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Acute kidney injury (AKI) is recognized as a complication of COVID-19 among hospitalized patients. Lung ultrasonography (LUS) can be a useful tool in the management of COVID-19 pneumonia when interpreted correctly. However, the role of LUS in management of severe AKI in the setting of COVID-19 remains to be defined. We report a 61-year-old male who was hospitalized with acute respiratory failure from COVID-19 pneumonia. In addition to requiring invasive mechanical ventilation, our patient developed AKI and severe hyperkalemia requiring urgent dialytic therapy during his hospital stay. Our patient remained dialysis dependent despite subsequent recovery of lung function. Three days following discontinuation of mechanical ventilation, our patient developed a hypotensive episode during his maintenance hemodialysis treatment. A point of care LUS performed soon after the intradialytic hypotensive episode found no extravascular lung water. Hemodialysis was discontinued and the patient was initiated on intravenous fluids for one week. AKI subsequently resolved. We consider LUS an important tool in identifying COVID-19 patients that would benefit from intravenous fluids following recovery of lung function.

Background: Idiopathic genu valgum beyond physiological limits may require treatment, which is based on age, growth remaining, and the magnitude of the deformity. There is no consensus on clinical, or radiologic evaluation, indications, and management of idiopathic genu valgum, which can range from observation to surgical treatment using various modalities. If available, such guidelines will help surgeons offer optimal treatment to their patients. The aim of our study was to establish an expert consensus on the evaluation and treatment of idiopathic genu valgum., Methods: An international panel of 29 pediatric orthopaedic surgeons from 17 countries with clinical and research experience in the management of limb deformity participated in a modified Delphi survey. Surgeons were provided with patient and deformity characteristics and voted on 46 statements on history, clinical examination, radiographic evaluation, and treatment options for idiopathic genu valgum in round 1. Consensus was defined as when statements received ≥70% votes. Statements that were important but received <70% votes were reworded for clarity in round 2 (n=13)., Results: Consensus was achieved for 28/46 statements and included obtaining a full-length standing radiograph of the lower extremities and measuring joint orientation angles. Participants did not agree to offer surgical treatment based only on the intermalleolar distance. They recommended surgical treatment if the mechanical axis falls in zone 2 or beyond on the lateral side and using guided growth by tension-band plating when the growth remaining is at least 2 years. The panel agreed on performing common peroneal nerve decompression for specific indications such as acute, opening wedge osteotomy of >20 degrees, but not for gradual correction. Consensus was not reached for indications and methods of bone age assessment, treatment when growth remaining is <1 year, indications for implant removal after guided growth in younger children, and the type of osteotomy for acute deformity correction., Conclusions: We have generated consensus statements to guide the management of idiopathic genu valgum. Statements that lack consensus are areas for future multicenter research., Level of Evidence: Level V., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Kyphomelic dysplasia is a rare heterogenous group of skeletal dysplasia, characterized by bowing of the limbs, severely affecting femora with distinct facial features. Despite its first description nearly four decades ago, the precise molecular basis of this condition remained elusive until the recent discovery of de novo variants in the KIF5B-related kyphomelic dysplasia. We ascertained two unrelated consanguineous families with kyphomelic dysplasia. They had six affected offsprings and we performed a detailed clinical evaluation, skeletal survey, and exome sequencing in three probands. All the probands had short stature, cleft palate, and micro-retrognathia. Radiographs revealed kyphomelic femora, bowing of long bones, radial head dislocations and mild platyspondyly. We noted two novel homozygous variants in CCN2 as possible candidates that segregated with the phenotype in the families: a missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779&#95;786del; p.(Pro260LeufsTer7) in exon 5. CCN2 is crucial for proliferation and differentiation of chondrocytes. Earlier studies have shown that Ccn2-deficient mice exhibit twisted limbs, short and kinked sterna, broad vertebrae, domed cranial vault, shorter mandibles, and cleft palate. We studied the impact of CCN2 knockout in zebrafish models via CRISPR-Cas9 gene editing. F0 knockouts of ccn2a in zebrafish showed altered body curvature, impaired cartilage formation in craniofacial region and either bent or missing tails. Our observations in humans and zebrafish combined with previously described skeletal phenotype of Ccn2 knock out mice, confirm that biallelic loss of function variants in CCN2 result in an autosomal recessive kyphomelic dysplasia., Competing Interests: Competing interests: The authors declare no competing interests. KMG holds shares and is a director of Suma Genomics Private Limited that has interests in clinical diagnostics. Ethics approval: Informed consents were obtained from the participants for the study and publication of clinical photographs. The research protocol is approved by the Institutional Ethics Committee, Kasturba Medical College and Hospital, Manipal (IEC: 363/2020) and Institutional Review Board Ethics and Research Committee members of the Christian Medical College, Vellore (Ref: IRB Min. No. 0424162). All experiments with zebrafish were done in a CCSEA-approved zebrafish facility at Dr. Reddy’s Institute of Life Sciences (1100/po/Re/s/07/CPCSEA) in Hyderabad, India. The facility also has US-NIH OLAW assurance (F22-00539). All procedures and protocols were reviewed and approved by the Institutional Animal Ethics Committee (Protocol approval DRILS/IAEC/AS/2021-1). The “Guidelines for Experimentation on Fishes, 2021” published by CPCSEA was used as a reference., (© 2024. The Author(s).)

