Unlocking the Genetic Secrets of Acromegaly: Exploring the Role of Genetics in a Rare Disorder.

Acromegaly is a rare endocrine disorder characterized by the excessive production of growth hormone (GH) in adulthood. Currently, it is understood that certain pituitary neuroendocrine tumors (PitNETs) exhibit a hereditary predisposition. These tumors' genetic patterns fall into two categories: isolated and syndromic tumors. The isolated forms are characterized by molecular defects that predispose exclusively to PitNETs, including familial isolated pituitary adenomas (FIPAs) and sporadic genetic defects not characterized by hereditary predisposition. All the categories involve either germline or somatic mutations, or both, each associated with varying levels of penetrance and different phenotypes. This highlights the importance of genetic testing and the need for a more comprehensive view of the whole disease. Despite the availability of multiple treatment options, diagnosis often occurs after several years, and management is still difficult. Early detection and intervention are crucial for preventing complications and enhancing the quality of life for affected individuals. This review aims to elucidate the molecular, clinical, and histological characteristics of GH-secreting PitNETs, providing insights into their prevalence, treatment nuances, and the benefits of genetic testing for each type of genetic disorder associated with acromegaly.

Hydatidiform Mole-Between Chromosomal Abnormality, Uniparental Disomy and Monogenic Variants: A Narrative Review.

A hydatidiform mole (HM) or molar pregnancy is the most common benign form of gestational trophoblastic disease characterized by a proliferation of the trophoblastic epithelium and villous edema. Hydatidiform moles are classified into two forms: complete and partial hydatidiform moles. These two types of HM present morphologic, histopathologic and cytogenetic differences. Usually, hydatidiform moles are a unique event, but some women present a recurrent form of complete hydatidiform moles that can be sporadic or familial. The appearance of hydatidiform moles is correlated with some genetic events (like uniparental disomy, triploidy or diandry) specific to meiosis and is the first step of embryo development. The familial forms are determined by variants in some genes, with NLRP7 and KHDC3L being the most important ones. The identification of different types of hydatidiform moles and their subsequent mechanisms is important to calculate the recurrence risk and estimate the method of progression to a malign form. This review synthesizes the heterogeneous mechanisms and their implications in genetic counseling.

Cancer Predisposition Syndromes and Thyroid Cancer: Keys for a Short Two-Way Street.

Cancer predisposition syndromes are entities determined especially by germinal pathogenic variants, with most of them autosomal dominantly inherited. The risk of a form of cancer is variable throughout life and affects various organs, including the thyroid. Knowing the heterogeneous clinical picture and the existing genotype-phenotype correlations in some forms of thyroid cancer associated with these syndromes is important for adequate and early management of patients and families. This review synthesizes the current knowledge on genes and proteins involved in cancer predisposition syndromes with thyroid cancer and the phenomena of heterogeneity (locus, allelic, mutational, and clinical).

A Scoping Review of the Relationship between Intermittent Fasting and the Human Gut Microbiota: Current Knowledge and Future Directions.

Intermittent fasting (IF) has been promoted as an alternative to dietary caloric restriction for the treatment of obesity. IF restricts the amount of food consumed and improves the metabolic balance by synchronizing it with the circadian rhythm. Dietary changes have a rapid effect on the gut microbiota, modulating the interaction between meal timing and host circadian rhythms. Our paper aims to review the relationships between IF and human gut microbiota. In this study, the primary area of focus was the effect of IF on the diversity and composition of gut microbiota and its relationship with weight loss and metabolomic alterations, which are particularly significant for metabolic syndrome characteristics. We discussed each of these findings according to the type of IF involved, i.e., time-restricted feeding, Ramadan fasting, alternate-day fasting, and the 5:2 diet. Favorable metabolic effects regarding the reciprocity between IF and gut microbiota changes have also been highlighted. In conclusion, IF may enhance metabolic health by modifying the gut microbiota. However additional research is required to draw definitive conclusions about this outcome because of the limited number and diverse designs of existing studies.

Exome sequencing in a Romanian Bardet-Biedl syndrome cohort revealed an overabundance of causal BBS12 variants.

