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Total knee arthroplasty (TKA) in patients who have skeletal dysplasia (SD) is a technically challenging surgery due to deformity, joint contracture, and associated comorbidities. Patients presenting with this condition have traditionally been treated with conservative measures, leading to poor outcomes. The aim of this study was to follow-up on patients who had SD following TKA, specifically with regards to clinical outcomes. A total of 31 knees (22 patients) with SD that had undergone TKA in our institution were included in our study. The mean follow-up from index surgery was 110.3 months (range: 20 to 291). The type of dysplasia, implant used, and clinical outcomes with patient-reported outcome measures are presented. There were 8 patients (36.3%) who had a diagnosis of achondroplasia, followed by multiple epiphyseal dysplasia (31.8%) and spondyloepiphyseal dysplasia (22.7%). There were 14 men and 8 women who had a mean age of 51 years (range: 28 to 73). Custom implants were required in 12 cases (38.7%), custom jigs were used in 6 cases (19.4%), and robotic-assisted surgery was used in 2 (6.5%) TKAs. Hinged prostheses were used in 17 cases (54.8%), posterior-stabilized in 9 (29.0%), and cruciate-retaining implants in 5 (16.1%). There was 1 patient who sustained an intraoperative medial tibial plateau fracture treated with concomitant open reduction and internal fixation. There was 1 revision that occurred during the follow-up period with a patella resurfacing for continued anterior knee pain. Postoperatively, Oxford Knee Scores improved on average by 12.2 points. The 10-year and 20-year all-cause revision-free survival was 96.8, respectively. Despite the technical challenges and complexity associated with this unique patient cohort, we demonstrated excellent implant survivorship and clinical outcomes post-TKA with mid-term to long-term follow-up of more than 20 years. We recommend preoperative cross-sectional imaging for precise planning and implant templating with multidisciplinary team decision-making. Despite our results, functional outcomes remain inferior to primary arthroplasty within the general population, although we still recommend this treatment modality to appropriately counseled patients. III. [ABSTRACT FROM AUTHOR]

We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of "brain abnormalities, neurodegeneration, and dysosteosclerosis" (BANDDOS) and discuss its link with "adult leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy‐resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T‐cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro‐imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate. [ABSTRACT FROM AUTHOR]

Background Hypothesis/Objectives Animals Methods Results Conclusions and Clinical Importance Skeletal dysplasia encompasses a heterogeneous group of genetic disorders characterized by an abnormal development of bones, joints, and cartilage. Two Chianina half‐sibling calves from consanguineous mating with congenital skeletal malformations and cardiac abnormalities were identified.To characterize the disease phenotype, to evaluate its genetic cause, and to determine the prevalence of the deleterious alleles in the Chianina population.Two affected calves, their parents and 332 Chianina bulls.The affected animals underwent clinicopathological investigation. Whole‐genome sequencing trio‐approach and PCR‐based assessment of the frequency of TDP‐glucose 4,6‐dehydratase (TGDS) and laminin subunit alpha 4 (LAMA4) alleles were performed.The cases presented with retarded growth, poor nutritional status associated with muscular atrophy and angular deformities of the hindlimbs. Radiologic examination identified generalized osteopenia and shortening of the limb long bones. Necropsy showed osteochondrodysplastic limbs and dilatation of the heart right ventricle. On histological examination, the physeal cartilages were characterized by multifocal mild to moderate loss of the normal columnar arrangement of chondrocytes. Osteopenia also was observed. Genetic analysis identified a missense variant in TGDS and a splice‐site variant in LAMA4, both of which were homozygous in the 2 cases. Parents were heterozygous and allele frequency in the Chianina population for the TGDS variant was 5% and for the LAMA4 variant was 2%.Genetic findings identified 2 potentially pathogenic alleles in TGDS and LAMA4, but no clear mode of inheritance could be determined. [ABSTRACT FROM AUTHOR]

Background: X-linked recessive chondrodysplasia punctata 1 (CDPX1) is a rare congenital skeletal dysplasia characterized by stippled epiphyses, nasal hypoplasia, and brachytelephalangy. ARSL (formerly known as ARSE), a member of the sulfatase gene family located on Xp22.3, has been identified as the causative gene for CDPX1. The high clinical and genetic heterogeneity of CDPX1 presents a challenge to prenatal diagnosis. Case presentation: A G1P0 woman in her 30s with an unremarkable prenatal course presented in the second trimester. Maternal diseases, tobacco, alcohol, and drug history during pregnancy were denied. Obstetrical ultrasound examination revealed a flattened nose and a flattened midface with echogenic alterations of lumbar spinous process in the fetus. Amniocentesis was performed for genetic testing. A normal karyotype and a negative result of CNV-seq were obtained. However, Whole exome sequencing (WES) in trios revealed a hemizygous ARSL variant [NM_000047.3:c.1108del p.(Trp370Glyfs*35)] in the fetus, which was maternally inherited as confirmed by Sanger sequencing. This variant was absent from the genomAD and HGMD databases. According to the ACMG guidelines, this variant was interpreted as likely pathogenic (PVS1 + PM2_Supporting). The couple decided to terminate the pregnancy. After induction of labour, a severe nasal hypoplasia was noted; and brachytelephalangy was not remarkable. Postmortem digital X-ray imaging revealed symmetrical stippled epiphyses of the vertebrae in all spine regions and enlargement of spinous process of L1-L4 vertebrae. Conclusion: A novel frameshift deletion variant of ARSL and the associated fetal phenotype have been identified. This study provides useful information for prenatal diagnosis and genetic counseling of CDPX1. [ABSTRACT FROM AUTHOR]

