A 15-year-old Girl with a Lateral Neck Mass Turning Out to Be Papillary Thyroid Carcinoma-Lateral Ectopic Papillary Thyroid Carcinoma or Lymph Node Metastasis?

Lateral neck lesions in children are common and involve various infectious or inflammatory etiologies as well as embryological remnants such as branchial cleft cysts. Although unusual, ectopic thyroid tissue can also present as a lateral neck mass. Here, we present an unusual case of a 15-year-old girl treated for an asymptomatic lateral neck mass that after surgical removal was found to be papillary thyroid carcinoma (PTC). However, after removal of the thyroid gland, no primary thyroid tumor was found. The question arose whether the lateral neck lesion was a lymph node metastasis without identifiable primary tumor (at histological evaluation) or rather malignant degeneration of ectopic thyroid tissue. Total thyroidectomy was performed with postoperative adjuvant radioactive iodine ablation. Even though PTC in a lateral neck mass without a primary thyroid tumor has been described previously, pediatric cases have not been reported. In this report we share our experience on diagnosis, treatment and follow-up, and review the existing literature.

Identification of a Novel CYP11B2 Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency.

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2, resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8:NM_000498.3:c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient's asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the performed biochemical and genetic work-up and describe potential pitfalls of CYP11B2 sequencing due to its homology to CYP11B2.

The Effect of Pre-Thyroidectomy Calcitriol Prophylaxis on Post-Thyroidectomy Hypocalcaemia in Children.

INTRODUCTION: Transient or persistent hypoparathyroidism is one of the most well-known complications of total thyroidectomy and may lead to symptomatic hypocalcaemia. In children, treatment of post-thyroidectomy hypocalcaemia usually consists of postoperative calcium and/or vitamin D supplementation. In 2013, we implemented prophylactic pre-thyroidectomy calcitriol supplementation for all children undergoing total thyroidectomy at the Amsterdam UMC. The objective of this study was to evaluate the efficacy of this prophylactic calcitriol supplementation in preventing post-thyroidectomy hypocalcaemia in children. METHODS: In a retrospective case study, we included all children (age <18 years), who underwent a total or completion thyroidectomy in the Amsterdam UMC, between 2000 and 2020. Patients were divided into two groups, patients with preoperative calcitriol supplementation and those without (controls). Hypocalcaemia was defined as total serum calcium concentration of <2.0 mmol/L. The primary outcome measure was the occurrence of hypocalcaemia in the first 72 h after surgery. Secondary outcome measures were occurrence of symptomatic hypocalcaemia, need for medical intervention within the first 72 h after surgery, and length of hospitalization. RESULTS: A total of 51 patients were included; 26 with calcitriol prophylaxis and 25 controls. There was no significant difference in occurrence of hypocalcaemia (17/26 prophylaxis group; 18/25 control group). Median postoperative calcium concentrations in the first 72 h were significantly higher in the group with prophylaxis at 30-35 h (2.26 vs. 2.01 mmol/L) and 36-41 h (2.17 vs. 1.92 mmol/L). Occurrence of symptomatic hypocalcaemia, need for medical intervention, and length of hospitalization were not significantly different between the groups. CONCLUSION: Calcitriol prophylaxis resulted in somewhat higher postoperative calcium concentrations but did not reduce the occurrence of hypocalcaemia or affect clinical outcome measures such as occurrence of symptomatic hypocalcaemia and length of postoperative hospitalization.

Long-Term Oncological Outcomes of Papillary Thyroid Cancer and Follicular Thyroid Cancer in Children: A Nationwide Population-Based Study.

Introduction: Pediatric thyroid carcinoma is a rare malignancy and data on long-term oncological outcomes are sparse. The aim of this study was to describe the long-term oncological outcomes of pediatric papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) in a national cohort, and to identify risk factors for recurrence. Methods: We conducted a nationwide, retrospective cohort study, in which we combined two national databases. Patients aged <18 years, diagnosed with PTC or FTC in the Netherlands between 2000 and 2016, were included. pT-stage, pN-stage, multifocality and angioinvasion were included in a Cox-regression analysis for the identification of risk factors for recurrence. Results: 133 patients were included: 110 with PTC and 23 with FTC. Patients with PTC most often presented with pT2 tumors (24%) and pN1b (45%). During a median follow-up of 11.3 years, 21 patients with PTC developed a recurrence (19%). Nineteen recurrences were regional (91%) and 2 were pulmonary (9%). No risk factors for recurrence could be determined. One patient who developed pulmonary recurrence died two years later. Cause of death was not captured. Patients with FTC most often presented with pT2 tumors (57%). One patient presented with pN1b (4%). In 70%, no lymph nodes were collected. None of the patients with FTC developed a recurrence or died. Conclusion: Pediatric PTC and FTC are two distinct diseases. Recurrence in pediatric PTC is common, but in FTC it is not. Survival for both pediatric PTC and FTC is very good.

