BACKGROUND: Spondyloepimetaphyseal dysplasias (SEMD) are a large group of skeletal disorders represented by abnormalities of vertebrae in addition to epiphyseal and metaphyseal areas of bones. Several genes have been identified underlying different forms. ACAN gene mutations were found to cause Aggrecan-related bone disorders (spondyloepimetaphyseal dysplasias,spondyloepiphyseal dysplasias, familial osteochondritis dissecans and short stature syndromes). This study aims to find the disease causing variant in Egyptian patient with SEMD using whole exome sequencing.
METHODS: Whole-exome sequencing was performed for an Egyptian male patient who presented with short stature, clinical and radiological features suggestive of unclassified SEMD.
RESULTS: The study identified a novel de novo heterozygous ACAN gene variant (c.7378G>A; p.Gly2460Arg) in G3 domain. Mutations in ACAN gene have been more commonly associated with short stature than SEMD. The phenotype of our patient was intermediate in severity between spondyloepiphyseal dysplasia presentation; Kimberley type(SEDK) and Spondyloepimetaphyseal dysplasias Aggrecan (SEMDAG) CONCLUSIONS: Whole exome sequencing revealed a novel de novo ACAN gene variant in patient with SEDK. The clinical and skeletal phenotype of our patient was much severe than those reported originally and showed more metaphyseal involvement. To the best of our knowledge, two previous studies reported a heterozygous variant in ACAN with spondyloepiphyseal dysplasia presentation; Kimberley type.

Cleidocranial dysplasia (CCD), also known as Marie-Sainton syndrome, is a rare disorder of autosomal dominant type that presents specific characteristics at the skeletal and dental level. The diagnosis of CCD is based on clinical and radiographic findings. Panoramic, cephalometric and anterior poster radiographs have been used for its diagnosis in dentistry. However, these radiological techniques have limitations, and advances in technology with new imaging studies such as magnetic resonance imaging (MRI) and ultrasound have emerged, contributing to the diagnosis of CCD. Therefore, the aim of this review was to identify and describe current imaging studies that contribute to both the diagnosis and adequate and efficient treatment planning of CCD, and describe the clinical and radiographic characteristics of patients with this syndrome.
La displasia cleidocraneal (DCC), también conocida como síndrome de Marie-Sainton, es un trastorno poco común de tipo autosómico dominante, que presenta características específicas a nivel esquelético y dental. El diagnóstico de DCC se basa en hallazgos clínicos y radiográficos. Las radiografías panorámicas, cefalométricas y posteroanteriores se han utilizado para su diagnóstico en el área de la odontología, pero con los avances de la tecnología y debido a las limitaciones de estas técnicas radiológicas han surgido nuevos estudios de imagen como la resonancia magnética (RM) y la ecografía, que contribuyen al diagnóstico de DCC. Por lo tanto, el propósito de esta revisión fue identificar y describir los estudios de imagen actuales que aportan tanto al diagnóstico como a la planificación del tratamiento adecuado y eficiente de la DCC, y permiten describir las características clínicas y radiográficas de los pacientes con este síndrome.

BACKGROUND: Ultrasonography (US) is the first-line diagnostic tool used to assess fetal musculoskeletal (MSK) anomalies. Associated anomalies in other organ systems may benefit from evaluation via Magnetic Resonance Imaging (MRI). In this study, we compared the diagnostic accuracy of US and MRI to diagnose fetal MSK (primary objective) and non-MSK anomalies (secondary objective). We describe additional findings by low-dose computerized tomography (CT) in two cases incompletely characterized via US and MRI.
METHODS: This was an IRB-approved retrospective study of consecutive patients with suspected fetal MSK anomalies examined between December 2015 and June 2020. We compared individual MSK and non-MSK anomalies identified via US, MRI, and CT with postnatal outcomes. Sensitivity and specificity for US and MRI were calculated and compared.
RESULTS: A total of 31 patients with 112 MSK and 43 non-MSK anomalies were included. The sensitivity of MRI and US for MSK anomalies was not significantly different (76.6% vs. 61.3%, p = 0.3). Low-dose CT identified eight additional skeletal anomalies. MRI diagnosed a higher number of non-MSK anomalies compared to US (81.4% vs. 37.2%, p < 0.05).
CONCLUSIONS: Fetal MRI and US have comparable sensitivity for MSK anomalies. In selected cases, low-dose CT may provide additional information. Fetal MRI detected a larger number of non-MSK anomalies in other organ systems compared to US. Multimodality imaging combining all the information provided by MRI, US, and CT, if necessary, ultimately achieved a sensitivity of 89.2% (95% CI: 83.4% to 95.0%) for the diagnosis of musculoskeletal anomalies and 81.4% for additional anomalies in other organs and systems.