Background: Short stature is a complex disorder with phenotypic and genetic heterogeneity. This study aimed to investigate clinical phenotypes and molecular basis of a cohort of patients with short stature. Methods: Trio whole-exome sequencing (Trio-WES) was performed to explore the genetic aetiology and obtain a molecular diagnosis in twenty Chinese probands with syndromic and isolated short stature. Results: Of the twenty probands, six (6/20, 30%) patients with syndromic short stature obtained a molecular diagnosis. One novel COMP pathogenic variant c.1359delC, p.N453fs*62 and one LZTR1 likely pathogenic variant c.509G>A, p.R170Q were identified in a patient with short stature and skeletal dysplasia. One novel de novo NAA15 pathogenic variant c.63T>G, p.Y21X and one novel de novo KMT2A pathogenic variant c.3516T>A, p.N1172K was identified in two probands with short stature, intellectual disability and abnormal behaviours, respectively. One patient with short stature, cataract, and muscle weakness had a de novo POLG pathogenic variant c.2863 T>C, p.Y955H. One PHEX pathogenic variant c.1104G>A, p.W368X was identified in a patient with short stature and rickets. Maternal uniparental disomy 7 (mUPD7) was pathogenic in a patient with pre and postnatal growth retardation, wide forehead, triangular face, micrognathia and clinodactyly. Thirteen patients with isolated short stature had negative results. Conclusion: Trio-WES is an important strategy for identifying genetic variants and UPD in patients with syndromic short stature, in which dual genetic variants are existent in some individuals. It is important to differentiate between syndromic and isolated short stature. Genetic testing has a high yield for syndromic patients but low for isolated patients. [ABSTRACT FROM AUTHOR]

Fibronectin (FN) is an extracellular matrix glycoprotein essential for the development and function of major vertebrate organ systems. Mutations in FN result in an autosomal dominant skeletal dysplasia termed corner fracture-type spondylometaphyseal dysplasia (SMDCF). The precise pathomechanisms through which mutant FN induces impaired skeletal development remain elusive. Here, we have generated patient-derived induced pluripotent stem cells as a cell culture model for SMDCF to investigate the consequences of FN mutations on mesenchymal stem cells (MSCs) and their differentiation into cartilage-producing chondrocytes. In line with our previous data, FN mutations disrupted protein secretion from MSCs, causing a notable increase in intracellular FN and a significant decrease in extracellular FN levels. Analyses of plasma samples from SMDCF patients also showed reduced FN in circulation. FN and endoplasmic reticulum (ER) protein folding chaperones (BIP, HSP47) accumulated in MSCs within ribosome-covered cytosolic vesicles that emerged from the ER. Massive amounts of these vesicles were not cleared from the cytosol, and a smaller subset showed the presence of lysosomal markers. The accumulation of intracellular FN and ER proteins elevated cellular stress markers and altered mitochondrial structure. Bulk RNA sequencing revealed a specific transcriptomic dysregulation of the patient-derived cells relative to controls. Analysis of MSC differentiation into chondrocytes showed impaired mesenchymal condensation, reduced chondrogenic markers, and compromised cell proliferation in mutant cells. Moreover, FN mutant cells exhibited significantly lower transforming growth factor beta-1 (TGFβ1) expression, crucial for mesenchymal condensation. Exogenous FN or TGFβ1 supplementation effectively improved the MSC condensation and promoted chondrogenesis in FN mutant cells. These findings demonstrate the cellular consequences of FN mutations in SMDCF and explain the molecular pathways involved in the associated altered chondrogenesis. Significance/Highlights: • SMDCF-causing mutations in fibronectin impair protein secretion in iPSC-derived mesenchymal stem cells. • Mutant fibronectin and ER protein folding chaperones are directly exported from the rough endoplasmic reticulum into vesicles covered with ribosomes, some of which are positive for lysosomal markers. • The FN mutant cells are characterized by massive accumulation of cytosolic vesicles. • Mutations in fibronectin impair stem cell proliferation, mesenchymal condensation, and the differentiation of MSCs into chondrocytes. • Exogenous addition of purified fibronectin or TGFβ-1 improves mesenchymal condensation and chondrogenesis of the FN mutant stem cells. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe the prenatal ultrasound findings of fetuses with skeletal dysplasia and to evaluate the genetic variations by molecular genetic analysis. Between August 1, 2018 and March 1, 2023, we conducted a retrospective case series at a tertiary referral center involving patients with fetal skeletal abnormalities. For cases referred for a possible diagnosis of fetal skeletal dysplasia, an ultrasound database and prenatal genetic counseling records were first searched. Terminated cases diagnosed with skeletal dysplasia by pathologic and radiologic findings and cases with skeletal dysplasia proven by postnatal clinical findings were included in the study. Between 2018 and 2023, a total of 64 cases were diagnosed as skeletal dysplasia based on radiologic findings, pathologic findings, and clinical features. The median week of the first ultrasound performed on patients is 19 0/7 weeks, while the median week of the ultrasound in which skeletal dysplasia is suspected is 21 3/7 weeks. Although micromelia was evaluated as a common feature in all cases, the most common concomitant anomaly was thoracic hypoplasia. Exome sequencing analysis was achieved in 31 (48 %) of cases. In 31 cases, in total of 35 pathogenic single gene mutations and 5 VUS (variants of uncertain significance) variants composing of 23 autosomal dominant, 10 autosomal recessive and 2 X linked recessive mutations were determined. Prenatal ultrasound findings can lead us to specific diagnoses, and with the appropriate molecular analysis method, a definitive diagnosis can be made without wasting time and money. [ABSTRACT FROM AUTHOR]

Purpose: To report the case of a young boy with early onset high myopia (eoHM), foveal hypoplasia and skeletal dysplasia due to a homozygous LOXL3 pathogenic variant. Atypically, this was from a paternal uniparental isodisomy (UPiD) of chromosome 2. Clinical Case: Four-year-old boy with several months history of holding items close to his face was found to have reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (−8.50D). A skeletal survey showed spondylo-epi-metaphyseal dysplasia. Whole-exome sequencing (WES) revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2. Conclusion: To our knowledge, this is the first reported case of LOXL3-associated eoHM, foveal hypoplasia and mild skeletal dysplasia due to the rare phenomenon of paternal UPiD of chromosome 2. This case further delineates the phenotype associated with LOXL3 pathogenic variants and supports truncating LOXL3 pathogenic variants being associated with a phenotypic spectrum; from isolated eoHM through to a Stickler syndrome-like phenotype. [ABSTRACT FROM AUTHOR]