Skeletal dysplasias are a clinically and genetically heterogeneous group of rare disorders. Studies from large cohorts are essential to provide insights into the disease epidemiology, phenotypic spectrum, and mutational profiles. Here we enumerate additional 248 Indians from 197 families with a skeletal dysplasia, following a similar study earlier. We achieved a clinical-molecular diagnosis in 145 families by targeted analysis in 37 and next generation sequencing (exomes and genomes) in 108 families that resulted in a diagnostic yield of 73.6% (145 of 197 families). We identified 149 causal variants, of which 85 were novel, across 73 genes. Eighty-one distinct monogenic forms of skeletal dysplasia were observed with a high proportion of autosomal recessive skeletal dysplasias (60%, 84 families). We observed consanguinity in 35% of the families. Lysosomal storage diseases with skeletal involvement, FGFR3-related skeletal dysplasia and disorders of bone mineralisation were most frequent in this cohort. We expand the phenotypic and genotypic spectrum of rarely reported conditions (RAB33B, TRIP11, NEPRO, RPL13, COL27A1, PTHR1, EXOC6B, PRKACA, FUZ and RSPRY1) and noted novel gene-disease relationships for PISD, BNIP1, TONSL, CCN2 and SCUBE3 related skeletal dysplasia. We successfully implemented genomic testing for skeletal dysplasia in clinical and research settings. Our study provides valuable information on the spectrum of skeletal dysplasia and disease-causing variants for Asian Indians., Competing Interests: Competing interests: KMG is the director of Suma Genomics Private Limited and holds shares of the company that has interests in genetic testing. Ethical approval: We obtained the informed consents from the families for genetic testing, publication of data and clinical photographs. This study has the approvals from the Institutional Ethics Committee at the Kasturba Medical College and Kasturba Hospital, Manipal (IEC:921/2018; IEC:363/2020, IEC: 430/2013, IEC: 570/2015, IEC: 302/2013)., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Distal femur physeal fractures in children, particularly Hoffa fractures, are rare and prone to complications. This study aims to evaluate the outcomes of surgical intervention in children presenting with delayed intra-articular distal femur physeal fractures. A multicentric retrospective study involved six pediatric patients with delayed presentation of distal femur physeal fractures. Five patients underwent surgical intervention involving osteotomy and anatomical re-fixation of the malunited fragments. One patient opted for conservative management. The age at presentation, time since injury, surgical procedures, and clinical and radiological outcomes were evaluated at the final follow-up. Fixation with lag screws was sufficient in three patients, while two required additional plate stabilization. The mean age of patients was 12.2 years, comprising four boys and two girls. The average delay in presentation was 30.8 months (ranging from 3 months to 8 years). For the surgical group ( n  = 5), the knee range of motion improved from an average of 16°-66° preoperatively to 6°-128° post-operatively at a mean follow-up of 60 months. The mean limb shortening was 3 cm (range 0.5-5 cm). Two patients required additional procedures for distal femur varus malalignment. The conservatively managed patient showed no improvement in knee movements at the 12-month follow-up, serving as a control. Surgical intervention involving osteotomy and anatomical reduction for malunited intra-articular Salter-Harris-type III and IV fractures of the distal femur in children yields good to excellent outcomes. Limb length discrepancy and malalignment, if present, can be addressed separately. Longer follow-up until skeletal maturity is necessary to evaluate final outcomes in these patients. Level of evidence : Level IV (case series). Therapeutic., Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-024-01291-4., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Indian Orthopaedics Association 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Introduction: The wide-abduction A-frame brace contains the femoral head to improve its remodeling in Legg-Calvé-Perthes disease (LCPD). There is no study of the effect of brace adherence on hip outcomes. The purpose of this study was to determine if patient adherence to A-frame brace treatment is associated with improved hip abduction range of motion and radiographic outcomes in children with LCPD., Methods: This retrospective study included patients aged 4 to 11 years with LCPD treated with an A-frame brace. Patients aged >11 and those treated with osteotomy before completing brace treatment were excluded. Built-in temperature sensors measured brace wear. Hip abduction was measured on examination before and after bracing. Deformity index (DI) and sphericity deviation score (SDS) were measured from radiographs at the 2-year follow-up and healed stage, respectively. Pearson correlation and multiple regression analyses were performed., Results: Fifty-seven patients (44 male; 77%) were included with a mean age of 7.0±1.6 at brace treatment and mean adherence of 0.66±0.28. Brace adherence was associated with increased hip abduction ( R =0.36; P =0.006) and decreased DI ( R =-0.37; P =0.042) across all patients, and decreased SDS in patients <9 years old at the time of brace treatment ( R =-0.58; P =0.024). A +0.50 increase in adherence was associated with +9.4° hip abduction ( P =0.018), -0.13 DI ( P =0.027), and -17.7 SDS ( P =0.019)., Conclusions: Adherence to A-frame brace treatment was associated with increased hip abduction, decreased femoral head deformity, and increased sphericity. Patients and parents can be counseled regarding brace adherence to maximize outcomes of treatment., Level of Evidence: III-Therapeutic Study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To the best of our knowledge, there is no study comparing the inter and intraobserver reliability of current classifications for postseptic hip sequelae in children. The current study aims to assess the interobserver and intraobserver reliability of four current classifications and identify hips that could not be classified in each classification system., Methods: The hip radiographs of 148 consecutive children with sequelae of sepsis of the hip from 2 centers were assessed after a minimum of 2 years of follow-up after sepsis. All hips (affected and normal sides) were classified according to the 4 original descriptions of the authors of the respective classifications. If a hip did not fall into any subtype of the classification, the rater was asked to mark it as nonclassifiable and state the reason for being unable to classify the hip in the respective classification. The intraclass correlation coefficient was computed to assess the reproducibility of each classification., Results: Interrater reliability and intrarater reliability were moderate (0.57 to 0.72) while including all hips. The reliability was poor (0.35 to 0.49) in all 4 classifications, with an evaluation of only affected 180 hips. A few sequelae of infection, including caput valgus (n = 7), acetabular dysplasia (4), joint space narrowing (2), and bony ankylosis (1), were not included in any of the 4 current existing classification systems., Conclusion: The reliability of all current classifications of sequelae of septic arthritis of the hip is moderate. A proportion of sequelae do not find a place in all current classifications., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome (MIM# 208250) is a rare monogenic disorder, characterized by early onset of camptodactyly, progressive coxa vara, bilateral arthropathy and constrictive pericarditis. The syndrome is caused by biallelic loss-of-function variants in PRG4 . Deficiency of PRG4 results in progressive worsening of joint deformity with age. Thirteen individuals with CACP syndrome from eight consanguineous Indian families were evaluated. We used exome sequencing to elucidate disease-causing variants in all the probands. These variants were further validated and segregated by Sanger sequencing, confirming the diagnosis of CACP syndrome in them. Seven females and six males aged 2-23 years were studied. Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13) [wrists (11/13), ankle (11/13), elbow (10/13) and knee (10/13)] were observed commonly. Five novel disease-causing variants (c.3636G>T, c.1935del, c.1134dup, c.1699del and c.962T>A) and two previously reported variants (c.1910&#95;1911del and c.2816&#95;2817del) were identified in homozygous state in PRG4 . We describe the phenotype and mutations in one of the large cohorts of patients with CACP syndrome, from India., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Biallelic variants in RSPRY1 have been found to result in spondyloepimetaphyseal dysplasia. Two siblings presenting with short stature, facial dysmorphism, progressive vertebral defects, small epiphysis, cupping and fraying of metaphyses, brachydactyly, and short metatarsals harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene. The phenotype in our patients resembles spondyloepimetaphyseal dysplasia, Faden-Alkuraya type. Thus, our study provides further evidence to support the association of RSPRY1 variants with spondyloepimetaphyseal dysplasia. We observed joint dislocation as a novel clinical feature of this condition., (© 2024 Wiley Periodicals LLC.)

