Volume 38, Issue 12

Objectives The aims of this review are to describe the rates of diagnosis of true thyroid disease (and subsequent treatment) in children with an elevated TSH referred to pediatric endocrinology, risk factors associated with elevated TSH secondary to thyroid disease, and TSH threshold level associated with thyroid disease. Methods To accomplish these aims, our team searched through four databases to curate 211 articles regarding TSH values in healthy children ages 1–18 years without an underlying risk for hypothyroidism. Results Five studies met our criteria and were analyzed to create the conclusions about rates of hypothyroidism requiring treatment (6.3–59 %), risk factors to developing hypothyroidism (TSH>10 mIU/L, goiter, and anti-thyroid antibodies), and high-risk TSH value (9.6 mIU/L when averaged among four studies). Conclusions The results are helpful in guiding practitioners about when to repeat TSH value before considering referral to endocrinology, when to refer, and when to anticipate the need of thyroid hormone replacement.

Objectives Automated insulin delivery (AID) improves glycaemic outcomes in children and young people (CYP) with type 1 diabetes (T1D), but effects on body weight are less clear. We evaluated longitudinal changes in BMI z-score following AID initiation and examined predictors using mixed-effects modelling. Methods We retrospectively studied 170 CYP with T1D starting AID at a tertiary centre. BMI z-score was assessed at baseline, six, and twelve months. Predictors of six-month BMI change (ΔBMI) included demographic, socioeconomic, and glycaemic variables with sensor-weighted glucose metrics. Results Baseline BMI z-score was 0.75 (SD 1.27), rising to 0.90 at six months (p<0.001) and stable at twelve (p=0.851 vs. six). Increases occurred in underweight (+1.12, 95 % CI 0.61–1.62, p<0.001) and below-average healthy weight (+0.38, 95 % CI 0.20–0.57, p<0.001), with minimal change in overweight or obese groups. Mixed-effects modelling identified baseline BMI z-score (B = −0.14, p<0.001), baseline mean blood glucose (MBG; B = +0.07, p<0.001), and their interaction (B = −0.04, p=0.025) as independent predictors. Age, sex, socioeconomic status, ethnicity, therapy type, HbA 1c , and sensor wear were not significant. Across groups, AID increased time in range by 15–17 % and reduced HbA 1c by 6 mmol/mol without increasing hypoglycaemia. Conclusions AID supports weight restoration in underweight CYP while maintaining stability in overweight or obese groups. BMI change is determined by baseline BMI and MBG, independent of demographic or treatment factors.

Objectives Summarize the clinical phenotypes and genotypic characteristics of Chinese pediatric patients with maturity-onset diabetes of the young due to HNF1β  variants ( HNF1β -MODY).  Methods Retrospective analysis of clinical characteristics, blood biochemical indexes, and genetic testing data was conducted on six children diagnosed with HNF1β -MODY followed in a single institution in Wenzhou from July 2020 to July 2024. Results Among the six children, three males and three females with a median age of diabetes onset at 12.3, four presented with pancreatic dysplasia. Extra-pancreatic manifestations included renal structural abnormalities(6/6), hypomagnesemia(6/6), hyperuricemia(4/6), elevated liver enzymes(4/6), hyperlipidemia(3/6), and genital tract malformation(1/6). Genetic testing identified a heterozygous HNF1β exon: 1–9 deletion in one patient, while the other five 17q12 microdeletions. Four children started insulin therapy at diagnosis, demonstrating no progressive decline in insulin secretion function and well-maintained insulin dependency. Six children received oral magnesium supplementation, and blood magnesium levels persisted at the lower limit of normal, without neuromuscular complications. Combined therapy with urinary alkalinizing agents and uricosuric drugs in three patients effectively maintained the serum urate levels, without observed progression. Hepatoprotective therapy decreased liver enzymes in two cases. Conclusions The clinical phenotype of HNF1β -MODY encompasses early-onset diabetes mellitus, pancreatic dysplasia, kidney disease, liver dysfunction, and genitourinary tract malformations, with refractory hypomagnesemia and hyperuricemia representing pathognomonic features. Early genetic confirmation can facilitate timely insulin initiation, guide targeted correction of electrolyte imbalances and metabolic disorders, and trigger proactive multi-organ monitoring for disease evolution.

