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Endokrynologia Polska Jun 2024Not required for Clinical Vignette.
Not required for Clinical Vignette.
PubMed: 38887117
DOI: 10.5603/ep.99040 -
Anatolian Journal of Cardiology Jun 2024Mendelian forms of renin-angiotensin-aldosterone system (RAAS)-related hypertension, commonly referred to as monogenic hypertension, represent a rare but significant...
Mendelian forms of renin-angiotensin-aldosterone system (RAAS)-related hypertension, commonly referred to as monogenic hypertension, represent a rare but significant subset of hypertensive disorders characterized by genetic mutations that disrupt the normal physiological mechanisms of blood pressure regulation. This review focuses on elucidating the germline mutations affecting RAAS pathways that lead to distinct forms of heritable hypertension. By understanding the pathophysiological basis of conditions such as Gordon's syndrome, Liddle syndrome, congenital adrenal hyperplasia, and familial hyperaldosteronism types, this review aims to highlight the unique clinical features, diagnostic challenges, and therapeutic implications associated with these disorders. Recognizing specific clinical presentations and family histories indicative of monogenic hypertension is crucial for diagnosis, particularly as it often manifests as early-onset hypertension, abnormalities in potassium and blood pH, and occasionally, abnormal sexual development or related syndromes. Therefore, employing a targeted diagnostic approach through next-generation sequencing is essential to pinpoint the responsible genetic mutations, enabling accurate and individualized treatment plans. The critical importance of certain readily available specific channel blockers, such as thiazides or low-dose corticosteroids, in managing these disorders must be emphasized, as they play a key role in preventing serious complications, including cerebrovascular events. As advancements in genetic and molecular sciences continue to evolve, a deeper comprehension of the mechanisms underlying RAAS-related monogenic hypertension promises to revolutionize the management of this complex disorder, offering hope for more effective and individualized treatment options.
PubMed: 38872497
DOI: 10.14744/AnatolJCardiol.2024.4480 -
Science (New York, N.Y.) Jun 2024Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic...
Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.
Topics: Animals; Female; Humans; Mice; Rats; Androgens; Artemisinins; Cholesterol Side-Chain Cleavage Enzyme; Disease Models, Animal; Hyperandrogenism; Mitochondrial Proteins; Ovary; Polycystic Ovary Syndrome; Proteolysis; Mice, Inbred C57BL; Young Adult; Adult; Rats, Sprague-Dawley; ATP-Dependent Proteases
PubMed: 38870290
DOI: 10.1126/science.adk5382 -
European Journal of Endocrinology Jun 2024
Correction to: Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study.
PubMed: 38870250
DOI: 10.1093/ejendo/lvae066 -
Zhonghua Yi Xue Za Zhi Jun 2024This study reports a family of patients with 11β-hydroxylase deficiency (11β-OHD) caused by a novel mutation in the CYP11B1 gene, and analyzes its clinical and genetic...
This study reports a family of patients with 11β-hydroxylase deficiency (11β-OHD) caused by a novel mutation in the CYP11B1 gene, and analyzes its clinical and genetic characteristics. The clinical data of a patient with intractable hypertension at Air Force Medical Center on May 16, 2014 were retrospectively analyzed. The patient was clinically diagnosed with congenital adrenal cortical hyperplasia. The clinical data of the patient were further collected and the peripheral blood samples of the patient, his parents and his sister were collected for CYP11B1(NM_000497) gene sequencing, suggesting that the patient had compound heterozygous mutations in exon 1:c.199delG, p.Glu67Lysfs*9 and exon 5:c.905_907 delATGinsTT, p.Asp302Valfs*23, both of which were pathogenic variants. The patient's father and sister carried heterozygous mutations in exon 1:c.199delG, p.Glu67Lysfs*9, and the mother carried heterozygous mutations in exon 5:c.905_907delATGinsTT, p.Asp302Valfs*23. This study is the first to report a new compound heterozygous mutation in exon 1:c.199delG and exon 5 c.905_907 delATGinsTT of CYP11B1 gene, enriching the database of 11β-OHD mutations and providing information to further understand the genetic mechanism of the disease.
