Mutation distributions among patients with congenital adrenal hyperplasia from five regions of Brazil: a systematic review

ABSTRACT Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by CYP21A2 gene mutations, and its molecular diagnosis is widely used in clinical practice to confirm the hormonal diagnosis. Hence, considering the miscegenation of the Brazilian population, it is important to determine a mutations panel to optimise the molecular diagnosis. The objective was to review the CYP21A2 mutations' distribution among Brazilian regions.Two reviewers screened Brazilian papers up to February 2020 in five databases. The pair-wise comparison test and Holm method were used in the statistical analysis. Nine studies were selected, comprising 769 patients from all regions. Low proportion of males and salt-wasters was identified in the North and Northeast regions, although without significant difference. Large gene rearrangements also had a low frequency, except in the Center-West and South regions (p < 0.05). The most frequent mutations were p.I172N, IVS2-13A/C>G, p.V281L and p.Q318X, and significant differences in their distributions were found: p.V281L was more frequent in the Southeast and p.Q318X in the Center-West and Northeast regions (p < 0.05). Thirteen new mutations were identified in 3.8%-15.2% of alleles, being more prevalent in the North region, and six mutations presented a founder effect gene. Genotype-phenotype correlation varied from 75.9%-97.3% among regions. The low prevalence of the salt-wasting form, affected males and severe mutations in some regions indicated pitfalls in the clinical diagnosis. The good genotype-phenotype correlation confirms the usefulness of molecular diagnosis; however, the Brazilian population also presents significant prevalence of novel mutations, which should be considered for a molecular panel.

Analysis of gene variation and long-term follow-up in children with phenylalanine hydroxylase deficiency diagnosed by newborn screening / 浙江大学学报·医学版

OBJECTIVES@#To retrospectively analyze the variation and characteristics of phenylalanine hydroxylase (PAH) gene, and to observe the long-term treatment effect and follow-up of newborns with PAH deficiency.@*METHODS@#Clinical data, treatment and follow-up results of 198 patients with PAH deficiency diagnosed by newborn screening in Jinan from 1996 to 2021 were collected. The genetic analysis of 55 patients with PAH deficiency diagnosed by newborn screening in Jinan and 213 patients referred from the surrounding areas of Jinan were summarized. Gene variations were checked by a customized Panel gene detection method. Blood phenylalanine-concentration and physical development indicators including height and weight were regularly monitored. Intellectual development was assessed using a neuropsychological development scale for patients aged 0-6 years and academic performance, and brain injury in patients was assessed using brain magnetic resonance imaging.@*RESULTS@#c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. The genotype of c.158G>A variation is compound heterozygous variation, with mainly a mild hyperpheny-lalaninemia. 168 patients with PAH deficiency who were followed-up regularly had normal physical development without dwarfism or malnutrition. Among the 33 preschool patients who underwent mental development assessment, 2 were mentally retarded and the initial treatment age was older than 6 months. Nine patients with an average age of (17.13±2.42) years completed brain magnetic resonance imaging, one case was normal, and 8 cases were abnormal. There were patchy or patchy hyperintense foci near the bilateral lateral ventricles on T2WI, and the intellectual development was normal. Compared with the other eight patients, the blood phenylalanine concentration of the normal child was better and stably controlled within the ideal range.@*CONCLUSIONS@#c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. After standardized treatment, most patients with PAH deficiency diagnosed by screening can obtain normal growth and intellectual development in adolescence, but there are different degrees of organic lesions in the cerebral white matter.