Bardet-Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly, cognitive impairment, renal dysfunction, and hypogonadism. Twenty-eight genes involved in ciliary structure or function have been implicated in BBS, and explain the molecular basis for ~75%-80% of individuals. To investigate the mutational spectrum of BBS in Romania, we ascertained a cohort of 24 individuals in 23 families. Following informed consent, we performed proband exome sequencing (ES). We detected 17 different putative disease-causing single nucleotide variants or small insertion-deletions and two pathogenic exon disruptive copy number variants in known BBS genes in 17 pedigrees. The most frequently impacted genes were BBS12 (35%), followed by BBS4, BBS7, and BBS10 (9% each) and BBS1, BBS2, and BBS5 (4% each). Homozygous BBS12 p.Arg355* variants were present in seven pedigrees of both Eastern European and Romani origin. Our data show that although the diagnostic rate of BBS in Romania is likely consistent with other worldwide cohorts (74%), we observed a unique distribution of causal BBS genes, including overrepresentation of BBS12 due to a recurrent nonsense variant, that has implications for regional diagnostics.

Narrative Review: Update on the Molecular Diagnosis of Fragile X Syndrome.

The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG interruptions. A high number of repeats (>200) in the fragile X messenger ribonucleoprotein 1 gene (FMR1) results in hypermethylation of promoter and gene silencing. The actual molecular diagnosis is performed using a Southern blot, TP-PCR (Triplet-Repeat PCR), MS-PCR (Methylation-Specific PCR), and MS-MLPA (Methylation-Specific MLPA) with some limitations, with multiple assays being necessary to completely characterise a patient with FXS. The actual gold standard diagnosis uses Southern blot; however, it cannot accurately characterise all cases. Optical genome mapping is a new technology that has also been developed to approach the diagnosis of fragile X syndrome. Long-range sequencing represented by PacBio and Oxford Nanopore has the potential to replace the actual diagnosis and offers a complete characterization of molecular profiles in a single test. The new technologies have improved the diagnosis of fragile X syndrome and revealed unknown aberrations, but they are a long way from being used routinely in clinical practice.

Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling.

Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.

From the Sun to the Cell: Examining Obesity through the Lens of Vitamin D and Inflammation.

Obesity affects more than one billion people worldwide and often leads to cardiometabolic chronic comorbidities. It induces senescence-related alterations in adipose tissue, and senescence is closely linked to obesity. Fully elucidating the pathways through which vitamin D exerts anti-inflammatory effects may improve our understanding of local adipose tissue inflammation and the pathogenesis of metabolic disorders. In this narrative review, we compiled and analyzed the literature from diverse academic sources, focusing on recent developments to provide a comprehensive overview of the effect of vitamin D on inflammation associated with obesity and senescence. The article reveals that the activation of the NF-κB (nuclear factor kappa B subunit 1) and NLRP3 inflammasome (nucleotide-binding domain, leucine-rich-containing, pyrin domain-containing-3) pathways through the toll-like receptors, which increases oxidative stress and cytokine release, is a common mechanism underlying inflammation associated with obesity and senescence, and it discusses the potential beneficial effect of vitamin D in alleviating the development of subclinical inflammation. Investigating the main target cells and pathways of vitamin D action in adipose tissue could help uncover complex mechanisms of obesity and cellular senescence. This review summarizes significant findings related to opportunities for improving metabolic health.

Monitoring and Management of Bardet-Biedl Syndrome: What the Multi-Disciplinary Team Can Do.

Bardet - Biedl syndrome is a rare autosomal recessive multisystem non-motile ciliopathy. It has heterogeneous clinical manifestations. It is caused by mutations in 26 genes encoding BBSome proteins, chaperonines, and IFT complex. The main clinical features are: retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary anomalies, and kidney disease. The onset of clinical manifestations is variable which makes the diagnosis difficult in some patients. Because of the multiple system involvement, a multidisciplinary approach is necessary. The purpose of this review is to provide monitoring and management directions for a better approach to these patients.

Pituitary hypoplasia and growth hormone deficiency in a patient with Coffin-Siris syndrome and severe short stature: case report and literature review.

