Hormone Research in Paediatrics最新文献

Introduction: Pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID) syndrome is a rare disease, and part of the cluster histiocytosis-lymphadenopathy plus syndrome (H syndrome), which is associated with mutations in the SLC29A3 gene. Patients with PHID show clinical features of H syndrome but also have insulin-dependent diabetes mellitus. The PHID has previously been described as predominantly in absence of pancreatic autoantibodies. Case Series Presentation: Through an open call in two international diabetes registers, clinical and genetic characteristics of 7 PHID patients in 6 treatment centres were collected after informed consent. All of them had consanguinity in their families, and their origins were located in North-African and Middle Eastern regions. Four out of 7 patients had at least one positive pancreatic autoantibody.

Discussion and conclusion: Our case series reveals that PHID exhibits a wide range of clinical symptoms and signs. When consanguinity is present in a patient with newly diagnosed diabetes, and/or if other atypical symptoms such as dysmorphic features, skin lesions, haematological abnormalities, and developmental delay are present, threshold for genetic analysis should be low. Moreover, the presence of autoantibodies should not withhold genetic testing as our case series contradicts the previous observation of predominant autoantibody absence in PHID.

Introduction: Menarche is the last stage of pubertal development, which coincides with the completion of longitudinal growth. As a consequence of the lack of national and up-to-date data related to post-menarcheal (PM) growth, the aim of our work was to evaluate PM growth in a group of contemporary healthy Chilean girls followed, prospectively, until 4 years PM.

Methods: This study was nested within the GOCS cohort, in a prospective fashion. The girls were followed yearly after menarche for at least for 4 years. We modeled each girl's growth using a SuperImposition by Translation and Rotation (SITAR) model.

Results: A total of 534 girls were evaluated prospectively; 399 girls had height measured 2 years after menarche, 421 after 3 years, and 364 of 534 had height measured at 4 years PM. Expected height gained PM in the complete study group was 6.6 ± 2.5 cm. We observed that the largest gain in height occurred after the first year PM (3.8 ± 1.5 cm). According to the age of menarche, the group with earlier menarche (<11 years old) had a greater height gain in cm after 4 years PM (8.2 ± 3.2 cm) and the smallest gain was among girls with menarche at an age older than 13 years (4.4 ± 1.6) (p < 0.001). Age at menarche was significantly associated with all PM growth patterns (size, timing, and intensity), indicating that girls with older age at menarche grew taller, later, and slower than girls with younger age at menarche. Adjusting the PM growth pattern by BMI maintained all these associations. Applying the SITAR model specifically, girls experiencing menarche after the age of 13 years exhibited slower growth, occurring slightly earlier and with less intensity when adjusted by BMI at menarche.

Conclusion: In a national and updated dataset, we observed that girls grew until 4 years PM an average of 6.6 ± 2.5 cm, with greatest gain occurring in the first year PM (3.8 ± 1.5 cm). Age at menarche was associated with menarche growth patterns.

Background: Short stature is one of the most common reasons for referral to a pediatric endocrinologist that can be due to multitude of conditions, including an ever-growing list of genetic etiologies. Despite the numerous different causes, options for medical therapy remain quite limited, with the primary medication available being recombinant human growth hormone. A second option is recombinant insulin-like growth factor 1 (rIGF-1) in select patients with severe primary IGF-1 deficiency. Alternative strategies to increase height have been attempted such as delaying the onset of puberty with a gonadotropin-releasing hormone agonist or delaying epiphyseal fusion with an aromatase inhibitor. However, these options focus on increasing the duration of growth as opposed to directly stimulating growth at the growth plate.

Summary: Novel approaches to growth promotion have recently been developed, including analogs of C-type natriuretic peptide (CNP). The purpose of this study is to review the function of CNP and its potential use in different conditions.

Key messages: Alterations in the CNP/FGFR3 pathway can lead to multiple defined genetic causes of short stature. The CNP pathway has become the focus for treatment of children with short stature that suffer from such genetic conditions, with promising outcomes.

Introduction: Aldosterone synthase deficiency is a rare autosomal recessive disease characterized by vomiting, dehydration, salt wasting, life-threatening hyperkalemia in infancy, followed by failure to thrive. It results from pathogenic variants in CYP11B2.

Case presentation: A boy, born in Montreal to Lebanese parents who are first cousins, was referred at 9 days of life for severe dehydration. A diagnosis of primary adrenal insufficiency was made, and treatment was started with fludrocortisone and hydrocortisone. Exome sequencing revealed a homozygous variant p.(Asn201Asp)(N201D) in CYP11B2. In silico, this variant was considered benign, but in vitro functional expression studies established it caused the severe aldosterone deficiency. It ended the diagnostic odyssey and allowed to safely stop hydrocortisone replacement.

