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Introduction: Among girls assessed for pubertal precocity, pelvic ultrasound (pUS) may represent a pivotal tool to predict the time expected to elapse between sonographic assessment and the onset of menarche (TUS-M). Accordingly, the present analysis is meant to define the statistical relationship between sonographic parameters and TUS-M, in order to identify the most reliable predictor of the timing of menarche. Methods: Retrospective, multicenter analysis. Girls assessed for sexual precocity and showing sonographic and clinical findings consistent with pubertal onset upon referral were considered eligible. Patients treated with GnRH analogues were excluded and only those who had subsequently achieved complete and spontaneous pubertal attainment and for whom the exact date of menarche was available were included. Overall, we enrolled 184 girls from five tertiary care Italian Centers. Results: The time elapsed (months) between baseline endocrine assessment and spontaneous achievement of menarche showed a negative statistically significant correlation (p<0.0001) with LH (r:-0.61), FSH (r:-0.59), estradiol (r:-0.52) and stimulated LH values (r:-0.58). Among pUS parameters, ovarian volume (r:-0.17 left, -0.30 right) and uterine body-to-cervix ratio (r:-0.18) poorly correlated with TUS-M, while uterine diameters (r:-0.61 longitudinal, -0.64 anteroposterior) and volume (r:-0.70) achieved a highly statistical significance (p<0.0001). Uterine volume (UV) showed a negative logarithmic relationship with TUS-M and represented the most reliable predictor of the timing of menarche in uni- and multivariable analyses (p <0.001). ROC analyses identified the UV thresholds that best predict the onset of menarche within 18, 12 and 6 months, respectively: 3.76, 6.02 and 8.80 ml. Conclusion: The logarithm of UV shows the best statistical performance in predicting the timing of menarche in girls assessed for pubertal precocity. Accordingly, we developed a user-friendly online application that provides clinicians with an estimation of the months expected to elapse before menarche, based on the UV recorded upon pUS.
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Menarca , Puberdade Precoce , Ultrassonografia , Útero , Humanos , Feminino , Menarca/fisiologia , Ultrassonografia/métodos , Criança , Estudos Retrospectivos , Puberdade Precoce/diagnóstico por imagem , Útero/diagnóstico por imagem , Pelve/diagnóstico por imagem , Puberdade/fisiologia , Tamanho do Órgão , AdolescenteRESUMO
Chronic kidney disease (CKD) is a significant challenge for pediatric endocrinologists, as children with CKD may present a variety of endocrine complications. Growth failure is common in CKD, and its severity is correlated with the degree of renal insufficiency. Management strategies include addressing reversible comorbidities, optimizing nutrition, and ensuring metabolic control. Kidney replacement therapy, including transplantation, determines a significant improvement in growth. According to a recent Consensus Statement, children with CKD stage 3-or on dialysis older >6 months-are eligible for treatment with recombinant growth hormone (rGH) in the case of persistent growth failure. Treatment with rGH may be considered for those with height between the 3rd and 10th percentile and persistent growth deceleration. In children who received kidney transplantation but continue to experience growth failure, initiation of GH therapy is recommended one year post-transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not an option. In children with CKD, due to nephropathic cystinosis and persistent growth failure, GH therapy should be considered at all stages of CKD. Potential adverse effects and benefits must be regularly assessed during therapy. Treatment with GH is safe in children with CKD. However, its general efficacy is still controversial. All possible problems with a negative impact on growth should be timely addressed and resolved, whenever possible with a personalized approach to the patient. GH therapy may be useful in promoting catch-up growth in children with residual growth potential. Future research should focus on refining effective therapeutic strategies and establishing consensus guidelines to optimize growth outcomes in this population.
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CONTEXT: In the last decade the Sanger method of DNA sequencing has been replaced by next-generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM). OBJECTIVE: To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) vs 2013-2022 (NGS). METHODS: We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM + c.SIR) of the Italian dataset. RESULTS: Fifty-five patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103 340 (NDM) and 1:1 240 082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11, INS, ABCC8, 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6, PDX1, GATA6, HNF1B, FOXP3, IL2RA, LRBA, BSCL2) during 2013-2022 (8/42 or 19%, P = .034 vs 2003-2012). Notably, among rare genes 5 were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3, IL2RA, LRBA) were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6, PDX1) were supplemented with pancreatic enzymes, and the individual with lipodystrophy caused by BSCL2 was started on metreleptin. CONCLUSION: NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and c.SIR in Italy.
