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1.
Orphanet J Rare Dis ; 16(1): 416, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34627348

RESUMO

BACKGROUND: 46, XY disorders of sex development (46, XY DSD) are congenital disorders with 46, XY chromosomal karyotype but inconsistent gonadal/phenotypic sex. One of the biggest concerns for parents and clinicians is the gender assignment. However, there is no standard uniform of care nor consensus at present. We sought to evaluate the current treatment's rationality and provide a reference basis for the gender reassignment in 46, XY DSD patients with a specific diagnosis. METHODS: We conducted a cross-sectional survey of gender role with the Pre-school Activities Inventory (PSAI), the Children's Sex Role Inventory (CSRI) in 46, XY DSD patients and set up control groups comparison. Psychiatrist assessed gender dysphoria in patients ≥ 8-year-old with the criteria of diagnostic and statistical manual of mental disorders, 5th edition (DSM-5). RESULTS: A total of 112 responders of 136 patients participated in this study (82.4%, aged 2-17.8 years, median age: 4-year-old). The follow-up period was from 6 months to 10 years (median: 2 years). Twenty-five females were reassigned to the male gender after a specific diagnosis (16/25 (64%) in 5 alfa-reductase-2 deficiency (5α-RD2), 5/25 (20%) in partial androgen insensitivity syndrome (PAIS), 4/25 (16%) in NR5A1gene mutation). Male gender assignment increased from 55.3 (n = 62) to 77.7% (n = 87). The median PSAI score was similar to the control males in 5α-RD2, PAIS, and NR5A1 gene mutation groups (p > 0.05); while identical to the control females in complete androgen insensitivity syndrome (CAIS) and CYP17A1 gene mutation groups (p > 0.05). PSAI score of children raised as male was higher than those of CAIS and CYP17A1 groups raised as female (p < 0.05). CSRI scale showed no statistical differences in the consistency of gender roles and reassigned gender between 46, XY DSD patients and control groups (p > 0.05). None of the patients over 8-year-old (n = 44) had gender dysphoria. CONCLUSION: The reassigned gender in 46, XY DSD patients is consistent with their gender role during early childhood. None of them had gender dysphoria. The molecular diagnosis, gonadal function, and the gender reassignment are congruent within our Chinese cohort. Long-term follow-up and more evaluation are still required.

2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 912-916, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487543

RESUMO

MAMLD1 gene has been implicated in 46,XY disorders of sex development (DSD) in recent years. Patients carrying MAMLD1 gene variants showed a "continuous spectrum" of simple micropenis, mild, moderate and severe hypospadias with micropenis, cryptorchidism, split scrotum and even complete gonadal dysplasia. The function of MAMLD1 gene in sexual development has not been fully elucidated, and its role in DSD has remained controversial. This article has reviewed recent findings on the role of the MAMLD1 gene in DSD, including the MAMLD1 gene, its encoded protein, genetic variants, clinical phenotype and possible pathogenic mechanism in DSD.


Assuntos
Proteínas de Ligação a DNA , Transtornos do Desenvolvimento Sexual , Proteínas de Ligação a DNA/genética , Transtornos do Desenvolvimento Sexual/genética , Humanos , Masculino , Mutação , Proteínas Nucleares/genética , Fenótipo , Desenvolvimento Sexual , Fatores de Transcrição/genética
3.
Front Endocrinol (Lausanne) ; 12: 711991, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589056

RESUMO

Purpose: Congenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis. Methods: We retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis. Results: In 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients. Conclusion: Our study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.

