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1.
Mymensingh Med J ; 33(4): 1075-1080, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39351728

RESUMEN

There is a scarcity of data on congenital adrenal hyperplasia (CAH) in Bangladesh. This study aimed to collect baseline information and identify relevant issues specific to the disease. We analyzed the retrospective analysis of medical records of pediatric patients attending Dhaka Shishu (Children) Hospital, Dhaka, for serum 17-Hydroxyprogesterone (17-OHP) measurement and documented to have CAH from December 2008 to December 2020. The diagnosis was supported by biochemical findings and confirmed by serum 17-OHP assay and karyotyping. The relevant clinical data were descriptively analyzed. A total of sixty (60) patients with the diagnosis of CAH were enrolled. Among them, 40(66.7%), 15(25.0%) and 5(8.3%) patients had salt-wasting (SW), simple virilizing (SV) and non-classical (NC) CAH, respectively. Karyotypically, 45(75.0%) were girls and 15(25.0%) were boys. At presentation, 30(50.0%) were initially assigned as female and 24(40.0%) were male and in 6(10.0%) cases, the sex was not assigned. All six cases of unassigned sex were proven to be female by karyotype, while ninecases assigned as males were proven to be females; overall, 15(25.0%) patients were incorrectly assigned sex at the initial presentation. Patients with SW form of disease presented at an earlier age (median age 1.0 months) than those with SV form (median age 12.0 months). Boys were diagnosed later than girls. CAH should be diagnosed earlier, irrespective of the sex of the child, to prevent death from the salt-losing crisis and proper gender assignment. In a resource-poor country like Bangladesh, we should emphasize building awareness among the general population and caregivers for early clinical identification of the cases and proper referral.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Humanos , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/epidemiología , Femenino , Masculino , Bangladesh/epidemiología , Estudios Retrospectivos , Lactante , Preescolar , Niño , 17-alfa-Hidroxiprogesterona/sangre , Recién Nacido , Cariotipificación , Hospitales Pediátricos/estadística & datos numéricos
2.
Front Endocrinol (Lausanne) ; 15: 1411774, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39351530

RESUMEN

Primary adrenal insufficiency (PAI) is a rare medical condition, characterized by a deficiency in adrenal hormones. Although rare, PAI is a life-threatening disease requiring prompt recognition and treatment. However, symptoms of PAI are often non-specific and diagnosis can be challenging, causing frequent diagnostic delays. In adults, autoimmunity is the most common cause of PAI in industrialized countries, whereas in children, the most frequent etiology is represented by congenital defects of steroidogenesis and, in particular, by congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. A few recent case series from different countries have reported that autoimmunity is the second most common etiology of PAI in the pediatric age group. However, data on autoimmune PAI in children are still scant and the exact epidemiology, clinical manifestations, and long-term outcomes of this condition have yet to be defined. The scope of this review is to summarize the current knowledge on the etiology, presentation, and treatment of autoimmune PAI in childhood and to increase physicians' awareness of the signs that should raise an early suspicion of this condition.


Asunto(s)
Enfermedad de Addison , Enfermedades Autoinmunes , Humanos , Enfermedad de Addison/diagnóstico , Enfermedad de Addison/epidemiología , Enfermedad de Addison/inmunología , Niño , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/inmunología , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/epidemiología , Autoinmunidad
3.
BMC Endocr Disord ; 24(1): 215, 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39402525