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Diabetes Mellitus , Humanos , Itália/epidemiologia , Recém-Nascido , Masculino , Feminino , Lactente , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Sequenciamento de Nucleotídeos em Larga Escala , Doenças do Recém-Nascido/epidemiologia , Doenças do Recém-Nascido/genética , Testes Genéticos/métodos , Resistência à Insulina/genética , Mutação , Incidência , Estudos RetrospectivosRESUMO
X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal ß-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.
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Doença de Addison , Córtex Suprarrenal , Adrenoleucodistrofia , Adulto , Humanos , Masculino , Feminino , Criança , Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/epidemiologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Addison/complicações , Doença de Addison/diagnóstico , Doença de Addison/genética , Ácidos Graxos/metabolismo , Córtex Suprarrenal/metabolismo , Glucocorticoides/uso terapêuticoRESUMO
No data are available on insulin clearance (ClI) trends during the pubertal transition. The aim of this study was to investigate in 973 youths with obesity whether ClI in fasting and post-oral glucose challenge (OGTT) conditions varies at the pubertal transition in relation to the severity of obesity and the presence of steatosis liver disease (SLD). The severity of obesity was graded according to the Centers for Disease Control. SLD was graded as absent, mild and severe based on alanine amino transferase levels. ClI was defined as the molar ratio of fasting C-peptide to insulin and of the areas under the insulin to glucose curves during an OGTT. In total, 35% of participants were prepubertal, 72.6% had obesity class II, and 52.6% had mild SLD. Fasting ClI (nmol/pmol × 10-2) was significantly lower in pubertal [0.11 (0.08-0.14)] than in prepubertal individuals [0.12 (0.09-0.16)] and higher in class III [0.15 (0.11-0.16)] than in class I obesity [0.11 (0.09-0.14)]. OGTT ClI was higher in boys [0.08 (0.06-0.10)] than in girls [0.07 (0.06-0.09)]; in prepubertal [0.08 (0.06-0.11)] than in pubertal individuals [0.07 (0.05-0.09)]; in class III [0.14 (0.08-0.17)] than in class I obesity [0.07 (0.05-0.10)]; and in severe SLD [0.09 (0.04-0.14)] than in no steatosis [0.06 (0.04-0.17)]. It was lower in participants with prediabetes [0.06 (0.04-0.07)]. OGTT ClI was lower in youths with obesity at puberty along with insulin sensitivity and greater secretion. The findings suggest that the initial increase in ClI in youth with severe obesity and SLD is likely to compensate for hyperinsulinemia and its subsequent decrease at the onset of prediabetes and other metabolic abnormalities.
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Fígado Gorduroso , Resistência à Insulina , Estado Pré-Diabético , Masculino , Feminino , Humanos , Adolescente , Insulina , Obesidade/metabolismo , Glucose , Insulina Regular Humana , Glicemia/metabolismoRESUMO
Objective: Since the outbreak of COVID-19 pandemic, several centers of pediatric endocrinology worldwide have observed a significant increase in the number of girls presenting with precocious or early puberty. We aimed to compare the incidence rates of female precocious puberty before and during the different phases of COVID-19 pandemic. Methods: We have retrospectively analyzed all the consultations recorded in the outpatient clinic database of the Endocrinology Unit of Bambino Gesù Children's Hospital, Rome, Italy, from the lockdown start in March 2020 up to September 2020, in comparison with the consultations recorded in the same months of 2019, 2021 and 2022. Age, height, weight, body mass index, Tanner's pubertal stage and bone age at presentation, birth weight, ethnicity, family history of central precocious puberty (CPP), maternal age at menarche, history of adoption were retrieved from clinical records. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) both at baseline and after gonadotropin-releasing hormone (GnRH) stimulation, and basal estradiol levels were collected. Results: In 2019, 78 girls with suspected precocious puberty were referred for endocrinological consultation, compared to 202 girls in 2020, 158 girls in 2021 and 112 girls in 2022. A significant increase in the proportion of girls diagnosed with rapidly progressive CPP was observed in 2020, compared to 2019 (86/202 vs. 18/78, p<0.01). In the following periods of 2021 and 2022, a gradual decrease in the number of cases of progressive CPP was evident, so much that the number of cases was not significantly different from that observed in 2019 (56/158 in 2021 and 35/112 in 2022, p=0.054 and p=0.216 respectively, compared to 2019). Conclusions: Our research suggests that drastic lifestyle changes, such as those imposed by COVID-19 lockdown, and the consequent stress may affect the regulation of pubertal timing. The remarkable increase in CPP cases observed during the 2020 first pandemic wave seems to be reduced in 2021 and 2022, concurrently with the progressive resumption of daily activities. These data seem to support the hypothesis of a direct relationship between profound life-style changes related to the pandemic and the rise in precocious puberty cases.
