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Annales de Biologie Clinique Apr 2024Newborn screening is a major public health concern. In France, it was established in 1972 with systematic screening for phenylketonuria. Subsequently, other screenings,...
Newborn screening is a major public health concern. In France, it was established in 1972 with systematic screening for phenylketonuria. Subsequently, other screenings, including congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, and sickle cell disease, were added. The introduction of tandem mass spectrometry in screening laboratories in 2020 enabled the inclusion of eight additional inherited metabolic diseases: aminoacidopathies (tyrosinemia type I, maple syrup urine disease, and homocystinuria), organic acidurias (isovaleric and glutaric type I acidurias), and disorders of fatty acid metabolism (MCADD, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), and primary carnitine deficiency). We briefly present these newly added diseases, of which public awareness is still incomplete.
Topics: Infant, Newborn; Humans; Neonatal Screening; Amino Acid Metabolism, Inborn Errors; Metabolic Diseases; Phenylketonurias; France
PubMed: 38638016
DOI: 10.1684/abc.2024.1869 -
Orphanet Journal of Rare Diseases Apr 2024The report covers the current and past activities of the department Molecular Genetics-Function and Therapy (MGFT) at the Cyprus Institute of Neurology and Genetics...
The report covers the current and past activities of the department Molecular Genetics-Function and Therapy (MGFT) at the Cyprus Institute of Neurology and Genetics (CING), an affiliated Reference Center for the European Reference Network on Rare Endocrine Conditions (Endo-ERN).The presented data is the outcome of > 15 years long standing collaboration between MGFT and endocrine specialists from the local government hospitals and the private sector. Up-to-date > 2000 genetic tests have been performed for the diagnosis of inherited rare endocrine disorders. The major clinical entities included Congenital Adrenal Hyperplasia (CAH) due to pathogenic variants in CYP21A2 gene and Multiple Endocrine Neoplasia (MEN) type 2 due to pathogenic variants in the RET proto-oncogene. Other rare and novel pathogenic variants in ANOS1, WDR11, FGFR1, RNF216, and CHD7 genes were also found in patients with Congenital Hypogonadotropic Hypogonadism. Interestingly, a few patients with Disorders of Sexual Differentiation (DSD) shared rare pathogenic variants in the SRD5A2, HSD17B3 and HSD3B2 while patients with Glucose and Insulin Homeostasis carried theirs in GCK and HNF1A genes. Lastly, MGFT over the last few years has established an esteemed diagnostic and research program on premature puberty with emphasis on the implication of MKRN3 gene on the onset of the disease and the identification of other prognosis biomarkers.As an Endo-ERN member MGFT department belongs to this large European network and holds the same humanistic ideals which aim toward the improvements of health care for patients with rare endocrine conditions in respect to improved and faster diagnosis.
Topics: Humans; Cyprus; Multiple Endocrine Neoplasia Type 2a; Endocrine System Diseases; Adrenal Hyperplasia, Congenital; Genetic Testing; Ubiquitin-Protein Ligases; Steroid 21-Hydroxylase; Membrane Proteins; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
PubMed: 38637882
DOI: 10.1186/s13023-024-03171-4 -
Nature Reviews. Disease Primers Apr 2024Despite affecting ~11-13% of women globally, polycystic ovary syndrome (PCOS) is a substantially understudied condition. PCOS, possibly extending to men's health,... (Review)
Review
Despite affecting ~11-13% of women globally, polycystic ovary syndrome (PCOS) is a substantially understudied condition. PCOS, possibly extending to men's health, imposes a considerable health and economic burden worldwide. Diagnosis in adults follows the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome, requiring two out of three criteria - clinical or biochemical hyperandrogenism, ovulatory dysfunction, and/or specific ovarian morphological characteristics or elevated anti-Müllerian hormone. However, diagnosing adolescents omits ovarian morphology and anti-Müllerian hormone considerations. PCOS, marked by insulin resistance and hyperandrogenism, strongly contributes to early-onset type 2 diabetes, with increased odds for cardiovascular diseases. Reproduction-related implications include irregular menstrual cycles, anovulatory infertility, heightened risks of pregnancy complications and endometrial cancer. Beyond physiological manifestations, PCOS is associated with anxiety, depression, eating disorders, psychosexual dysfunction and negative body image, collectively contributing to diminished health-related quality of life in patients. Despite its high prevalence persisting into menopause, diagnosing PCOS often involves extended timelines and multiple health-care visits. Treatment remains ad hoc owing to limited understanding of underlying mechanisms, highlighting the need for research delineating the aetiology and pathophysiology of the syndrome. Identifying factors contributing to PCOS will pave the way for personalized medicine approaches. Additionally, exploring novel biomarkers, refining diagnostic criteria and advancing treatment modalities will be crucial in enhancing the precision and efficacy of interventions that will positively impact the lives of patients.