Microcephalic osteodysplastic primordial dwarfism type I (MOPDI) is a very rare and severe autosomal recessive disorder characterized by marked intrauterine growth retardation, skeletal dysplasia, microcephaly and brain malformations. MOPDI is caused by biallelic mutations in RNU4ATAC, a non‐coding gene involved in U12‐type splicing of 1% of the introns in the genome, which are recognized by their specific splicing consensus sequences. Here, we describe a unique observation of immunodeficiency in twin sisters with mild MOPDI, who harbor a novel n.108_126del mutation, encompassing part of the U4atac snRNA 3′ stem‐loop and Sm protein binding site, and the previously reported n.111G>A mutation. Interestingly, both twin sisters show mild B‐cell anomalies, including low naive B‐cell counts and increased memory B‐cell and plasmablasts counts, suggesting partial and transitory blockage of B‐cell maturation and/or excessive activation of naive B‐cells. Hence, the localization of a mutation in stem II of U4atac snRNA, as observed in another RNU4ATAC‐opathy with immunodeficiency, that is, Roifman syndrome (RFMN), is not required for the occurrence of an immune deficiency. Finally, we emphasize the importance of considering immunodeficiency in MOPDI management to reduce the risk of serious infectious episodes. [ABSTRACT FROM AUTHOR]

Dyggve–Melchior–Clausen dysplasia (DMC) and Smith–McCort dysplasia (SMC types 1 and 2) are rare spondylo‐epi‐metaphyseal dysplasias with identical radiological and clinical findings. DMC and SMC type 1 are allelic disorders caused by homozygous or compound heterozygous variants in DYM, while biallelic causative variants in RAB33B lead to SMC type 2. The terminology "skeletal golgipathies" has been recently used to describe these conditions, highlighting the pivotal role of these two genes in the organization and intracellular trafficking of the Golgi apparatus. In this study, we investigated 17 affected individuals (8 males, 9 females) from 10 unrelated consanguineous families, 10 diagnosed with DMC and seven with SMC type 2. The mean age at diagnosis was 9.61 ± 9.72 years, ranging from 20 months to 34 years, and the average height at diagnosis was 92.85 ± 15.50 cm. All patients exhibited variable degrees of short trunk with a barrel chest, protruding abdomen, hyperlordosis, and decreased joint mobility. A total of nine different biallelic variants were identified, with six being located in the DYM gene and the remaining three detected in RAB33B. Notably, five variants were classified as novel, four in the DYM gene and one in the RAB33B gene. This study aims to comprehensively assess clinical, radiological, and molecular findings along with the long‐term follow‐up findings in 17 patients with DMC and SMC type 2. Our results suggest that clinical symptoms of the disorder typically appear from infancy to early childhood. The central notches of the vertebral bodies were identified as early as 20 months and tended to become rectangular, particularly around 15 years of age. Pseudoepiphysis was observed in five patients; we believe this finding should be taken into consideration when evaluating hand radiographs in clinical assessments. Furthermore, our research contributes to an enhanced understanding of clinical and molecular aspects in these rare "skeletal golgipathies," expanding the mutational spectrum and offering insights into long‐term disease outcomes. [ABSTRACT FROM AUTHOR]

N‐acetyl‐d‐neuraminic acid synthase‐congenital disorder of glycosylation (NANS‐CDG) is a rare autosomal recessive defect in the N‐acetyl‐neuraminic acid biosynthesis pathway. Herein, we report the first Korean NANS‐CDG patient. A 10‐year‐old boy was referred to our clinic because of incidental radiographic findings indicating spondyloepimetaphyseal dysplasia. The patient had microcephaly, cavum septum pellucidum, and ventriculomegaly at birth, and at 10 years, a very short stature. He had a history of idiopathic chronic immune thrombocytopenia, central adrenal insufficiency, and hypothyroidism since infancy. The first unprovoked seizure occurred at the age of 2 years, and he was subsequently admitted to the hospital frequently because of respiratory infections and intractable seizures. Exome sequencing identified unreported biallelic variants of the NANS gene. Clinical and genetic confirmation of NANS‐CDG highlights its expanding phenotypic and genotypic diversity. [ABSTRACT FROM AUTHOR]

Macrophage and osteoclast proliferation, differentiation and survival are regulated by colony-stimulating factor 1 receptor (CSF1R) signaling. Osteopetrosis associated with Csf1 and Csf1r mutations has been attributed to the loss of osteoclasts and deficiency in bone resorption. Here, we demonstrate that homozygous Csf1r mutation in rat leads to delayed postnatal skeletal ossification associated with substantial loss of osteal macrophages in addition to osteoclasts. Osteosclerosis and site-specific skeletal abnormalities were reversed by intraperitoneal transfer of wild-type bone marrow cells (bone marrow cell transfer, BMT) at weaning. Following BMT, IBA1+ macrophages were detected before TRAP+ osteoclasts at sites of ossification restoration. These observations extend evidence that osteal macrophages independently contribute to bone anabolism and are required for normal postnatal bone growth and morphogenesis. [ABSTRACT FROM AUTHOR]

Objective: To determine the diagnostic performance of ultrasound markers associated with life‐limiting fetal skeletal dysplasia in a fortified cohort. Methods: Retrospective review from 2013 to 2023 of pregnancies with suspected fetal skeletal dysplasia. Ultrasound evaluation included measurements predictive of a life‐limiting dysplasia: thoracic circumference/abdominal circumference (TC/AC) < 0.6, femur length/abdominal circumference (FL/AC) < 0.16, and thoracic circumference (TC) < 2.5th percentile. Demographics, ultrasound findings, genetic testing, and fetal/neonatal outcome were reviewed. Results: Of 96 fetuses with complete outcome data, 47 (49%) had a non‐life‐limiting dysplasia and 49 (51%) had a life‐limiting dysplasia. 22 (23%) had no life‐limiting markers, 42 (44%) had one, 27 (28%) had two, and 5 (5%) had three. FL/AC < 0.16 and TC < 2.5th percentile were associated with life‐limiting dysplasia (p < 0.001; p < 0.001), while TC/AC < 0.6 was rare and did not reach statistical significance (p = 0.056). The positive predictive value (PPV) for predicting life‐limiting dysplasia increased from 50% to 78% to 100% with one, two, or three markers. The PPV of the two life‐limiting markers was significantly higher in those diagnosed at < versus ≥ 28 weeks (90% vs. 43%, p = 0.02) but the analysis was limited by small numbers in the ≥ 28 weeks cohort. The negative predictive value of no life‐limiting markers was 91%. Conclusions: In our cohort, the presence of two life‐limiting ultrasound markers prior to 28 weeks was highly suggestive of a life‐limiting dysplasia, whereas the absence of life‐limiting markers was strongly associated with a non‐life‐limiting dysplasia throughout gestation. Nonetheless, individual markers had a poor predictive value of lethality, and a life‐limiting diagnosis ≥ 28 weeks is challenging based on ultrasound markers alone. This highlights the importance of integrating thorough sonography, genetic testing, and balanced parental counseling. [ABSTRACT FROM AUTHOR]