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COVID-19 , Puberdade Precoce , Criança , Feminino , Humanos , Puberdade Precoce/diagnóstico , Pandemias , Estudos Retrospectivos , COVID-19/epidemiologia , COVID-19/complicações , Controle de Doenças Transmissíveis , Itália/epidemiologiaRESUMO
Background: Despite the optimization of replacement therapy, adrenal crises still represent life-threatening emergencies in many children with adrenal insufficiency. Objective: We summarized current standards of clinical practice for adrenal crisis and investigated the prevalence of suspected/incipient adrenal crisis, in relation to different treatment modalities, in a group of children with adrenal insufficiency. Results: Fifty-one children were investigated. Forty-one patients (32 patients <4 yrs and 9 patients >4 yrs) used quartered non-diluted 10 mg tablets. Two patients <4 yrs used a micronized weighted formulation obtained from 10 mg tablets. Two patients <4 yrs used a liquid formulation. Six patients >4 yrs used crushed non-diluted 10 mg tablets. The overall number of episodes of adrenal crisis was 7.3/patient/yr in patients <4yrs and 4.9/patient/yr in patients >4 yrs. The mean number of hospital admissions was 0.5/patient/yr in children <4 yrs and 0.53/patient/yr in children >4 yrs. There was a wide variability in the individual number of events reported. Both children on therapy with a micronized weighted formulation reported no episode of suspected adrenal crisis during the 6-month observation period. Conclusion: Parental education on oral stress dosing and switching to parenteral hydrocortisone when necessary are the essential approaches to prevent adrenal crisis in children.
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Insuficiência Adrenal , Hidrocortisona , Humanos , Criança , Lactente , Pré-Escolar , Hidrocortisona/uso terapêutico , Doença Aguda , Escolaridade , Terapia de Reposição Hormonal , Insuficiência Adrenal/tratamento farmacológico , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/prevenção & controleRESUMO
INTRODUCTION: Monogenic diabetes, a form of diabetes mellitus, is caused by a mutation in a single gene and may account for 1-2% of all clinical forms of diabetes. To date, more than 40 loci have been associated with either isolated or syndromic monogenic diabetes. AREAS COVERED: While the request of a genetic test is mandatory for cases with diabetes onset in the first 6 months of life, a decision may be difficult for childhood or adolescent diabetes. In an effort to assist the clinician in this task, we have grouped monogenic diabetes genes according to the age of onset (or incidental discovery) of hyperglycemia and described the additional clinical features found in syndromic diabetes. The therapeutic options available are reviewed. EXPERT OPINION: Technical improvements in DNA sequencing allow for rapid, simultaneous analysis of all genes involved in monogenic diabetes, progressively shrinking the area of unsolved cases. However, the complexity of the analysis of genetic data requires close cooperation between the geneticist and the diabetologist, who should play a proactive role by providing a detailed clinical phenotype that might match a specific disease gene.
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Diabetes Mellitus Tipo 2 , Medicina de Precisão , Adolescente , Criança , Diabetes Mellitus Tipo 2/genética , Testes Genéticos , Humanos , Mutação , FenótipoRESUMO
BACKGROUND: To evaluate prevalence of prediabetes (impaired fasting glucose, IFG; impaired glucose tolerance, IGT; and high glycated haemoglobin, h-HbA1c) in children and adolescents in relation to class of age and obesity; to appraise association with estimates of insulin metabolism, cardiovascular risk factors and alanine aminotransferase (ALT) levels. METHODS: Study of marginal prevalence (i.e., as function of sex, age and obesity class) of isolated and combined IFG, IGT and h-HbA1c in children (age 4-9.9 years) and adolescents (age 10-17.9 years) and association to blood pressure (BP), total, HDL and non-HDL cholesterol, triglycerides, ALT and insulin sensitivity/secretion indexes. RESULTS: Data of 3110 participants (51% males, 33% children; 33% overweight, 39% obesity class I, 20.5% class II, 7.5% class III) were available. Unadjusted prevalence of prediabetes was 13.9% in children (2.1% IFG, 6.7% IGT, 3.9% h-HbA1c, IFG-IGT 0.06%) and 24.6% in adolescents (3.4% IFG, 9.4% IGT, 5.5% h-HbA1c, IFG-IGT 0.09%). Combined h-HBA1c was found in very few adolescents. Prevalence of prediabetes increased significantly by class of obesity up to 20.5% in children and 31.6% in adolescents. Phenotypes of prediabetes were differently but significantly associated with increased systolic and diastolic BP (by 2-7.3 and ~8 mmHg, respectively), triglycerides (by 23-66 mg/dl), and ALT levels (by 10-22 UI/L) depending on the prediabetes phenotype. CONCLUSION AND RELEVANCE: It is worth screening prediabetes in children aged <10 years old with obesity classes II and III and in adolescents. In those with prediabetes, monitoring of blood pressure, triglycerides and ALT levels must be encouraged.