Genetic diagnosis of non-classical 21-hydroxylase deficiency by the new nanopore sequencing detection method / 中华检验医学杂志

Objective:To summarize initial experience of applying nanopore third-generation sequencing detection method (nanopore sequencing) for genetic diagnosis of non-classical 21 hydroxylase deficiency (NC 21-OHD), and to explore its performance and application prospects.Methods:Clinical data of the two NC 21-OHD patients, who were hospitalized at the First Affiliated Hospital of Zhengzhou University in May 2019, were collected. Peripheral venous blood was collected and genome DNA extracted. Genetic variants was detected by nanopore sequencing and underwent bioinformatic analysis. Pathogenetic mutations in CYP21A2 gene were validated with PCR-sanger sequencing in the two patients and their parents.Results:The average reads length and sequence depth in the patient one was 12, 792 bp and 27.19×. The average reads length and sequence depth in the patient two was 13, 123 bp and 21.34×. Compound variants of c.293-13C>G/c.844G>T (p.Val282Leu) and c.332_339delGAGACTAC (p.Gly111Valfs)/c.844G>T (p.Val282Leu) were detected in these two patients, which were consistent with clinical phenotype of NC 21-OHD. Further analysis showed that c.293-13C>G mutation was inherited from her father and c.844G>T (p.Val282Leu) mutation was inherited from her mother for the patient one. The c.844G>T (p.Val282Leu) mutation was inherited from her father and c.332_339delGAGACTAC (p.Gly111Valfs) mutation from her mother.Conclusions:The heterozygous mutations in CYP21A2 gene are the cause of NC 21-OHD in these two patients. Nanopore sequencing technique is a reliable new detection method for patients with NC 21-OHD.

Effects of 21-hydroxylase deficiency on male fertility / 中华内分泌代谢杂志

Congenital adrenal hyperplasia(CAH) is a group of autosomal recessive disorders caused by deficiency of specific enzymes in the adrenocortical hormone synthesis pathway, resulting in impaired corticosteroid synthesis. 21-hydroxylase deficiency is the most common type of CAH, and the disorder can lead to impaired fertility in patients. Most current studies have focused on fertility problems in female CAH patients. The most common causes of impaired fertility in men with 21-OHD include testicular adrenal rest tumors(TART), low gonadotropin secretion, and inappropriate glucocorticoid therapy. This article reviews the causes of impaired fertility and its treatment in male patients with 21-OHD, with the aim of providing guidance for improving the fertility of male patients with 21-OHD.

Five patients with 11β-hydroxylase deficiency due to CYP11B1 gene mutation: A case study / 中华内分泌代谢杂志

Objective:To investigate the clinical and molecular characteristics of 11β-hydroxylase deficiency(11β-OHD) to improve the understanding of this disorder.Methods:The clinical manifestation, hormone level, imaging examination, characteristics of gene variation and follow-up of five patients with 11β-OHD diagnosed in Henan Children′s Hospital from 2016 to 2021 were carefully reviewed.Results:Among the 5 children, 3 were male and 2 were female, all without positive family history. The age at diagnosis was 1 year 5 months to 7 years(average 3 years and 9 months), and the bone age was 3 years 6 months to 16 years(average 10 years and 3 months). Two cases were misdiagnosed as 21-hydroxylase deficiency(21-OHD) and treated with long-term mineralocorticoids. Three patients presented with hypertension and one patient had testicular adrenal rest tumor. Adrenal CT showed bilateral adrenal hyperplasia in five patients. ACTH, 17-hydroxyprogesterone, testosterone, and androstenedione levels were increased in 5 children, and hypokalemia occurred in 1 patient. One patient carried homozygous novel missense variant, and four patients had compound heterozygous variants. Four patients carried missence mutations, two patients had deletion and one patient harbored a chimeric CYP11B2 exon1-6/CYP11B1 exon7-9. Three novel CYP11B1 mutations, including c. 1385T>C(p.L462P), c.64C>T(p.Q22*)and c. 1354G>A(p.G452R) were identified. The final height of 2 male children were 164.4 cm and 150.2 cm, respectively, and the related hormone levels of the other 3 children were normal.Conclusion:11β-OHD is easily misdiagnosed, leading to severe impairment of final height. CYP11B1 gene variation is complex and diverse, which requires variety of gene detection methods.