Introduction: One of the most popular containment procedures for Legg-Calvé-Perthes disease (LCPD) is proximal femur varus osteotomy (PFO). While generally successful in achieving containment, PFO can cause limb length discrepancy, abductor weakness, and (of most concern for families) a persistent limp. While many studies have focused on radiographic outcomes following containment surgery, none have analyzed predictors of this persistent limp. The aim of this study was to determine clinical, radiographic, and surgical risk factors for persistent limp 2 years after PFO in children with LCPD., Methods: A retrospective review of a prospectively collected multicenter database was conducted for patients aged 6 to 11 years at disease onset with unilateral early-stage LCPD (Waldenström I) who underwent PFO. Limp status (no, mild, and severe), age, BMI, and pain scores were obtained at initial presentation, 3-month, and 2-year postoperative visits. Preoperative and follow-up radiographs were used to measure traditional morphologic hip metrics including acetabular index (AI), lateral center-edge angle (LCEA), and femoral neck-shaft angle (NSA). Univariate analysis as well as multivariate logistic regression models were used to analyze factors associated with mild and severe limp at the 2-year visit., Results: A total of 95 patients met the inclusion criteria, and of these 50 patients underwent concomitant greater trochanter apophysiodesis (GTA) at the time of PFO. At the 2-year visit, there were 38 patients (40%) with a mild or severe limp. Multivariate logistic regression revealed no significant radiographic factors associated with a persistent limp. However, lower 2-year BMI and undergoing GTA were associated with decreased rates of persistent limp regardless of age ( P <0.05). When stratifying by age of disease onset, apophysiodesis appeared to be protective against any severity of limp in patients aged 6 to 8 years old ( P = 0.03), but not in patients 8 years or older ( P = 0.49)., Conclusions: Persistent limp following PFO is a frustrating problem that was seen in 40% of patients at 2 years. However, lower follow-up BMI and performing a greater trochanter apophysiodesis, particularly in patients younger than 8 years of age, correlated with a lower risk of postoperative limp., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Congenital vertical talus (CVT) and congenital oblique talus (COT) are rocker-bottom foot deformities that have similar names and no objective definitions. This has led to confusion for practitioners, as well as scientific challenges for researchers. Our goal was to provide objective radiographic criteria to define and differentiate CVT and COT., Methods: We evaluated 62 pairs of maximum dorsiflexion and plantar flexion lateral radiographs of infant feet that had been clinically diagnosed with CVT. The dorsiflexion tibiotalar angle, the plantar flexion talus-first metatarsal angle, and the plantar flexion foot center of rotation of angulation (foot-CORA) were measured using transparent overlay tools. Freehand measurements were made on a subset of 10 pairs of radiographs to confirm clinical applicability. Nine contralateral pairs of radiographs of normal feet were measured for comparison., Results: Specific values for the radiographic measurements were identified that, together, reliably differentiated the shapes of rocker-bottom feet with CVT, COT, and flexible flatfoot with a short tendo-Achilles (FFF-STA), as well as the shape of the normal foot. More severe and rigid rocker-bottom foot deformities were diagnosed with CVT. Less severe and more flexible deformities were diagnosed with COT., Conclusions: CVT, COT, FFF-STA, and normal feet can be reliably differentiated using 2 angular measurements and 1 bone position measurement on dorsiflexion and plantar flexion lateral radiographs. Our data indicated that the differentiation of CVT and COT is based primarily on the rigidity of the navicular dislocation rather than the verticality of the talus. The data further supported the proposition that COT is a foot deformity along a spectrum of valgus/eversion deformities of the hindfoot that requires early treatment. Application of these diagnostic criteria should lead to clinical studies that identify a specific treatment, treatment outcome, and prognosis for each deformity., Level of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: No external funding was received for this work. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A651)., (Copyright © 2024 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