Coffin-Siris syndrome (CSS) is a rare genetic disorder caused by the haploinsufficiency of one of the various genes that are part of the Brahma/BRG1-associated factor (BAF) complex. The BAF complex is one of the chromatin remodeling complexes, involved in embryonic and neural development, and various gene mutations are associated with cognitive impairment. CSS has a highly variable genotype and phenotype expression, thus lacking standardized criteria for diagnosis. It is generally accepted to associate 5th digit/nail hypoplasia, intellectual disability (ID)/developmental delay and specific coarse facial features. CSS patients usually display miscellaneous cardiac, genitourinary and central nervous system (CNS) anomalies. Many patients also associate intrauterine growth restriction, failure to thrive and short stature, with several cases demonstrating growth hormone deficiency (GHD). We report the case of a 4-year-old girl with severe short stature (-3.2 standard deviations) due to pituitary hypoplasia and GHD that associated hypoplastic distal phalanx of the 5th digit in the hands and feet, severe ID, coarse facial features (bushy eyebrows, bulbous nose, flat nasal bridge, dental anomalies, thick lips, dental anomalies, bilateral epicanthal fold) and CNS anomalies (agenesis of the corpus callosum and bilateral hippocampal atrophy), thus meeting clinical criteria for the diagnosis of CSS. Karyotype was 46,XX. The patient was started on GH replacement therapy, with favorable outcomes. Current practical knowledge regarding CSS diagnosis and management from the endocrinological point of view is also reviewed.

Genetic Heterogeneity in Bartter Syndrome: Clinical and Practical Importance.

Bartter syndrome (BS) is a rare tubulopathy that causes polyuria, hypokalemia, hypochloremic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism. It is characterized by locus, clinical, and allelic heterogeneity. Types 1-4 of BS are inherited according to an autosomal recessive pattern, while type 5, which is transient, is X linked. There are specific correlations between the clinical expression and the molecular defect, but since it is a rare disease, such studies are rare. Therapeutic interventions are different, being correlated with types of BS.

Epidermolysis Bullosa-A Different Genetic Approach in Correlation with Genetic Heterogeneity.

Epidermolysis bullosa is a heterogeneous group of rare genetic disorders characterized by mucocutaneous fragility and blister formation after minor friction or trauma. There are four major epidermolysis bullosa types based on the ultrastructural level of tissue cleavage: simplex, junctional, dystrophic, and Kindler epidermolysis bullosa. They are caused by mutations in genes that encode the proteins that are part of the hemidesmosomes and focal adhesion complex. Some of these disorders can be associated with extracutaneous manifestations, which are sometimes fatal. They are inherited in an autosomal recessive or autosomal dominant manner. This review is focused on the phenomena of heterogeneity (locus, allelic, mutational, and clinical) in epidermolysis bullosa, and on the correlation genotype-phenotype.

Genetic Counseling and Management: The First Study to Report NIPT Findings in a Romanian Population.

Background and Objectives: Non-invasive prenatal testing (NIPT) has been confirmed as the most accurate screening test for trisomies 21, 18, 13, sex chromosomes aneuploidies and several microdeletions. This study aimed to assess the accuracy of cell free DNA testing based on low-level whole-genome sequencing to screen for these chromosomal abnormalities and to evaluate the clinical performance of NIPT. Materials and Methods: 380 consecutive cases from a single genetic center, from Western Romania were included in this retrospective study. Cell-free nucleic acid extraction from maternal blood, DNA sequencing and analysis of sequenced regions were performed by BGI Hong Kong and Invitae USA to determine the risk of specific fetal chromosomal abnormalities. In high-risk cases the results were checked by direct analysis of fetal cells obtained by invasive methods: 6 chorionic villus sampling and 10 amniocenteses followed by combinations of QF-PCR, karyotyping and aCGH. Results: NIPT results indicated low risk in 95.76% of cases and high risk in 4.23%. Seven aneuploidies and one microdeletion were confirmed, the other results were found to be a false-positive. A gestational age of up to 22 weeks had no influence on fetal fraction. There were no significant differences in fetal fraction across the high and low risk groups. Conclusions: This is the first study in Romania to report the NIPT results. The confirmation rate was higher for autosomal aneuploidies compared to sex chromosome aneuploidies and microdeletions. All cases at risk for trisomy 21 were confirmed. Only one large fetal microdeletion detected by NIPT has been confirmed. False positive NIPT results, not confirmed by invasive methods, led to the decision to continue the pregnancy. The main limitation of the study is the small number of patients included. NIPT can be used as a screening method for all pregnancies, but in high-risk cases, an invasive confirmation test was performed.