Corticotropin releasing factor type 1 receptor antagonist: a promising therapy for 21-hydroxylase deficiency / 中华实用儿科临床杂志

21-hydroxylase deficiency(21-OHD) is mainly characterized by cortisol deficiency with or without aldosterone deficiency and hyperandrogenemia.The disease requires lifelong exogenous glucocorticoid/salt supplementation.Excessive doses of exogenous glucocorticoids are often needed to control hyperandrogenemia, but the effect is not satisfactory.Corticotropin releasing factor (CRF) type 1 receptor antagonist can directly block the production of adrenocorticotropin, inhibit the generation of adrenogenic androgen, reduce the dose of glucocorticoid therapy, and thus lower the incidence of adverse reactions.In this article, the current research progress on 21-OHD therapy and CRF1 receptor antagonist was reviewed.

Irregular Menstruation-Hirsutism-Infertility: Clinical Management of Non-Classic Congenital Adrenal Hyperplasia / 罕见病研究

A 38-year-old female presented with irregular menstruation and hirsutism that started at age of 16 and diagnosed with polycystic ovary syndrome at age of 29 with elevated testosterone. When treated with ethinestradiol cyproterone tablets, her menstruation returned to normal and androgen levels was not changed. At age of 38 she was referred to the hospital with infertility, a diagnosis of nonclassical 21-hydroxylase deficiency was confirmed using 17-hydroxyprogesterone, dehydroepiandrosterone-sulfate, a cosyntropin-stimulation test and genetic test. This case suggested that nonclassical congenital adrenal hyperplasia should be considered when a patient is presented with oligomenorrhea, hirsutism with hyperandrogenemia and infertility.

Clinical features of unrecognized congenital adrenal hyperplasia due to 17α-hydroxylase deficiency since adolescence: A case report / Journal of the ASEAN Federation of Endocrine Societies

@#The majority of patients with congenital adrenal hyperplasia (CAH) present with a deficiency of 21-hydroxylase or 11-beta-hydroxylase, which account for 90% and 7% of cases, respectively. However, CAH due to 17α-hydroxylase deficiency (17OHD) is an extremely rare form of CAH (<1% of all CAH cases) that leads to a deficiency of cortisol and sex steroids, along with features of aldosterone excess. This is a case of a 51-year-old single female who was referred to us for the evaluation of new-onset hypertension and hypokalaemia of one-year duration. She was born out of a second-degree consanguineous marriage and reared as a female. She was diagnosed to have testicular feminization syndrome when she presented with a history of primary amenorrhea, absence of secondary sexual characteristics, and bilateral labial swellings at pubertal age. Subsequently, she underwent gonadectomy at the age of 16. Due to the presence of hypertension, metabolic alkalosis and bilaterally enlarged adrenals on CT scan, 46, XY disorders of sexual development (DSD) was considered. A karyotype confirmed the presence of 46, XY chromosomal sex, and genetic analysis revealed a mutation in the CYP17A1 gene, thus confirming the diagnosis of 17a-hydroxylase deficiency.

Anthropometric and Pubertal Outcomes in Girls With Classical Congenital Adrenal Hyperplasia

Objective: To evaluate the anthropometric and pubertal outcomes, over a spectrum of treatment regimens and compliance. Methods: We reviewed records of the patients with classical CAH seen at the endocrinology clinic of a tertiary care center between 1995 and 2016. Results: 25 females were included in the study, the majority (80%) with simple virilizing variant. All patients had genital ambiguity since birth, yet 40% (10/25) presented much later with menstrual complaints. All patients received hydrocortisone, but some switched to dexamethasone (n=7) or prednisolone (n=4). 7/9 (77.9%) girls who achieved target height, were on hydrocortisone. Menarche occurred with corticosteroid treatment in 60% (15/25) patients at a median (IQR) age of 16 (12-22) years. Conclusion: Hydrocortisone seems to have a beneficial effect on linear growth. Once target height is achieved, dexamethasone may be considered as an alternative.

