Hurthle cell carcinoma in childhood: A retrospective analysis of five cases and review of pediatric literature.

BACKGROUND: the available studies on Hurthle cell carcinoma (HCC) in pediatric age are scarce and based on isolated case reports. Aims of the present study were to review the available pediatric literature on HCC (2000-2019), to describe the cohort of children with this cancer histotype, and to estimate its relative prevalence in pediatric age. PROCEDURE: We retrospectively reconstructed an HCC course in five patients < 19 years who were identified in our departments during the period 2000-2019, and we reviewed the available pediatric studies on this differentiated thyroid cancer (DTC) variant. RESULTS: HCC occurred with a relative prevalence of 5.8% at a median chronological age of 12.5 years. None of HCC patients exhibited, at diagnosis, thyroid dysfunction, extensive lateral neck disease, or distant metastases, and all showed a persistent remission over time. Three patients showed, at diagnosis, antecedents of other diseases (Hashimoto's thyroiditis, neurofibromatosis type 1, and osteosarcoma). CONCLUSIONS: (1) In childhood, the relative prevalence of HCC among different thyroid cancer histotypes is 5.8%, that is close to the one previously reported both in the general population and in other less numerous children's cohorts; (2) HCC may develop even early, at the age of 7; (3) in childhood, HCC does not seem to have a more aggressive behavior when compared with other DTC histotypes; (4) antecedents of other diseases are not infrequent in the history of children with HCC.

Key-role of thyrotropin deficiency in disclosing craniopharyngioma diagnosis in a short girl with Hashimoto's thyroiditis.

In a short girl with celiac disease and Hashimoto's thyroiditis (HT), suspicion of an associated pituitary lesion was suggested by the finding of a thyroid function pattern that was not compatible with HT-related hypothyroidism (low FT4 with normal TSH). This case report reinforces the view that the finding of a normal TSH in presence of a low FT4 should always alert pediatricians and raise suspicion of central hypothyroidism, even when a primary thyroid disease has been already identified. In this case TSH deficiency played a critical role in disclosing diagnosis of craniopharyngioma (CP). Therefore, the subsequent work-up was directed towards investigating pituitary function and morphology. Endocrinological investigations evidenced a picture of TSH and other pituitary hormone deficiency, whereas magnetic resonance imaging revealed an intrasellar CP. Therefore, in this case TSH deficiency played a key-role in disclosing CP diagnosis.

Thyroid function in pediatric patients with juvenile idiopathic arthritis.

PURPOSE: Juvenile Idiopathic Arthritis (JIA) is a chronic inflammatory disease characterized by chronic synovitis, sometimes associated with fever, rash, pericarditis and uveitis. Limited data are available concerning autoimmune diseases associated with JIA in childhood. THE AIMS OF OUR STUDY WERE: (a) evaluating the thyroid function in a group of Italian children affected by JIA; (b) identifying which Autoimmune Thyroid Diseases (ATDs) are related to JIA in this population. METHODS: A population of 51 patients with JIA was investigated. Each patient enrolled was evaluated clinically (family history for Autoimmune Diseases (ADs), personal history and physical examination). In the sample were evaluated thyroid function, inflammation's index and anti-thyroid antibodies. RESULTS: The 68.6% (35) of our patients had the oligoarticular form, 27.5% (14) had the polyarticular one, 2% (1) had systemic onset and 2% (1) had undifferentiated arthritis. We focused our attention on the differences between the first two forms. We did not find any difference on the gender prevalence (p > 0.05). A higher presence of anti-TPO antibodies was found in the polyarticular form, with a significant difference with the oligoarticular one (p = 0.032). We researched the anti-hTG antibodies (p > 0.05) and ANA for each group (p > 0.05). We found a significant prevalence of family history for ADs in the polyarticular form (p < 0.05). CONCLUSION: Our findings show the necessity to focus on thyroid function in patients with JIA. Although the oligoarticular form is the most frequent, the polyarticular form shows a higher frequency of thyroid function's alteration. This suggests the need for specific attention in polyarticular form.

Long term treatment with omalizumab in adolescent with refractory solar urticaria.