[A girl with a tumor at the base of the tongue]. / Een meisje met een zwelling op de tongbasis.

An 8-year-old girl with a lingual thyroid was evaluated because of a tumor at the base of the tongue. Ultrasound showed a hypoechogenic homogeneous parenchymatous structure at the base of the tongue consistent with thyroid tissue. Suboptimal levothyroxine treatment resulted in longstanding TSH stimulation causing a lingual goiter.

2022 European Thyroid Association Guideline for the management of pediatric Graves' disease.

Hyperthyroidism caused by Graves' disease (GD) is a relatively rare disease in children. Treatment options are the same as in adults - antithyroid drugs (ATD), radioactive iodine (RAI) or thyroid surgery, but the risks and benefits of each modality are different. The European Thyroid Association guideline provides new recommendations for the management of pediatric GD with and without orbitopathy. Clinicians should be alert that GD may present with behavioral changes or declining academic performance in children. Measurement of serum TSH receptor antibodies is recommended for all pediatric patients with hyperthyroidism. Management recommendations include the first-line use of a prolonged course of methimazole/carbimazole ATD treatment (3 years or more), a preference for dose titration instead of block and replace ATD, and to avoid propylthiouracil use. Where definitive treatment is required either total thyroidectomy or RAI is recommended, aiming for complete thyroid ablation with a personalized RAI activity. We recommend avoiding RAI in children under 10 years of age but favor surgery in patients with large goiter. Pediatric endocrinologists should be involved in all cases.

Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency.

CONTEXT: Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice daily, but there is debate about the optimal timing of the highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening). OBJECTIVE: We aimed to compare 2 standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure (BP), and sleep and activity scores. METHODS: This 6-week crossover study included 39 patients (aged 4-19 years) with 21OHD. Patients were treated for 3 weeks with the highest hydrocortisone dose in the morning, followed by 3 weeks with the highest dose in the evening (n = 21), or vice versa (n = 18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5 am; 7 am; 3 pm; and 11 pm during the last 2 days of each treatment period. The main outcome measure was comparison of saliva 17OHP and A4 levels between the 2 treatment strategies. RESULTS: Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The 2 treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal BP, and activity and sleep scores. CONCLUSION: No clear benefit for either treatment schedule was established. Given the variation in individual responses, we recommend individually optimizing dose distribution and monitoring disease control at multiple time points.

Pediatric Graves' orbitopathy: a multicentre study.

PURPOSE: Graves' orbitopathy (GO) is a rare condition in children often considered to be a less severe condition than at an older age. The aim of our study was to analyse if there are any factors that distinguish paediatric from adult GO in order to provide guidelines for assessing and managing paediatric GO. METHODS: Study design is a multicentre retrospective observational case series; 115 paediatric patients diagnosed with GO who visited our university medical centres in the Netherlands and Iran between 2003 and 2019 were submitted for complete ophthalmological examinations, serological testing and/or orbital imaging. Main outcome measures focussed on the natural course and clinical picture as well as medical and surgical treatment in paediatric GO. RESULTS: Clinical findings included proptosis (n = 97; 84.3%), eyelid retraction (n = 77; 67%) and diplopia (n = 13; 11.3%). Ninety-two patients (80%) presented with mild disease, 21 (18.3%) with moderate-severe disease and two (1.7%) with severe GO. Five patients (4.3%) underwent intravenous glucocorticoids and 25 patients underwent orbital decompression surgery. Strabismus surgery due to primary involvement of extraocular muscles was performed in two patients (1.7%). Overall, rehabilitative surgical treatment was planned in 31 patients (26.9%) with inactive disease. Two patients experienced reactivation of the disease. CONCLUSION: Despite the fact that paediatric and adult GO are considered two separate entities, they might be the same disease with two different clinical phenotypes. Paediatric GO population presents with a comparable clinical picture regarding both soft tissue involvement and proptosis, which may require surgical intervention. Proptosis was present in the majority of paediatric GO patients. Orbital decompression was performed in 21.7% of patients.

Complications After Thyroidectomy in Children: Lymph Node Dissection Is a Risk Factor for Permanent Hypocalcemia.