Distonías primarias respondedoras a levodopa (DRD): búsqueda sistemática en Latinoamérica / Dopa-responsive dystonia (DRD): systematic search in Latin America

RESUMEN Las distonías que responden a levodopa (DRD, siglas en inglés) abarcan un grupo de distonías primarias, causadas por deficiencias enzimáticas en la vía metabólica de las aminas y, por definición, comparten como característica principal su respuesta favorable y sostenida a levodopa. Existen hasta seis genes asociados a DRD, siendo el gen GCH1 el más frecuentemente involucrado. La presentación típica de esta entidad se caracteriza por su aparición en la niñez, distonía de inicio en miembros inferiores con fluctuación diurna, leve parkinsonismo y respuesta clara a dosis bajas de levodopa. Se incluye una búsqueda sistemática de la literatura con casos de DRD publicados en Latinoamérica.

SUMMARY Dopa-responsive dystonia (DRD) encompasses a heterogenous group of primary dystonias, caused by enzymatic deficiencies across the amines pathway and, by definition, show as their main characteristic a favorable and sustained response to levodopa. There are up to 6 genes associated with DRD, including pathogenic variants of the GCH1 gene as the most frequently involved. The typical presentation of DRD is characterized by start in childhood, lower limb-onset dystonia with daytime fluctuation, mild parkinsonism, and a sustained response to low doses of levodopa. A systematic literature search on DRD reported cases in Latin America is presented.

Abordagem da hiperplasia adrenal congênita pela deficiência da enzima 21-hidroxilase em crianças e adolescentes: revisão / Management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children and adolescents: review

Objetivo: Descrever o diagnóstico e manejo clínico da deficiência da 21-hidroxilase (D-21OH), no contexto atual de inclusão da doença nos programas de triagem neonatal, bem como características genéticas, fisiopatológicas e manifestações na infância e adolescência. Fonte de Dados: Revisão integrativa realizada nas bases de dados MEDLINE (PubMed), LILACS (BVS), Scopus, Web of Science nos últimos vinte anos, em língua inglesa e portuguesa; população-alvo: crianças da primeira infância à adolescência; com o uso dos termos "triagem neonatal", "hiperplasia adrenal congênita", "deficiência da 21-hidroxilase", "glucocorticoide" e "polimorfismos do gene NR3C1". Síntese de Dados: A hiperplasia adrenal congênita (HAC) constitui um grupo de doenças caracterizadas por deficiências enzimáticas na esteroidogênese do córtex adrenal. A D-21OH é responsável por 95% dos casos e, se não tratada precocemente, pode levar ao óbito no período neonatal em sua forma clássica. A triagem neonatal para a HAC consiste na dosagem do precursor 17-hidroxiprogesterona (17OHP) no sangue de recém-nascidos, permitindo rápida confirmação diagnóstica e instituição da terapêutica. A implantação da triagem neonatal constitui um avanço, mas o controle dos pacientes pediátricos com D-21OH é complexo e deve ser sempre individualizado. Conclusão: A instituição dos programas de triagem neonatal para HAC tem trazido benefícios para o prognóstico das crianças com D-21OH. Seu manejo é multiprofissional, individualizado e ainda um desafio mesmo para o especialista. Ampla divulgação do conhecimento sobre a doença é desejável para permitir melhor condução dessas crianças, especialmente de meninas com a doença que apresentam genitália atípica.