PRKACA-related, atrial defects-polydactyly-multiple congenital malformation syndrome is a recently described skeletal ciliopathy, which is caused by disease-causing variants in PRKACA. The primary phenotypic description includes atrial septal defects, and limb anomalies including polydactyly and short limbs. To date, only four molecularly proven patients have been reported in the literature with a recurrent variant, c.409G>A p.Gly137Arg in PRKACA. In this study, we report the fifth affected individual with the same variant and review the clinical features and radiographic findings of this rare syndrome., (© 2024 Wiley Periodicals LLC.)

Skeletal dysplasias (SKDs) are a heterogeneous group of more than 750 genetic disorders characterized by abnormal development, growth, and maintenance of bones or cartilage in the human skeleton. SKDs are often caused by variants in early patterning genes and in many cases part of multiple malformation syndromes and occur in combination with non-skeletal phenotypes. The aim of this study was to investigate the underlying genetic cause of congenital SKDs in highly consanguineous Pakistani families, as well as in sporadic and familial SKD cases from India using multigene panel sequencing analysis. Therefore, we performed panel sequencing of 386 bone-related genes in 7 highly consanguineous families from Pakistan and 27 cases from India affected with SKDs. In the highly consanguineous families, we were able to identify the underlying genetic cause in five out of seven families, resulting in a diagnostic yield of 71%. Whereas, in the sporadic and familial SKD cases, we identified 12 causative variants, corresponding to a diagnostic yield of 44%. The genetic heterogeneity in our cohorts was very high and we were able to detect various types of variants, including missense, nonsense, and frameshift variants, across multiple genes known to cause different types of SKDs. In conclusion, panel sequencing proved to be a highly effective way to decipher the genetic basis of SKDs in highly consanguineous families as well as sporadic and or familial cases from South Asia. Furthermore, our findings expand the allelic spectrum of skeletal dysplasias., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

CHST3-related chondrodysplasia with congenital joint dislocations (CDCJD, #MIM 143095), is a rare genetic skeletal disorder caused by biallelic loss of function variants in CHST3. CHST3 is critical for the sulfation of chondroitin sulfate. This study delineates the clinical presentation of nine individuals featuring the key symptoms of CDCJD; congenital joint (knee and elbow) dislocations, short trunk short stature progressive vertebral anomalies, and metacarpal shortening. Additional manifestations include irregular distal femoral epiphysis, supernumerary carpal ossification centers, bifid humerus, club foot, and cardiac abnormalities. Sanger sequencing was carried out to investigate molecular etiology in eight patients and exome sequencing in one. Genetic testing revealed five homozygous variants in CHST3 (four were novel and one was previously reported). All these variants are located on sulfotransferase domain of CHST3 protein and were classified as pathogenic/ likely pathogenic. We thus report on nine individuals with CHST3-related chondrodysplasia with congenital joint dislocations from India and suggest monitoring the health of cardiac valves in this condition., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