Topics: Humans; Steroid 11-beta-Hydroxylase; Adrenal Hyperplasia, Congenital; Male; Mutation; Female; Retrospective Studies; Exons; Heterozygote; Pedigree
PubMed: 38858218
DOI: 10.3760/cma.j.cn112137-20240204-00271 -
European Journal of Medical Genetics Jun 202421-hydroxylase deficiency stands as the most prevalent form of congenital adrenal hyperplasia, primarily resulting from mutations in the CYP21A2 gene. On the other hand,...
21-hydroxylase deficiency stands as the most prevalent form of congenital adrenal hyperplasia, primarily resulting from mutations in the CYP21A2 gene. On the other hand, mutations within the CYP17A1 gene lead to 17α-hydroxylase/17,20-lyase enzyme deficiencies. The scarcity of 17-OH deficiency is noteworthy, accounting for less than 1% of all congenital adrenal hyperplasia cases. The male patient, born from a first-degree cousin marriage, exhibited several symptoms, including left undescended testis, micropenis, penile chord, left sensorineural hearing loss, and gynecomastia. He reported micropenis as a concern at the age of 13.5 years. His hormone profile revealed high levels of serum 17-hydroxyprogesterone, progesterone, and pregnenolone. In this case with a 46 XY karyotype, suspicions arose regarding Cytochrome P450 oxidoreductase deficiency due to ambiguous genitalia and an atypical hormone profile. Analysis unveiled two distinct homozygous and pathogenic variants in the CYP21A2 and CYP17A1 genes. Notably, mineralocorticoid precursors escalated, while cortisol and sex steroid precursors decreased during the high (250 mcg) dose ACTH stimulation test. The mutation c.1169C > G (p.Thr390Arg) in CYP17A1, which is the second documented case in literature, stands out due to its unique set of accompanying features. Mutations occurring in CYP21A2 and CYP17A1 result in complete or partial enzyme deficiencies, and the detection of homozygous mutations in two different enzyme systems within the steroidogenic pathway is noteworthy.
Topics: Humans; Adrenal Hyperplasia, Congenital; Male; Steroid 17-alpha-Hydroxylase; Steroid 21-Hydroxylase; Adolescent; Mutation
PubMed: 38852772
DOI: 10.1016/j.ejmg.2024.104952 -
Hormone Research in Paediatrics Jun 2024Normal hypothalamic-pituitary-ovarian (HPO) endocrine function is essential for female pubertal and psychosocial development and for ongoing adult physical, sexual and... (Review)
Review
BACKGROUND
Normal hypothalamic-pituitary-ovarian (HPO) endocrine function is essential for female pubertal and psychosocial development and for ongoing adult physical, sexual and psychosocial health. Girls with hypogonadism, any endocrine disorder causing abnormal uterine bleeding (AUB) or with contraception needs may require sex hormone treatment. Challenges include evolving needs of a young girl through the course of sexual maturation, potential health risks related to the use of sex hormones for pubertal induction, hormone replacement therapy (HRT), menstrual management and/or contraception.
SUMMARY
To ensure optimal sex hormone treatment, both a comprehensive understanding of the underlying disorder affecting HPO endocrine function and a professional communication with the patient and physicians involved are warranted. In this narrative mini-review, we discuss pubertal induction and HRT for girls with hypogonadism and the management of AUB and contraception for young women up to age 30 years. Additionally, we provide advice on management of AUB and contraception in young women with common conditions including polycystic ovary syndrome, congenital adrenal hyperplasia and others. A PubMed-literature search including articles published over the last 20 years, together with clinical experience of the authors was integrated to provide treatment recommendations.
KEY MESSAGE
Sex hormone treatment, where needed, requires comprehensive understanding of a range of available options. When tailored to individual needs, with flexibility to accommodate changing circumstance in young women it is safe, well tolerated and provides both physical and psychosocial health.
PubMed: 38852580
DOI: 10.1159/000539697 -
Frontiers in Endocrinology 2024The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or... (Review)
Review
46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes.