Topics: Pregnancy; Adult; Adolescent; Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Diabetes Mellitus, Type 2; Quality of Life; Anti-Mullerian Hormone
PubMed: 38637590
DOI: 10.1038/s41572-024-00511-3 -
European Journal of Endocrinology May 2024
Topics: Humans; Adrenal Hyperplasia, Congenital; Child; Adolescent; Female; Male; Blood Glucose; Blood Glucose Self-Monitoring; Child, Preschool; Hypoglycemia; Continuous Glucose Monitoring
PubMed: 38630639
DOI: 10.1093/ejendo/lvae036 -
ACS Medicinal Chemistry Letters Apr 2024A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure-activity...
A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure-activity relationship (SAR) studies led to the discovery of (CRN04894), a highly potent and subtype-selective first-in-class MC2R antagonist, which demonstrated remarkable efficacy in a rat model of adrenocorticotrophic hormone (ACTH)-stimulated corticosterone secretion. Oral administration of suppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg. With its satisfactory pharmaceutical properties, was advanced to Phase 1 human clinical trials in healthy volunteers with the goal of moving into patient trials to evaluate CRN04894 for the treatment of ACTH-dependent diseases, including congenital adrenal hyperplasia (CAH) and Cushing's disease (CD).
PubMed: 38628803
DOI: 10.1021/acsmedchemlett.3c00514 -
Dermatology Reports Mar 2024Acne is a multifactorial and common disorder among young people and a frequent reason for dermatology consultation. When moderate-to-severe acne is not responsive to...
Acne is a multifactorial and common disorder among young people and a frequent reason for dermatology consultation. When moderate-to-severe acne is not responsive to conventional treatments, oral isotretinoin is a very effective solution. However, there are cases in which this treatment fails to produce the expected results. In this case, an 18-year-old male patient with acne, unresponsive to traditional acne therapies, experienced only a partial benefit from oral isotretinoin. Endocrinology consultation and hormonal work-up revealed androgen metabolism anomalies suggestive of a non-classical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. In this case report, the authors discuss when to suspect, how to diagnose, and how to manage similar cases.
PubMed: 38623375
DOI: 10.4081/dr.2023.9717 -
Avicenna Journal of Medical... 2024gene mutations are responsible for more than 95% of Congenital Adrenal Hyperplasia (CAH) disorders with autosomal recessive inheritance. Most of these pathogenic...
BACKGROUND
gene mutations are responsible for more than 95% of Congenital Adrenal Hyperplasia (CAH) disorders with autosomal recessive inheritance. Most of these pathogenic mutations originate from the , a neighboring pseudogene with 98% homology, due to unequal crossing over or gene conversion events. Mutation identification of the gene could be beneficial for accurate diagnosis and outcome prediction.
METHODS
Twelve unrelated patients with CAH diagnosis were recruited for genetic counseling. To ensure distinct amplification of the gene rather than its pseudogene, the complete sequence of the gene was amplified through two overlapping fragments by specific primers. The entire sequences were screened by direct Sanger sequencing using new sequencing primers.