4.
Front Endocrinol (Lausanne) ; 12: 583114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211433

RESUMO

Purpose: To investigate the features and treatment status of children with type 1 diabetes mellitus (T1DM) in China. Methods: We recruited patients <14 years of age with T1DM from 33 medical centers in 25 major cities of China between January 2012 and March 2015. All patients completed a questionnaire that was conducted by their pediatric endocrinologists at all centers. Results: A total of 1,603 children (755 males and 848 females) with T1DM participated in this survey. Of these, 834 (52.03%) of the patients exhibited diabetic ketoacidosis (DKA) at onset, while 769 patients (47.97%) did not exhibit DKA (non-DKA) at onset. There was a higher proportion of females (55.71%) in the cohort of patients exhibiting DKA at onset than in the non-DKA cohort (49.33%). The mean age of patients exhibiting DKA at presentation was 7.12 ± 0.14 years; this was significantly younger than that in non-DKA group (7.79 ± 0.15 years; P < 0.005). The frequency of DKA in 3 years old, 3-7 years old, and 7 years old or more was 77.21%, 26.17%, and 37.62%, respectively. Upon initial diagnosis, 29.4%, 15.2% and 11.8% of patients showed positivity for glutamic acid decarboxylase antibody (GADA), Insulin autoantibodies (IAA), or islet cell antibody (ICA), respectively. During six months follow-up, 244 patients (15.21%) reported receiving insulin pump therapy, and more than 60% of patients monitored their blood glucose levels less than 35 times per week. Although the majority of patients had no problems with obtaining insulin, 4.74% of the children surveyed were not able to receive insulin due to financial reasons, a shortage of insulin preparations, or the failure of the parents or guardians to acquire the appropriate medicine. Conclusion: DKA is more common in very young children. Treatment and follow-up of T1DM in China still face very serious challenges.

5.
Diabetes Metab Syndr Obes ; 14: 3323-3335, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34321899

RESUMO

Objective: To investigate the prevalence and associated factors of childhood overweight/obesity in the Shunyi district of Beijing, China. Methods: This study adopted a cross-sectional survey and included 10,855 children aged 6-18 years in the Shunyi district of Beijing, China. Analyses were stratified by age group (6-8, 9-11, 12-14, and 15-18 years). Results: The prevalence of overweight and obesity among children aged 6-18 years was high with 17.62% and 29.05% in boys, 17.57% and 18.04% in girls, respectively. Both boys and girls aged 9-11 years had the highest rate of obesity in comparison with the other age groups, though the differences in children aged 9-11 years and 12-14 years were not statistically significant. Compared with age 6-8 years, age 9-11 years (OR=1.59, 95% CI 1.41-1.79, P<0.01) and 12-14 years (OR=1.26, 95% CI 1.48-1.73, P<0.01) were independently positively associated with obesity. Importantly, in all subjects, the percentages of being physically active (exercise time ≥120 minutes/week) were lower in children aged 9-11 years in comparison to children in other age groups. This phenomenon remained when this comparison was performed respectively in the normal-weight, overweight, and obesity groups. Even after adjustment for other potential confounders, the probability of being physically active (exercise time ≥120 minutes/week) was lower in children aged 9-11 years (OR=0.86, 95% CI 0.78-0.94, P<0.01), but higher in children aged 12-14 years (OR=1.91, 95% CI 1.69-2.17, P<0.01) and aged 15-18 years (OR=2.22, 95% CI 1.85-2.66, P<0.01), when compared with children aged 6-8 years. Conclusion: Children aged 9-11 years had a higher prevalence of obesity, but a lower percentage of being physically active. Targeted intervention programs in this key group are needed to address this problem in China.

6.
J Genet Genomics ; 48(5): 396-402, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34006472

RESUMO

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations. Although the diagnostic utility of clinical genetic testing in short stature has been implicated, the genetic architecture and the utility of genomic studies such as exome sequencing (ES) in a sizable cohort of patients with short stature have not been investigated systematically. In this study, we recruited 561 individuals with short stature from two centers in China during a 4-year period. We performed ES for all patients and available parents. All patients were retrospectively divided into two groups: an isolated short stature group (group I, n = 257) and an apparently syndromic short stature group (group II, n = 304). Causal variants were identified in 135 of 561 (24.1%) patients. In group I, 29 of 257 (11.3%) of the patients were solved by variants in 24 genes. In group II, 106 of 304 (34.9%) patients were solved by variants in 57 genes. Genes involved in fundamental cellular process played an important role in the genetic architecture of syndromic short stature. Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.