The growth and development of the skeleton is regulated by bone morphogenetic proteins of which several are linked to genetic skeletal disorders. So far, no human skeletal malformations have been associated with variants in BMP5. Here, we report a patient with biallelic loss of function variants in BMP5 and a syndromic phenotype including skeletal dysostosis, dysmorphic features, hypermobility, laryngo‐tracheo‐bronchomalacia and atrioventricular septal defect. We discuss the phenotype in relation to the known tissue‐specific expression of Bmp5 and similar morphological abnormalities previously reported in experimental animal models. Our findings suggest a new association between BMP5 variants and a range of developmental anomalies, involving ears, heart and skeleton, thereby increasing understanding of BMP5's role in human development. [ABSTRACT FROM AUTHOR]

Congenital skeletal disorders are a heterogeneous group of anomalies that become evident during gestation. They are expressed in the shape and growth of the bones during development because of a defective genetic background. With the follow‐up of pregnant women and the advances in prenatal ultrasonographic examination and molecular genetic tests, nowadays, congenital skeletal disorders are identified at an early gestational age. If they are considered lethal, the termination of pregnancy is advised. This work unveils an exceptional instance of a rare pathological condition identified in a perinate (birth ± 2 weeks) from the 17th to 19th centuries, recovered during an excavation at the cloister of the São Domingos Convent in Lisbon, Portugal. The skeleton presents with exuberant modifications that include, among others, severe shortening (micromelia) and bowing of the long bones of the upper and lower limbs. The main skeletal findings indicated a presumptive general diagnosis of skeletal dysplasia, while the differential diagnosis includes hypophosphatasia, campomelic dysplasia, achondrogenesis, thanatophoric dysplasia, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) as the most plausible causes for the observed skeletal changes. Even though an exact diagnosis is unattainable based only on the macroscopic analysis of the bones, the phenotypic features observed in this perinate are more consistent with thanatophoric dysplasia type 1. [ABSTRACT FROM AUTHOR]

Multiple osteochondromas (MO) is an autosomal dominant disorder and the most common genetic skeletal dysplasia, characterized by the growth of bone outgrowths capped by cartilage, called osteochondromas. Most MO cases are caused by mutations in the exostosin-1 (EXT1) and exostosin-2 (EXT2) genes. Only 5% of MO-causative variants are represented by single or multiple exon deletions; to date, no pathogenic large duplication has been described in the literature. In the present study, we describe the novel in-tandem intragenic duplication c.(1128_1202)_(1284+29_1344)dup involving exon 4 of EXT1 (NM_000127.2), detected in a three-generation family with MO. The variant has been detected by MLPA (multiplex ligation-dependent probe amplification) and then confirmed with qPCR (quantitative PCR). Our finding expands the spectrum of MO-causing variants describing a pathogenic large duplication, underlying the importance of quantitative analysis in patients with negative sequencing. [ABSTRACT FROM AUTHOR]

Background: Fetal and neonatal mortality serves as the most sensitive index of maternal and neonatal care. Congenital malformations remain a common cause of perinatal deaths and account for 10-15% in developing countries. Antenatal anomaly scan has become a standard element of obstetric care and their time for a fetal malformation is about 18 weeks. Fetal autopsy serves as a methodology to confirm the sonogram findings with regard to fetal anomalies. Aims and Objectives: The aim of our present study is to review and evaluate fetal autopsy of stillbirth/fetal losses and to confirm the malformations that were diagnosed by ultrasound. Materials and Methods: A cross-sectional study of a total of 10 cases received during the period of September 2023-October 2023 at the Institute of Obstetrics and Gynaecology. All the cases were spontaneous fetal losses. A standard protocol of autopsy procedure was followed which included external, internal, and histopathological examination. In fetuses with prenatally diagnosed malformations, ultrasound findings were compared with autopsy findings. Results: We analyzed a total of 10 fetuses, which included one chromosomal abnormality, four cardiac anomalies, one multiple anomaly, three central nervous system (CNS) anomalies, and one lethal skeletal dysplasia. The fetal autopsy confirmed the prenatal ultrasound findings in eight cases. Fetuses with CNS abnormality were not appreciated grossly due to early autolysis of the brain in the post-mortem. Conclusion: Prenatal imaging and screening are considered milestone development which detects fetal anomalies. However, the time-tested clinical autopsy which used to be conducted for all hospital deaths to find the cause of death was the norm of yesteryears which threw light on many unidentified causes and many syndromic associations not detected antemortem. Likewise, this case highlights the importance of autopsy correlation with prenatal imaging to highlight the same findings and to detect findings not picked up during imaging. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the possible outcomes of fetuses diagnosed with short femur length (FL) and to guide diagnosis through a step-wise imaging algorithm. Methods: This was a prospective cohort study of 42 pregnancies with fetal femur length (FL) below the 5th centile for gestational age. The cases were divided into two categories of isolated short FL & non-isolated short FL and followed up to determine the etiology. Results: There were 11 cases of non-isolated short FL with skeletal dysplasia observed in 7 and chromosomal abnormalities in 4 cases. There were 31 cases with isolated short FL in which fetal growth restriction (FGR) occurred in 14/31 (45%) cases; 13 out of 31 (42%) were constitutional (short for gestational age, SGA) whereas 4/31(13%) showed normal interval growth on follow up (false positive). Conclusion: Short femur can be isolated or non-isolated. Short femur length can be a good predictor and early sign of FGR. Serial follow up scan of the all cases of isolated short FL is important since a majority of them are normal and not require any further intervention. Cases of non-isolated short FL require step-wise approach to differentiate into dysplasia or aneuploidy. [ABSTRACT FROM AUTHOR]