Objectives The rise in obesity has led to a higher incidence of metabolic diseases in children. Overnutrition leads to increased intake and availability of tryptophan (TRP). Research indicates a link between indoleamine 2,3-dioxygenase (IDO) activity, the activation of the tryptophan catabolic pathway, and inflammation associated with obesity. This study investigated how pediatric obesity affects tryptophan metabolism and its potential link to metabolic syndrome. Methods This prospective cohort study included 86 children aged 10 years and older, 56 of whom were obese. Obese children with body mass index (BMI) >95th percentile were divided into two groups: obese (BMI greater than 120 % of the 95th percentile for age and sex) and severely obese (BMI greater than 140 % of the 95th percentile for age and sex). Serum levels of kynurenine pathway metabolites were determined by liquid chromatography-mass spectrometry/mass spectrometry system. Results The mean ages (13.6 and 13.2 years) and gender distribution (36.7 and 46.2 % male) were similar across the groups. There were significant differences in tryptophan levels between the groups, being higher in the obese groups (p<0.001). 3-hydroxykynurenine (3HK) was significantly higher in the obese group (p=0.029). 3-hydroxykynurenine/kynurenine (3HK/KYN) ratio also significantly correlated with increased GGT and triglyceride levels and low HDL. Also higher 3HK/KYN ratio was correlated with elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels. No significant relationship was found between the KYN/TRP ratio and obesity metabolic syndrome indicators. Conclusions Although plasma kynurenine pathway metabolites showed some changes in children with obesity, larger series studies are needed to determine the relationship with metabolic syndrome.

Objectives Mucolipidosis (ML) type II α/β (I-cell disease) and type III (Pseudo-Hurler polydystrophy) are rare autosomal recessive lysosomal storage disorders caused by mutations in the GNPTAB (ML III α/β) and GNPTG (ML III γ) genes, leading to impaired lysosomal enzyme trafficking. These disorders manifest as progressive multisystem diseases with skeletal, neurological, cardiovascular, and respiratory involvement. This study aims to characterise pediatric patients’ clinical, biochemical, genetic, and radiological findings with ML II α/β and IIIα/β or γ to enhance understanding of disease diagnosis and progression. Methods This retrospective cohort study included 19 pediatric patients (15 ML II α/β, 3 ML III γ, 1 ML III α/β) diagnosed at a tertiary referral center. Clinical data, including facial dysmorphism, skeletal abnormalities, organomegaly, cardiovascular involvement, and neurological findings, were recorded at baseline and follow-up. Biochemical analysis included urinary glycosaminoglycan (GAG) levels and lysosomal enzyme activities. For molecular diagnostics, next-generation sequencing (NGS) was utilized using a targeted gene panel that contained GNPTG and GNPTAB leukocytes from peripheral blood were used to harvest genomic DNA. Following the 2015 ACMG/AMP standards, variant interpretation was carried out by evaluating pathogenicity using in silico prediction methods, population frequency data, and segregation analysis. Radiological findings were evaluated via skeletal X-rays and brain MRI. Results The median age at diagnosis was 8 months (range: 1 day–252 months), with a consanguinity rate of 63.1 %. ML II α/β patients presented earlier and had more severe findings, including coarse facies, respiratory tract involvement, cardiac abnormalities, and joint contractures. Cardiac valve disease, kyphosis, and progressive hearing loss were frequent. The most common mutation in  GNPTAB was c.3503_3504delTC in ML II α/β, while GNPTG  variants were linked to ML III γ. Radiologic findings often included hip dysplasia; brain MRIs showed callosal and subarachnoid abnormalities in a few cases. Median survival in ML II α/β was 28 months, mainly due to respiratory failure. Enzyme assays revealed elevated β-hexosaminidase A and A+B, α-D-mannosidase, and α-L-fucosidase activities in both leukocyte and DBS samples, consistent with molecular diagnoses. Conclusions In addition to reporting six novel GNPTAB/GNPTG mutations, this study highlights the diagnostic potential of dried blood spot (DBS) samples, where elevated lysosomal enzyme activity may offer a valuable, minimally invasive screening method for ML II/III.