7.
Front Cell Dev Biol ; 9: 661747, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937263

RESUMO

Purpose: ROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of ROR2 in children with short stature and to identify the underlying molecular mechanisms. Methods: We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of ROR2. We subsequently examined the changes in protein expression and subcellular location in ROR2 caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a-ROR2 pathway was also examined. Results: We identified 12 mutations in ROR2 in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments in vitro. The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2. Conclusion: We expanded the mutational spectrum of ROR2 in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in ROR2 might affect the expression of downstream Wnt5a-ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.

8.
Chin Med J (Engl) ; 134(10): 1152-1159, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33813517

RESUMO

BACKGROUND: Compared to adult studies, studies which involve the treatment of pediatric congenital hypogonadotropic hypogonadism (CHH) are limited and no universal treatment regimen is available. The aim of this study was to evaluate the feasibility of human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) therapy for treating male adolescents with CHH. METHODS: Male adolescent CHH patients were treated with hCG/hMG (n = 20) or a gonadotropin-releasing hormone (GnRH) pump (n = 21). The treatment was divided into a study phase (0-3 months) and a follow-up phase (3-12 months). The testicular volume (TV), penile length (PL), penis diameter (PD), and sex hormone levels were compared between the two groups. The TV and other indicators between the groups were analyzed using a t-test (equal variance) or a rank sum test (unequal variance). RESULTS: Before treatment, there was no statistical difference between the two groups in terms of the biochemistry, hormones, and other demographic indicators. After 3 months of treatment, the TV of the hCG/hMG and GnRH groups increased to 5.1 ±â€Š2.3 mL and 4.1 ±â€Š1.8 mL, respectively; however, the difference was not statistically significant (P > 0.05, t = 1.394). The PL reached 6.9 ±â€Š1.8 cm and 5.1 ±â€Š1.6 cm (P < 0.05, t = 3.083), the PD reached 2.4 ±â€Š0.5 cm and 2.0 ±â€Š0.6 cm (P < 0.05, t = 2.224), respectively, in the two groups. At the end of 6 months of treatment, biomarkers were in normal range in the two groups. Compared with the GnRH group, the testosterone (T) level and growth of PL and PD were significantly greater in the hCG/hMG group (all P < 0.05). While the TV of both groups increased, the difference was not statistically significant (P > 0.05, t = 0.314). After 9 to 12 months of treatment, the T level was higher in the hCG/hMG group. Other parameters did not exhibit a statistical difference. CONCLUSIONS: The hCG/hMG regimen is feasible and effective for treating male adolescents with CHH. The initial 3 months of treatment may be a window to optimally observe the strongest effects of therapy. Furthermore, results from the extended time-period showed positive outcomes at the 1-year mark; however, the long-term effectiveness, strengths, and weaknesses of the hCG/hMG regimen require further research. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02880280; https://clinicaltrials.gov/ct2/show/NCT02880280.


Assuntos
Hipogonadismo , Menotropinas , Adolescente , Adulto , Criança , Gonadotropina Coriônica/uso terapêutico , Hormônio Liberador de Gonadotropina , Humanos , Hipogonadismo/tratamento farmacológico , Masculino , Menotropinas/uso terapêutico , Espermatogênese , Testosterona
9.
Orphanet J Rare Dis ; 16(1): 159, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827627