Objective: To describe the diagnosis and clinical management of 21-hydroxylase deficiency (21OH-D), in the current context of including the disease in neonatal screening programs, as well as genetic, pathophysiological characteristics, and manifestations in childhood and adolescence. Data Source: Integrative review performed in MEDLINE (PubMed), LILACS (BVS), Scopus, Web of Science databases in the last twenty years, in English and Portuguese; target population: children from early childhood to adolescence; with the use of the terms "neonatal screening"; "congenital adrenal hyperplasia"; "21-hydroxylase deficiency"; "glucocorticoid"; "polymorphisms of the NR3C1 gene". Data Synthesis: Congenital adrenal hyperplasia (CAH) is a group of diseases characterized by enzyme deficiencies in adrenal cortex steroidogenesis. 21OH-D is responsible for 95% of cases and, if not treated early, can lead to death in the neonatal period in its classic form. Neonatal screening for CAH consists of measuring the precursor 17-hydroxyprogesterone (17OHP) in the blood of newborns, allowing rapid diagnostic confirmation and institution of therapy. The implementation of neonatal screening is an advance, but the control of pediatric patients with 21OH-D is complex and must always be individualized. Conclusion: The institution of newborn screening programs for CAH has benefits for the prognosis of children with 21OH-D. Its management is multi-professional, individualized and still a challenge even for the specialist. Wide dissemination of knowledge about the disease is desirable to allow better management of these children, especially girls with the disease who have atypical genitalia.

Research on the follow-up value of steroid hormones for 21-hydroxylase deficiency / 中华检验医学杂志

Objective:This study explored the consistency of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassay for the detection of steroid hormones. The diagnostic value of multiple steroid hormones in 21-hydroxylase deficiency (21-OHD) was investigated and the follow-up indicators were screened.Methods:This experimental group included 109 patients with typical 21-OHD who received standard treatment, and the control group included 94 normal children. 17-hydroxyprogesterone (17-OHP), androstenedione (Δ4-A), testosterone and cortisol were detected by immunoassay and LC-MS/MS method. At the same time, 16 other adrenal steroids were detected by LC-MS/MS method. The experimental group was divided into: (1) overtreatment group: 17OHP<4 ng/ml; (2) well controlled group: 4 ng/ml≤17-OHP<12 ng/ml; (3) poorly controlled group: 17-OHP≥12 ng/ml. The following studies were carried out. (1) The consistency of immunoassay and LC-MS/MS detection results was analyzed; (2) The serum concentrations of various steroid hormones in patients with 21-OHD and the control group were compared to explore the diagnostic value of multiple steroid hormones detection; (3) The concentration differences of 20 kinds of steroid hormones in 21-OHD patients with different therapeutic effects were compared to screen more valuable follow-up indicators.Results:(1) among the four indicators detected by LC-MS/MS and immunoassay, the consistency of T and 17-OHP was high. The concentrations of cortisol and Δ4-A determined by immunoassay were higher than those determined by LC-MS/MS. (2) Among the 20 kinds of steroid hormones secreted by adrenal gland detected by LC-MS/MS, 6 kinds of hormones were significantly higher and 6 kinds of hormones were significantly lower in 21-OHD patients compared with the control group, ,and 8 kinds of steroids showed no statistical difference. (3) 17-OHP decreased and 11-deoxycortisol increased in over-inhibition group, while 17-OHP, pregnenolone, progesterone, 17-hydroxypregnenolone, 21-deoxycortisol, Δ4-A and estrone increased in the poorly controlled group.Conclusions:LC-MS/MS can detect many kinds of steroid hormones at one time with better evaluate dimensions. During the follow-up, only 8 of the 20 hormones were closely related to the control status of patients, suggesting that unnecessary testing work could be reduced.

Phenotype and genotype analysis of 6 patients with 21-hydroxylase deficiency / 中华全科医师杂志

The clinical data of 6 patients with 21-hydroxylase deficiency(21-OHD) diagnosed in The People′s Hospital of Xinjiang Uygur Autonomous Region from 2015 to 2020 were retrospectively analyzed. There were 2 male cases manifesting shorter height, high progesterone level and infertility. And 4 cases were females, manifesting primary amenorrhea, heterosexual precocious puberty, fatigue during emergency, decreased physical strength, dark skin, clitoral hypertrophy and vulva fusion. None of the parents had a history of consanguinity. All but one patient received glucocorticoid replacement therapy. The sequencing of exons and introns of 21CYPA2 gene showed tuat 1 case was homozygous mutation and 5 cases were complex heterozygous mutation. In terms of clinical phenotype, 1 case was non-classical (complex heterozygous mutation) and 5 cases were simple virilizing phenotype.