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Intolerância à Glucose , Estado Pré-Diabético , Adolescente , Glicemia/metabolismo , Jejum , Feminino , Intolerância à Glucose/epidemiologia , Hemoglobinas Glicadas/análise , Humanos , Masculino , Obesidade/complicações , Prevalência , TriglicerídeosRESUMO
Objective: This retrospective study aimed to evaluate children observed for suspected precocious puberty in five Italian centers of Pediatric Endocrinology during the first wave of coronavirus disease 2019 pandemic (March-September 2020), compared to subjects observed in the same period of the previous year. Design: The study population (490 children) was divided according to the year of observation and final diagnosis: transient thelarche, non-progressive precocious puberty, central precocious puberty (CPP), or early puberty. Results: Between March and September 2020, 338 subjects were referred for suspected precocious puberty, compared to 152 subjects in the same period of 2019 (+122%). The increase was observed in girls (328 subjects in 2020 vs 140 in 2019, P < 0.05), especially during the second half of the period considered (92 girls from March to May vs 236 girls from June to September); while no difference was observed in boys (10 subjects in 2020 vs 12 in 2019). The percentage of girls with confirmed CPP was higher in 2020, compared to 2019 (135/328 girls (41%) vs 37/140 (26%), P < 0.01). Anthropometric and hormonal parameters in 2019 and 2020 CPP girls were not different; 2020 CPP girls showed more prolonged use of electronic devices and a more sedentary lifestyle both before and during the pandemic, compared to the rest of the 2020 population. Conclusions: The present findings corroborate the recently reported association between the complex lifestyle changes related to the lockdown and a higher incidence of CPP in Italian girls.
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BACKGROUND/AIMS: Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases. METHODS: Variant screening was used to identify the cause of neonatal diabetes, and continuous glucose monitoring was used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis. RESULTS: We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [p.Tyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (intermediate DEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. CONCLUSIONS: In this subject, the KCNJ11 (c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution and highlights the need for molecular analysis of such mutations.
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Diabetes Mellitus , Doenças do Recém-Nascido , Canais de Potássio Corretores do Fluxo de Internalização , Glicemia , Criança , Diabetes Mellitus/genética , Mutação com Ganho de Função , Humanos , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/genética , Canais KATP/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Compostos de Sulfonilureia/uso terapêutico , Receptores de Sulfonilureias/genéticaRESUMO
Background and Objectives: Diagnostic delay is common in attenuated Mucopolysaccharidosis Type I (MPS Ia) due to the rarity of the disease and the variability of clinical presentation. Short stature and impaired growth velocity are frequent findings in MPS Ia, but they rarely raise suspicion as paediatric endocrinologists are generally poorly trained to detect earlier and milder clinical signs of this condition. Materials and Methods: Following a consensus-based methodology, a multidisciplinary panel including paediatric endocrinologists, paediatricians with expertise in metabolic disorders, radiologists, and rheumatologists shared their experience on a possible clinical approach to the diagnosis of MPS Ia in children with short stature or stunted growth. Results: The result was the formation of an algorithm that illustrates how to raise the suspicion of MPS Ia in a patient older than 5 years with short stature and suggestive clinical signs. Conclusion: The proposed algorithm may represent a useful tool to improve the awareness of paediatric endocrinologists and reduce the diagnostic delay for patients with MPS Ia.