RESULTS
Only two pathogenic point mutations were identified. The c.293-13C>G, also known as In2G, and the c.955C>T mutations were found in 37.5 and 33.3% of alleles, respectively. One patient showed homozygous gene deletion. We also reviewed recent reports on gene mutations in Iran.
CONCLUSION
Evaluating the ethnicity-specific gene mutation data is significant for populations with diverse ethnic groups including the Iranian population. Although several common mutations have been reported as causative mutations among CAH patients, identifying only two common point mutations in Fars province would help prioritize exon sequencing and reduce the cost and time of genotyping.
PubMed: 38618509
DOI: 10.18502/ajmb.v16i2.14864 -
Cureus Mar 2024Adrenocortical insufficiency, also known as adrenal insufficiency (AI), is an endocrine disorder characterized by inadequate production of adrenal hormones, including... (Review)
Review
Adrenocortical insufficiency, also known as adrenal insufficiency (AI), is an endocrine disorder characterized by inadequate production of adrenal hormones, including glucocorticoids and mineralocorticoids (MCs). The condition can be categorized as primary, secondary, or tertiary AI, depending on the location of the defect. Classical symptoms of AI include weakness, fatigue, abdominal pain, tachycardia, hypotension, electrolyte imbalances, and hyperpigmentation. In children, the most common cause of AI is classical congenital adrenal hyperplasia, which results from a deficiency in the 21-hydroxylase enzyme. The 21-hydroxylase enzyme produces all steroids, such as cortisol and aldosterone. AI management primarily involves hormone replacement therapy, typically with oral hydrocortisone and MC supplementation. However, the administration of hydrocortisone to pediatric patients presents challenges related to the lack of available dose-appropriate formulations. Historically, crushed or split adult tablets were used for the pediatric treatment of AI, although this poses an increased risk of under- or overtreatment. Inadequate dosing in the pediatric population can adversely affect growth, development, and metabolic health. Alkindi Sprinkle is a pediatric-specific hydrocortisone oral granule preparation that manages cortisol levels to help facilitate accurate therapeutic dosing. Alkindi offers several advantages, including accurate dosing, taste masking, and ease of administration. The present investigation describes AI, the management of AI, and the treatment of pediatric AI using Alkindi Sprinkle, including clinical efficacy.
PubMed: 38606228
DOI: 10.7759/cureus.56031 -
Molecular Human Reproduction Apr 2024Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the...
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated β-galactosidase and the SASP-related factor interleukin-6 was significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS, and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.
Topics: Polycystic Ovary Syndrome; Female; Cellular Senescence; Humans; Animals; Granulosa Cells; Quercetin; Mice; Senescence-Associated Secretory Phenotype; Adult; Dasatinib; Disease Models, Animal; Senotherapeutics; Hyperandrogenism; Interleukin-6; Dehydroepiandrosterone
PubMed: 38603629
DOI: 10.1093/molehr/gaae015 -
Internal Medicine (Tokyo, Japan) Apr 202417α-hydroxylase deficiency is a type of congenital adrenocortical hyperplasia that is typically diagnosed in childhood or adolescence. It manifests as hypertension with...
17α-hydroxylase deficiency is a type of congenital adrenocortical hyperplasia that is typically diagnosed in childhood or adolescence. It manifests as hypertension with gonadal dysfunction as the primary symptom. We herein report 17α-hydroxylase/17,20-lyase deficiency (17OHD) diagnosed at the age of 45 years. The patient presented with hypertension, irregular menstruation, and hyperaldosteronism. The clinical manifestations of 17OHD vary based on the specific variant pattern of CYP17A1. In this case, the variant was c.157_159 TCC del p. Phe53del, which has been frequently reported in Japan. The enzymatic deficiency due to this variant is partial, leading to a delay in making a correct diagnosis.
PubMed: 38599871
DOI: 10.2169/internalmedicine.3084-23