RESUMO

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disorder, which is caused by loss-of-function mutations in the ALPL gene. HPP is a heterogeneous disease that has a wide spectrum of phenotypes. Few studies were carried out in the Chinese population with HPP, especially in children. METHODS: The clinical and genetic characteristics of 10 Chinese children with HPP who were referred to the Beijing Children's Hospital were described. Previously reported HPP cases of children in China were also reviewed. RESULTS: A total of 33 cases were identified, which included 2 perinatal lethal HPP, 10 infantile HPP, 10 childhood HPP, and 11 odonto HPP. The male-to-female ratio was 24:9. The average age at onset was 0.69 years (ranged from 2 h after birth to 14 years), while the average age at clinical diagnosis was 3.87 years (ranged from 2 h after birth to 19 years). Serum alkaline phosphatase (ALP) levels were significantly decreased in patients with perinatal lethal/infantile HPP when compared with those with the mild forms of HPP childhood/odonto HPP (P < 0.01). Although serum phosphate levels were not different (P > 0.05), serum calcium levels were elevated, and serum intact parathyroid hormone levels were decreased in patients with perinatal lethal/infantile HPP in comparison with those with the childhood/odonto HPP (P all < 0.01). Genetic analyses identified 40 mutations in 31 HPP cases, including 28 missense mutations, 9 frameshift mutations, 2 splice junction alterations, and 1 regulatory mutation. Of which, 5 novel mutations were identified in our present study: 2 frameshift mutations (p.Arg138GlyfsTer27, p.Leu511Profs*272); 2 missense mutations (p.Ala176Val, p.Phe268Leu), and 1 splice junction alteration (c.297+5G>A). Compound heterozygous mutations accounted for 80.6% of all variants. No mutational "hot-spot" was found. Most mutations of ALPL were located in exons 5, 7, 10, and 3. Notably, subjects that carrying single heterozygous mutations showed milder phenotypes of HPP, while subjects with nonsense mutations were associated with a severer phenotype. CONCLUSIONS: HPP is a rare disease with often delayed diagnosis, and the incidence of HPP in China may be seriously underestimated. The present study expands the phenotypic and genotypic spectrum and the understanding of HPP in Chinese children. These findings will be useful for clinical assessment and shorten the diagnosis time for pediatric HPP in China.


Assuntos
Hipofosfatasia , Fosfatase Alcalina/genética , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Hipofosfatasia/epidemiologia , Hipofosfatasia/genética , Masculino , Mutação/genética , Fenótipo
10.
Pediatr Investig ; 5(1): 28-32, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33778424

RESUMO

Importance: Extensive population-based studies have explored the prevalence of primary hypertension (HTN) in children and adolescents. However, there is little published data on the characteristics of different types of pediatric HTN and the causes of secondary HTN. Objective: To investigate the characteristics of different types of pediatric HTN and the causes of secondary HTN in a hospital setting. Methods: The study cohort comprised pediatric inpatients (<18 years of age) discharged with a diagnosis of HTN from Beijing Children's Hospital during 2015-2020. Pediatric patients with HTN were allocated to secondary and primary HTN groups on the basis of comprehensive analyses of their diagnoses, family history of HTN, and findings on physical examination, as documented in their medical records. The Mann-Whitney U test, χ 2 and Fisher's exact test were used to assess differences in characteristics of patients with different HTN types and causes of secondary HTN. Results: Data of 1470 inpatients with HTN from 18 clinical departments were included in the analysis. Among them, 458 (31.2%) had primary HTN, and 1012 (68.8%) had secondary HTN. Compared with patients had primary HTN, children with secondary HTN were younger and had lower body mass indexes and longer lengths of stay. Moreover, children with primary HTN had mostly been managed by the Endocrinology and Cardiology Departments, 75.8% of them having obesity-related comorbidities. In contrast, most patients with secondary HTN had been managed by the Nephrology Department, renal diseases being the leading cause of their HTN (46.3%). Interpretation: Secondary HTN is more common than primary HTN in pediatric clinical settings, renal diseases being the leading cause of secondary HTN.