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Mucopolissacaridoses , Mucopolissacaridose I , Algoritmos , Criança , Diagnóstico Tardio , Transtornos do Crescimento/diagnóstico , Humanos , Mucopolissacaridose I/diagnósticoRESUMO
INTRODUCTION: Subjects with hypo- or hypergonadotropic hypogonadism need hormone replacement therapy (HRT) to initiate puberty and maintain it with a normal hormonal status. While general recommendations for the management of HRT in adults have been published, no systematic suggestions focused on adolescents and young adults. The focus of this review is the HRT in males and females with hypogonadism, from puberty to late reproductive age, covering the different management options, encompassing sex steroid or gonadotropin therapy, with discussion of benefits, limitations and specific considerations of the different treatments. EVIDENCE ACQUISITION: We conducted an extensive search in the 3 major scientific databases (PubMed, EMBASE and Google Scholar) using the keywords "hormonal replacement therapy," "hypogonadism," "bone mineral density," "estradiol/testosterone," "puberty induction," "delayed puberty." Case-control studies, case series, reviews and meta-analysis published in English from 1990 to date were included. EVIDENCE SYNTHESIS: By considering the available opportunities for fertility induction and preservation, we hereby present the proposals of practical schemes to induce puberty, and a decisional algorithm to approach HRT in postpubertal adolescents. CONCLUSIONS: A condition of hypogonadism can underlie different etiologies involving the hypothalamic-pituitary-gonadal axis at different levels. Since the long-terms effects of hypogonadism may vary and include not only physical outcomes related to sex hormone deficiencies, but also psychological problems and implications on fertility, the initiation, maintenance and consolidation of puberty with different pharmaceutical options is of utmost importance and beside pubertal development, optimal uterine and testicular growth and adequate bone health should consider also the psychosocial wellbeing and the potential fertility.
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Hipogonadismo , Puberdade Tardia , Adolescente , Feminino , Gonadotropinas/uso terapêutico , Terapia de Reposição Hormonal , Humanos , Hipogonadismo/tratamento farmacológico , Masculino , Puberdade Tardia/tratamento farmacológico , Testosterona/uso terapêutico , Adulto JovemRESUMO
Puberty represents a milestone during a person's life and is characterized by several physical and psychological changes which end with the achievement of sexual maturation and of fertility. Puberty onset depends on a series of sophisticated, not completely understood, mechanisms certainly involving Gonadotropin-Releasing Hormone (GnRH) and its effects on pituitary gonadotropins. As recent evidence has demonstrated that pubertal timing deeply affects future adult health life, many efforts have been performed in order to clarify the exact actors involved in the onset and progression of puberty. Genetic factors are undoubtedly essential players in the regulation of pubertal development, accounting for approximately 50-80% of its variability. Mutations in genes such as KISS1, MKRN3, and DLK1 have been associated with central precocious puberty. Interestingly, a possible involvement of epigenetic mechanisms has been proposed as additional element able to affect pubertal phase. Environmental factors have recently attracted much attention. Indeed, an overall decrease in the age of puberty has been observed in the last decades. As genetic factors require long time to exert their effect, other players, such as environmental ones, may be involved. Special focus has been posed on nutritional status, endocrine-disrupting chemicals with non-conclusive results. Pubertal timing deeply affects future life, suggesting the need to clarify mechanisms driving pubertal onset and progression, in order to identify tailored therapeutic strategies and targets.
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Hereditariedade , Puberdade Precoce , Relógios Biológicos , Genes Supressores de Tumor , Humanos , Puberdade , Puberdade Precoce/genética , Ubiquitina-Proteína LigasesRESUMO
Differences/disorders of sex development (DSD) are defined as a group of congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical. The incidence of DSD is 1:4500 births. The current classification divides DSDs into 3 categories according to chromosomal sex: 46,XX DSD, 46,XY DSD and sex chromosome DSD. DSD phenotypes can be concordant with the genotype (apparently normal external genitalia associated with gonadal dysgenesis), or can range from simply hypospadias to completely masculinised or feminised genitalia with a discordant karyotype. Numerous genes implicated in genital development have been reported. The search of genetic variants represents a central element of the extended investigation, as an improved knowledge of the genetic aetiology helps the immediate and long-term management of children with DSDs, in term of sex of rearing, hormone therapy, surgery, fertility and cancer risk. This review aims to assess the current role of molecular diagnosis in DSD management.