LPIN2 -related Majeed syndrome (MIM# 609628) is a rare non-inflammasome autoinflammatory disease, caused due to biallelic variants in LPIN2 (MIM* 605519). To date, only 31 individuals from 18 families have been reported with this rare condition. Exome sequencing was done in two affected individuals from two unrelated families. Additionally, phenotypic, and genotypic information from the literature was reviewed. Two novel homozygous missense variants, c.2207G>A p. (Arg736His) and c.1157C>G p. (Ser386Ter) in LPIN2 , were identified in family 1 and family 2 respectively. Chronic recurrent osteomyelitis involving the lower extremities was the most common clinical presentation. LPIN2 -related Majeed syndrome should be considered as a differential diagnosis in an individual with clinical or radiological evidence of recurrent sterile osteomyelitis and chronic anaemia., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To understand the phenotypic and genotypic spectrum of genetic forms of rickets in 10 families., Methods: Detailed clinical, radiographic, and biochemical evaluation of 10 families with phenotypes suggestive of a genetic cause of rickets was performed. Molecular testing using exome sequencing aided in the diagnosis of six different forms of known genetic causes., Results: Eleven disease-causing variants including five previously reported variants (CYP27B1:c.1319&#95;1325dup, p.(Phe443Profs*24), VDR:c.1171C>T, p.(Arg391Cys), PHEX: c.1586&#95;1586+1del, PHEX: c.1482+5G>C, PHEX: c.58C>T, p.(Arg20*)) and six novel variants (CYP27B1:c.974C>T, p.(Thr325Met), CYP27B1: c.1376G>A, p.(Arg459His), CYP2R1: c.595C>T, p.(Arg199*), CYP2R1:c.1330G>C, p.(Gly444Arg),SLC34A3:c.1336-11&#95;1336-1del, SLC2A2: c.589G>C, p.(Val197Leu)) in the genes known to cause monogenic rickets were identified., Conclusion: The authors hereby report a case series of individuals from India with a molecular diagnosis of rickets and provide the literature review which would help in enhancing the clinical and molecular profile for rapid and differential diagnosis of rickets., (© 2023. The Author(s).)

Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM&#95;000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants' impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition., (© 2023. The Author(s).)

Background: Legg-Calvé-Perthes disease is a self-limiting disorder that develops in children following interruption of the blood supply to the capital femoral epiphysis. This review outlines the current knowledge on the epidemiology, natural evolution, clinical spectrum, and management of the disease., Methods: The literature pertaining to these aspects of the disease were studied and summarized in this review., Results: Epidemiological studies suggest that environmental factors contribute to the causation of the disease. Incidence rates monitored over time indicate that the incidence of Legg-Calvé-Perthes disease is declining. The natural evolution followed on sequential plain radiographs enables division of the disease into Stages Ia, Ib, IIa, IIb, IIIa, IIIb, and IV. Reversible deformation of the capital occurs in Stages Ia-IIa simply on standing while irreversible deformation may occur in Stages IIb and IIIa. Treatment of Legg-Calvé-Perthes disease in Stages Ia-IIa aims to prevent the femoral head from getting deformed by containment and avoidance of weight-bearing. In Stages IIb and IIIa, treatment aims to remedy the effects of early irreversible deformation of the femoral head. In Stage IIIb and IV, treatment is directed to correcting the altered shape of the femoral head. The impression that these treatment methods are helpful is based on poor quality evidence., Conclusion: There is an urgent need to undertake Level I studies to establish the efficacy of currently treatment., Level of Evidence: level V., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Genetic mutations are involved in Mendelian disorders. Unbuffered intronic mutations in gene variants can generate aberrant splice sites in mutant transcripts, resulting in mutant isoforms of proteins with modulated expression, stability, and function in diseased cells. Here, we identify a deep intronic variant, c.794&#95;1403A>G, in CRTAP by genome sequencing of a male fetus with osteogenesis imperfecta (OI) type VII. The mutation introduces cryptic splice sites in intron-3 of CRTAP, resulting in two mature mutant transcripts with cryptic exons. While transcript-1 translates to a truncated isoform (277 amino acids) with thirteen C-terminal non-wild-type amino acids, transcript-2 translates to a wild-type protein sequence, except that this isoform contains an in-frame fusion of non-wild-type twenty-five amino acids in a tetratricopeptide repeat sequence. Both mutant isoforms of CRTAP are unstable due to the presence of a unique 'GWxxI' degron, which finally leads to loss of proline hydroxylation and aggregation of type I collagen. Although type I collagen aggregates undergo autophagy, the overall proteotoxicity resulted in death of the proband cells by senescence. In summary, we present a genetic disease pathomechanism by linking a novel deep intronic mutation in CRTAP to unstable mutant isoforms of the protein in lethal OI type VII., Competing Interests: Declaration of competing interest Authors report no competing conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Autosomal recessive osteopetrosis (ARO) is a rare genetic disorder caused by impaired osteoclast activity. In this study, we describe a 4-year-old boy with increased bone density due to osteopetrosis, autosomal recessive 8. Using genome sequencing, we identified a large deletion in the 5'-untranslated region (UTR) of SNX10 (sorting nexin 10), where the regulatory region of this gene is located. This large deletion resulted in the absence of the SNX10 transcript and led to abnormal osteoclast activity. SNX10 is one of the nine genes known to cause ARO, shown to interact with V-ATPase (vacuolar type H( + )-ATPase), as it plays an important role in bone resorption. Our study highlights the importance of regulatory regions in the 5'-UTR of SNX10 for its expression while also demonstrating the importance of genome sequencing for detecting large deletion of the regulatory region of SNX10., (© 2022. The Author(s).)