11.
Gene ; 768: 145310, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33217533

RESUMO

BACKGROUND: Hyperlipidemia is a group of conditions with abnormally elevated levels of any or all lipids or lipoproteins in the blood. It is highly heterogeneous both genetically and clinically, which contributes to diagnostic challenges and results in many patients to be underdiagnosed and undertreated in China. Precise diagnosis and early management are critical to reduce the incidence of potential coronary artery disease and cardiovascular disease. RESULTS: We performed a single center study to demonstrate the clinical utility of the genome-first approach by whole exome sequencing (WES) for 12 pediatric patients with abnormal lipids or lipoproteins levels. In vitro experiments were performed in COS-7 cells to further evaluate the biological function of the novel variants. We identified ten pathogenic and likely pathogenic variants and three of them were novel. Molecular cause was uncovered in five (41.7%) patients including three lipoprotein lipase deficiency patients, one hypercholesterolemia patient and one sitosterolemia patient. We also found three patients with rare variants of uncertain significance. Copy number variant (CNV) analysis with WES data did not reveal any potential hyperlipidemia related CNVs in all patients. CONCLUSION: We expanded the mutation and phenotype spectra of familial hyperlipidemia. Our study demonstrated the effectiveness of genome-first approach for evaluation pediatric hyperlipidemia patients and showed that WES can be used as the first-tier test for patients with suspected Mendelian hyperlipidemia disorder.


Assuntos
Hiperlipidemias/diagnóstico , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma/métodos , Adolescente , Animais , Células COS , Criança , Pré-Escolar , China , Chlorocebus aethiops , Variações do Número de Cópias de DNA , Diagnóstico Precoce , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperlipidemias/genética , Lactente , Recém-Nascido
12.
BMC Med Genomics ; 13(1): 181, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33276791

RESUMO

BACKGROUND: Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants. METHODS: In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature. RESULTS: A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years. CONCLUSIONS: Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.


Assuntos
Facies , Histona-Lisina N-Metiltransferase/genética , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Mutação com Perda de Função , Proteínas Repressoras/genética , Síndrome de Wolf-Hirschhorn/genética , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , Nanismo/tratamento farmacológico , Nanismo/genética , Feminino , Seguimentos , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/genética , Histona-Lisina N-Metiltransferase/deficiência , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Linhagem , Fenótipo , Proteínas Repressoras/deficiência , Resultado do Tratamento , Sequenciamento Completo do Exoma , Síndrome de Wolf-Hirschhorn/tratamento farmacológico
13.
Pediatr Investig ; 4(3): 198-203, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33150314

RESUMO

Importance: Graves' disease (GD) is rare in children under the age of 7 years. Children with this disease exhibit greater thyrotoxicity at diagnosis and require a longer course of medical therapy, compared with pubertal and postpubertal children and adults. Objective: To investigate the clinical features and identify predictors of remission in children under the age of 7 years with GD. Methods: This retrospective study included 77 children who were diagnosed with GD under the age of 7 years and were treated in the Department of Endocrinology, Beijing Children's Hospital from 2010 to 2018. Clinical manifestations, laboratory data, and follow-up records were collected for all patients. Children who achieved remission of treatment with methimazole were compared with those who had persistent disease to identify which variables were associated with remission; multiple logistic regression and Cox regression analyses were used to evaluate interactions among predictive variables. Results: Sixty-three boys and 14 girls were included; the median age at diagnosis was 4.2 years (interquartile range: 3.2-5.3 years). Forty-six (56.7%) patients had no family history of thyroid disease, 17 patients had family history of thyroid disease and 14 patients with unknown family history. Of the 77 patients, 18 (23.4%) patients achieved remission of treatment with methimazole and 59 patients did not; moreover, 51 (66.2%) had Graves' ophthalmopathy. Univariate analyses revealed no significant differences between the remission group and non-remission group in terms of age at diagnosis, sex, initial goiter size, or initial thyroid hormone concentration. However, there were a trend of correlation between the initial level of thyroid peroxidase antibody (TPOAb) and remission status (univariate analysis OR 1.002, P = 0.038; multivariate analysis OR 1.004, P = 0.019). Similar results were observed in univariate analysis of the initial thyrotropin receptor antibody (TRAb) level, but this association was not significant in multivariate analysis. Cox regression analyses revealed that children with high TRAb level required longer duration of remission, compared with low TRAb level (OR 0.950, 95% CI 0.904-0.997, P = 0.037). Interpretation: Initial TRAb level was an independent predictor of remission outcome in young children under the age of 7 years with GD. Initial TRAb level may predict the likelihood of remission in patients with young-age-of-onset GD.