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Transtornos do Desenvolvimento Sexual , Hipospadia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual , Genitália , Humanos , Masculino , Desenvolvimento SexualRESUMO
At the end of 2019, an emerging atypical pneumonia called COVID-19 (coronavirus disease 2019), caused by the novel coronavirus defined as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), was first reported. COVID-19 rapidly expanded leading to an epidemic in China, followed by a global pandemic during the year 2020. In few weeks Italy was assaulted by a severe health emergency, constraining the Italian government to put in place extraordinary restrictive measures, such as school closures and a strict lockdown extended to the entire country at the beginning of March 2020. Since the beginning of lockdown, the Endocrinology Unit of Bambino Gesù Children's Hospital has recorded a rapid increase of the outpatient consultations for suspected precocious or early puberty. We have now retrospectively analyzed all the consultations recorded in the database of our outpatient clinic from March to September 2020, and compared them with the consultations recorded in the same database from March to September 2019. Our preliminary data suggest a significant increase of precocious puberty cases in girls during the first period of COVID-19 pandemic. Further investigations in larger cohorts of children are needed in order to correlate the observed increase of precocious puberty with specific pathogenic factors.
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COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Pandemias , Puberdade Precoce/epidemiologia , Quarentena , Criança , Feminino , Humanos , Itália/epidemiologia , Estudos Retrospectivos , Centros de Atenção TerciáriaRESUMO
OBJECTIVE: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. DESIGN: Retrospective analysis of the Italian data set of patients with TNDM. METHODS: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. RESULTS: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. CONCLUSIONS: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.
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Diabetes Mellitus , Doenças do Recém-Nascido , Conjuntos de Dados como Assunto , Diabetes Mellitus/classificação , Diabetes Mellitus/congênito , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Diagnóstico Diferencial , Técnicas de Diagnóstico Endócrino/normas , Feminino , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/classificação , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/terapia , Itália , Masculino , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Indução de Remissão/métodos , Estudos Retrospectivos , Receptores de Sulfonilureias/genéticaRESUMO
INTRODUCTION: X-linked adrenoleukodystrophy (ALD) is a metabolic disorder in which very long chain fatty acids (VLCFAs) are accumulated in the nervous system and adrenal cortex, impairing their functions. Three main variants are described in males: adrenomyeloneuropathy (AMN), a cerebral form (cALD or cAMN) and Addison's disease only (AD), while for females no classification is used. To evaluate pain and the functional state of afferent fibers, a series of tests was carried out in male and female patients. METHODS: Chronic pain occurrence and sensory phenotype profile were assessed in 30 patients (20 male: 10 AMN, 1 cAMN, 1 cALD, 8 AD; and 10 female). A set of instruments assessed the intensity, quality and extent of pain, while a battery of quantitative sensory testing (QST) procedures examined the functional status of Aß and Aδ fibers. Principal component analysis and hierarchical clustering with sensory responses input were used to identify distinct clusters. RESULTS: Nearly half of the subjects reported pain, with a high prevalence in females and male AMN patients. No sex differences in pain dimensions were found. The sensory responses were heterogeneous, differing among the clinical variants and between genders. Male AMN/cAMN/cALD patients showed the worst impairment. Aß and Aδ fibers were affected in males and females, but Aß fibers appeared undamaged in females when tactile sensitivity was tested. Abnormal responses were localized in the lower body district, according to the dying-back pattern of the neuropathy. Cluster analysis showed discrete clusters for each function examined, with well-interpretable sensory and clinical phenotypes. CONCLUSION: The study of pain and of the sensory profile appears to indicate a difference in the mechanisms underlying the AMN/cAMN/cALD and AD clinical forms and in the treatment of the respective generated pain types.
RESUMO
We describe a 46,XX girl with Denys-Drash syndrome, showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and magnetic resonance imaging showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone was increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy. Histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were elevated four months after gonadectomy (157 ng/dL). Recent medical history revealed chronic daily comsumption of high dose biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry, was within reference intervals. Similar testosterone levels were detected on repeat immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should raise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.
Assuntos
Biotina/efeitos adversos , Síndrome de Denys-Drash/genética , Suplementos Nutricionais/efeitos adversos , Adolescente , Castração , Síndrome de Denys-Drash/complicações , Síndrome de Denys-Drash/diagnóstico , Síndrome de Denys-Drash/terapia , Erros de Diagnóstico , Feminino , Humanos , Hiperandrogenismo/sangue , Hiperandrogenismo/diagnóstico , Hiperandrogenismo/cirurgia , Imunoensaio , Falência Renal Crônica/etiologia , Valor Preditivo dos Testes , Testosterona/sangueRESUMO
CONTEXT: Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children. OBJECTIVE: To describe causes, presentation, auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI. PATIENTS AND METHODS: Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected. RESULTS: The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was -0.70 ± 1.20 standard deviation score. CONCLUSIONS: We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.