Diagnosis and treatment of 21-hydroxylase deficiency with testicular adrenal rest tumors:a report of three cases and literature review / 中华内科杂志

Objective:To provide insight into the diagnosis for clinicians, the clinical characteristics, diagnosis and treatment history of 3 patients with 21-hydroxylase deficiency (21-OHD) and testicular adrenal rest tumors (TART) were analyzed.Methods:The clinical, laboratory and imaging data of 3 male patients with 21-OHD and TART, confirmed with CYP21 gene sequencing, from May 2010 to May 2021 in the First Medical Center of Chinese PLA General Hospital were analyzed retrospectively. The treatment strategy and clinical outcome were followed up.Results:All the 3 patients were first diagnosed with bilateral adrenal mass at the age of 27-42 years old. They were 145-162 cm tall. The levels of progesterone, 17-hydroxyprogesterone, and adrenocorticotropic hormone (ACTH) of the 3 patients were relatively high, and that of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) of the 3 patients were low. Testosterone level of 1 patient was significantly elevated, and that of the other 2 patients was below the lower limit of normal range. Testicular ultrasound showed heterogeneous hyperechoic masses in both testes. CT of the adrenal glands showed bilateral adrenal enlargement with mass. All 3 patients were treated with dexamethasone. After 4-96 months of follow-up, 17-hydroxyprogesterone level was kept above the median normal level. One of the patients got married and had a baby after treatment. The sizes of adrenal hyperplasia and testicular masses reduced to various degrees with the change of the testicular masses being proportional to that of adrenal hyperplasia.Conclusions:Patients with 21-OHD are prone to have TART, leading to the impaired testicular function. Early glucocorticold therapy is beneficial to the reduction of TART and restoration of testicular function.

Clinical characteristics of 5 patients with 17α-hydroxylase deficiency and LC-MS/MS method for the measurement of steroid hormones / 中华内分泌代谢杂志

Objective:To analyze clinical characteristics of 17α-hydroxylase deficiency, and to facilitate the understanding and management of the disease.Methods:A retrospective analysis of the clinical characteristics and biochemical results of 5 cases with 17α-hydroxylase deficiency diagnosed and treated from 2018 to 2020.Results:All 5 patients were female as social gender, and reached adulthood upon first clinic visit to our department and got diagnosed. All 5 cases had hypertension, hypokalemia, bilateral adrenal hyperplasia or adenoma, osteoporosis, and typical hormone changes related to steroid synthesis.Conclusion:Steroid hormone tests with liquid chromatography tandem mass spectrometry(LC-MS/MS) enable early diagnosis of 17α-hydroxylase deficiency, assessment of the type and degree of enzyme deficiency, and choice of treatment. For such patients, it is necessary to give appropriate anti-osteoporosis therapy.

Preliminary screening of therapeutic drugs for phenylalanine hydroxylase deficiency / 中国基层医药

Objective:To screen new drugs for treatment of phenylalanine hydroxylase deficiency.Methods:From October 2019 to October 2020, virtual drug screening was performed in Center of Genetic Medicine, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University computer according to the characteristics of the binding ability of phenylalanine hydroxylase to drug spatial structure. Ten candidate drugs were screened from the FDA drug library (including 2 697 kinds of active pharmaceutical ingredients). A eukaryotic expression system was used to determine the effects of drugs on the activity of phenylalanine hydroxylase at the molecular level. Drug-sensitive mutants were screened.Results:Among the 10 candidate drugs, neoplasm hydrochloride, fluocinonide acetate and risperidone increased 23% [ t = 18.21, P < 0.001, vs. non-drug-treated phenylalanine hydroxylase group (i.e., only solvent and no drug added to the reaction system)], 21% ( t = 3.44, P < 0.05, vs. non-drug-treated phenylalanine hydroxylase group), 31% ( t = 19.57, P < 0.001, vs. non-drug-treated phenylalanine hydroxylase group) of the activity of phenylalanine hydroxylase. The remaining drugs exhibited weak even inhibitory effects on the activity of phenylalanine hydroxylase. 25% of p.D101N mutant could be activated by risperidone ( t = 15.86, P < 0.001, vs. non-drug-treated p.D101N mutant group). Conclusion:Neoplasm hydrochloride, fluocinonide acetate and risperidone can be used as potential therapeutic drugs for phenylalanine hydroxylase deficiency, and p.D101N mutant can be used as the drug-sensitive mutation site.