RESUMEN

BACKGROUND: 11ß-hydroxylase deficiency (11ß-OHD), caused by homozygosity or compound heterozygosity CYP11B1 variants, is the second most common cause of congenital adrenal hyperplasia (CAH). Due to the high degree of sequence identity between CYP11B1 and CYP11B2, chimeric genes, and complex structural variants (SVs), the conventional approach to gene testing for 11ß-OHD is facing challenges. The study aimed to clarify the underlying genetic causes of two siblings of a Chinese family with 11ß-OHD. METHODS: Peripheral blood samples and clinical information were collected from subjects and their family members. Sex steroid concentrations were measured using LC-MS/MS. Long-range PCR-based next-generation sequencing (NGS), PCR assay and target long-read sequencing were used to detect the pathogenic variants. RESULTS: Early onset hypertension, increased serum levels of adrenocorticotropin (ACTH), progesterone, testosterone, and decreased cortisol and potassium were detected in both affected siblings. Long-range PCR-based NGS identified a heterozygous missense variant (NM_000497.4:c.281 C > T, p.P94> L) in CYP11B1 gene in the two siblings. PCR detected no chimeric CYP11B2/CYP11B1 gene. We finally identified a second pathogenic variant in CYP11B1 gene via target long-read sequencing (T-LRS). This novel variant was a deletion-insertion variant and located chr8:143957269-143,957,579 (hg19) with the insertion of 'ACAG' (NM_000497.4:c.954 + 78_980delinsACAG), which was in trans with CYP11B1: c.281 C > T. CONCLUSIONS: Our study suggests that the integrated long-range PCR-based NGS and T-LRS seem to be the most reliable and accurate method for 11ß-OHD genetic diagnosis and carrier sequencing.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Secuenciación de Nucleótidos de Alto Rendimiento , Esteroide 11-beta-Hidroxilasa , Humanos , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/sangre , Femenino , Masculino , Esteroide 11-beta-Hidroxilasa/genética , Linaje , Adulto , Pronóstico , Mutación Missense
4.
Malays J Pathol ; 46(2): 247-257, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39207002

RESUMEN

Congenital Adrenal Hyperplasia (CAH) is primarily caused by mutations in genes responsible to produce enzymes involved in the synthesis of cortisol, aldosterone, or both. This study aims to determine the prevalence, sociodemographic distributions, and clinical factors associated with CAH in the Malaysian population. This retrospective study reviewed laboratory records of 17-hydroxyprogesterone (17OHP) test requests received at the Institute for Medical Research, Kuala Lumpur from January 2021 to December 2021. Descriptive statistics were employed for most variables, and logistic regression analysis was conducted to determine factors associated with CAH. The dataset included a total of 775 patients (64.2%) from 1,207 test requests screened. The prevalence of newly diagnosed CAH in the year 2021 was 13.5% (n=105). The majority were Malays (15.1%), neonates (13.8%), and females (45.7%). Higher baseline 17-OHP (cOR:1.31, 95% CI:1.19, 1.45), unknown gender at birth (cOR:7.82, 95% CI:2.86, 21.37), and neonatal age group at presentation (cOR:29.3, 95% CI:12.07, 71.03) independently predict CAH. The high prevalence of CAH in our region has been speculated to be due to the cultural consanguinity norms, resulting in genetic aberrations. CAH may manifest as ambiguous genitalia, particularly in females, due to the overproduction of androgens in-utero, resulting in atypical genitalia, necessitating thorough investigation. To the best of our knowledge, the data presented are the latest report on CAH prevalence, distribution, and description of positive CAH cases in the Malaysian population. These findings are essential for further public health planning to improve the diagnostic capacity and clinical management of CAH.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Humanos , Hiperplasia Suprarrenal Congénita/epidemiología , Hiperplasia Suprarrenal Congénita/diagnóstico , Malasia/epidemiología , Femenino , Masculino , Estudios Retrospectivos , Recién Nacido , Adulto , Lactante , Adolescente , Niño , Preescolar , Prevalencia , Adulto Joven , 17-alfa-Hidroxiprogesterona/sangre , Persona de Mediana Edad
5.
Eur J Endocrinol ; 191(2): 204-210, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-39137138