Background: Thyroidectomy is a treatment option in some benign thyroid disorders and the definitive treatment option for thyroid cancer. As postoperative mortality is extremely rare data on postoperative complications and long-term health consequences are important. Objective: To evaluate the frequencies of short- and long-term complications, and their risk factors in pediatric patients (0-18 years) who underwent a thyroidectomy in a tertiary children's hospital. Methods: A retrospective single center study was performed including all pediatric patients who underwent a thyroidectomy between January 2013 and February 2020. Results: Forty-eight patients were included in this study (mean age 14.6 years). Twenty-nine total thyroidectomies and 19 hemithyroidectomies were conducted. Thyroid carcinoma was the indication to perform a thyroidectomy in 12 patients, 36 patients underwent a thyroidectomy because of a benign thyroid disorder. Postoperative hypocalcemia was evaluated in patients who underwent a total thyroidectomy. Rapidly resolved hypocalcemia was observed in three patients (10.3%), transient hypocalcemia in 10 patients (34.5%) and permanent hypocalcemia in six patients (20.7%). Permanent hypocalcemia was only seen in patients who underwent a thyroidectomy combined with additional lymph node dissection because of thyroid carcinoma [thyroid carcinoma: OR 43.73, 95% CI (2.11-904.95); lymph node dissection: OR 76.14, 95% CI (3.49-458.98)]. Transient and permanent recurrent laryngeal nerve injury was reported in four (8.3%) and one (2.1%) of all patients, respectively. Conclusion: Permanent postoperative complications after thyroidectomy are rare in pediatric patients undergoing a thyroidectomy without lymph node dissection. However, in this age group permanent hypocalcemia occurs more frequently after thyroidectomy with additional lymph node dissection because of thyroid cancer. With respect to quality of life, especially of pediatric thyroid cancer patients, reducing this complication is an important goal.

The Efficacy and Short- and Long-Term Side Effects of Radioactive Iodine Treatment in Pediatric Graves' Disease: A Systematic Review.

BACKGROUND: Graves's disease (GD) is the most common cause of hyperthyroidism. Maximal 30% of pediatric GD patients achieve remission with antithyroid drugs. The majority of patients therefore require definitive treatment. Both thyroidectomy and radioactive iodine (RAI) are often used as definitive treatment for GD. However, data on efficacy and short- and long-term side effects of RAI treatment for pediatric GD are relatively scarce. METHODS: A systematic review of the literature (PubMed and Embase) was performed to identify studies reporting the efficacy or short- and long-term side effects of RAI treatment in pediatric GD. RESULTS: Twenty-three studies evaluating 1,283 children and adolescents treated with RAI for GD were included. The treatment goal of RAI treatment changed over time, from trying to achieve euthyroidism in the past to aiming at complete thyroid destruction and subsequent hypothyroidism in the last 3 decades. The reported efficacy of a first RAI treatment when aiming at hypothyroidism ranged from 42.8 to 97.5%, depending on the activity administered. The efficacy seems to increase with higher RAI activities. When aiming at hypothyroidism, both short- and long-term side effects of treatment are very rare. Long-term side effects were mainly seen in patients in whom treatment aimed at achieving euthyroidism. CONCLUSION: RAI is a safe definitive treatment option for pediatric GD when aiming at complete thyroid destruction. When aiming at hypothyroidism, the efficacy of treatment seems to increase with a higher RAI activity. Prospective studies are needed to determine the optimal RAI dosing regimen in pediatric GD.

Methimazole-induced remission rates in pediatric Graves' disease: a systematic review.

Objective: Comparison of studies on remission rates in pediatric Graves' disease is complicated by lack of uniformity in treatment protocols, remission definition, and follow-up duration. We performed a systematic review on remission rates in pediatric Graves' disease and attempted to create uniformity by recalculating remission rates based on an intention-to-treat analysis. Methods: PubMed and Embase were searched in August 2020 for studies on patients with Graves' disease: (i) 2 to 18 years of age, (ii) initially treated with methimazole or carbimazole for at least 18 months, (iii) with a follow-up duration of at least 1 year after cessation of methimazole or carbimazole. All reported remission rates were recalculated using an intention-to-treat analysis. Results: Of 1890 articles, 29 articles consisting of 24 patient cohorts were included with a total of 3057 patients (82.6% female). Methimazole or carbimazole was initially prescribed in 2864 patients (93.7%). Recalculation based on intention-to-treat analysis resulted in an overall remission rate of 28.8% (829/2880). Pooled remission rates based on treatment duration were 23.7, 31.0, 43.7, and 75% respectively after 1.5-2.5 years, 2.5-5 years, 5-6 years (two studies), and 9 years (single study) treatment duration. The occurrence of adverse events was 419 in 2377 patients (17.6%), with major side effects in 25 patients (1.1%). Conclusions: Using a standardized calculation, the overall remission rate in methimazole-treated pediatric GD is 28.8%. A few small studies indicate that longer treatment increases the remission rate. However, evidence is limited and further research is necessary to investigate the efficacy of longer treatment durations.