Clinical analysis of nine infants with tyrosine hydroxylase deficiency / 中华神经科杂志

Objective:To explore the clinical characteristics of children with tyrosine hydroxylase deficiency (THD) in order to recognize this disease early as to optimize the treatment to improve the prognosis.Methods:A retrospective analysis was done on the clinical data of nine children with THD who were diagnosed at the Children′s Hospital of Fudan University from May 2018 to May 2020, including name, gender, age, age of onset, age of presentation, age of diagnosis, clinical manifestations, head imaging, tyrosine hydroxylase gene mutation, treatment, follow-up, and other results, which were classified according to Willemsen′s method, and the clinical characteristics were summarized and a literature review was carried out.Results:There were five males and four females with the age at onset ranged from newborn to two years and six months (median three months). The duration of diagnosis ranged from four months to five years and seven months (median nine months). The presenting symptom was motor retardation in seven cases. Clinical symptoms included hypokinesia in eight cases, limb dystonia in five cases, truncal hypotonia in four cases, dysphagia/dysarthria in four cases, oculogyric crises in four cases, tremor in three cases, rigidity in three cases, mask faces in three cases, bilateral ptosis in two cases, hypersalivation/sweating in two cases, diurnal fluctuation in two cases, myoclonic jerks in one case, and status dystonicus in one case. Cranial magnetic resonance imaging was normal in seven cases and non-specific in two cases (backward myelination in one case and bilateral ventricle enlargement and decreased white matter in another one). Eight tyrosine hydroxylase gene variants were found, including four missense variants, two frameshift variants, one shear variants and one nonsense variant, as well as three novel variants [c.1505_1518dup (p.R507Afs *23), c.1128_1138del (p.Q377Gfs *12), c.1058A>G(p.H353R)]. All patients were treated with levodopa and benserazide hydrochloride tables. The initial and maintenance doses of type A were 1.7-8.3 mg·kg -1·d -1 and 4.5-20.0 mg·kg -1·d -1, respectively. The initial and maintenance doses of type B were 1.7-12.5 mg·kg -1·d -1 and 4.6-12.0 mg·kg -1·d -1, respectively. In type A, four patients had dyskinesis which was relieved by decreasing the dose or maintaining the same dose of levodopa. One case of type B had dyskinesis which was self-resolving. Conclusions:Although the clinical manifestations of this disease are varied, the initial symptoms in children with onset within the first year of life are mostly hypokinesia, truncal hypotonia, and dystonia in limbs. It is recommended that children with THD, regardless of clinical type, should start at the minimum dose for easy segmentation in the range of 1.0-5.0 mg·kg -1·d -1, and the maintenance dose can be adjusted according to the individual response of the child. The incidence of dyskinesia of this disease is not low, but most can be treated by decreasing the initial dose and delaying the dosage rate.

New advances in diagnosis and treatment of 21-hydroxylase deficiency / 中华实用儿科临床杂志

21-hydroxylase deficiency (21-OHD) is an autosomal recessive hereditary disease,which results in reduced synthesis of aldosterone and cortisol and increased adrenal androgens due to lack or reduced activity of 21-hydroxylase during the synthesis of adrenal steroids.In recent years,the " backdoor" metabolic pathway of adrenal androgen synthesis and the role of adrenal specific 11-oxygenated C19 steroid in 21-OHD have been recognized,and some adrenal specific androgen sources are gradually becoming diagnostic and therapeutic indicators for 21-OHD.On basis of original glucocorticoid and salt corticosteroid replacement therapy,new drugs and treatments are gradually developed and applied in clinical practice.Nov,the latest progress in diagnosis,treatment and monitoring of 21-OHD is reviewed.