RESUMEN

OBJECTIVE, DESIGN, AND METHODS: Although 17-hydroxyprogesterone (17OHP) has historically been the steroid assayed in the diagnosis of congenital adrenal 21-hydroxylase deficiency (CAH-21D), its C11-hydroxylated metabolite, 21-deoxycortisol (21DF), which is strictly of adrenal origin, is assayed in parallel in this pathology. This steroid (21DF) is oxidized by 11beta-hydroxysteroid dehydrogenase type 2 into 21-deoxycortisone (21DE). In the context of CAH-21D confirmation testing, confounding factors (such as intensive care unit admission, stress, prematurity, early sampling, and variations of sex development) can interfere with the interpretation of the gold-standard biomarkers (17OHP and 21DF). Since its tissue concentrations are especially high in the placenta, we hypothesized that 21DE quantification in the neonatal periods could be an interesting biomarker in addition to 17OHP and 21DF. To verify this hypothesis, we developed a new mass spectrometry-based assay for 21DE in serum and applied it to newborns screened for CAH-21D. RESULTS: In newborns with CAH-21D, the mean serum levels of 21DE reached 17.56 ng/mL (ranging from 8.58 ng/mL to 23.20 ng/mL), and the mean 21DE:21DF ratio was 4.99. In contrast, in newborns without CAH-21D, the 21DE serum levels were low and not statistically different from the analytical 21DE limit of quantification (0.01 ng/mL). CONCLUSION: Basal serum 21DE appears to be a novel sensitive and specific biomarker of CAH-21D in newborns.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Biomarcadores , Cortodoxona , Humanos , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/sangre , Recién Nacido , Femenino , Cortodoxona/sangre , Biomarcadores/sangre , Masculino , 17-alfa-Hidroxiprogesterona/sangre , Tamizaje Neonatal/métodos , Sensibilidad y Especificidad
6.
Clin Chem Lab Med ; 62(10): 1938-1949, 2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39044644

RESUMEN

Emerging technology in laboratory medicine can be defined as an analytical method (including biomarkers) or device (software, applications, and algorithms) that by its stage of development, translation into broad routine clinical practice, or geographical adoption and implementation has the potential to add value to clinical diagnostics. Paediatric laboratory medicine itself may be considered an emerging area of specialisation that is established relatively recently following increased appreciation and understanding of the unique physiology and healthcare needs of the children. Through four clinical (neonatal hypoglycaemia, neonatal hyperbilirubinaemia, sickle cell disorder, congenital adrenal hyperplasia) and six technological (microassays, noninvasive testing, alternative matrices, next generation sequencing, exosome analysis, machine learning) illustrations, key takeaways of application of emerging technology for each area are summarised. Additionally, nine key considerations when applying emerging technology in paediatric laboratory medicine setting are discussed.


Asunto(s)
Pediatría , Humanos , Pediatría/métodos , Niño , Recién Nacido , Secuenciación de Nucleótidos de Alto Rendimiento , Hiperplasia Suprarrenal Congénita/diagnóstico , Anemia de Células Falciformes/diagnóstico , Biomarcadores/análisis , Biomarcadores/sangre , Hiperbilirrubinemia Neonatal/diagnóstico , Hiperbilirrubinemia Neonatal/sangre , Aprendizaje Automático , Técnicas de Laboratorio Clínico/métodos
7.
Arch Pediatr ; 31(6): 400-402, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39003161

RESUMEN

17α-Hydroxylase and 17,20-lyase are enzymes encoded by the CYP17A1 gene and are necessary for the production of cortisol and sex steroids. Females with 17α-hydroxylase deficiency usually present with primary amenorrhea and delayed puberty accompanied by hypertension and electrolyte imbalance. Here, we report the case of a 14-year-old female patient who presented with severe short stature and delayed puberty without any complaint suggestive of 17-hydroxylase enzyme deficiency. Laboratory test results showed low cortisol and dehydroepiandrosterone sulfate (DHEA-S) along with high luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Turner syndrome was excluded after genetic analysis showed a 46,XX karyotype, and 17α-hydroxylase deficiency was diagnosed by detecting a c.1319G>A (p.Arg440His) variation/alternation in the patient's CYP17A1 gene.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Esteroide 17-alfa-Hidroxilasa , Humanos , Femenino , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/complicaciones , Adolescente , Esteroide 17-alfa-Hidroxilasa/genética , Pubertad Tardía/diagnóstico , Pubertad Tardía/genética , Pubertad Tardía/etiología , Enanismo/genética , Enanismo/diagnóstico
8.
BMC Endocr Disord ; 24(1): 103, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38977992

