A series of clinical cases of familial hypocalciuric hypercalcemia syndrome

Familial hypocalciuric hypercalcemia (FHH) - rare disease with predominantly autosomal dominant inheritance. FHH typically develops due to a heterozygous inactivating mutation in the calcium-sensitive receptor gene (CASR), less commonly due to heterozygous mutations in GNA11 and AP2S1. CASR mutations lead to an increase in the threshold for calcium sensitivity, which requires a higher concentration in serum to reduce the release of PTH. These changes are accompanied by an increase of calcium and magnesium reabsorption in the proximal tubules, which leads to hypercalcemia and hypocalciuria. Basically, FHH may be asymptomatic or accompanied by mild hypercalcemia. FHH doesn't require surgical treatment, unlike primary hyperparathyroidism (PHPT), therefore, differential diagnosis of these two conditions is extremely important. In addition, immediate relatives of a proband with FHH also require the exclusion of disease inheritance. We analyzed a series of clinical cases with a genetically confirmed diagnosis of FHH. Our clinical cases indicate a variety of clinical manifestations and the difficulties of differential diagnosis with PHPT.

Mutations Causing Mild or No Structural Damage in Interfaces of Multimerization of the Fibrinogen γ-Module More Likely Confer Negative Dominant Behaviors

Different pathogenic variants in the same protein or even within the same domain of a protein may differ in their patterns of disease inheritance, with some of the variants behaving as negative dominant and others as autosomal recessive mutations. Here is presented a structural analysis and comparison of the molecular characteristics of the sites in fibrinogen γ-module, a fibrinogen component critical in multimerization processes, targeted by pathogenic variants (HGMD database) and by variants found in the healthy population (gnomAD database). The main result of this study is the identification of the molecular pathogenic mechanisms defining which pattern of disease inheritance is selected by mutations at the crossroad of autosomal recessive and negative dominant modalities. The observations in this analysis also warn about the possibility that several variants reported in the non-pathogenic gnomAD database might indeed be a hidden source of diseases with autosomal recessive inheritance or requiring a combination with other disease-causing mutations. Disease presentation might remain mostly unrevealed simply because the very low variant frequency rarely results in biallelic pathogenic mutations or the coupling with mutations in other genes contributing to the same disease. The results here presented provide hints for a deeper search of pathogenic mechanisms and modalities of disease inheritance for protein mutants participating in multimerization phenomena.

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases

Background: Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information’s (NCBI) Hackathon-model to take full advantage of local expertise in building “Iron Hack”, a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich’s ataxia, pitched at general audiences. Methods: The hackathon was structured to begin each day with presentations by expert clinicians, genetic counselors, researchers focused on molecular and cellular biology, public health/global health, genetics/genomics, computational biology, bioinformatics, biomolecular science, bioengineering, and computer science, as well as guest speakers from the American Porphyria Foundation (APF) and Friedreich’s Ataxia Research Alliance (FARA) to inform participants as to the human impact of these diseases. Results: As a result of this hackathon, we developed resources that are relevant not only to these specific disease-models, but also to other rare diseases and general bioinformatics problems. Within two and a half days, “Iron Hack” participants successfully built collaborative projects to visualize data, build databases, improve rare disease diagnosis, and study rare-disease inheritance. Conclusions: The purpose of this manuscript is to demonstrate the utility of a hackathon model to generate prototypes of generalizable tools for a given disease and train clinicians and data scientists to interact more effectively.

Neurogenetic disease

There are many genetic diseases which affect the nervous system. Although some of these are extremely rare, several are quite common and, as a group, they comprise a significant proportion of neurological disease. Almost all clinical neurological syndromes can have a genetic cause. Not all of these have been genetically elucidated, but some have been extensively characterized in terms of clinical phenotype, molecular genetics, and cellular pathophysiology. Given the improvement in laboratory techniques and subsequent reduction in the cost of direct DNA sequencing, there is likely to be a rapid expansion over the next decade in the identification of causative genes and hence the availability of genetic tests. Thus, all clinicians should have a basic understanding about genetic disease; inheritance patterns; availability of genetic tests; genetic counselling; and ethics. Particular subspeciality areas where neurogenetic disease is common include neuromuscular disease and movement disorders.

Analysis of the physical growth and markers of connective tissue dysplasia in patients with Perthes disease

Introduction. The pathogenesis of Perthes disease is not fully understood and requires a greater understanding of the physical development, external and internal markers of connective tissue dysplasia. Objective. To analyze the deviations in physical development and connective tissue dysplasia in children with Perthes disease to determine its phenotypes. Materials and methods. We examined 52 patients and 36 children (control group) aged of 4–17 years. We estimated and compared their physical and proportional growth by using centile charts and Vervec’s index and defined external and internal manifestations of connective tissue dysplasia in major organs, systems, and topographic regions. Complete genealogical histories were taken by with examining the genealogies of 52 probands, including clinical examination of 136 first and second degree relatives. Results. Deviations in physical growth were observed in 33 patients (63.5%). The body height of 27 (51.9%) patients aged 4–17 years ranged from 1–2 lines (3–10%) and was significantly lower than that of the control group within 5 lines (p < 0.5). Six (11.6%) children had body lengths higher than the average 7th line (75–90%). Vervec’s index in 34 (65.4%) children ranged from 1.25–0.85 and represented mesomorphy, moderate brachy, or dolichomorphia. The primary pathology of external organs and systems was skeletal anomalies in 36 (69.2%) children, followed by dermal in 23 (44.2%) and organs of vision in 9 (17.3%). Among visceral disorders, the primary pathology was cardiovascular diseases in 17 (32,7%) children followed by surgical and urological pathologies in 7 (13.5%) and digestive system disorders in 5 (9.6%). Disease inheritance was sporadical in 48 (92.3%) children. Conclusion. The Perthes disease phenotype was related to the undifferentiated form of collagenopathies.