Renal ciliopathies are a group of genetic disorders that affect the function of the primary cilium in the kidney, as well as other organs. Since primary cilia are important for regulation of cell signaling pathways, ciliary dysfunction results in a range of clinical manifestations, including renal failure, cyst formation, and hypertension. We summarize the current understanding of the pathophysiological and pathological features of renal ciliopathies in childhood, including autosomal dominant and recessive polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome, as well as skeletal dysplasia associated renal ciliopathies. The genetic basis of these disorders is now well-established in many cases, with mutations in a large number of cilia-related genes such as PKD1, PKD2, BBS, MKS, and NPHP being responsible for the majority of cases. Renal ciliopathies are broadly characterized by development of interstitial fibrosis and formation of multiple renal cysts which gradually enlarge and replace normal renal tissue, with each condition demonstrating subtle differences in the degree, location, and age-related development of cysts and fibrosis. Presentation varies from prenatal diagnosis of congenital multisystem syndromes to an asymptomatic childhood with development of complications in later adulthood and therefore clinicopathological correlation is important, including increasing use of targeted genetic testing or whole genome sequencing, allowing greater understanding of genetic pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019–April 2022). Median (range) age was 8 (0–90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx‐positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx‐positive following family testing. Follow‐up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx‐positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results. [ABSTRACT FROM AUTHOR]

Jeune syndrome, a rare autosomal recessive disorder, is characterized by skeletal abnormalities, particularly a narrow, bell-shaped chest, leading to severe respiratory distress in newborns. This case report details a full-term female neonate presenting with significant respiratory challenges, typical skeletal features, and early-onset renal dysfunction. Despite normal initial imaging, persistent renal abnormalities were observed, underscoring the need for early diagnosis, vigilant monitoring, and a multidisciplinary management approach to optimize outcomes for patients with Jeune syndrome.

Background: Evans syndrome is an autoimmune condition that manifests as two or more autoimmune cytopenia. We present a case of Evans syndrome diagnosed with an underlying skeletal dysplasia; Schimke immune-osseous dysplasia (SIOD). The condition is characterized by spondyloepiphyseal dysplasia, progressive nephropathy, and T-cell immunodeficiency with cytopenia. Notably, our patient did not exhibit any signs of renal involvement. Case report: A five-and-a-half-year-old female child presented with a short history of bleeding manifestations along with a history of poor weight and height gain. She was subsequently diagnosed with Evans syndrome secondary to an underlying SMARCAL1 mutation, which could be well controlled with oral steroids. Conclusion: SIOD is a rare multisystem disorder affecting the skeletal, renal, immune, and vascular systems. Autoimmune cytopenia was the chief presentation of our patient. Such entities should be suspected in patients with growth failure, bone deformities, and hematological involvement. Early genetic testing will help to reduce disease-related comorbidities and aid in rationalizing treatment strategies.

Introduction Methods and Results Conclusion The filamins are cytoskeletal binding proteins that dynamically crosslink actin into orthogonal networks or bundle it into stress fibres. The domain structure of filamin proteins is very well characterised, with an N‐terminal actin‐binding region, followed by 24 immunoglobulin‐like repeat units. The repeat domains are separated into distinct segments by two regions of low‐complexity known as hinge‐1 and hinge‐2. The role of hinge‐1 especially has been proposed to be essential for protein function as it provides flexibility to the otherwise rigid protein, and is a target for cleavage by calpain. Hinge‐1 protects cells from otherwise destructive forces, and the products of calpain cleavage are involved in critical cellular signalling processes, such as survival during hypoxia. Pathogenic variants in FLNA encoding Filamin A, including those that remove the hinge‐1 domain, cause a wide range of survivable developmental disorders. In contrast, complete loss of function of this gene is embryonic lethal in human and mouse.In this study, we show that removing filamin A hinge‐1 from mouse (FlnaΔH1), while preserving its expression level leads to no obvious developmental phenotype. Detailed characterisation of the skeletons of FlnaΔH1 mice showed no skeletal phenotype reminiscent of that found in the FLNA‐causing skeletal dysplasia. Furthermore, nuclear functions of FLNA are maintained with loss of Filamin A hinge‐1.We conclude that hinge‐1 is dispensable for filamin A protein function during development over the murine lifespan. [ABSTRACT FROM AUTHOR]

