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Background Neuromusculoskeletal anomalies generally in combination with severe clinical symptoms, comprise a heterogeneous group of fairly common and mostly fatal disorders in man and animals. Osteogenesis imperfecta (OI), also known as brittle bone disease, causes bone fragility and deformity. Prominent extra-skeletal accessory manifestations of OI comprise blue/gray sclerae, hearing impairment, lung abnormalities and hypercalciuria. Cases of OI in cattle have been reported. However, no causative mutations have been identified in cattle so far. Aim To report a possible oligogenic origin identified in a calf from clinically healthy parents suffering from OI. Materials and Methods A neonatal embryo transfer male Holstein calf developing multiple fractures with bone tissue showing marked osteopenia was used for whole genome re-sequencing as well as its parents. In addition, 2,612 randomly chosen healthy Holstein cattle were genotyped as well as controls. Results Sixteen candidate genes with potential protein-altering variants were selected revealing non-synonymous variants only within IFITM5 and CRTAP genes. However, in-depth gene analysis did not result in the identification of a single causative mutation in the OI calf. Conclusion The analysis of the OI case revealed a possible oligogenic origin of the disease attributable to additive effects of three candidate genes, i.e., ABCA13, QRFPR, and IFTIM5. Clinical relevance Most OI cases in humans and domestic animals reported so far are caused by distinct dominant or recessive monogenic mutations, therefore a potential oligogenic additive genetic effect is a novel finding. Furthermore, the case presented here demonstrates that cross-species genetic analyses might not always be straightforward.

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain‐of‐function mutations in the regulatory (SUR2) and pore‐forming (Kir6.1) subunits of KATP channels, respectively, suggesting that channel‐blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg–1 kg–1 day–1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg−1 kg−1day−1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS. [ABSTRACT FROM AUTHOR]

Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), or Taybi-Linder syndrome is characterized by distinctive skeletal dysplasia, severe intrauterine and postnatal growth retardation, microcephaly, dysmorphic features, and neurological malformations. It is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the RNU4ATAC gene resulting in impaired function of the minor spliceosome. Here, we present the first report on bone morphology, bone density and bone microstructure in two adult MOPD1 patients and applied radiographs, dual energy X-ray absorptiometry, high-resolution peripheral quantitative computed tomography and biochemical evaluation. The MOPD1 patients presented with short stature, low BMI but normal macroscopic bone configuration. Bone mineral density was low. Compared to Danish reference data, total bone area, cortical bone area, cortical thickness, total bone density, cortical bone density, trabecular bone density and trabecular bone volume per tissue volume (BV/TV) were all low. These findings may correlate to the short stature and low body weight of the MOPD1 patients. Our findings suggest that minor spliceosome malfunction may be associated with altered bone modelling. [ABSTRACT FROM AUTHOR]

In this review, we discuss aspects of the prenatal diagnosis of fetal skeletal malformations, concentrating on the advantages offered by different imaging techniques and the approaches that are of value in evaluating a suspected skeletal dysplasia. We also briefly address the findings in some of the commoner malformations of the fetal skeleton that may be encountered. [ABSTRACT FROM AUTHOR]

Nasu-Hakola disease (NHD), also known as polycystic lipomembranous osteodysplasia and sclerosing leukoencephalopathy, is a rare and fatal hereditary disease with less than 200 cases reported in the literature [Madry H, Prudlo J, Grgic A, Freyschmidt J. Nasu-Hakola disease (PLOSL): report of five cases and review of the literature. Clin Orthop Relat Res 2007;454:262-269]. This progressive disease is characterized by multiple cystic bone lesions, complicated with pathologic fractures and progressive dementia. Here in this article we report the imaging findings including magnetic resonance imaging of a newly diagnosed NHD case, with emphasis on the awareness of the radiologist for prompt recognition of this rare entity. [ABSTRACT FROM AUTHOR]

The skeletal dysplasias are a large heterogeneous group of genetic conditions characterized by abnormal shape, growth, or integrity of bones. Often, there may be prominent features associated with other organ systems as part of a more encompassing skeletal malformation syndrome. Tremendous advances have been made in the clinical and molecular delineation of these conditions over the past 20–30 years. We have progressed from initial broad clinical classifications of these conditions in the first two-thirds of this century, to extensive delineation based on radiographic features in the 1970s and 1980s, to the present reconsideration and grouping of these conditions according to their molecular pathogenesis. This has in part been spurred on by advances in the understanding of the developmental pathways which govern skeletal development, as well as by the human genome sequencing effort, which has provided a plethora of positional candidate genes for many of these conditions. The pathogenetic correlations derived from such studies are often based on parallels between the human phenotype and mouse models of the human condition, and have sometimes revealed novel developmental functions. [ABSTRACT FROM AUTHOR]