Persisting symptoms in patients with Hashimoto's disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role? A systematic review.

OBJECTIVE: Patients with hypothyroidism due to Hashimoto's disease (HD) may experience persisting symptoms despite normal serum thyroid hormone (TH) levels. Several hypotheses have been postulated to explain these persisting symptoms. We hypothesized that thyroid autoimmunity may play a role. DESIGN: A systematic literature review. METHODS: A PubMed search was performed to find studies investigating the relation between the presence of thyroid autoimmunity and (persisting) symptoms. Included studies were critically appraised by the Newcastle - Ottawa Scale (NOS) and then subdivided into (A) disease-based studies, comparing biochemically euthyroid patients with HD, and euthyroid patients with non-autoimmune hypothyroidism or euthyroid benign goitre, and (B) (general) population-based studies. Due to different outcome measures among all studies, meta-analysis of data could not be performed. RESULTS: Thirty out of 1259 articles found in the PubMed search were included in this systematic review. Five out of seven disease-based studies found an association between thyroid autoimmunity and symptoms or lower quality of life (QoL). Sixteen of 23 population-based studies found a comparable positive association. In total, the majority of included studies reported an association between thyroid autoimmunity and persisting symptoms or lower QoL in biochemically euthyroid patients. CONCLUSION: (Thyroid) autoimmunity seems to be associated with persisting symptoms or lower QoL in biochemically euthyroid HD patients. As outcome measures differed among the included studies, we propose the use of similar outcome measures in future studies. To prove causality, a necessary next step is to design and conduct intervention studies, for example immunomodulation vs. placebo preferably in the form of a randomized controlled trial, with symptoms and QoL as main outcomes.

Chondrodysplasia, enchondromas and a chest deformity causing severe pulmonary morbidity in a boy with a PTHLH duplication: A case report.

Parathyroid hormone-like hormone (PTHLH) plays an important role in bone formation. Several skeletal dysplasias have been described that are associated with disruption of PTHLH functioning. Here we report on a new patient with a 898 Kb duplication on chromosome 12p11.22 including the PTHLH gene. The boy has multiple skeletal abnormalities including chondrodysplasia, lesions radiographically resembling enchondromas and posterior rib deformities leading to a severe chest deformity. Severe pulmonary symptoms were thought to be caused by limited mobility and secondary sputum evacuation problems due to the chest deformity. Imaging studies during follow-up revealed progression of the number of skeletal lesions over time. This case extends the phenotypic spectrum associated with copy number variation of PTHLH.

Pasireotide treatment for severe congenital hyperinsulinism due to a homozygous ABCC8 mutation.

ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI.

Thyroidectomy in Pediatric Patients with Graves' Disease: A Systematic Review of Postoperative Morbidity.

BACKGROUND: Graves' disease (GD) is the most common cause of hyperthyroidism. In children, the overall relapse frequency after treatment with antithyroid drugs is high. Therefore, many pediatric GD patients eventually require thyroidectomy as definitive treatment. However, the postoperative complications of thyroidectomy in pediatric GD patients are poorly reported. OBJECTIVE: To identify the frequency of short- and long-term postoperative morbidities after thyroidectomy in pediatric GD patients. METHODS: A systematic review of the literature (PubMed and Embase) was performed to identify studies reporting short- and long-term postoperative morbidities after thyroidectomy in pediatric GD patients according to the PRISMA guidelines. RESULTS: Twenty-two mainly retrospective cohort studies were included in this review evaluating short- and long-term morbidities in 1,424 children and adolescents. The frequency of transient hypocalcemia was 22.2% (269/1,210), with a range of 5.0-50.0%. The frequency of permanent hypocalcemia was 2.5% (36/1,424), with a range of 0-20.0%. Two studies reported high frequencies of permanent hypocalcemia, 20.0 (6/30) and 17.4% (9/52), respectively. The 20% frequency could be explained by low-volume surgeons in poorly controlled GD patients. Only 21 cases of permanent hypocalcemia were reported in the 1,342 patients included in the other 20 studies (1.6%). Transient and permanent recurrent laryngeal nerve injury were reported less frequently, with frequencies between 0-20.0 and 0-7.1%, respectively. Infection, hemorrhage/hematoma, and keloid development were only rarely reported as postoperative complications. CONCLUSION: The results of this systematic review suggest that thyroidectomy is a safe treatment option for pediatric GD patients. The minority of patients will experience transient and benign morbidities, with hypocalcemia being the most common transient postoperative morbidity. Permanent postoperative morbidities are relatively rare.

Corrigendum: Adrenoleukodystrophy Newborn Screening in the Netherlands (SCAN Study): The X-Factor.

[This corrects the article DOI: 10.3389/fcell.2020.00499.].