RESUMEN

BACKGROUND: Congenital adrenal hyperplasia (CAH) encompassed a bunch of autosomal recessive disorders characterized by impaired cortisol levels due to an enzymatic deficiency in steroid synthesis. In adult male patients with CAH, a frequent complication related to poor disease control is the development of ectopic adrenocortical tissue in the testes, named testicular adrenal rest tumors (TART). Conversely, ovarian adrenal rest tumors (OART) in females are extremely rare and adrenal rests in sites other than gonads are so uncommon to have been described only few times in literature. CASE PRESENTATION: We report a case of a male patient with untreated CAH and oncologic history of pleomorphic sarcoma who presented with massive bilateral adrenal enlargement and adrenal rest tumors in peri-lumbar and peri-cecal sites, which mimicked metastasis from sarcoma. CONCLUSIONS: The development of massive adrenal enlargement and ectopic adrenal rest tumors in sites other than gonads, even if very uncommon, should be suspected in patients with CAH and prolonged periods of undertreatment.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Tumor de Resto Suprarrenal , Humanos , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/patología , Hiperplasia Suprarrenal Congénita/diagnóstico , Masculino , Tumor de Resto Suprarrenal/patología , Tumor de Resto Suprarrenal/diagnóstico , Tumor de Resto Suprarrenal/etiología , Diagnóstico Diferencial , Sarcoma/diagnóstico , Sarcoma/patología , Adulto , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/secundario , Pronóstico
9.
J Pediatr Endocrinol Metab ; 37(9): 835-839, 2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39042921

RESUMEN

OBJECTIVES: Lipoid congenital adrenal hyperplasia (LCAH) is a rare autosomal recessive disease caused by mutations in the steroidogenic acute regulatory protein (STAR) gene, expressed in the adrenal and gonadal tissues. In classical LCAH, individuals with 46, XY chromosomes present with a female appearance of the external genitalia due to insufficient androgen production. In the non-classical form, a milder phenotype is observed with male external genitalia. Here, we present a non-classical LCAH diagnosis with a newly identified c.266T>A (p.Ile89Asn) likely pathogenic homozygous variant in a 46, XY infant. CASE PRESENTATION: A three-month-and-thirteen-day-old male proband presented with clinical features of cortisol and mineralocorticoid deficiencies. The manifestation of salt-wasting syndrome occurred relatively late, and although the external genitalia appeared male, there was a mild virilization defect. The combination of mild impairment in androgen production and severe salt-wasting syndrome is an intriguing finding in our patient. Peripheral blood samples were obtained from the patient and his family. The newly identified variant, determined by next-generation sequencing analysis, was confirmed by segregation analysis showing carrier status in both parents. CONCLUSIONS: We aim to contribute to the literature by elucidating molecular mechanisms by presenting an atypical presentation and a newly identified variant.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Fosfoproteínas , Humanos , Masculino , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/patología , Turquía , Lactante , Fosfoproteínas/genética , Trastorno del Desarrollo Sexual 46,XY/genética , Trastorno del Desarrollo Sexual 46,XY/diagnóstico , Mutación , Pronóstico , Femenino , Fenotipo , Linaje , Recién Nacido
10.
Endocrinol Metab Clin North Am ; 53(3): 391-407, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39084815

RESUMEN

Over the last several decades, children with all forms of classic congenital adrenal hyperplasia (CAH) are identified early and treated appropriately throughout childhood. As adults, women with CAH may desire to become mothers and their usual chronic therapy and disease control is often inadequate for conception. Subsequently, little data exist on their management during pregnancy. Pregnancy in women with various forms of CAH is possible with appropriate treatment. Achieving pregnancy is more complex than disease management during pregnancy.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Complicaciones del Embarazo , Humanos , Hiperplasia Suprarrenal Congénita/terapia , Hiperplasia Suprarrenal Congénita/diagnóstico , Femenino , Embarazo , Complicaciones del Embarazo/terapia
11.
Anal Bioanal Chem ; 416(20): 4635-4645, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38949681