We have been treating children with Legg-Calvé-Perthes disease (LCPD) with a femoral varus osteotomy (PFVO) and weight relief till the disease evolves to the latter part of the stage of reconstitution (Stage IIIb). This entails weight relief for 18 to 24 months. We undertook this case-control study to test if a shorter period of weight relief would compromise the chance of retaining the spherical shape of the femoral head when the disease healed. Forty-one children diagnosed in the early stages of LCPD (Stages Ia, Ib, and IIa), were treated by PFVO and non-weight-bearing for a period of 6 months following surgery (6m group). Eighty-two children with LCPD matched for age, sex, and stage at surgery, who resumed weight-bearing only once they reached Stage IIIb, served as the control group (3b group). Both groups were followed up till the disease healed. The sphericity deviation score was calculated, and the height and width of the epiphysis were measured on the first radiograph designated as Stage IV. The median sphericity deviation score value at healing was 3 in the 3b group and 11 in the 6m group (P<0.001). The frequency of spherical heads was 76% in the 3b group and 49% in the 6m group (P<0.003). The Odds Ratio of the disease healing with an aspherical head in 6-month group was 3.05 (CI: 1.28 to 7.22) compared with the 3b group. The percentage increase in width of the femoral epiphysis at healing was greater in the 6 group (111.5±8.5% vs. 106.5±7.2%; P<0.001). The study confirms that containment by PFVO performed early in the course of LCPD combined with weight relief till the disease has evolved to Stage IIIb is likely to result in spherical hips in 75% of children. Reducing the period of weight relief to 6 months may yield significantly poorer results with only 49% spherical femoral heads., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aberrant forms of endoplasmic reticulum (ER)-resident chaperones are implicated in loss of protein quality control in rare diseases. Here we report a novel mutation (p.Asp233Asn) in the ER retention signal of MESD by whole exome sequencing of an individual diagnosed with osteogenesis imperfecta (OI) type XX. While MESD D233N has similar stability and chaperone activity as wild-type MESD, its mislocalization to cytoplasm leads to imbalance of ER proteostasis, resulting in improper folding and aggregation of proteins, including LRP5 and type I collagen. Aggregated LRP5 loses its plasma membrane localization to disrupt the expression of WNT-responsive genes, such as BMP2, BMP4, in proband fibroblasts. We show that MESD is a direct chaperone of pro-α1(I) [COL1A1], and absence of MESD D233N in ER results in cytosolic type I collagen aggregates that remain mostly not secreted. While cytosolic type I collagen aggregates block the intercellular nanotubes, decreased extracellular type I collagen also results in loss of interaction of ITGB1 with type I collagen and weaker attachment of fibroblasts to matrix. Although proband fibroblasts show increased autophagy to degrade the aggregated type I collagen, an overall cellular stress overwhelms the proband fibroblasts. In summary, we present an essential chaperone function of MESD for LRP5 and type I collagen and demonstrating how the D233N mutation in MESD correlates with impaired WNT signaling and proteostasis in OI., Competing Interests: Conflict of interest KMG is a founder and a director of Suma Genomics Private Limited, interested in rare disease diagnosis. Other authors report no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study was undertaken to evaluate the results of patella tendon shortening to correct patella alta in the context of surgery for the management of severe crouch gait. Our aim was to ascertain whether the corrected position of the patella and improvement of the power of the quadriceps were maintained for 4 years or more. Twenty older children (mean age: 14.2 years) with long-standing crouch gait secondary to cerebral diplegia underwent surgery to correct crouch gait that included the patellar tendon shortening. The technique for plicating the tendon differed for skeletally mature and immature patients. The length of the patellar tendon was measured by the Koshino Index. The strength of the quadriceps muscle was assessed by manual muscle testing and with a dynamometer and extensor lag, if present, was measured with a goniometer. In all 40 knees, the patella was brought to a more distal position and the position was maintained for a mean duration of 84 months (Koshino Index: preoperative 1.3 ± 0.10; 3-month postoperative 0.95 ± 0.05; final follow-up 0.95 ± 0.04). The results were the same for the techniques used for skeletally mature and immature patients. The power of the quadriceps improved [Medical Research Council (MRC) grade 3 to MRC grade 4] and the improvement was maintained. The technique of patella tendon shortening was effective in correcting patella alta and improving quadriceps power. The shortened patellar tendon did not stretch over the period of follow-up. Level of evidence: III., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3. In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c.2122+15447&#95;2197-59588del and c.401T>G in EXOC6B identified by exome sequencing. One of the affected individuals had an intellectual disability and central nervous system anomalies, including hydrocephalus, hypoplastic mesencephalon, and thin corpus callosum. Using the fibroblast cell lines, we demonstrate the primary evidence for the abrogation of exocytosis in an individual with SEMDLJ3 leading to impaired primary ciliogenesis. Osteogenesis differentiation and pathways related to the extracellular matrix were also found to be reduced. Additionally, we provide a review of the clinical and molecular profile of all the mutation-proven patients reported hitherto, thereby further characterizing SEMDJL3. SEMDJL3 with biallelic pathogenic variants in EXOC6B might represent yet another ciliopathy with central nervous system involvement and joint dislocations., (© 2022 Wiley Periodicals LLC.)

