Journal of Clinical Research in Pediatric Endocrinology最新文献

Hereditary forms of medullary thyroid carcinoma (MTC) are rare. Different phenotypes with the same mutation may be due to differences in the timing of rearranged during transfection (RET) activation steps, additional mutations in other regions of the gene, or the co-occurrence of germline and somatic mutations, which is an infrequent possibility. Here, we present the different features and challenges during the follow-up of three family members with the same germline mutation. A 4-year-old male patient with respiratory distress was diagnosed with MTC and found to have a heterozygous germline mutation C.2671T>G(S891A) in the RET gene (classified as intermediate risk by the American Thyroid Association. As the tumor was inoperable, treatment with a tyrosine kinase inhibitor (sorafenib) was initiated. This treatment with sorafenib prevented tumor progression for seven years. Whole exome sequencing did not identify additional mutations. Segregation analysis showed the same mutation in the asymptomatic mother and sister. In the proband, thyroid tissues were examined for somatic mutations, and SDHA c.1223C>T (p.S408L) was found. The clinical presentation of rare mutations such as RET p.S891A differed among family members carrying the same germline mutation. Our index case’s more severe clinical presentation may be due to an additional somatic mutation. Sorafenib treatment can be an option for advanced MTC and may prevent disease progression.

Maple Syrup Urine Disease (MSUD) and Type 1 Diabetes Mellitus (T1DM) are two distinct metabolic disorders with unique dietary management requirements. While MSUD necessitates strict restriction of branched-chain amino acids (BCAAs), T1DM requires precise carbohydrate counting to maintain optimal glycemic control. We report two cases of patients diagnosed with both MSUD and T1DM, highlighting the challenges and strategies in dietary management. Case 1, a 5-year-old girl, was diagnosed with T1DM after presenting with hyperglycemia and metabolic acidosis, despite previously stable MSUD management. The dietary regimen was modified to include a leucine-free amino acid formula and controlled carbohydrate intake to stabilize both leucine and glucose levels. Case 2, an 11-year-old boy with the diagnosis of MSUD, presented with hyperglycemia during a routine follow-up. Dietary management involved increasing the leucine-free formula while reducing carbohydrate intake to maintain metabolic control. Both cases emphasize the importance of individualized dietary plans, integrating BCAA restriction and carbohydrate regulation to prevent metabolic crises and achieve optimal glycemic control. These cases also underscore the need for a multidisciplinary approach involving pediatric endocrinologists, metabolic specialists, and dietitians to navigate the complexities of dual metabolic disorders effectively. Further studies are warranted to explore long-term outcomes and potential therapeutic targets in patients with concurrent MSUD and T1DM.

Setmelanotide is a recently approved medication for patients over two years of age with monogenic obesity that emerges from POMC, LEPR, PCSK1 mutations, or Bardet-Biedl syndrome. While primarily targeting melanocortin-4 receptors (MC4R), setmelanotide also weakly stimulates melanocortin-1 receptors (MC1R), which may affect pigmentation. Clinical outcomes of this treatment modality remain limited due to the rarity of disorders mentioned above. We present a 12-year-old boy with a homozygous LEPR mutation who experienced skin hyperpigmentation shortly after the initiation of setmelanotide treatment. By the third month of treatment, gradual darkening of nevi was noted. At six-month follow-up, two nevi were excised due to pigmentation changes, and histopathology revealed dysplastic features in both. This case raises concerns about potential MC1R-mediated melanocytic activity during setmelanotide treatment. Therapy was temporarily discontinued. To our knowledge, this is the first reported pediatric case with LEPR-related monogenic obesity developing dysplastic nevi during setmelanotide use.