Achondroplasia is the most common skeletal dysplasia and is associated with serious complications such as foramen magnum stenosis (FMS). This case report describes an infant with achondroplasia who presented with a syndrome of inappropriate antidiuretic hormone secretion (SIADH), secondary to significant FMS and myelocompression. A 2-month-old boy with prenatally diagnosed achondroplasia was referred due to disordered breathing and altered consciousness. On admission, apathy, hypotonus, and hypothermia with typical features of achondroplasia were noticed. Laboratory investigations revealed severe hyponatremia and hypochloridaemia with normal glucose and urea levels. The diagnosis of SIADH was made based on low serum osmolality in the presence of high urine osmolality, along with an elevated copeptin level. An emergency computerized tomography showed a high-grade stenosis at the cranio-cervical junction; subsequent magnetic resonance imaging demonstrated myelocompression. The patient underwent decompression surgery the next day; serum osmolality increased after the operation. Spontaneous breathing after extubation was sufficient whereas tetraplegia persisted despite intensive physiotherapy. Clinicians should be aware of SIADH as a presenting sign of FMS in children with achondroplasia. Further discussion is warranted regarding improving parental education and timing of screening recommendations. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate the presence of monogenic causes of systemic lupus erythematosus (SLE) in our early-onset SLE patients. Methods: Fifteen pediatric SLE cases who had early disease onset (≤6 years) were enrolled in this study. All patients fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria. Genomic DNA was used for whole exome sequencing (WES). Pathogenic variants were confirmed by Sanger sequencing. Results: The median age at diagnosis of 15 early-onset SLE patients included in the study was 4 (2-6) years (F/M = 12/3). Significant gene mutations were detected in five of these patients (33.3%). Patients 1 and 2 with homozygous DNASE1L3 mutations [ c.320+4_320+7del and G188 A (c.563 G>C) variants] had skin involvement and oral ulcers. One of them (patient 1) had arthritis and nephritis, and another (patient 2) had nonscarring alopecia and thrombocytopenia. They are currently clinically inactive but have positive serological findings. Patient 3 with homozygous pathogenic ACP5 mutation [ G109 R (c.325 G>A) variant] had arthritis, nephritis, short stature, and skeletal dysplasia. Patient 4 with a heterozygote novel IFIH1 mutation [ L809 F (c.2425 C>T) variant] had skin findings and leukopenia. Patient 5 with novel C1S variant [homozygous C147 W (c.441 C>G) variant] had marked skin findings, oral ulcers, nonscarring alopecia, pancytopenia, and low total hemolytic complement CH50 level. All patients have responded to the treatments and have low Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, on therapy. Conclusion: Genetic causes should be investigated in early-onset SLE, for better management and genetic counseling. On the other hand, multicenter studies may help to further define genotype-phenotype associations. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of calvarial graft (CG) in craniovertebral fusion procedures in children at a single single center. Methods: Paediatric patients in whom CG had been used as the sole construct, or to augment a semi-rigid construct were identified from a prospective operative database. Age, underlying diagnosis and clinical presentation were obtained from review of the electronic patient record. The primary outcome was bony fusion confirmed on CT. Additional outcome measures were donor site morbidity and need for further surgery. Results: From 82 paediatric CVJ procedures, CG was used in 15 patients with a mean age of 4.1 (± 3.52) years. Aetiology comprised skeletal dysplasia (n = 12), congenital anomaly of segmentation (n = 1) and cervical trauma (n = 2). Myelopathy was the most common clinical finding (9/15), followed by cervical pain (3/15). The indications for surgery comprised atlanto-axial subluxation (8/15), basilar invagination with compression (2/15), and cervicomedullary compression without instability but deemed at risk of instability following decompression (4/15). CG was used in three scenarios: (i) CG + wire only (n = 10); (ii) CG + semirigid instrumentation (n = 3); (iii) CG to augment rigid instrumented fixation (n = 2). In 13 patients a Halo-body Jacket was used peri-operatively. At a mean time of 4.4 months following surgery, 80% of cases had radiological evidence of fusion. Conclusion: Full thickness calvarial bone graft is readily available, has good structural integrity and is associated with minimal donor site morbidity. CG should be considered for use as a sole construct, or to augment semi-rigid constructs when instrumented fixation is precluded. [ABSTRACT FROM AUTHOR]

Skeletal dysplasias are group of rare genetic diseases resulting from mutations in genes encoding structural proteins of the cartilage extracellular matrix (ECM), signaling molecules, transcription factors, epigenetic modifiers, and several intracellular proteins. Cell division, organelle maintenance, and intracellular transport are all orchestrated by the cytoskeleton-associated proteins, and intracellular processes affected through microtubule-associated movement are important for the function of skeletal cells. Among microtubule-associated motor proteins, kinesins in particular have been shown to play a key role in cell cycle dynamics, including chromosome segregation, mitotic spindle formation, and ciliogenesis, in addition to cargo trafficking, receptor recycling, and endocytosis. Recent studies highlight the fundamental role of kinesins in embryonic development and morphogenesis and have shown that mutations in kinesin genes lead to several skeletal dysplasias. However, many questions concerning the specific functions of kinesins and their adaptor molecules as well as specific molecular mechanisms in which the kinesin proteins are involved during skeletal development remain unanswered. Here we present a review of the skeletal dysplasias resulting from defects in kinesins and discuss the involvement of kinesin proteins in the molecular mechanisms that are active during skeletal development. [ABSTRACT FROM AUTHOR]

Simple Summary: This case report highlights two wild juvenile American black bears that were admitted to a rehabilitation facility but were euthanized due to severe immobility and joint laxity. Known musculoskeletal diseases of young bears are usually caused by trauma in the wild, or potentially rickets (a form of malnutrition) if raised in captivity. However, Case 1 was diagnosed with abnormal cartilage development (chondrodysplasia), likely of genetic origin, and Case 2 had osteoporosis and unidentified collagen abnormalities which are both unique to the current literature. With growing black bear populations, and increasing wildlife–human interface, we advise wildlife biologists and veterinarians to monitor and evaluate similar cases to help us further understand these uncommon diseases. Severe musculoskeletal disease characterized by marked joint laxity was the cause of euthanasia in two wild juvenile American black bears (Ursus americanus) admitted to a rehabilitation facility in eastern Tennessee in 2023. Previously, almost all reported musculoskeletal diseases in this population were of traumatic etiology, even in malnourished yearlings. Case 1 was an orphaned 11-month-old male cub exhibiting disproportionate dwarfism, progressive immobility, and joint laxity. Necropsy findings suggested either chondrodysplasia or rickets, and imaging findings supported a skeletal dysplasia. Case 2 was a 14-month-old emaciated male yearling exhibiting joint laxity and immobility. Necropsy findings showed osteoporosis and serous atrophy of fat, and imaging findings were inconsistent with a skeletal dysplasia. Both cases were clinically inconsistent with rickets based on normal calcium, phosphorous, and parathyroid hormone concentrations; however, Case 1 had hypovitaminosis D (9 nmol/L) compared to healthy juvenile black bears. We hypothesize that Case 1 had a genetic chondrodysplasia while the osteoporosis of Case 2 was due to chronic malnutrition. The goal of this case report is to inform wildlife agencies and facilities to monitor for similar, non-trauma-related debilitating musculoskeletal disease in free-ranging bears and evaluate cases that allow us to further understand the disease processes involved. [ABSTRACT FROM AUTHOR]

Objective: This study reported a family with most members affected by Czech dysplasia. We examined the patients' clinical, laboratory, and imaging characteristics and evaluated their functional capacity using the Stanford Health Assessment Questionnaire-Disability Index. Methods: The method used was case series description and literature review. Results: This study showed that the pathogenic variant c.823C>T in the COL2A1 gene, which is a characteristic of Czech dysplasia, was found in 12 Brazilian individuals. Half of the patients in this family met the criteria for rheumatoid arthritis (RA) based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria. Patients had arthritis in their hand joints, synovitis detected by ultrasound, and alterations in inflammatory tests. The Stanford Health Assessment Questionnaire-Disability Index assessment revealed that all patients exhibited moderate-to-severe functional disability. What distinguish Czech dysplasia from RA are an autosomal dominant inheritance pattern, platyspondyly, sensorineural hearing loss, and shortening of the metatarsal bones. Conclusions: It is important to consider Czech dysplasia as a potential differential diagnosis for RA. This autosomal dominant skeletal dysplasia is associated with normal height, short metatarsals, platyspondyly, hearing loss, enlarged epiphyses, and precocious osteoarthritis. Inflammatory findings such as arthritis, synovitis, and alteration of inflammatory markers may also be present in individuals with Czech dysplasia. [ABSTRACT FROM AUTHOR]