BACKGROUND: Solar urticaria represents an uncomfortable form of chronic inducible urticaria. First and second-line treatments are ineffective in some patients, leading to an impairment in their quality of life. Omalizumab represents a safe therapeutic option in case of refractory solar urticaria. CASE PRESENTATION: We update a case of a 21-year-old Caucasian girl affected by solar urticaria from the age of 14. Poor disease control was achieved with standard or high-dose of H1-antihistamines. Several omalizumab courses, including a 1-year-long course, were practiced resulting in clinical remission and significant improvement in patient's quality of life. CONCLUSION: Our experience confirms the effectiveness and safety of omalizumab for the management of refractory solar urticaria. Future studies are awaited in order to monitor long term effects and chronic doses of this treatment, particularly in patients who need concomitant therapy with antihistamines.

Biologics in food allergy: up-to-date.

Introduction: In recent years, the advent of immunotherapy has remarkably improved the management of IgE-mediated food allergy. However, some barriers still exist. Therefore, the effort of researchers aims to investigate new perspectives in the field of non-allergen specific therapy, also based on the current knowledge of the pathogenesis of this disease.Areas covered: This review aims to focus on the role of biologics as a treatment option in patients with IgE-mediated food allergy. These agents are characterized by their ability to inactivate the Th2 pro-inflammatory pathways. Biologics can be used both alone and in association with immunotherapy. Monoclonal antibodies targeting IgE, the IL-4/IL-13 axis, IL-5, and alarmins have been proposed and investigated for treating food allergy.Expert opinion: The clinical efficacy and safety of biologics have been demonstrated in several preclinical studies and randomized controlled trials. Future studies are still required to address current unmet needs, including the identification of the optimal dose to be used by ensuring the effectiveness of therapy.

Scurvy may occur even in children with no underlying risk factors: a case report.

BACKGROUND: Since ancient times, scurvy has been considered one of the most fearsome nutritional deficiency diseases. In modern developed countries, this condition has become very rare and is only occasionally encountered, especially in the pediatric population. Underlying medical conditions, such as neuropsychiatric disorders, anorexia nervosa, celiac disease, Crohn disease, hemodialysis, and severe allergies to food products may enhance the risk of developing scurvy. CASE PRESENTATION: We report the case of an otherwise healthy 3-year-old white boy who developed scurvy due to a selective restrictive diet derived from his refusal to try new food. He presented to our clinic with asthenia and refusal to walk. During hospitalization he developed severe anemia and hematochezia. A diagnosis of scurvy was assessed on the basis of nutritional history, clinical features, radiographic findings, and laboratory findings. Supplementation of ascorbic acid enabled a prompt resolution of symptoms. CONCLUSIONS: Scurvy is caused by vitamin C deficiency. Cutaneous bleeding, mucosal bleeding, and anemia represent typical manifestations of the disease. These symptoms are directly connected to ascorbic acid involvement in collagen biosynthesis. Some radiographic findings can be useful for the diagnosis. Treatment aims to normalize serum levels of vitamin C in order to counteract the deprivation symptoms. The present case report demonstrates that scurvy may sporadically occur in pediatric patients, even in individuals with no predisposing medical conditions and/or potential risk factors.

Menarcheal timing in intensively treated girls with type 1 diabetes mellitus.

BACKGROUND AND AIM: Previous studies on menarcheal age (MA) in type 1 diabetes mellitus (T1DM) have shown conflicting results about the effects of DM, but most lack a control group. The present study design is peculiar in that it covers a study population of 73 intensively treated menarcheal adolescents with premenarcheal onset of T1DM (Group A), whose MA was compared with that recorded in three control populations: the first one consisting of 280 healthy adolescents, the second one consisting of 20 T1DM adolescents with postmenarcheal DM onset (Group B) and the third one represented by the respective mothers. METHODS AND RESULTS: MA of Group A patients was significantly delayed when compared with the respective mothers, healthy controls and Group B patients. By contrast MA of Group B girls was superimposable to the one of both their respective mothers and healthy controls. In Group A MA was strongly related (p<0.0005) to HbA1c at the time of menarche and to average HbA1c concentrations during the last years before menarche. In Group A no relationship between patients' and mothers' MAs was found, whilst such a correlation was significant in Group B. CONCLUSIONS: (a) MA is significantly delayed in girls with premenarcheal presentation of T1DM, even if intensively treated; (b) menarcheal retardation is more severe in the patients with suboptimal metabolic control at the time of menarche; and (c) MA in premenarcheal presenting T1DM is irrespective of maternal MA, age and HbA1c concentrations at DM presentation, body mass index and daily insulin dose at menarche.