Spondyloepiphyseal dysplasia is a type II collagenopathy with resulting spinal and extremity deformities. The clinical manifestations include short stature, hearing loss, kyphoscoliosis, and complex knee deformities. Genu recurvatum can be a challenging surgical problem, especially when the deformity is severe. In this report, we present a case of severe genu recurvatum in a 14-year-old female that was treated with a pediatric circular fixator with the addition of two z-plates. At one year follow-up, the patient demonstrated improved knee range of motion, tibial alignment with the radiographic union, and good ambulatory ability. The hexapod fixator with the use of two Z-plates may help ensure that appropriate ring strut angles are achieved. Larger studies regarding the efficacy of this treatment option in spondyloepiphyseal dysplasia are required.

Progressive pseudorheumatoid dysplasia can be confused with juvenile idiopathic arthritis. Treatment is mainly symptomatic and the prescription of immunosupressive agents is unnecessary. Surgery may be indicated at advanced stages of the disease.

Skeletal dysplasias (SDs) are common birth defects, but they are difficult to diagnose accurately according to only the limited phenotypic information available from ultrasound during the pregnancy. To evaluate the application of whole-exome sequencing (WES) and expand the data in the prenatal molecular diagnosis of fetuses with SDs, we collected 55 fetuses with SDs based on ultrasonographic features. WES of the fetuses or parent-fetus trio were subjected to sequential tests and produced a diagnostic yield of 64% (35/55). 65% (11/17) of families with a history of adverse pregnancies were diagnosed, 16 genes were involved and 37 different pathogenic or likely pathogenic variants were identified, including 14 novel variants, which were first reported in this study. De novo variants were identified in 21 cases (60%, 21/35) among the fetuses with a genetic diagnosis. The pathogenicity of two novel splice-site variants was confirmed by constructing minigene in vitro. Our results revealed that WES can provide new evidence for the relationship between the genotype and phenotype of fetuses with SDs, as well as broaden the mutation spectrum of detected genes, which is significant for prenatal diagnosis and genetic counseling.

Delineating the genetic background and the underlying pathophysiology of rare skeletal dysplasias enables a broader understanding of these disorders as well as novel perspectives regarding differential diagnosis and targeted development of therapeutic approaches. Hypophosphatasia (HPP) due to genetically determined Alkaline Phosphatase deficiency exemplifies this development. While an enzyme replacement therapy could be established for severe HPP with the prevailing bone manifestation, the clinical impact of not immediately bone-related manifestations just being successively understood. Correspondingly, the elucidation of the pathophysiology underlying renal phosphate wasting expanded our knowledge regarding phosphate metabolism and bone health and facilitated the development of an anti-FGF-23 Antibody for targeted treatment of X‑linked Hypophosphatemia (XLH). Evolutions regarding the nosology of osteogenesis imperfecta (OI) along with the identification of further causative genes also detected in the context of genetically determined osteoporosis illustrate the pathophysiologic interrelation between monogenetic bone dysplasias and multifactorial osteoporosis. While current therapeutic strategies for OI follow osteoporosis treatment, the expanding knowledge about OI forms the fundament for establishing improved treatment strategies-for both OI and osteoporosis. Similar developments are emerging regarding rare skeletal disorders like Achondroplasia, Fibrodysplasia ossificans progressive and Morbus Morquio (Mukopolysaccharidosis Type IV).
UNASSIGNED: Die Identifizierung des genetischen Hintergrunds und der Pathophysiologie seltener osteologischer Erkrankungen bildet die Grundlage für deren breites Verständnis sowie neue differentialtherapeutische Perspektiven und ermöglicht letztlich auch die Entwicklung gezielter Therapieansätze. Die Hypophosphatasie (HPP) aufgrund einer erblichen Defizienz der alkalischen Phosphatase reflektiert diese Entwicklung beispielhaft. Während für die schweren Formen mit im Vordergrund stehender Knochenmanifestation eine Enzymersatztherapie etabliert werden konnte, wird sukzessive auch das klinische Bild der nicht primär skelettbezogenen Formen besser verstanden. In Analogie dazu ermöglichte Aufklärung der pathophysiologischen Mechanismen des Phosphatdiabetes jenseits von Erkenntnissen zur Bedeutung des Phosphatstoffwechsels für die Knochengesundheit auch die Entwicklung eines Antikörpers gegen FGF-23 als gezielte Behandlungsstrategie für die X‑chromosomale Hypophosphatämie (XLH). Die weiter entwickelte nosologische Differenzierung der Osteogenesis imperfecta (OI) und die Identifizierung von weiteren kausalen Genen, die man auch im Kontext genetisch determinierter Osteoporosen findet, verdeutlicht den fließenden Übergang zwischen monogenetischen skeletalen Erkrankungen und multifaktorieller Osteoporose. Während heutige Therapiekonzepte der OI sich an der Osteoporosetherapie orientieren, bildet deren Verständnis die Grundlage für die Etablierung differenzierter, individualisierter Behandlungskonzepte – für die OI und die Osteoporose. Auch bei weiteren genetisch determinierten Skeletterkrankungen wie der Achondroplasie, der Fibrodysplasia ossificans progressiva und dem Morbus Morquio (Mukopolysaccharidose Typ IV) zeichnen sich vergleichbare Entwicklungen ab.