Conclusion: If a gene variant co-segregates with a phenotype, in vitro functional studies are required even if in silico studies are negative.

Introduction: Thyrotoxic hypokalemic periodic paralysis (THPP) is a rare but severe complication of hyperthyroidism characterized by acute muscle weakness. This study reports the first case of THPP in an adolescent with type 1 diabetes mellitus (T1DM) and Graves' disease, triggered by high-dose insulin, high carbohydrate intake, and strenuous exercise. It highlights the clinical presentation, management, and implications of THPP in this context.

Case presentation: A 17-year-old male patient with T1DM and Graves' disease presented to the emergency department with weakness in the extremities. The patient had engaged in strenuous exercise and high-dose rapid-acting insulin, and consumed a large amount of rice shortly before the onset of the symptoms. He exhibited hypertension and tachycardia, with diminished muscle strength and deep tendon reflexes with severe hypokalemia (1.6 mmol/L). Treatment with potassium and magnesium replacements was initiated. The patient's symptoms resolved within 5 h, and his neurological examination was normalized. Hypokalemia did not recur during follow-up. All symptoms improved rapidly with potassium replacement, β-blocker therapy, and antithyroid treatment.

Conclusion: This case represents the first documented instance of THPP in an adolescent with T1DM and Graves' disease. This entity should be included in the differential diagnosis of acute paralysis in patients with known thyrotoxicosis or those exhibiting symptoms such as tachycardia and hypertension. Insulin treatment in a hyperthyroid diabetic patient may increase the risk of THPP.

Introduction: Most of the loss-of-function mutations described in children with central precocious puberty (CPP) are located in the coding regions of MKRN3 or DLK1 genes. Notably, potential abnormalities in the regulatory regions of these CPP genes are rarely explored. The objective of this work was to identify pathogenic allelic variants in the regulatory regions of MKRN3 and DLK1 genes in patients with familial or idiopathic CPP.

Methods: A cohort of 217 individuals with CPP (205 girls and 12 boys; 143 sporadic cases and 74 familial cases) was investigated. Rare and potentially pathogenic variants in the coding regions of both genes were previously excluded. Analyses of the regulatory regions of MKRN3 and DLK1 were performed using polymerase chain reaction and direct automated sequencing (Sanger method). Circulating serum levels of MKRN3 and DLK1 proteins were measured using an ELISA assay.

Results: We identified a heterozygous allelic variant (c.-265G>A), previously associated with CPP, located in the promoter region of the MKRN3 gene in three girls from two unrelated families. In silico prediction analysis indicated that the c.-265G>A variant was in the ZNF384 binding region. ZNF384 gene encodes a C2H2-type zinc finger protein, which might act as a transcription factor. MKRN3 serum levels varied from 197.5 pg/mL to 1,907 pg/mL and were relatively lower in patients with CPP who carried the c.-265G>A variant. No pathogenic allelic variant was found in the regulatory region of the DLK1 gene.

Conclusion: Pathogenic variants in the regulatory region of MKRN3 gene are rare and can be associated with the CPP phenotype.

Introduction: Premature adrenarche in girls is defined biochemically by an increase in adrenal androgen (DHEAS) levels above the age-specific reference range before age 8 years. Recently, increased levels of 11-oxyandrogens have also been reported in girls with premature adrenarche. Epigenetic modifications, specifically CpG methylation, may affect gene expression and/or activity of steroidogenic enzymes during developmental changes in adrenal androgen secretion.

Objective: The aim of the study was to determine whether circulating 11-oxyandrogen levels in post-menarcheal girls are associated with the methylation status of genes involved in 11-oxyandrogen steroidogenesis.

Methods: Ninety-seven healthy girls followed since the age of 3 years were classified, according to DHEAS serum concentration at age 6-7 years, as normal DHEAS (<42 μg/dL [75th percentile for population]) or high DHEAS (≥42 μg/dL). At Tanner stage 2, the methylation status of CpG sites located in CYP11B1 and HSD11B2 genes was analyzed in genomic DNA from peripheral blood leukocytes by the melting curve analysis methylation assay. Eleven-oxyandrogen concentrations were assessed at 4 years post menarche.