SHOX Deletion and Idiopathic Short Stature: What Does the Clinician Need to Know? Case Series Report.

Children diagnosticated with idiopathic short stature (ISS) are probably, in most cases, underdiagnosticated. The genetic causes of ISS may be mutations of genes involved in local regulation of the growth plate or genes involved in the GH-IGF1 axis physiology. We present a kindred of five children evaluated for short stature or low normal stature, initially diagnosticated as idiopathic short stature, familial short stature, or being small for gestational age. Clinical signs suggestive of SHOX deletion screening in a child with short stature are low arm span/height ratio, increased sitting height/height ratio, BMI > 50% percentile, Madelung deformity, cubitus valgus, bowing and shortening of the forearm, dislocation of the ulna (at the elbow), and the appearance of muscular hypertrophy. Radiological characteristics suggestive of SHOX deficiency are triangularisation of the distal radial epiphysis, an enlarged diaphysis of the radius plus bowing of the radius, the convexity of the distal radial metaphysis, short fourth and fifth metacarpals, pyramidalization of the carpal row. Treatment with rGH is approved for children with SHOX gene deficiency and short stature. This kindred is an example that familial short stature, idiopathic short stature, and short stature due to a small gestational age are not final diagnoses. Complex investigations are necessary to identify the precise cause, leading to optimal clinical management. Treatment with rGH is an option for some of them; for others, it has no therapeutic response and, in some cases, is even harmful.

Genomics and Epigenomics in the Molecular Biology of Melanoma-A Prerequisite for Biomarkers Studies.

Melanoma is a common and aggressive tumor originating from melanocytes. The increasing incidence of cutaneous melanoma in recent last decades highlights the need for predictive biomarkers studies. Melanoma development is a complex process, involving the interplay of genetic, epigenetic, and environmental factors. Genetic aberrations include BRAF, NRAS, NF1, MAP2K1/MAP2K2, KIT, GNAQ, GNA11, CDKN2A, TERT mutations, and translocations of kinases. Epigenetic alterations involve microRNAs, non-coding RNAs, histones modifications, and abnormal DNA methylations. Genetic aberrations and epigenetic marks are important as biomarkers for the diagnosis, prognosis, and prediction of disease recurrence, and for therapeutic targets. This review summarizes our current knowledge of the genomic and epigenetic changes in melanoma and discusses the latest scientific information.

Circular RNA-Is the Circle Perfect?

Circular RNA (circRNA) is a distinct class of non-coding RNA produced, in principle, using a back-splicing mechanism, conserved during evolution, with increased stability and a tissue-dependent expression. Circular RNA represents a functional molecule with roles in the regulation of transcription and splicing, microRNA sponge, and the modulation of protein-protein interaction. CircRNAs are involved in essential processes of life such as apoptosis, cell cycle, and proliferation. Due to the regulatory role (upregulation/downregulation) in pathogenic mechanisms of some diseases (including cancer), its potential roles as a biomarker or therapeutic target in these diseases were studied. This review focuses on the importance of circular RNA in cancer.

A Case of Inherited t(4;10)(q26;q26.2) Chromosomal Translocation Elucidated by Multiple Chromosomal and Molecular Analyses. Case Report and Review of the Literature.