Carney Complex (CNC) is a rare autosomal dominant syndrome characterized by skin pigmentation abnormalities, endocrine tumors, and cardiac myxomas. This report presents an 11-year-old girl with a history of pontine glioma treated with chemotherapy and radiotherapy at 2.5 years of age, who presented with complaints of weight gain and short stature, along with syndromic features (multiple nevi around the mouth and nose, four café-au-lait spots, and bilateral clinodactyly of the fourth toes) identified during physical examination. Genetic testing revealed a novel pathogenic PRKAR1A variant, confirming the diagnosis of CNC. The patient was diagnosed with Cushing's syndrome due to unsuppressed cortisol levels observed in a high-dose dexamethasone suppression test. Pathological evaluation following unilateral adrenalectomy confirmed the presence of primary pigmented nodular adrenocortical disease (PPNAD). This case highlights the importance of recognizing the atypical course of CNC to prevent delays in diagnosis and treatment.

Hereditaryhypophosphatemic rickets with hypercalciuria ( HHRH) is a rare genetic condition with Autosomal recessive inheritance with a prevalence of 1 in 250000. It is due to mutation in SLC4A3 gene. Correct diagnosis of this condition is important as treatment with active vitamin D metabolites are contraindicated. Evolution of the disease despite initial completely normal bio chemistry has ben observed causing diagnostic confusion. First child presented at the age of 5.5 year with features of rickets. He had abnormal bone profile with normal vitamin D levels. urinary phosphate studies were compatible with HHRH. He was treated with phosphate supplementation and Potassium citrate. He has well responded to the treatment. Second child initially presented at 1.5 years of age with bowing and family history of hypercalciuria. All investigation findings including urinary phosphate studies were within normal limits. At the age of 2.5 year, he again presented with worsening of bowing. Bio chemical and urinary investigations were repeated. Laboratory findings were compatible with HHRH. It highlights the importance of repeated investigations despite initial normal parameters if the initial clinical suspicion is strong and clinical and investigation based diagnosis of this rare genetic disease in resource limited setting.

Objective: Endocrine-disrupting chemicals (EDC) may influence the process of puberty including the development of premature thelarche (PT). This study aimed to investigate the relation between exposure to bisphenol A (BPA) and parabens with PT among a sample of Iranian girls.

Methods: This case-control study was conducted in 2022-2023 on girls with a mean (SD) age of 7.5(0.6) years in Isfahan, Iran. Participants were 90 newly diagnosed PT cases and 114 healthy controls. Spot urine samples were collected from both groups to measure the levels of BPA and paraben metabolites. We performed analyses of BPA and paraben metabolites including methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP) and benzylparaben (BzP) using gas chromatography-mass spectrometry. The association between concentrations of creatinine-standardized urinary bisphenol A and parabens and PT was analyzed with multiple logistic regression models, after adjusting for potential confounders.

Results: The results showed that individuals in the highest quartile of methyl paraben (OR=4.3, 95% CI:1.2-14.9, P=0.023), ethyl paraben (OR=4.7, 95% CI:1.3-17.2, P=0.018) and BPA (OR=5.03, 95% CI:1.4-17.9, P=0.013) had a significantly higher odds for PT compared to those in the lowest quartile.

Conclusion: The findings of this study suggest that exposure to BPA, MeP and EtP is related to increased odds of early breast development in girls. Limiting the exposure to these chemicals may help to reduce the risk of precocious puberty.