Background: Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I-IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described., Methods: In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK , respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis., Results: The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS., Conclusion: Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Among a cohort of 402 children with Legg-Calvé-Perthes disease (LCPD), 32 children presented with sclerosis and severe collapse of the entire femoral epiphysis that closely resembled a discus.This study was undertaken to identify the characteristics of children with this form of a "discoid epiphysis," compare them with typical LCPD and ascertain the radiologic outcome of their hips when the disease healed., Methods: Sequential radiographs of the children were studied to monitor disease evolution. Femoral epiphyseal extrusion was measured on the initial anteroposterior radiograph. Thirty-one of the 32 children were treated with a proximal femoral varus osteotomy and weight-bearing was deferred till the disease reached stage IIIb. The pattern of fragmentation of the epiphysis was noted and the Sphericity Deviation Score (SDS) was computed once the disease healed., Results: The mean age of children with a discoid epiphysis was 6.81±1.57 years at onset of symptoms while that of children with the typical presentation was 7.54±1.64 years (P<0.017). Perfusion magnetic resonance imaging scans of three children with a discoid epiphysis done in stage Ib of the disease showed that over 95% of the epiphysis was avascular. Femoral head extrusion was frequently present on the initial radiographs (mean Reimer's migration index 27.08±8.7; range: 6.4 to 42.55).In operated children with a discoid epiphysis, the disease evolved typically with fragmentation of the epiphysis followed by reconstitution. The height of the epiphysis was never restored; when the disease healed the mean epiphyseal height was 51.31±10.44% of the normal contralateral epiphysis as compared with 82.46±11.24% in children with typical LCPD (P<0.001).The SDS at healing of operated children with a discoid epiphysis was 14.95±10.86 while the SDS for operated children without a discoid epiphysis was 9.77±11.7 (P<0.019). However, the SDS of children with typical onset LCPD who had Catterall IV involvement and Herring C collapse was 15.25±15.19 (P=0.49 NS)., Conclusion: The outcome of treatment of children with a discoid epiphysis is comparable to that of children with typical onset LCPD with Catterall IV (whole-head involvement) and Herring C collapse of the lateral pillar. About a third of these children who undergo early surgical containment may have spherical heads when the disease heals., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Steel syndrome (MIM# 615155) is an autosomal recessive skeletal disorder, characterized by dislocations of the hips and radial heads, carpal coalition, short stature, facial dysmorphism, and scoliosis. Until date 47 patients have been reported. However, disease causing variants have been identified only in twenty Puerto Rican and nine non-Puerto Rican families. Here we report two monozygotic twins and a boy from two families with novel missense variants, c.295G > A p.(Ala99 Thr), c.3056C > A p.(Pro1019His) and c.2521G > A p.(Gly841Arg) in COL27A1. We describe for the first time, cleft palate and delayed carpal bone ossification as features of Steel syndrome. We reviewed clinical features in all mutation-proven Steel syndrome patients. Short stature and dislocation/subluxation of hip joint are consistently observed. Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay. Seven missense variants and eight null variants are reported in COL27A1 until date. We also looked into the genotype-phenotype correlation in Puerto Rican and non-Puerto Rican patients., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

BNIP1 (BCL2 interacting protein 1) is a soluble N-ethylmaleimide-sensitive factor-attachment protein receptor involved in ER membrane fusion. We identified the homozygous BNIP1 intronic variant c.84+3A>T in the apparently unrelated patients 1 and 2 with disproportionate short stature. Radiographs showed abnormalities affecting both the axial and appendicular skeleton and spondylo-epiphyseal dysplasia. We detected ~80% aberrantly spliced BNIP1 pre-mRNAs, reduced BNIP1 mRNA level to ~80%, and BNIP1 protein level reduction by ~50% in patient 1 compared to control fibroblasts. The BNIP1 ortholog in Drosophila, Sec20, regulates autophagy and lysosomal degradation. We assessed lysosome positioning and identified a decrease in lysosomes in the perinuclear region and an increase in the cell periphery in patient 1 cells. Immunofluorescence microscopy and immunoblotting demonstrated an increase in LC3B-positive structures and LC3B-II levels, respectively, in patient 1 fibroblasts under steady-state condition. Treatment of serum-starved fibroblasts with or without bafilomycin A1 identified significantly decreased autophagic flux in patient 1 cells. Our data suggest a block at the terminal stage of autolysosome formation and/or clearance in patient fibroblasts. BNIP1 together with RAB33B and VPS16, disease genes for Smith-McCort dysplasia 2 and a multisystem disorder with short stature, respectively, highlight the importance of autophagy in skeletal development., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Competing Interests: The authors declare no conflicts of interest.

The magnitude of association of skeletal anomalies with maternal diabetes is not known. The systemic review was done to detect the frequency of congenital skeletal malformations with diabetes mellitus in pregnancy in the literature evidence of the past 50 years. Literature on maternal diabetes and skeletal malformation was searched by two independent authors by following PRISMA guidelines. Strict inclusion and exclusion criteria were followed. After quality assessment, 21 original articles were included. The frequency of congenital malformation, skeletal malformation was extracted from the included studies. 11,574 congenital anomalies were detected diabetic mothers. 1182 skeletal anomalies were noted in 20,11 552 diabetic mothers. The skeletal malformation was noted in 20.4% of total anomalies. The most common skeletal malformation was the defect of the spine (39.9%). The limb deficiency was found in 32.8% of the infants of diabetic mothers. The skeletal malformations were higher, that is, 24.6% in pre-gestational diabetes. The incidence of skeletal malformation from the evidence was 1.5% (range: 0.03-4.27%) in maternal diabetes. Pre-gestation diabetes is more frequently associated with skeletal malformations, which is 1.9% (range: 0.07-5.89%). The association of congenital malformations and skeletal malformations in diabetic pregnancy is significant and hence, effective management of diabetes in childbearing age is essential to reduce this incidence and related long-term morbidity., (© 2022 Japanese Teratology Society.)