Results: Significantly lower methylation levels were detected in the CYP11B1 gene in girls with high versus normal serum DHEAS levels, with no differences found in HSD11B2 gene. Additionally, CYP11B1 methylation status correlated inversely with 11β-hydroxy-androstenedione and 11-ketotestosterone levels. Furthermore, CYP11B1 methylation in the full cohort correlated inversely with insulin concentration at Tanner 1 and with body mass index at Tanner stage 1 and 2.

Conclusion: This pilot study proposes the hypothesis that a lower methylation of CYP11B1 may be a mechanism contributing to increased concentrations of 11-oxyandrogens in premature adrenarche and its associated metabolic risk.

Introduction: The incidence of diabetic ketoacidosis (DKA) at the time of diagnosis of type 1 diabetes in youth varies between countries and is influenced by socioeconomic factors. We investigated the relationship between regional deprivation indices and DKA at the diagnosis of type 1 diabetes in six countries.

Methods: We analyzed children 0.5-17.0 years old diagnosed with type 1 diabetes between 2019 and 2022 across six diabetes registries. Regional deprivation index within each country was standardized to compare each individual's socioeconomic status internationally. Log-binomial regression models assessed the association between the standardized deprivation index and DKA, with sex, age group, and year as covariates.

Results: Among 21,020 children (mean age 9.08 [SD 4.19] years), the DKA rate of 36.5%. Cohorts were Germany (n = 13,561, DKA 32.5%), Italy (4,659, 42.5%), Colorado, USA (1,318, 54.9%), Wales (769, 35.2%), New Zealand (407, 43.7%), and Slovenia (306, 37.6%). Deprivation was associated with the increased risk of DKA in children 0.5-<6 (OR 1.16 [95% CI: 1.10-1.23], p < 0.0001) and 6-<12 years of age (1.05 [1.05-1.11], p = 0.02). Female sex increased risk of DKA (1.06 [1.00-1.13], p = 0.04). The proportion of DKA was lower in 2019 than in 2020, 2021, and 2022 (each p < 0.0001).

Conclusion: Deprivation was significantly associated with the risk of DKA at the diagnosis of type 1 diabetes, and DKA was more common during the pandemic years 2020-2022 than in 2019. Younger children appear to be more vulnerable to deprivation than older patients. Understanding and reducing local and demographic-specific disparities are essential for effective intervention.

Introduction: Laron syndrome (LS) is a rare autosomal recessive disorder caused by mutations in the growth hormone (GH) receptor gene, resulting in GH resistance and reduced levels of insulin-like growth factor 1 (IGF-1). Patients with LS exhibit severe growth retardation, low IGF-1 levels, elevated basal GH, and poor response to GH stimulation. Recombinant IGF-1 is the only approved treatment and has been shown to improve linear growth. This study evaluates the long-term efficacy and safety of IGF-1 therapy in a large cohort of LS patients treated at King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh, Saudi Arabia over 22 years.

Methods: We conducted a retrospective review of medical records for 28 patients with growth hormone insensitivity syndrome, including 12 males and 16 females, treated with IGF-1 from 1998 to 2020. Patients were selected based on criteria including age over 2 years, height standard deviation score (SDS) ≤-2.8, normal or elevated GH secretion (>2.5 ng/mL), IGF-1 levels <50 ng/mL, and insensitivity to exogenous GH. IGF-1 was administered initially at 40 μg/kg/dose subcutaneously twice daily, escalating to a maximum of 120 μg/kg/dose as tolerated. Dosage was adjusted to minimize hypoglycemia risk, with blood glucose monitored frequently during hospitalization. In addition, molecular genetic results were reviewed for each patient in the cohort.

Results: IGF-1 treatment significantly increased height velocity (HV) from a baseline of 3.4 cm/year to 6.5 cm/year in the first year (mean difference of 3.1 cm/year, p < 0.0001). In the second year, HV remained elevated at 5 cm/year (mean difference of 1.6 cm/year, p = 0.0015). Long-term follow-up over 10 years demonstrated sustained improvements in HV compared to baseline, with the most substantial gains occurring within the initial 5 years. Weight SDSs also showed significant improvement. Age at the start of therapy did not notably affect growth outcomes, though longer treatment durations were associated with greater growth. Ten disease-causing variants in the GHR gene were identified in 24 of the 28 LS patients.

Conclusion: IGF-1 therapy significantly enhanced linear growth in children with Laron syndrome and was generally well tolerated. Although many patients did not reach normal adult height, the growth achieved with IGF-1 treatment was markedly better than expected without therapy. This study underscores the effectiveness of IGF-1 in improving growth outcomes and highlights the need for continued longitudinal studies to optimize treatment strategies and manage potential complications.