The cancellous bone of the skeleton usually shows striking alterations when metastatic carcinoma has involved the bone marrow. These changes, termed carcinomatous osteodysplasia (COD), have been analyzed in 1164 iliac crest biopsies of unselected patients with a variety of primary tumours. Semithin (3 μ) sections of undecalcified biopsies embedded in methacrylate were examined for foreign cells. Metastases were found in 462 of the 1164 biopsies and 91% of these, as well as 17% of the negative biopsies, showed some degree of COD. Osteodysplasia was more frequent in biopsies of patients with signs of systemic spread than in those without. COD includes a variable, local increase in active osteoblasts and osteoclasts, in blood vessels and in other stromal tissues. The incidence of COD was higher in the adenomatous and scirrhous metastases than in the other histological varieties. COD was subdivided into primarily osteolytic, osteosclerotic, and mixed types, and five different forms of bone resorption and formation were identified. These forms showed a characteristic association with the degree of mesenchymal activation on the one hand and the structural type of the metastases on the other, and correlated with certain cytological characteristics of the neoplastic cells. We conclude that COD is a significant consequence of the biological activities of metastatic cancer and it is readily accesible for observation by bone biopsy. The morphological classification of COD proposed in this study provides a basis for further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) II has recently been defined as a PCNT gene defect. Historically, it has been a disorder of interest because of the severe intrauterine growth restriction and postnatal short stature. The very shortest/smallest mature human being undoubtedly had this disorder. Maria Zarate lived between 1864 and 1890 and traveled in sideshows to England and all over North America. Her exceeding short stature was well documented in photographs and by a group of physicians in England. She was Mexican and also had an affected brother. A museum, Museo Casa Grande, about her still exists in Cempoala, Mexico. [Copyright &y& Elsevier]

Background: Neuromusculoskeletal anomalies generally in combination with severe clinical symptoms, comprise a heterogeneous group of fairly common and mostly fatal disorders in man and animals. Osteogenesis imperfecta (OI), also known as brittle bone disease, causes bone fragility and deformity. Prominent extra-skeletal accessory manifestations of OI comprise blue/gray sclerae, hearing impairment, lung abnormalities and hypercalciuria. Cases of OI in cattle have been reported. However, no causative mutations have been identified in cattle so far. Aim: To report a possible oligogenic origin identified in a calf from clinically healthy parents suffering from OI. Materials and Methods: A neonatal embryo transfer male Holstein calf developing multiple fractures with bone tissue showing marked osteopenia was used for whole genome re-sequencing as well as its parents. In addition, 2,612 randomly chosen healthy Holstein cattle were genotyped as well as controls. Results: Sixteen candidate genes with potential protein-altering variants were selected revealing non-synonymous variants only within IFITM5 and CRTAP genes. However, in-depth gene analysis did not result in the identification of a single causative mutation in the OI calf. Conclusion: The analysis of the OI case revealed a possible oligogenic origin of the disease attributable to additive effects of three candidate genes, i.e., ABCA13 , QRFPR , and IFTIM5 . Clinical relevance: Most OI cases in humans and domestic animals reported so far are caused by distinct dominant or recessive monogenic mutations, therefore a potential oligogenic additive genetic effect is a novel finding. Furthermore, the case presented here demonstrates that cross-species genetic analyses might not always be straightforward.

Hajdu-Cheney syndrome is a rare congenital disease with acro-osteolysis, osteoporotic changes of the spine and long bones of extremities and marked basilar invagination with an unusually deformed skull. Magnetic resonance imaging of a 32-year-old male revealed the deformed skull and almost horizontal basal angle and the elongated and upwardly shifted brain stem caused by the tip of the odontoid process of the second cervical vertebra invaginating the base of the skull. In addition there were atrophic pituitary gland, widely open sella turcica and symmetrical fluid collections along the optic nerve sheath. [ABSTRACT FROM AUTHOR]