Objectives Studies investigating the underlying genetic profile in pediatric patients diagnosed with differentiated thyroid cancer (DTC) are quite limited. This study aimed to identify genetic alterations in patients diagnosed with DTC. Methods A total of 20 patients with confirmed DTC were included in the study; however, five were excluded due to the unavailability of thyroid tumor samples. Somatic mutation analysis of the DICER1, BRAF, KRAS, NRAS, and HRAS genes was performed using next-generation sequencing. In addition, gene fusions involving ALK, RET, PTC, ETV6, and NTRK3 were assessed using fluorescence in situ hybridization. A family screening was also conducted, and thyroid ultrasonography was performed. Fine-needle aspiration biopsy was carried out for family members when deemed necessary. Results The mean age at diagnosis was 14.42 ± 2.88 years. Somatic mutations were identified in nine patients (60 %). The detected mutations were as follows: RET/PTC fusion (n=3), BRAF V600E (n=2), NRAS Q61R (n=1), NRAS A59D (n=1), DICER1 E1705K (n=1), and ETV6/NTRK3 fusion (n=1). No statistically significant differences in prognostic factors were observed between patients with and without somatic mutations. As part of the family screening, suspicious thyroid nodules were detected in four parents. One parent underwent hemithyroidectomy, and final pathology revealed papillary thyroid carcinoma. Conclusions Considering the limited number of similar studies on childhood thyroid cancer, these findings provide a valuable contribution to the existing literature. In particular, the results obtained from family screening may support advancements in early diagnosis, risk stratification, and the development of targeted therapeutic approaches.

Objectives This multicentre retrospective study aimed to characterise progression-free survival (PFS) patterns and identify clinicopathological factors associated with disease progression in childhood and adolescent differentiated thyroid carcinoma (caDTC) patients with intermediate-to high-risk persistent disease. Methods All patients underwent initial treatment comprising total or near-total thyroidectomy, followed by radioiodine therapy and thyroid-stimulating hormone suppression. Univariate analysis using the log-rank test was performed to evaluate prognostic factors associated with PFS in caDTC patients. The median follow-up duration was 56.1 months (range: 15–112 months). Results The 1-, 3-, and 5-year PFS rates among intermediate- and high-risk caDTC patients with persistent disease were 82 , 55, and 32 %, respectively. The median PFS in the structural/functional persistent disease (S/FPD) group was significantly shorter than that in the biochemical persistent disease group (21.5 vs. 51.0 months, p<0.001). High-risk American Thyroid Association (ATA) recurrence risk stratification, stimulated thyroglobulin (sTg) levels ≥ 32.9 ng/mL, and S/FPD response to initial radioiodine therapy (RIT) were significantly associated with poor PFS. The optimal sTg cut-off value for predicting S/FPD status was 32.9 ng/mL, with an area under the receiver operating characteristic curve of 0.76. Sensitivity and specificity were 68 and 88 %, respectively. Conclusions Among caDTC patients with intermediate-to high-risk persistent disease, those with high-risk ATA recurrence stratification, sTg levels ≥ 32.9 ng/mL, and S/FPD response to initial RIT might require more aggressive treatment and closer clinical surveillance.

Objectives Rathke cleft cysts (RCC) in childhood are rare, often asymptomatic, and thus discovered incidentally. We aimed to summarize clinical features and pituitary function of patients with symptomatic RCC. Methods This retrospective study included 14 patients (8 male) from the university hospital’s database (period 2005–2023). Results RCC diagnosis based on magnetic resonance imaging at 12.2 (1.8–17.6) years. Presenting symptoms were headaches (n=8), occurring alone (n=1) or with nausea/fatigue (n=2), polydipsia (n=2), or dizziness (n=3), followed by growth retardation (n=5), occurring alone (n=4) or with polydipsia (n=1). Two patients exhibited visual disturbances. Endocrinological evaluation revealed pituitary insufficiency in 10, including isolated or combined growth hormone (GH) deficiency (n=5), arginine-vasopressin deficiency (AVP-D; n=5), central hypothyroidism (n=2), and hypocortisolism (n=2). Three patients had hyperprolactinemia. Nine patients were monitored by regular imaging; five underwent surgery. In the observation group, cyst size remained unchanged in seven and decreased in two patients, while it increased in four patients treated surgically. At last presentation after 6.4 (0.33–14.8) years of follow-up, the endocrine status of the conservatively followed patients was normal in n=6, and pathological in n=3. Pituitary function did not normalize after surgery. Five patients developed hypogonadotropic hypogonadism, including two children who were followed conservatively. Conclusions We found a high incidence of pituitary insufficiency among symptomatic pediatric RCC patients. Pituitary function was not closely related to cyst size or location and did not improve after surgery. Regular clinical and radiological follow-up is mandatory for both conservatively and surgically treated patients.