AKT2 is a serine/threonine kinase that plays a key role in regulating insulin signalling. The gain-of-function alteration in the AKT2 gene (c.49G>A, p.Glu17Lys) has been described in 9 patients with clinical findings consisting in severe persistent hypoketotic, hypofattyacidaemic, hypoinsulinaemic fasting hypoglycaemia, hemihypertrophy and obesity. A new patient with the same activating AKT2 alteration leading to autonomous activation of the insulin signalling pathway and dysmorphic features is reported. Moreover, to our knowledge, this is the first report using continuous glucose monitoring (CGM) for diagnoses and follow-up in this condition. 12-year-old boy who started follow-up by neuropaediatric clinic for long-term history of seizures started at 8 months old, having been diagnosed with epilepsy in his country of origin. Physical examination revealed proptosis and abnormal fat distribution with lipomastia. Intellectual disability was confirmed. Due to the phenotype and the intellectual impairment, a whole-exome sequencing was done identifying a heterozygous missense variant in AKT2 NM 001626:c.49G>A:p.(Glu17Lys). With this finding, CGM was started revealing severe hypoglycaemia below 40 mg/dl (2.2 mmol/L) with dawn predominance, coinciding with nocturnal focal seizures. To achieve euglycaemia, a high carbohydrate intake (milk with cereals and cocoa powder) with short fasting periods (maximum 3-4 hours) was indicated, with an improvement of hypoglycaemia episodes and resolution of symptomatic seizures. This report reinforces the phenotypic variability of gain-of-function change in AKT2, as our patient exhibits symmetric overgrowth. The reported patient was diagnosed later than those previously reported, already displaying abnormal fat distribution suggesting a dependence on genetic alteration rather than caloric excess. Responding favourably to reduced fasting time, our patient's management has been aided by continuous glucose monitoring (CGM), proving useful for both diagnosis and follow-up.

Objective: To evaluate the associations between obesity, overweight, and central obesity and the risk of early puberty in boys.

Methods: A comprehensive systematic search was conducted in accordance with PRISMA guidelines using the Web of Science and PubMed databases up to December 31, 2024. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Statistical analyses were performed using R software (version 4.4.2), with odds ratios (ORs) and 95% confidence intervals (CIs) calculated.

Results: A total of 15,452 studies were initially identified, of which 6 high-quality studies (n=64,485) met the inclusion criteria after screening. The analysis revealed that obesity (defined by BMI) was significantly associated with an increased risk of testicular enlargement (OR=1.27, 95% CI: 1.19-1.36). Overweight also increased the risk of testicular enlargement (OR=1.20, 95% CI: 1.11-1.29). Obesity was significantly associated with an increased risk of pubarche (OR=1.37, 95% CI: 1.23-1.53). Funnel plots and sensitivity analyses indicated no significant publication bias, and the results remained robust.

Conclusion: This study demonstrates that obesity and overweight are significantly associated with an increased risk of early puberty in boys. Childhood obesity represents an important determinant of earlier pubertal onset, though the relationship may follow a non-linear pattern at extreme BMI levels. The potential implications for adult reproductive health warrant further investigation.

TPIT is a transcription factor required for POMC gene expression and pituitary corticotroph cell differentiation and is encoded by TBX19. Variants in TBX19 cause early onset congenital isolated ACTH insufficiency with a mortality rate of up to 25% in the neonatal period. Mild dysmorphic findings may accompany some cases. Here, we report a case of isolated ACTH deficiency due to a TBX19 variant diagnosed in the neonatal period, which was followed up until adulthood. The patient with hypoglycemia and convulsions on the first day of life were evaluated for hypocortisolemia and low ACTH. While neonatal cholestasis and hyperbilirubinemia were prominent, facial dysmorphism was unremarkable. He was diagnosed with isolated ACTH deficiency, and hydrocortisone replacement therapy was initiated. TBX19 analysis revealed NM 005149 c.512T>C (p.Ile171Thr). Epileptic seizures were observed and antiepileptic treatment was initiated. Cranial MRI revealed an arachnoid cyst, cortical atrophy, and gliotic changes. The patient, which was also included in the first case report describing the gene encoding TPIT, reached the final height. He was 22 years old at the last follow-up, and his physical and mental development was normal. Neuromotor development and growth were normal. TBX19 variants present with hypoglycemic convulsions in the early hours of the neonatal period and may lead to life-threatening neonatal death. Early hydrocortisone replacement therapy is significant for survival without sequelae. Continuing to monitor patients for long-term issues and additional discoveries could be beneficial for elucidating the genotype-phenotype correlation.