RESUMEN

17α-Hydroxyprogesterone (17α-OHP) quantification in dried blood spots (DBS) is essential for newborn screening for congenital adrenal hyperplasia (CAH), which is challenging due to its low physiological concentration. The high false-positive rates of immunoassays necessitate the development of more accurate methods. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers increased specificity and sensitivity, yet standardized procedures for 17α-OHP measurement are required for clinical application. A candidate reference measurement procedure (cRMP) using isotope dilution LC-MS/MS was developed for 17α-OHP quantification in DBS. By utilizing stable isotope-labeled D8-17α-OHP as an internal standard, the cRMP was optimized, covering sample preparation, calibration, and LC-MS/MS analysis. The method performance was validated across several parameters, including precision, accuracy, specificity, detection limits, and matrix effects. Clinical applicability was further assessed through the establishment of reference intervals for healthy newborns. The developed cRMP exhibited a linear range of 1.00 to 80.00 ng/mL for 17α-OHP, with detection and quantification limits of 0.14 ng/mL and 0.52 ng/mL, respectively. Inter- and intraday precision demonstrated coefficients of variation within 1.27 to 5.69%. The recovery rates and matrix effects were well within acceptable limits, ensuring method reliability. Clinical application showed distinct reference intervals for healthy newborns that were unaffected by sex but influenced by weight and gestational age. This method significantly enhances CAH diagnostic accuracy in newborns, providing a valuable tool for clinical laboratories and improving newborn screening program standardization and traceability.


Asunto(s)
17-alfa-Hidroxiprogesterona , Pruebas con Sangre Seca , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Pruebas con Sangre Seca/métodos , 17-alfa-Hidroxiprogesterona/sangre , Recién Nacido , Cromatografía Liquida/métodos , Límite de Detección , Estándares de Referencia , Hiperplasia Suprarrenal Congénita/sangre , Hiperplasia Suprarrenal Congénita/diagnóstico , Tamizaje Neonatal/métodos , Reproducibilidad de los Resultados , Técnicas de Dilución del Indicador , Femenino , Valores de Referencia
12.
Gynecol Endocrinol ; 40(1): 2373741, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39034929

RESUMEN

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to adrenal steroid biosynthesis, and mainly caused by mutations in the CYP21A2 gene encoding 21-hydroxylase. Adrenal tumors are common in CAH, but functional adrenal tumors are rare. Here, we report a 17-year-old female with virilized external genitalia and primary amenorrhea, accompanied by a right adrenal tumor. Her 17-OHP level was normal, cortisol and androgen levels were significantly elevated, and the tumor pathology showed adrenal cortical adenoma. Gene testing for CYP21A2 showed c.518T > A in exon 4 and c.29313C > G in intron 2. The possibility of untreated classic CAH with 21-OH deficiency causing functional adrenal cortical adenoma should be considered. When clinical diagnosis highly considers CAH and cannot rule out the influence of functional adrenal tumors' secretion function on 17-OHP, gene mutation analysis should be performed.


Asunto(s)
Neoplasias de la Corteza Suprarrenal , Hiperplasia Suprarrenal Congénita , Adenoma Corticosuprarrenal , Esteroide 21-Hidroxilasa , Humanos , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/complicaciones , Femenino , Adolescente , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/diagnóstico , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/diagnóstico , Adenoma Corticosuprarrenal/complicaciones , Esteroide 21-Hidroxilasa/genética , Esteroide 21-Hidroxilasa/metabolismo
13.
Adv Pediatr ; 71(1): 135-149, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38944479

RESUMEN

Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic condition caused by various enzyme deficiencies that result in disruptions of pathways of adrenal steroidogenesis. 21-hydroxylase deficiency is the most common form of CAH and has a variable phenotype which ranges a spectrum, from the most severe salt-wasting type to the simple-virilizing type and the least severe nonclassical form. Patients with CAH are at risk for various comorbidities due to the underlying adrenal hormone production imbalance as well as the treatment of the condition, which typically includes supraphysiologic glucocorticoid dosing. Children and adults require frequent monitoring and careful medication dosing adjustment. However, there are multiple novel therapies on the horizon that offer promise to patients with CAH in optimizing their treatment regimens and reducing the risk of comorbidities.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Glucocorticoides , Humanos , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/terapia , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Niño
14.
Eur J Med Genet ; 69: 104950, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38830573