The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or anatomical sex. DSD in individuals with a 46,XX karyotype can occur due to fetal or postnatal exposure to elevated amount of androgens or maldevelopment of internal genitalia. Clinical phenotype could be quite variable and for this reason these conditions could be diagnosed at birth, in newborns with atypical genitalia, but also even later in life, due to progressive virilization during adolescence, or pubertal delay. Understand the physiological development and the molecular bases of gonadal and adrenal structures is crucial to determine the diagnosis and best management and treatment for these patients. The most common cause of DSD in 46,XX newborns is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, determining primary adrenal insufficiency and androgen excess. In this review we will focus on the other rare causes of 46,XX DSD, outside CAH, summarizing the most relevant data on genetic, clinical aspects, puberty and fertility outcomes of these rare diseases.
Topics: Humans; Adrenal Hyperplasia, Congenital; Puberty; Hormone Replacement Therapy; Fertility; Female; Male; Disorders of Sex Development; Sexual Development
PubMed: 38841305
DOI: 10.3389/fendo.2024.1402579 -
Current Opinion in Pediatrics Jun 202421-Hydroxylase deficiency (21-OHD), the most common form of congenital adrenal hyperplasia, is an autosomal recessive disorder caused by pathogenic variants in CYP21A2....
PURPOSE OF REVIEW
21-Hydroxylase deficiency (21-OHD), the most common form of congenital adrenal hyperplasia, is an autosomal recessive disorder caused by pathogenic variants in CYP21A2. Although this disorder has been known for several decades, many challenges related to its monitoring and treatment remain to be addressed. The present review is written to describe an overview of biochemical monitoring of this entity, with particular focus on overnight fasting urine pregnanetriol.
RECENT FINDINGS
We have conducted a decade-long research project to investigate methods of monitoring 21-OHD in children. Our latest studies on this topic have recently been published. One is a review of methods for monitoring 21-OHD. The other was to demonstrate that measuring the first morning PT level may be more practical and useful for biochemical monitoring of 21-OHD. The first morning pregnanetriol (PT), which was previously reported to reflect a long-term auxological data during the prepubertal period, correlated more significantly than the other timing PT in this study, with 17-OHP, before the morning medication.
SUMMARY
In conclusion, although the optimal method of monitoring this disease is still uncertain, the use of overnight fasting urine pregnanetriol (P3) as a marker of 21-OHD is scientifically sound and may be clinically practical.
PubMed: 38832930
DOI: 10.1097/MOP.0000000000001369 -
European Journal of Medical Genetics Jun 2024Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) based on hormonal testing is successfully implemented in many countries. However, this method cannot...
Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) based on hormonal testing is successfully implemented in many countries. However, this method cannot detect non-classic CAH and has high false positive rates. We have developed a novel MALDI-TOF MS assay that can identify common variants and deletions of CYP21A2 in the Chinese population. Thirty-seven clinical patients with CAH confirmed by Sanger sequencing and MLPA analysis were detected by MALDI-TOF MS assay. Two CYP21A2 variants were detected in 30 patients and one CYP21A2 variant was detected in 7 patients. The MALDI-TOF MS assay detected 67 mutant alleles in 37 patients with a detection rate of 90.5%. Sanger sequencing revealed that three variants in seven patients were not included in the designed panel. Eleven distinct CYP21A2 variants were identified, including five missense variants, two nonsense variants, two large gene deletions, one splice variant, and one frameshift variant. The most frequent variant was c.293-13C > G (37.84%), followed by c.518T > A (21.62%) and exon 1-7 deletion (17.57%). The high-throughput MALDI-TOF MS assay that can simultaneously detect common variants and deletions of CYP21A2. This assay can be used for population-based genetic screening and rapid detection of suspected patients, and is expected to be a valuable complement to biochemical-based testing for the detection of CAH.
Topics: Humans; Steroid 21-Hydroxylase; Adrenal Hyperplasia, Congenital; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Female; Male; Infant, Newborn; Neonatal Screening; Infant; Genetic Testing; Gene Deletion
PubMed: 38830573
DOI: 10.1016/j.ejmg.2024.104950