Gynecomastia disclosing diagnosis of Leydig cell tumour in a man with thalassemia, secondary hypogonadism and testis microlithiasis.

Aim of this paper is to report about a 35-year old man suffering from beta-Thalassemia major and longstanding untreated hypogonadotropic hypogonadism, who was referred because of a recent onset and painful bilateral gynecomastia, with no palpable testicular masses. Due to the finding of a solid mass at left testis ultrasonography, monolateral testicular exeresis was performed and histology revealed a Leydig Cell Tumour and testicular microlithiasis. Post-surgical restoration of testosterone/estradiol ratio under testosterone therapy was followed by a very rapid reduction of gynecomastia. Our report confirms the usefulness of scrotal ultrasonography for finding an occult testicular tumour in a patient with painful and recent onset bilateral gynecomastia and underlines: a) the important role of testosterone/estradiol ratio in the pathophysiology of gynecomastia; b) the questionable significance of testicular microlithiasis as marker of testis tumours; c) the possible association between beta-Thalassemia and tumoral pathologies.

Phenotypic Expression of Autoimmunity in Children With Autoimmune Thyroid Disorders.

Autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), tend to aggregate with other non-thyroidal autoimmune diseases (NTADs). Aim of this Mini-review is to report the most recent insights concerning the clustering of NTADs in pediatric patients with either HT or GD, the pathophysiology of AITDs and the metamorphic thyroid autoimmunity. A systematic literature research of the last 15 years, according to EQUATOR statement, was carried out through MEDLINE via PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) Embase, CINAHL, Cochrane Library, based on the following keywords: (autoimmune thyroid disease OR Hashimoto thyroiditis OR Grave's disease) AND (autoimmune comorbidities OR extra-thyroidal autoimmune disorders) AND (children OR adolescents OR pediatrics) AND (celiac disease OR type 1 diabetes mellitus OR arthropathies OR cutaneous diseases) AND (Turner syndrome OR Down syndrome). One-hundred and twenty-eight manuscripts were extrapolated but only seventeen were eligible. On the basis of the available reports it may be inferred that clustering of NTADs can be significantly modified by both patients' age at AITDs presentation and association with Down's syndrome (DS). Particularly, the association of AITDs with celiac disease and type 1 diabetes was most commonly reported in children than in adults. A sequential shifting from HT to GD has been described in children with AITDs, and it seems to be more frequent in children with DS than in those without DS. Coexistence of autoimmune diseases might be the result of a complex interaction among genetics, environment and epigenetic modifications that are able to affect gene expression, immune system response and, finally, the pathogenesis of autoimmune diseases.

Subclinical Hypothyroidism in Children: When a Replacement Hormonal Treatment Might Be Advisable.

Aim of this mini review was to analyze the main variables which should be taken into account when the decision regarding a possible treatment with L-T4 has to be considered for a child with subclinical hypothyroidism (SH). The indications of periodical monitoring and vigilance have been also discussed. It was inferred that therapy should be recommended for children with underlying Hashimoto's thyroiditis and progressive deterioration of thyroid status over time, particularly in the cases with goiter and hypothyroid symptoms and in those with associated Turner syndrome or Down's syndrome and/or other autoimmune diseases. Treatment might also be recommended for children with proatherogenic metabolic abnormalities. Treatment is not advisable in children with idiopathic and mild SH, no goiter, no hypothyroid symptoms and negative anti-thyroid autoantibodies. In the absence of any therapeutic intervention, clinical status and thyroid function tests should be periodically monitored, in order to individuate the children who might benefit from treatment. It has been suggested that children with a persistent mild elevation of TSH, who are not treated with L-T4, should undergo biochemical monitoring of thyroid function and re-assessment of clinical status every 6 months. After 2 years with stable thyroid function tests, the interval between monitoring can be extended.