RESUMEN

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.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Esteroide 21-Hidroxilasa , Humanos , Esteroide 21-Hidroxilasa/genética , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/normas , Femenino , Masculino , Recién Nacido , Tamizaje Neonatal/métodos , Lactante , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Eliminación de Gen
15.
Curr Opin Pediatr ; 36(4): 456-462, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38832930

RESUMEN

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.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Ayuno , Pregnanotriol , Humanos , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/orina , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Niño , Pregnanotriol/orina , Ayuno/orina , Biomarcadores/orina , Biomarcadores/sangre , Esteroide 21-Hidroxilasa/genética , Esteroide 21-Hidroxilasa/orina , Monitoreo Biológico/métodos
16.
J Mol Diagn ; 26(9): 770-780, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38925455

RESUMEN

Genetic analysis of congenital adrenal hyperplasia (CAH) has been challenging because of high homology between CYP21A2 and its pseudogene CYP21A1P. This study aimed to evaluate the clinical utility of long-read sequencing (LRS) in diagnosis of CAH attributable to 21-hydroxylase deficiency by comparing with multiplex ligation-dependent probe amplification plus Sanger sequencing. In this retrospective study, 69 samples, including 49 probands from 47 families with high-risk of CAH, were enrolled and blindly subjected to detection of CAH by LRS. The genotype results were compared with control methods, and discordant samples were validated by additional Sanger sequencing. LRS successfully identified biallelic variants of CYP21A2 in the 39 probands diagnosed as having CAH. The remaining 10 probands were not patients with CAH. Additionally, LRS directly identified two pathogenic single-nucleotide variations (SNVs; c.293-13C/A>G and c.955C>T) in the presence of interference caused by nearby insertions/deletions (indels). The cis-trans configuration of two or more SNVs and indels identified in 18 samples was directly determined by LRS without family analysis. Eight CYP21A1P/A2 or TNXA/B deletion chimeras, composed of five subtypes, were identified; and the junction sites were precisely determined. Moreover, LRS determined the exact genotype in two probands who had three heterozygous SNVs/indels and duplication, which could not be clarified by control methods. These findings highlight that LRS could assist in more accurate genotype imputation and more precise CAH diagnosis.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Reacción en Cadena de la Polimerasa Multiplex , Esteroide 21-Hidroxilasa , Humanos , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Esteroide 21-Hidroxilasa/genética , Femenino , Reacción en Cadena de la Polimerasa Multiplex/métodos , Masculino , Estudios Retrospectivos , Polimorfismo de Nucleótido Simple , Genotipo , Preescolar , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación INDEL , Análisis de Secuencia de ADN/métodos , Niño , Seudogenes/genética , Lactante
17.
Front Endocrinol (Lausanne) ; 15: 1352552, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38699383

RESUMEN

Congenital adrenal hyperplasia (CAH) and Williams Syndrome (WS; MIM # 194050) are distinct genetic conditions characterized by unique clinical features. 21-Hydroxylase deficiency (21-OHD; MIM #201910), the most common form of CAH, arises from mutations in the CYP21A2 gene, resulting in virilization of the external genitalia in affected females, early puberty in males, and short stature. Williams syndrome, caused by a microdeletion of 7q11.23, presents with distinctive facial features, intellectual disability, unique personality traits, early puberty, and short stature. This case report describe the clinical features of a 4-year-old girl referred due to progressive virilization and developmental delay. Genetic analysis confirmed concurrent CAH and WS, identifying a novel mutation in the CYP21A2 gene (c.1442T>C). Following corticosteroid therapy initiation, the patient developed central precocious puberty. This case report delves into the pubertal change patterns in a patient affected by overlapping genetic conditions, providing valuable insights in to the intricate clinical manifestation and management of these rare complex disorders.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Pubertad Precoz , Virilismo , Síndrome de Williams , Humanos , Femenino , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Pubertad Precoz/diagnóstico , Pubertad Precoz/genética , Pubertad Precoz/etiología , Síndrome de Williams/complicaciones , Síndrome de Williams/genética , Síndrome de Williams/diagnóstico , Preescolar , Virilismo/genética , Virilismo/diagnóstico , Esteroide 21-Hidroxilasa/genética , Mutación
18.
Clin Endocrinol (Oxf) ; 101(2): 108-113, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38796770