15.
J Paediatr Child Health ; 56(10): 1590-1596, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32767607

RESUMO

AIM: This study investigated the pattern of liver enzymes in a large cohort of Chinese children and adolescents, including 16 383 individuals aged 4-18 years old recruited at six medical centres in China. METHODS: Clinical data were collected including weight, height, blood pressure, alanine aminotransferase, aspartate aminotransferase and fasting lipid panel. We used an unsupervised machine learning algorithm, the K-means clustering method, to identify different patterns of increased liver enzymes. RESULTS: Six clusters of elevated enzymes patterns were identified. The most common in 2.18% (325) of youth was elevated transaminases in the absence of features of metabolic syndrome(MetS), and they were thinner, and more likely to be from urban areas. The second cluster, with 1.47% (n = 220) youth had the most notable MetS features. They were older, obese and had central obesity, higher BP, triglycerides cholesterol and lower high-density lipoprotein cholesterol. Cluster 3 (0.6%, N = 90) had mild MetS, and cluster 4 (0.06%, N = 9), 5 (0.03%, N = 5) and 6 (0.007%, N = 1) were not related to MetS. CONCLUSIONS: We identified two distinct groups of children with both increased liver enzymes and MetS features in this population sample of Chinese children. One of the two groups had increased liver enzymes as the predominant clinical features at a younger age, suggesting genetic susceptibility to the condition. Further work to understand the increased MetS risk in cluster 2 is warranted.


Assuntos
Síndrome Metabólica , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , China/epidemiologia , Humanos , Fígado , Síndrome Metabólica/epidemiologia , Prevalência , Fatores de Risco
16.
Pediatr Investig ; 4(1): 29-36, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32851339

RESUMO

Importance: Octreotide is an off-label medicine for congenital hyperinsulinism (CHI), but is currently widely used for treatment of patients with CHI. Thus far, variable efficacy and adverse effects have been reported for octreotide. Objective: The present study evaluated the efficacy and safety of a subcutaneous octreotide injection for treatment of diazoxide-unresponsive CHI in China. Methods: This study was a retrospective review of children with diazoxide-unresponsive CHI who were treated with a subcutaneous octreotide injection. The efficacy and side effects of the treatment were assessed. Results: Twenty-five Chinese children (15 boys) were involved in the study. Their median age at diagnosis was 8 weeks (range, 1-24 weeks) and median age at the final follow-up was 1.8 years (range, 0.3-3.3 years). Octreotide therapy effectively increased blood glucose levels in all patients. The intravenous glucose infusion rate was reduced in all patients. Twenty-one patients gradually discontinued the intravenous glucose infusion while receiving octreotide combined with frequent carbohydrate/glucose-rich feeding. Among patients with a monoallelic ATP-sensitive potassium (KATP) channel mutation, 50.0% showed gradual remission during follow up, indicating that the octreotide treatment may be a feasible alternative to surgery, especially for patients with monoallelic KATP-channel mutations. Transient elevation of liver enzymes occurred in 20.0% of patients, while asymptomatic gallbladder pathology occurred in one patient. The growth rates of these patients were normal (height standard deviation score was 0.3 ± 1.5 at the final follow-up). Interpretation: Octreotide was a well-tolerated, effective therapy for most children with diazoxide-unresponsive CHI.