There have been two major eras in the history of gene discovery. The first was the era of linkage analysis, with approximately 1,300 disease-related genes identified by positional cloning by the turn of the millennium. The second era has been powered by two major breakthroughs: the publication of the human genome and the development of massively parallel sequencing (MPS). MPS has greatly accelerated disease gene identification, such that disease genes that would have taken years to map previously can now be determined in a matter of weeks. Additionally, the number of affected families needed to map a causative gene and the size of such families have fallen: de novo mutations, previously intractable by linkage analysis, can be identified through sequencing of the parent-child trio, and genes for recessive disease can be identified through MPS even of a single affected individual. MPS technologies include whole exome sequencing (WES), whole genome sequencing (WGS), and panel sequencing, each with their strengths. While WES has been responsible for most gene discoveries through MPS, WGS is superior in detecting copy number variants, chromosomal rearrangements, and repeat-rich regions. Panels are commonly used for diagnostic purposes as they are extremely cost-effective and generate manageable quantities of data, with no risk of unexpected findings. However, in instances of diagnostic uncertainty, it can be challenging to choose the right panel, and in these circumstances WES has a higher diagnostic yield. MPS has ethical, social, and legal implications, many of which are common to genetic testing generally but amplified due to the magnitude of data (e.g., relationship misattribution, identification of variants of uncertain significance, and genetic discrimination); others are unique to WES and WGS technologies (e.g., incidental or secondary findings). Nonetheless, MPS is rapidly translating into clinical practice as an extremely useful part of the clinical armamentarium.

Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive character. In this article, we review the state of clinical and research SD resources available in Latin America, including three specific countries (Brazil, Argentina, and Chile), that have established multidisciplinary clinics for the care of these patients. From the epidemiological point of view, the SD prevalence of 3.2 per 10,000 births from nine South American countries included in the ECLAMC network represents the most accurate estimate not just in Latin America, but worldwide. In Brazil, there are currently five groups focused on SD. The data from one of these groups including the website www.ocd.med.br, created to assist in the diagnosis of SD, are highlighted showing that telemedicine for this purpose represents a good strategy for the region. The experience of more than 30 years of the SD multidisciplinary clinic in an Argentinian Hospital is presented, evidencing a solid experience mainly in the follow-up of the most frequent SD, especially those belonging the FGFR3 group and OI. In Chile, a group with 20 years of experience presents its work with geneticists and pediatricians, focusing on diagnostic purposes and clinical management. Altogether, although SD health-care and research activities in Latin America are in their early stages, the experience in these three countries seems promising and stimulating for the region as a whole.

An understanding of genetics and genomics is increasingly important for all clinicians. Next-generation genomic sequencing technologies enable sequencing of the entire human genome in short timescales, and are increasingly being implemented in health care systems. Clinicians across all medical specialties will increasingly use results generated from genomic testing to inform their clinical practice and provide the best quality of care for patients. These innovations are already transforming the diagnostic pathways for rare genetic diseases, including skeletal dysplasias, with an inevitable impact on the traditional roles of diagnosticians. This article covers the fundamentals of human genetics, mechanisms of genetic variation and the technologies used to investigate the genetic basis of disease, with a specific focus on skeletal dysplasias and the potential impact of genomics on paediatric radiology.