Objectives Carnitine palmitoyltransferase 1 A (CPT1A) deficiency is an ultra-rare autosomal recessive disorder of the carnitine cycle caused by biallelic pathogenic variants in the CPT1A gene. It mainly presents with a hepatic phenotype and is a target disease of newborn screening programs worldwide. Disease-specific and diagnostic abnormalities of CPT1A deficiency comprise elevated concentrations of free carnitine as well as an elevated metabolite ratio [C0/(C16 + C18)] in blood, but the ideal sample material has been a matter of debate. Methods We present biochemical data of five CPT1A deficient patients, of whom four were diagnosed by newborn screening from dried blood spots. Results Our cases demonstrate that acylcarnitine profiles and especially concentrations of free carnitine can be normal in plasma in infants with CPT1AD at confirmation diagnosis after screening and during follow-up. Even the [C0/(C16 + C18)] ratio yielded normal results in some cases. Conclusions Our data show, that dried blood is the preferred sample material for the diagnosis of CPT1A deficiency as it is superior to serum/plasma with respect to diagnostic sensitivity and reliability in quantification of the ratio [C0/(C16 + C18)]. CPT1A deficiency can be missed, if the analysis is only performed in serum or plasma, and confirmatory diagnostics in serum or plasma after screening can be false negative.

Objectives This study evaluated denosumab for treating hyperphosphatemia in patients with loss-of-function FGF23 mutations and high bone density. Methods Three patients with hyperphosphatemia due to mutations in the FGF23 pathway (two FGF23 , one GALNT3 ) were treated. Conventional therapies, including phosphate binders, dietary restriction, and teriparatide, failed to reduce phosphate in the two symptomatic FGF23 patients. Denosumab, a RANKL inhibitor that decreases bone resorption, was administered for more than two years. Results Denosumab result in a marked and sustained reduction in serum phosphate in all three patients. The two symptomatic patients experienced significant relief from bone pain and improved appetite and well-being. Serum calcium decreased in all patients, with asymptomatic hypocalcemia seen in two cases. Bone density decreased in one patient and was unchanged in another. No significant side effects were observed, except for hypocalcemia. Conclusions Denosumab effectively reduced serum phosphate and improved symptoms in patients with FGF23 -related hyperphosphatemia that was resistant to standard treatments. Denosumab may represent a promising new therapy for treatment-resistant hyperphosphatemia in FGF23 pathway disorders, though further studies are needed to confirm these findings and determine optimal management strategies.

Objectives Combined malonic and methylmalonic aciduria (CMAMMA) is an inherited metabolic disorder caused by ACSF3 variants leading to malonyl-CoA synthetase (MCS) deficiency. Despite its well-defined genetic basis, the clinical spectrum of CMAMMA remains highly variable. Case presentation This study reports six patients from three unrelated families, aged 12 days to 30 years, presenting with heterogeneous clinical manifestations. Exome sequencing (ES) identified a homozygous ACSF3 variant, c.1470G>C [p.(Glu490Asp)], in five patients, and a novel variant, c.1145T>C [p.(Leu382Pro)], in one patient. Notably, in each family’s index case, ES revealed additional pathogenic variants consistent with a dual molecular diagnosis: a homozygous CHRNG variant in one patient; compound heterozygous BTD variants in two siblings, confirming biotinidase deficiency; and a novel CDK10 frameshift variant, c.520_521del [p.(Lys174Glyfs*34)], in another patient. Half of the patients with CMAMMA demonstrated mild to moderate developmental delay. Notably, the sibling with both CMAMMA and biotinidase deficiency exhibited developmental delay, whereas the sibling with isolated CMAMMA had normal development. Symptomatic individuals showed clinical improvement following dietary protein restriction and carnitine supplementation. Conclusions These findings highlight that CMAMMA may cause developmental delay, emphasizing the importance of early diagnosis and treatment. Furthermore, in patients with atypical features, high-throughput sequencing technologies offer a comprehensive approach to identifying additional pathogenic variants in genes beyond ACSF3.

Objectives Familial neurohypophyseal diabetes insipidus (DI) is a rare genetic disorder caused by vasopressin deficiency due to AVP gene mutations. This case report describes the genetic findings and clinical profiles of three generations within a family affected by hereditary central DI and managed with desmopressin. Case presentation An 8-month-old male infant was admitted due to persistent polyuria and polydipsia that had been present since birth. History revealed a daily fluid intake of 7,200 mL and required 13 full diapers. The water deprivation test revealed a serum osmolality >300 mOsm/kg with a concurrently low urine osmolality (<300 mOsm/kg), confirming the diagnosis of DI. Desmopressin therapy was initiated for the patient. Using next-generation sequencing, a heterozygous variant c.329G>A (p.Cys110Tyr) was detected in the AVP gene. Following our patient’s diagnosis, we evaluated first cousin once removed (on the maternal side) for similar symptoms. Upon identification of the heterozygous AVP variant via next-generation sequencing, desmopressin treatment was started. The same variant was detected in our patient’s grandfather, mother, aunt, great-uncle, and first cousin once removed. Polyuria and polydipsia were present in all patients included in our case series. The grandfather and great-uncle, who were initially diagnosed, experienced delayed diagnosis and later developed renal complications. In contrast, the following generations of the family were diagnosed early. Conclusions In familial cases, parents are often familiar with the clinical features of DI, allowing them to ensure adequate hydration, manage polyuria, and minimize the risk of dehydration. However, early diagnosis reduces the risk of long-term complications and enables effective family screening, allowing identification of previously unrecognized mild cases.