Constriction band syndrome (CBS) may be rarely associated with pseudarthrosis of tibia. Published literature includes only case reports. We evaluated the outcome of children with frank pseudarthrosis of the tibia with CBS and compared our results with other reported cases. We aimed to formulate a clinical classification of tibial involvement in CBS on the basis of the treatment guidelines. Seven patients with the presence of one or more constriction bands and radiological signs of tibial pseudarthrosis were included in the study. Eight reported cases of CBS with tibial involvement with management and follow-up details were reviewed. Only two tibial pseudarthrosis united spontaneously after the release of the constriction band. Two patients underwent simultaneous correction of tibial deformity and nailing with band release, one of which needed bone grafting for the pseudarthrosis union. Three patients subsequently needed an excision of tibial pseudarthrosis with nailing to achieve tibial union, two of them had autologous bone grafting along with nailing. Additional procedures were required for the correction of foot deformity and limb length discrepancy. Our findings were similar to the reported cases. The pseudarthrosis of the tibia with CBS does not always heal following band release. Additional surgeries may be required for persistent pseudarthrosis, limb length discrepancy and residual foot deformities. A functional and radiological classification is proposed for the treatment of tibial pseudarthrosis with CBS., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Pseudoachondroplasia (PSACH) is an autosomal dominant disorder characterized by rhizomelic short-limbed skeletal dysplasia. The primary clinical and radiographic features include disproportionate dwarfism, joint laxity and hyperextensibility, exaggerated lumbar lordosis, and late ossification of the epiphyses. Identification of disease-causing variants in heterozygous state in COMP establishes the molecular diagnosis of PSACH. We examined 11 families with clinical features suggestive of PSACH. In nine families, we used Sanger sequencing of exons 8-19 of COMP (NM&#95;000095.2) and in two families exome sequencing was used for confirming the diagnosis. We identified 10 de novo variants, including five known variants (c.925G>A, c.976G>A, c.1201G>T, c.1417&#95;1419del, and c.1511G>A) and five variants (c.874T>C, c.1201G>C, c.1309G>A, c.1416&#95;1421delCGACAA, and c.1445A>T) which are not reported outside Indian ethnicity. We hereby report the largest series of individuals with molecular diagnosis of PSACH from India and reiterate the well-known genotype-phenotype corelation in PSACH., (© 2021 Wiley Periodicals LLC.)

Introduction: This study was undertaken to compare the radiologic outcomes of bilateral and unilateral Perthes disease and also to evaluate the outcome of synchronous and metachronous bilateral Perthes disease., Methods: Of 353 children with Perthes disease followed up from presentation to healing during the last 10 years, 37 had bilateral involvement (11 synchronous and 26 metachronous onset). The radiologic outcomes of each hip of children with bilateral disease were compared with outcomes of 148 children with unilateral disease who were matched for age, sex, and treatment. Children with unilateral or bilateral diseases were treated with a proximal femoral varus derotation osteotomy if they fulfilled the criteria for surgery. The primary outcome measure was the shape of the femoral head at healing assessed by the Sphericity Deviation Score (SDS)., Results: The children with bilateral disease were younger than those with unilateral disease (6.2 vs. 7.03 y; P<0.001), and they had a longer duration of the disease. All other characteristics of bilateral and unilateral cases were similar. The SDS values of unilateral and bilateral disease were comparable, as were the SDS of synchronous and metachronous bilateral disease. The effect of early surgery on the evolution of the disease in bilateral cases was similar to that reported in unilateral disease. The age of onset of the disease alone influenced the SDS in bilateral cases., Conclusion: The age at onset of the bilateral disease is lower, the duration of the disease longer than that of unilateral disease, but the disease outcome is similar., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Treatment of Legg-Calvé-Perthes disease (LCPD) aims to preserve the spherical shape of the femoral head. The deformity index (DI) <0.3, measured 2 years from disease onset, is a surrogate measure that predicts that the femoral head will be Stulberg class I or II at skeletal maturity. There is no study that compares the predictive value of DI against a quantitative measure of the shape of the femoral head when the disease heals. We undertook this study to assess the reproducibility of a new method of measurement of DI and see if DI could predict the shape of the femoral head when the disease healed., Methods: DI was measured 2 years after disease onset and the Sphericity Deviation Score (SDS) was measured at healing of LCPD on radiographs of 43 children. Reproducibility of measurement was tested. Each healed femoral head was classified as spherical or aspherical based on subjective visual assessment. The DI values were compared with SDS values., Results: The reproducibility of measurement of SDS was excellent and superior to that of DI. The mean duration of disease was 3.97±0.96 years. Only 17 of 32 hips with DI values <0.3 at 2 years had spherical femoral heads at healing (SDS <10). Three hips with SDS values <10 had DI values >0.3. The positive and negative predictive values of a DI <0.3 in predicting if the femoral head will be spherical (SDS <10) when the disease healed were 53% and 73%, respectively., Conclusion: Though DI can be reproducibly measured the predictive value of a DI <0.3, to accurately identify hips that are likely to heal with spherical femoral heads, is not sufficiently high to justify its use as an outcome measure., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)