Thanatophoric dysplasia (TD) is a rare and severe type of skeletal dysplasia. Typical clinical findings include macrocephaly, shortening of the four limbs, underdeveloped lungs, and thoracic hypoplasia. Neonates with TD develop severe respiratory problems due to thoracic hypoplasia and require respiratory management for survival. Despite the resolution of respiratory problems, long‐term survival cases are rare. Previous studies have reported that surgical procedures in patients with TD are limited to those necessary for survival, including tracheostomy, laminectomy, and ventricular shunt. A 1‐year‐old boy with TD was treated with laparoscopic herniorrhaphy. To the best of our knowledge, this is the first report of TD treated with laparoscopic procedure. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF 1) is a multisystemic genetic disorder involving aberrant proliferation of multiple tissues of a neural crest origin. It represents a tumor predisposition syndrome characterized by a wide range of clinical manifestations, such as benign tumors, which primarily affect the skin and the nervous system. The most frequent clinical signs of NF 1 include café-au-lait spots all over the surface of the skin and axillary freckling; however, these signs can be accompanied by more severe manifestations such as the growth of both benign and malignant nervous system tumors and skeletal dysplasia, as well as a wide range of ocular manifestations. We report the rare case of retinal microvascular alterations and choroidal nodules in a 15 year old male patient with NF 1, detectable on optical coherence tomography angiography (OCTA). The hyperreflective choroidal nodules modified the profile of the choroidal vasculature. The retinal microvascular alterations in the form of clustered capillaries were detected in the superficial capillary plexus located nasally to the macular region. Retinal vascular abnormalities undetectable on fundus photography or fundoscopy can be present in patients with NF 1. Indirect ophthalmoscopy of our study patient was unremarkable. However, retinal vascular abnormalities were seen on OCTA scans in the superficial capillary plexus and choroidal nodules were detected on raster OCT scans. OCTA represents a useful imaging technique for detecting retinal microvascular abnormalities, which can be considered additional distinctive signs of NF 1. [ABSTRACT FROM AUTHOR]

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There is an emerging body of evidence showing that young patients, post haematopoietic stem cell transplantation (HSCT), can develop skeletal changes that mimic an osteochondrodysplasia process. The key discriminator is that these children have had otherwise normal growth and skeletal development before the therapeutic intervention (HSCT), typically for a haematological malignancy. Herein we present that case of a boy who underwent HSCT for Haemophagocytic Lymphohistiocytosis (HLH) aged 2 years. Following Intervention with HSCT this boy's growth has severely decelerated (stature less than 1st centile matched for age) and he has developed a spondyloepiphyseal dysplasia. [ABSTRACT FROM AUTHOR]

A 27‐year‐old multiparous woman conceived her fetus naturally. Early second‐trimester ultrasound showed short extremities with systemic subcutaneous edema. The pregnancy was artificially terminated at 19 weeks of gestation because of the abnormalities based on the parents' wishes. The parents desired whole‐exome sequencing to detect a causative gene using the umbilical cord and the parents' saliva. Compound heterozygous variants (NC_000003.11(NM_052989.3):c.230 T > G/NC_000003.11(NM_052985.4):c.1178A > T) were identified. We described a fetus with a novel compound heterozygous variant in IFT122. The phenotype of this case was severer than of other types of cranioectodermal dysplasia. [ABSTRACT FROM AUTHOR]

Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human NINEIN gene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia. Likewise, intramembranous ossification in the skull is more developed, leading to a premature closure of the interfrontal suture. We demonstrate that ninein is strongly expressed in osteoclasts of control mice, and that its absence reduces the fusion of precursor cells into syncytial osteoclasts, whereas the number of osteoblasts remains unaffected. As a consequence, ninein-deficient osteoclasts have a reduced capacity to resorb bone. At the cellular level, the absence of ninein interferes with centrosomal microtubule organization, reduces centrosome cohesion, and provokes the loss of centrosome clustering in multinucleated mature osteoclasts. We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and boneresorbing osteoclasts during skeletal development. [ABSTRACT FROM AUTHOR]

The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies. Two subsequent pregnancies were terminated due to multiple congenital malformations. Fetal DNA samples revealed the same homozygous variant in the POP1 gene. Expression of the RMRP was reduced in the proband compared with control and slightly reduced in both heterozygous parents, carriers for this variant. To our knowledge, this is the first report of this new phenotype, associated with a novel likely pathogenic variant in POP1. Our findings expand the phenotypic spectrum of POP1‐related disorders. [ABSTRACT FROM AUTHOR]

Background: The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features. Case Report: A fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio‐total whole‐exome sequencing (Trio‐WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio‐WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization. Conclusions: We reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio‐WES for diagnosis of skeletal dysplasia in fetuses. [ABSTRACT FROM AUTHOR]

Background: Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP‐glucuronate decarboxylase 1, which catalyzes synthesis of UDP‐xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so‐called linkeropathies, characterized by short stature, radio‐ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more. Methods: Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father's unaffected parents. Wild‐type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC–MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics. Results: The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn‐UXS1, in contrast to the wild‐type, was not able to convert UDP‐glucuronic acid to UDP‐xylose. Plasma glycosaminoglycan levels were decreased in both son and father. Conclusion: This is the first report linking UXS1 to short‐limbed short stature in humans. [ABSTRACT FROM AUTHOR]