Clinical features and genetic characteristics of 33 patients with simple virilizing form of 21-hydroxylase deficiency / 中华内科杂志

Objective To analyze the clinical features and genotypes of adult patients with simple virilizing form of 21-hydroxylase deficiency (SV 21-OHD).Methods This is a retrospective study including 33 patients with SV 21-OHD from January 2015 to March 2018 in the Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine.Results The diagnostic age of the patients was (26.3± 6.5) years old.All patients presented with signs of masculinization,such as short stature (100％),clitoromegaly/microphallus (89.65％,26/29),undeveloped breasts (82.76％,24/29),deep voice (55.17％,16/29) and primary amenorrhea (89.65％,26/29).The serum levels of 17-hydroxyprogesterone (17-OHP),androstenedione (AD) and testosterone were significantly elevated in 90.9％,93.9％ and 91.2％ of the patients,respectively.Thirteen types of mutations were identified in CYP21A2 from these patients.Among them,I173N accounted for 40％ and I2 G accounted for 18.33％.Four patients were found with multiple mutations in CYP21A2.Conclusions Short stature,clitoromegaly/microphallus and primary amenorrhea are the most common clinical features in adult patients with SV 21-OHD.Serum levels of 17-OHP and AD are important indices for the diagnosis and monitoring of the patients.I173N and I2 G are the two most prevalent mutations in patients of the present study.Limitation of clinical recognition and delay in treatment contribute to the short stature of the SV 21-OHD patients.

An evaluation of the risk factors for orchidism and the efficacy of intensive corticosteroids therapy for the complicating testicular adrenal rest tumors in the patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency during the childhood and pubescent stages / 中华内分泌代谢杂志

Objective To explore the risk factors for orchidism and the curative efficacy of intensive corticosteroids therapy for the testicular adrenal rest tumors ( TART ) in the patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency ( 21OHD) during childhood and pubescent periods. Methods A total 12 cases (27 case-times) with TART were adopted in intensive corticosteroids therapy, 7 cases (7case-times) as control group without intensive therapy. Retrospective analysis following parameters:( 1) The testicular volume and the echogenic characteristics of TART by B-mode ultrasound. ( 2 ) Serum levels of FSH, LH, testosterone, 17-hydroxyprogesterone, androstendion, and inhibin-B were measured. ( 3 ) Orchidism was defined by one of following events:serum level of inhibin-B≤3rd％ for norm, and/or serum level of testosterone<1. 47 ng/ml for the individual which is already in TannerⅣstage. ( 4) The relationship between regression of TART and intensive therapy project. Results The prevalence of TART in 21-OHD was 28.18％during 2-18 years old, and the youngest age with TART was 2. 48 year of old. The regression rate of TART by intensive therapy was higher than that of the control significantly, 20/30 and 1/11(tumor-times) respectively(P=0.004). When the dose of dexamethasone≥30％ of total doses of corticosteroids, the regression rate of TART was higher than those less than 30％ ones, or adopted hydrocortisone alone, were both respectively 16/20 and 4/10(P=0.045). The risk factors for orchidism related to early diagnosis:The TARTs stages in diagnosis (≥stages III;P=0.003) , the tumor in size, hyperechogenicity in B ultrasound of the tumors ( P = 0. 003 ) . Inhibin-B is the earliest displayed biochemical warker for orchidism. Conclusions The TART could regress when got early diagnosis and adopted intensive corticosteroids therapy on time. Delayed diagnosis was the main risk factor for orchidism. For early diagnosis of TART, we suggest to conduct the scrotal ultrasound regularly started from 2 years of age.