We present a complex chromosomal anomaly identified using cytogenetic and molecular methods. The child was diagnosed during the neonatal period with a multiple congenital anomalies syndrome characterized by: flattened occipital region; slight turricephaly; tall and broad forehead; hypertelorism; deep-set eyes; down slanting and short palpebral fissures; epicanthic folds; prominent nose with wide root and bulbous tip; microstomia; micro-retrognathia, large, short philtrum with prominent reliefs; low set, prominent ears; and congenital heart disease. The GTG banding karyotype showed a 46,XY,der(10)(10pter→10q26.2::4q26→4qter) chromosomal formula and his mother presented an apparently balanced reciprocal translocation: 46,XX,t(4;10)(q26;q26.2). The chromosomal anomalies of the child were confirmed by MLPA, and supplementary investigation discovered a quadruplication of the 4q35.2 region. The mother has a triplication of the same chromosomal fragment (4q35.2). Using array-CGH, we described the anomalies completely. Thus, the boy has a 71,057 kb triplication of the 4q26-q35.2 region, a 562 kb microdeletion in the 10q26.3 region, and a 795 kb quadruplication of the 4q35.2 region, while the mother presents a 795 kb triplication of the 4q35.2 region. Analyzing these data, we consider that the boy's phenotype is influenced only by the 4q partial trisomy. We compare our case with similar cases, and we review the literature data.

Bardet-Biedl Syndrome-Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype-Phenotype Correlations.

Bardet-Biedl Syndrome is a rare non-motile primary ciliopathy with multisystem involvement and autosomal recessive inheritance. The clinical picture is extremely polymorphic. The main clinical features are retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary abnormalities, and kidney disease. It is caused by various types of mutations, mainly in genes encoding BBSome proteins, chaperonins, and IFT complex. Variable expressivity and pleiotropy are correlated with the existence of multiple genes and variants modifiers. This review is focused on the phenomena of heterogeneity (locus, allelic, mutational, and clinical) in Bardet-Biedl Syndrome, its mechanisms, and importance in early diagnosis and proper management.

Novel Mutation in APC Gene Associated with Multiple Osteomas in a Family and Review of Genotype-Phenotype Correlations of Extracolonic Manifestations in Gardner Syndrome.

Gardner syndrome is a neoplasic disease that associates intestinal polyposis and colorectal adenocarcinoma with osteomas and soft tissue tumors determined by germline mutations in the APC gene. The early diagnosis and identification of high-risk individuals are important because patients have a 100% risk of colon cancer. We present the case of a family with Gardner syndrome. Cephalometric, panoramic X-rays and CBCT of the proband and her brother showed multiple osteomas affecting the skull bones, mandible and paranasal sinuses. The detailed family history showed an autosomal dominant transmission with the presence of the disease in the mother and maternal grandfather of the proband. Both had the typical signs of disease and died in the fourth decade of life. Based on these aspects the clinical diagnosis was Gardner syndrome. By gene sequencing, a novel pathogenic variant c.4609dup (p.Thr1537Asnfs*7) in heterozygous status was identified in the APC gene in both siblings. We reviewed literature data concerning the correlation between the localization of mutations in the APC gene and the extracolonic manifestations of familial adenomatous polyposis as well as their importance in early diagnosis and adequate oncological survey of patients and families based on abnormal genomic variants.

Gorham-Stout Disease with Multiple Bone Involvement-Challenging Diagnosis of a Rare Disease and Literature Review.

Gorham-Stout disease is a rare disorder, which may result in a poor prognosis. This disease, a rare lymphangiomatosis, is defined by progressive bone disappearance due to massive unicentric and multicentric osteolysis. Osteolytic lesions of the spine and pleura effusion are poor prognostic factors. Herein, we will present a case where the onset of disease occurred at the age of 18 with asthenia, myalgia, and major bone pain, followed by incomplete motor deficiency in the lower limbs and, later, in the upper limbs. Imaging studies (CT scan and MRI) of the patient revealed osteolytic lesions (cervical and thoracic vertebrae, rib, and clavicle) and a pathological fracture of the C7 vertebra. Surgical procedures undertaken involved replacing the affected vertebrae with bone grafting and prosthesis. The investigations performed allowed for the exclusion of inflammation, thyroid or parathyroid disease, lymphoma, neoplasia, or autoimmune disorders. A bone marrow biopsy showed osteolysis, the replacement of bone tissues with connective tissue, and chronic non-specific inflammation. The evolution was negative with almost complete osteolysis of the left clavicle, the emergence of new osteolysis areas in the lumbar vertebrae, pelvic bones, and the bilateral proximal femur, splenic nodules, chylothorax, and associated major neurological deficits. Unfortunately, this negative evolution resulted in the patient's death a year after onset.