17.
Mol Genet Genomic Med ; 8(10): e1431, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32713132

RESUMO

BACKGROUND: Patients with steroid 5α-reductase 2 deficiency (5α-RD) caused by SRD5A2 (OMIM #607306) variants present variable genotypes and phenotypes. The genotype-phenotype correlations remain unclear. METHODS: We investigated genotype-phenotype correlations of SRD5A2 variants in a large Chinese single-center cohort. Phenotypes were categorized using the external masculinization score (EMS), urethral meatus and gonad position, and penile length-standard deviation score. RESULTS: Of the 130 included patients, 113 had hypospadias, and 17 had a normal urethral meatus position. Testosterone/dihydrotestosterone (T/DHT) values were not significantly associated with phenotypic severity (p = 0.539-0.989). Of the 31 SRD5A2 variants, including 10 novel variants, p.R227Q was the most prevalent (39.62%), followed by p.Q6* (16.92%), p.R246Q (13.46%), and p.G203S (10.38%). Compared to biallelic missense mutations, biallelic nonsense mutations were associated with a lower EMS and urethral meatus score (p = 0.009 and p = 0.024, respectively). Patients homozygous for p.R227Q exhibited mild and variable phenotypes, while those homozygous for p.Q6*, p.R246Q, or p.G203S showed consistently severe phenotypes. The phenotypes were variable and milder in patients with compound heterozygosity for p.R227Q and these mutations. CONCLUSION: T/DHT does not predict phenotype severity. The most prevalent SRD5A2 variant in Han Chinese is p.R227Q, which is associated with milder phenotypes and greater phenotypic variability. SRD5A2 variants may significantly influence phenotypic variation.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Proteínas de Membrana/genética , Fenótipo , Pré-Escolar , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Genitália Masculina/patologia , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Testosterona/sangue
18.
Orphanet J Rare Dis ; 15(1): 188, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32690052

RESUMO

BACKGROUND: Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46,XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46,XY DSD. Cases of 46,XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children's Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated. RESULTS: Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.R356X, p.Q152X, and p.Q124X) and six missense (p.P334S, p.S662R, p.A421P,p.T992I, p.P542S, and p.R927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662R, and p.R927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function. CONCLUSION: Patients with 46,XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46,XY DSD.


Assuntos
Proteínas de Ligação a DNA , Transtorno 46,XY do Desenvolvimento Sexual , Criança , China , Proteínas de Ligação a DNA/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Humanos , Masculino , Mutação/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética
19.
Clin Endocrinol (Oxf) ; 93(6): 687-695, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32623730

RESUMO

BACKGROUND: Aromatase deficiency (AD) caused by cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1) variants is characterized by a deficiency in androgen-to-oestrogen conversion. OBJECTIVE: To investigate the clinical characteristics and accurate management of aromatase-deficient children. PATIENTS AND METHODS: We described three 46, XX aromatase-deficient children, searched PubMed with "(aromatase deficiency) AND (46, XX OR ovaries)" and manually searched citations in identified studies for the literature review. RESULTS: Two girls and one boy (3.4-9.2 years) with the 46, XX karyotype presented ambiguous genitalia and maternal antenatal virilization, normal-low height, delayed bone age, normal glucose and lipid profiles, markedly elevated follicle-stimulating hormone (FSH) levels and poor oestradiol responses to human menopausal gonadotropin stimulation. Ultrasound revealed normal-sized uterus and ovaries with undetectable follicles. Histopathology revealed primordial follicles and few primary follicles in ovaries. One patient presented granulosa and follicular membrane cell proliferation and interstitial sclerosis. We identified four CYP19A1 variants; c.146_158del and c.344G >A were unreported. We reviewed available data from thirty 46, XX patients (0.2-32 years). Some patients were not diagnosed until puberty/adulthood; three were initially misdiagnosed with congenital adrenocortical hyperplasia. The main characteristics were maternal antenatal virilization (21/29), ambiguous genitalia (mainly Prader IV or III, 19/23), delayed bone age (16/17), low bone mass (5/8), markedly elevated FSH levels and ovarian cysts (13/30). CONCLUSIONS: 46, XX AD is easily neglected or misdiagnosed. Ambiguous genitalia, maternal antenatal virilization and markedly elevated FSH levels are important diagnostic indicators. We described two novel variants, new histopathological features of ovaries and an early management strategy.

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