Objectives Parathyroid carcinoma is the rarest etiological cause of primary hyperparathyroidism and is exceedingly rare in the pediatric population. Clinical manifestations include severe hypercalcemia, pathological fractures, and bone pain. Diagnosis is typically established through surgical intervention and histopathological examination; however, genetic analyses can also support the diagnosis. Case presentation A 10-year-10-month-old female presented with fatigue, leg pain, and a pathological fracture in her left forearm. Laboratory tests revealed hypercalcemia, hypophosphatemic hypercalcemia, and hyperparathyroidism. Imaging studies identified a 17 mm hypervascular hypoechoic lesion in the left paratracheal area. Surgical intervention included left inferior and superior parathyroidectomy and left thyroidectomy. Histopathology showed atypical parathyroid neoplasia and thyroid hyperplasia. Genetic testing revealed a pathogenic CDC73 mutation (p.E48*, c.142G>T). The patient is under regular follow-up for hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid carcinoma. Conclusions This case highlights the importance of early genetic testing in pediatric primary hyperparathyroidism (PHP), particularly for detecting CDC73 gene mutations associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT). Early diagnosis allows for timely intervention, surgical planning, and long-term surveillance to manage potential complications such as parathyroid carcinoma and ossifying fibromas.

Objectives Glycerol kinase deficiency (GKD) is a rare X-linked metabolic disorder caused by pathogenic variants in the GK gene. It can be present in either isolated or complex forms and often mimics primary hyperlipidemia, leading to diagnostic challenges and unnecessary treatment. This study aims to highlight the phenotypic variability and diagnostic features of GKD through a case series. Case Presentation We describe three pediatric patients diagnosed with GKD. Two siblings with isolated GKD presented with persistent, asymptomatic hypertriglyceridemia, confirmed by glyceroluria and genetic testing revealing a hemizygous c.213_214delAT (p.Cys72Ter) mutation. The third patient, diagnosed with complex GKD, presented in infancy with multisystem involvement, including immunodeficiency, hypotonia, splenic abscesses, and elevated and creatine kinase levels. Genetic analysis revealed a 6.9 Mb contiguous deletion spanning Xp21.2–Xp11.4. In all cases, elevated triglyceride levels were unresponsive to therapy, and serum samples lacked lipemic appearance. Lipid-lowering treatments were discontinued following diagnosis, with no adverse outcomes. Conclusions This case series underscores the clinical and genetic heterogeneity of GKD. Urinary glycerol analysis and the absence of serum lipemia are key diagnostic clues. Early recognition is essential to prevent misdiagnosis and guide appropriate management, particularly in treatment-resistant hypertriglyceridemia.

Objectives Thyrotoxic myopathy (TM) is a muscle disorder associated with hyperthyroidism. Although TM is common in adults, its incidence in children is unknown due to the limited number of reports. TM usually improves with the treatment of hyperthyroidism. This is the first report of a patient with TM who experienced transient worsening of muscle weakness shortly after administration of methimazole (MMI) and metoprolol tartrate. Case presentation A 12-year-old Japanese girl with Graves’ disease was administered MMI and metoprolol tartrate. Within 12 h of treatment initiation, the patient experienced difficulty in standing from a chair. Examination revealed proximal lower-limb weakness and reduced grip strength. Based on the patient’s clinical course and blood test results, thyrotoxic periodic paralysis, myasthenia gravis, or polymyositis were considered unlikely. While the side effects of MMI and metoprolol tartrate were also considered as differential diagnoses, her history revealed mild pre-existing lower limb muscle weakness for 2 months before treatment, suggesting that the side effects of the medication were unlikely. Given the clinical course, the worsening of TM was the most probable cause, and treatment was continued cautiously. Muscle weakness gradually improved over 3 months as her thyroid hormone levels normalized. Magnetic resonance imaging taken 1 month later revealed gluteus muscle atrophy, which resolved within 10 months. Conclusions TM may show transient worsening after MMI and metoprolol tartrate administration, requiring the evaluation of TM, drug side effects, and other possible causes before continuing treatment. This case highlights the importance of recognizing TM in pediatric patients.