomineralization of the skeleton. Bone density at the base of the skull, causing changes in the craniofacial skeleton, leading to specific dysmorphic signs in the figures. Symptoms of the disease include prominent forehead, proptosis, nasal root sunk, hypoplastic middle part of the face, hypoplastic nose, mouth, triangular, Atresia Cowan and intracranial calcification. Bone density in the disease so that the disease osteopetrosis is wrong. Raine syndrome is an autosomal recessive hereditary disease, which is caused by mutations in the genes is FAM20A and FAM20C. This gene encodes a protein that phosphorylase-kinase activity has been implicated in bio-mineralization. In this study, a patient with Raine syndrome. Molecular analysis of the patient, a homozygous mutation new were identified. Already known about the patient’s Eighteenth in the world.

Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency.

Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three‐generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co‐segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals. Two further cases with SHOX deficiency and damaging CYP26C1 variants were identified in a cohort of 68 individuals with LWD. The identified CYP26C1 variants affected its catabolic activity, leading to an increased level of retinoic acid. High levels of retinoic acid significantly decrease SHOX expression in human primary chondrocytes and zebrafish embryos. Individual morpholino knockdown of either gene shortens the pectoral fins, whereas depletion of both genes leads to a more severe phenotype. Together, our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency.

INPPL1 gene mutations in opsismodysplasia.

The INPPL1 (inositol polyphosphate phosphatase-like 1) gene encodes the inositol phosphatase, SHIP2 (for src homology 2 domain-containing inositol phosphatase 2). SHIP2 functions to dephosphorylate, and negatively regulate, the lipid second messenger phosphatidylinositol (3,4,5)P3. SHIP2 has been well studied in the area of insulin resistance and obesity but has roles in cancer and other disorders. Recently, it was reported that mutations in INPPL1 cause opsismodysplasia, a rare, autosomal recessive severe skeletal dysplasia. This review focuses on the mutations associated with opsismodysplasia and explores the role of INPPL1/ SHIP2 in skeletal development.

Thanatophoric Dysplasia

Thanatophoric Dysplasia (TD) is a severe skeletal dysplasia that is lethal in the neonatal period. There are two defined TD subtypes which have been classified clinically. The incidence is approximately 1/20,000 to 1/50,000. Type I TD being more frequent than Type II. Most individuals with TD die within the first few hours.This condition has characteristic sonographic features detected antenatally by midgestation, although distinction from other short-limbed dysplasia syndromes may be difficult. We report a case of type I TD with typical clinicoradiological features who succumbed within one hour of life.J Nepal Paediatr Soc 2015;35(3):304-306.

NANS-mediated synthesis of sialic acid is required for brain and skeletal development.

We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.

Syndrome Raine, A Rare Autosomal Recessive Dysplasia Sclerotic Osteoarthritis, the First Reports of a New Mutation of Tabriz City in IRAN

Syndrome Raine, a severe skeletal dysplasia is usually caused the deaths of patients aged newborn. There are reports that patients with a milder form of the disease to live longer and have reached the age of a child. Radiological surveys show an increase in bone density generalized sclerosis and osteoarthritis. Bone density at the base of the skull, causing changes in the craniofacial skeleton, leading to specific dysmorphic signs in the figures. Symptoms of the disease include prominent forehead, proptosis, nasal root sunk, hypoplastic middle part of the face, hypoplastic nose, mouth, triangular, Atresia Cowan and intracranial calcification. Bone density in the disease so that the disease osteopetrosis is wrong. Raine syndrome is an autosomal recessive hereditary disease, which is caused by mutations in the gene is FAM20C. This gene encodes a protein that phosphorylase-kinase activity has been implicated in bio-mineralization. In this study, a patient with Raine syndrome is introduced from Iran. Based on available information, this patient is the first known case in Iran reported. Molecular analysis of the patient, a homozygous mutation new were identified. Already known about the patient's seventeenth in the world.

Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi-domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve-Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long-term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

EP07.12: Dyssegmental dysplasia: clinical, radiological and molecular findings of a challenging antenatal diagnosis in a dizygotic twin pregnancy

This study reports prenatal sonographic, postnatal clinical and radiological findings and molecular analysis results of a dizygotic twin with dyssegmental dysplasia, Silverman-Handmaker type (DDSH, MIM 224410). Fetal ultrasound findings, clinical course, postnatal skeletal and molecular analyses of heparan sulphate gene 2 (HSPG2) are presented. The patient was a dizygotic (male and female) twin from a consanguineous Pakistani couple. A second trimester anatomical survey raised suspicion of severe skeletal dysplasia in one twin. The mother presented at 35-weeks gestation with antenatal ultrasound findings of the male twin of shortened long bones below the fifth percentile, marked angulation of the femurs, severe scoliosis and short thorax. Postnatal clinical features included widened cranial sutures, short thorax with severe restrictive respiratory failure, severe scoliosis and shortened, bowed long bones. A skeletal survey confirmed findings of thoracolumbar kyphosis with lack of ossification of several vertebral bodies, multiple coronal clefts, moderate shortening, flaring and horizontalisation of the ribs and short, broad tubular bones with bowing and dumbbell appearance of the femora, tibiae and humeri. The patient passed away shortly after birth from respiratory complications. Clinical evolution and phenotype were consistent with DDSH. Molecular testing confirmed the diagnosis by identification of a homozygous mutation in the HSPG2 gene. Although DDSH can theoretically be detected by antenatal diagnosis as early as 13-weeks gestation, it remains a challenging antenatal diagnosis due to its rarity and overlapping phenotype with other severe skeletal dysplasias. The twin pregnancy added additional ultrasonographic and counselling challenges. Molecular testing remains the gold standard for accurate diagnosis of this condition and allows for preimplantation or prenatal diagnosis of this rare autosomal recessive condition for subsequent pregnancies.

Residents' journal review

Residents' journal review

Function and regulation of primary cilia and intraflagellar transport proteins in the skeleton.

Primary cilia are microtubule-based organelles that project from the cell surface to enable transduction of various developmental signaling pathways. The process of intraflagellar transport (IFT) is crucial for the building and maintenance of primary cilia. Ciliary dysfunction has been found in a range of disorders called ciliopathies, some of which display severe skeletal dysplasias. In recent years, interest has grown in uncovering the function of primary cilia/IFT proteins in bone development, mechanotransduction, and cellular regulation. We summarize recent advances in understanding the function of cilia and IFT proteins in the regulation of cell differentiation in osteoblasts, osteocytes, chondrocytes, and mesenchymal stem cells (MSCs). We also discuss the mechanosensory function of cilia and IFT proteins in bone cells, cilia orientation, and other functions of cilia in chondrocytes.