Objective: To analyze the value of prenatal ultrasound and molecular testing in diagnosing fetal skeletal dysplasia (SD). Methods: Clinical data, prenatal ultrasound data, and molecular results of pregnant women with fetal SD were collected in the ultrasound department of our clinic from May 2019 to December 2021. Results: A total of 40 pregnant women with fetal SD were included, with 82.5% exhibiting short limb deformity, followed by 25.0% with central nervous system malformations, 17.50% with facial malformations, 15% with cardiac malformations, and 12.5% with urinary system malformations. The genetic testing positive rate was 70.0% (28/40), with 92.8% (26/28) being single‐gene disorders due to mutations in FGFR3, COL1A1, COL1A2, EVC2, FLNB, LBR, and TRPV4 genes. The most common SD subtypes were osteogenesis imperfecta (OI), thanatophoric dysplasia (TD), and achondroplasia (ACH). The gestational age (GA) at initial diagnosis for TD, OI, and ACH was 16.6, 20.9, and 28.3 weeks, respectively (p < 0.05), with no significant difference in femoral shortening between the three groups (p > 0.05). Of the OI cases, 5 out of 12 had a family history. Conclusion: Short limb deformity is the most prevalent phenotype of SD. When fetal SD is suspected, detailed ultrasound screening should be conducted, combined with GA at initial diagnosis, family history, and molecular evidence, to facilitate more accurate diagnosis and enhance prenatal counseling and perinatal management. [ABSTRACT FROM AUTHOR]

ERI1 is a 3-to-5 exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3 end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Background: Patients with genetic skeletal dysplasias often require lower extremity total joint arthroplasty (TJA) due to early joint degeneration; however, little data exists regarding the outcomes of TJA in this population. Our purpose was to review the literature to determine the complication rates, revision rates, implant survivorship, and patient-reported outcomes of total knee arthroplasty and total hip arthroplasty (THA) in those with genetic skeletal dysplasias. Methods: A systematic literature review of online databases (PubMed and Google Scholar) was conducted. Studies that reported the outcomes of THA or total knee arthroplasty in patients with genetically confirmed skeletal dysplasias were included. Case reports and studies that defined dysplasia based on height alone were excluded. Fourteen studies met the criteria for data extraction and analysis. Results: Our review yielded a sample of 596 skeletal dysplasia patients with a median follow-up of 6.01 years (1.7-15.9). Mean age was 54.04 years, and mean body mass index was 29.1 kg/m2. Cementless fixation was utilized in 65.7% of THAs, while all knees were cemented. Hip implant survivorship was 79% at 10 years and 56% at 20 years. Knee implant survivorship was 92% at 10 years and 46% at 20 years. Hip and knee revisions were 15.3% and 13.5%, respectively. The most common indication was aseptic loosening and polyethylene wear. Patient-reported outcomes improved across all domains. Conclusions: The literature regarding lower extremity TJA in those with genetic skeletal dysplasias demonstrates appropriate 10-year implant survivorship and improvement in patient-reported outcomes across all survey domains.

Skeletal dysplasias or osteochondrodysplasias comprise a large heterogeneous group of genetic disorders and possess significant overlap on imaging, which adds to the dilemma of the reporting radiologist. These entities are routinely evaluated with a detailed skeletal survey and hand radiographs form a crucial part of a complete survey. Certain conditions have characteristic imaging findings that enable a diagnosis be made on hand radiograph alone. Additionally, hand radiographs may also demonstrate findings that may be suggestive of a particular diagnosis/differential diagnoses and would warrant further assessment for proving the same. We aim to demonstrate the use of hand radiographs in diagnosis of various such entities through this review. Although they cannot replace a complete skeletal survey in the diagnosis, hand radiographs performed for other indications might alert a radiologist to the diagnosis of an unsuspected skeletal dysplasia.

Proteoglycans through their sulfated glycosaminoglycans regulate cell-matrix signaling during tissue development, regeneration, and degeneration processes. Large extracellular proteoglycans such as aggrecan, versican, and perlecan are especially important for the structural integrity of the intervertebral disc and cartilage during development. In these tissues, proteoglycans are responsible for hydration, joint flexibility, and the absorption of mechanical loads. Loss or reduction of these molecules can lead to disc degeneration and skeletal dysplasia, evident from loss of disc height or defects in skeletal development respectively. In this review, we discuss the common proteoglycans found in the disc and cartilage and elaborate on various murine models and skeletal dysplasias in humans to highlight how their absence and/or aberrant expression causes accelerated disc degeneration and developmental defects.

Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common form of short-limbed skeletal dysplasia. Additionally, a pregnant patient who is morbidly obese warrants specific anatomical and physiological considerations, such as a difficult airway with potential hypoxia, full stomach precautions, and a reduced functional residual capacity. Achondroplasia increases the risks of maternal and fetal complications. Although neuraxial techniques are generally preferred for cesarean sections, there is no consensus among patients with achondroplasia. We aimed to discuss the anesthetic challenges in an achondroplastic patient and report our regional anesthesia approach for an elective cesarean section.

Objective: To evaluate the spectrum of skeletal dysplasia in short stature children at National Institute of Child Health (NICH), Pakistan. Study Design: Case Series study. Setting: Department of Endocrinology, NICH, Karachi, Pakistan. Period: January 2022 to November 2023. Methods: Short statured (height < -2.0 SD) children of either gender aged between 1 month up to 16 years and diagnosed with skeletal dysplasia were analyzed. At the time enrollment, gender, age, anthropometric measures, antenatal history, and family history were noted. Complete skeletal survey was performed. Results: In a total of 131 short statured children with skeletal dysplasia, 77 (58.8%) were male. The mean and median age were 5.54±4.33 and 5.0 (1.5-8) years. Consanguinity was reported in 85 (64.9%) cases whereas siblings were affected among 9 (6.9%) cases. The most frequent presenting complaints and clinical features were joint pain, facial dysmorphism, movement limitations, and infections, reported by 67 (51.1%), 67 (51.1%), 65 (49.6%), and 63 (48.1%) children respectively. Mucopolysaccharidosis (29.0%), achondrodysplasia (13.7%), and osteogenesis imperfecta (10.7%) were the most common types of skeletal dysplasia. Conclusion: Mucopolysaccharidosis, achondrodysplasia, and osteogenesis imperfecta were the most frequent types of skeletal dysplasia. The most frequent presenting complaints and clinical features were joint pain, facial dysmorphism, movement limitations, and infections. The high prevalence of consanguinity and familial history emphasizes a probable genetic basis for skeletal dysplasia. [ABSTRACT FROM AUTHOR]