RESUMEN

BACKGROUND: Newborn screening (NBS) reduces the risk of mortality in congenital adrenal hyperplasia (CAH), mainly due to the salt-wasting form of 21-hydroxylase deficiency. There is limited knowledge regarding the results of NBS in non-CAH primary adrenal insufficiency (non-CAH PAI). PATIENTS AND METHODS: Clinical and NBS for CAH data of neonates who were diagnosed with non-CAH PAI between January and December 2022 were examined. RESULTS: Patients (n = 6, 4 females) were presented with severe hyperpigmentation (n = 6), hypoglycemia (n = 4), hyponatremia (n = 3), hyperkalemia (n = 1), respiratory distress syndrome (n = 1) between 3rd hour to 2 months of life. All had normal NBS results. The median first-tier 17-hydroxyprogesterone (17OHP) concentration in NBS for CAH was 0.14 ng/mL (range; 0.05-0.85). Molecular studies revealed biallelic mutations in the MC2R (n = 4; 3 homozygous, 1 compound heterozygous), MRAP (n = 1) and STAR (n = 1) genes. Glucocorticoid with or without mineralocorticoid replacement was initiated once the diagnosis of non-CAH PAI was established. CONCLUSION: Neonates with non-CAH PAI have always normal NBS due to persistently low 17OHP, even when these newborn infants are severely symptomatic for adrenal insufficiency. Clinicians should be alert for signs of adrenal insufficiency in neonates, even if the patient has a 'normal' screening for CAH, so as not to delay diagnosis and treatment. This fact should be kept in mind particularly in countries where these conditions are more common than elsewhere.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Insuficiencia Suprarrenal , Tamizaje Neonatal , Humanos , Recién Nacido , Tamizaje Neonatal/métodos , Femenino , Masculino , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/sangre , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/sangre , 17-alfa-Hidroxiprogesterona/sangre , Mutación
19.
Curr Opin Pediatr ; 36(4): 463-466, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38747200

RESUMEN

PURPOSE OF REVIEW: Congenital adrenal hyperplasia (CAH) is a relatively common disorder and one of the most challenging conditions seen by pediatric endocrinologists. Poor linear growth in CAH has been recognized for many years. There are new insights to explain this abnormality and shed light on strategies to promote normal growth. RECENT FINDINGS: Published data suggest that the dose of hydrocortisone during two critical periods of rapid growth, namely infancy and at puberty, has a fundamental effect on growth velocity, and by definition adult height. To prevent over-treatment, hydrocortisone dosage should remain within the range of 10-15 mg/m 2 body surface area per day. Precursor steroids such as 17-hydroxy progesterone (17OHP) should not be suppressed to undetectable levels. In fact, 17OHP should always be measurable, as complete suppression suggests over-treatment. SUMMARY: CAH is a challenging disorder. High-quality compliance within the consultation setting, with the patient seeing the same specialist at every visit, will be rewarded by improved long-term growth potential. Quality auxological monitoring can avoid phases of growth suppression. New therapy with CRH receptor antagonists may lead to a more nuanced approach by allowing fine tuning of hydrocortisone replacement without the need to suppress ACTH secretion.


Asunto(s)
Hiperplasia Suprarrenal Congénita , Hidrocortisona , Humanos , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/diagnóstico , Niño , Adolescente , Hidrocortisona/uso terapéutico , Estatura/efectos de los fármacos , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/etiología , Lactante , Preescolar
20.
Front Endocrinol (Lausanne) ; 15: 1354759, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38812815

RESUMEN

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11ß-hydroxylase, 3ß-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.


Asunto(s)
Trastornos del Desarrollo Sexual 46, XX , Hiperplasia Suprarrenal Congénita , Humanos , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/terapia , Trastornos del Desarrollo Sexual 46, XX/genética , Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Femenino , Masculino , Trastornos del Desarrollo Sexual/genética , Trastornos del Desarrollo Sexual/diagnóstico
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