Thyrotropin serum levels and coexistence with Hashimoto's thyroiditis as predictors of malignancy in children with thyroid nodules.

Thyroid cancer (TC) in childhood is a rare disease characterized by an excellent prognosis. Thyroid nodules in children, although less common than in adults, have a greater risk of malignancies, particularly in those cases associated with anamnestic, clinical and ultrasonographic risk factors.Among the factors, which have been found to be linked with an increased relative risk of TC in children, an important role seems to be possibly played by an underlying nodular Hashimoto's thyroiditis (HT) and by the serum levels of TSH.Aim of this Commentary was to specifically address this last point.According to the available pediatric literature on the relationships between these risk factors and phenotypical expression of TC in children, it is possible to conclude that: 1) It is not completely clarified if HT per se predisposes to malignancy or if it represents an incidental histologic finding in cases with TC or if it may be the result of an immune response against tumoral cells. 2) It is unclear whether phenotypic expression of TC is more severe in the cases with associated HT but normal TSH serum levels. 3) Persistently elevated TSH levels play an independent role as predictors of the likelihood of TC, especially in children but also in adults. 4) Patients with nodular HT and subclinical hypothyroidism need to be treated with Levothyroxine in order to prevent the development of both TC and severe thyroid dysfunctions.

Non-classical 21-hydroxylase deficiency in boys with prepubertal or pubertal gynecomastia.

This report describes two boys who were evaluated for the first time at the ages of 9.8 (patient 1) and 13.4 years (patient 2), due to either prepubertal or pubertal gynecomastia. The diagnosis of non-classical (NC) 21-hydroxylase deficiency (21-OH-D) was substantiated by the finding of increased baseline and adrenocorticotropic hormone (ACTH)-stimulated 17-hydroxy-progesterone levels and was supported by molecular analyses of the CYP21A2 gene, which revealed V281L homozygosis in patient 1 and V281L/P30L compound heterozygosis in patient 2. In both boys, gynecomastia completely regressed 5-8 months after the institution of glucocorticoid substitutive treatment. We conclude that it is mandatory to suspect NC 21-OH-D in the clinical evaluation of either prepubertal or pubertal gynecomastia, since this association might be more frequent than reported so far, and that it is important that diagnosis is made by the first months after gynecomastia development, since a longstanding gynecomastia is unlikely to respond completely to medical therapy.

Phenotypic testicular abnormalities and pubertal development in boys with McCune-Albright syndrome.

Aim of this survey is to review the few available literature data on pathophysiologic and clinical aspects of pubertal development in boys with McCune-Albright syndrome (MAS). On the basis of such analysis, we concluded that:1) peripheral precocious puberty (PPP) is significantly more infrequent in boys than in girls; 2) the most common testicular abnormality at MAS presentation is macroorchidism, that may be either monolateral or bilateral; 3) macroorchidism is not always associated with clinical and biochemical evidence of PPP; 4) testicular microlothiasis is distinctly more frequent in boys with MAS than in those without MAS; 5) the available therapeutic schedules have to be adopted already at MAS presentation only in the cases with PPP.

Hypoceruloplasminemia: an unusual biochemical finding in a girl with Hashimoto's thyroiditis and severe hypothyroidism.

Clinical picture of Hashimoto's thyroiditis (HT) may significantly vary in pediatric age, ranging from euthyroidism to subclinical hypothyroidism or hyperthyroidism; only rarely HT presentation may be characterized by a severe hypothyroidism also in pediatric age. Here we describe a 3-year-old Caucasian girl who was admitted to our Clinic due to pericardial effusion, muscle weakness and weight gain. At clinical examination, she presented with bradycardia, pale and round face, pseudohypertrophy of calf muscles and no pitting edema of the limbs. Routine blood investigations showed high serum aspartate and alanine aminotransferase levels, low serum ceruloplasmin without clinical signs of Wilson's disease, dyslipidemia. Thyroid function tests revealed a picture of severe hypothyroidism associated with HT. After the replacement treatment with L-T4, thyroid-stimulating hormone serum levels gradually decreased, with concomitant resolution of pericardial effusion and normalization of ceruloplasmin levels.

Atypical phenotypic aspects of autoimmune thyroid disorders in young patients with Turner syndrome.

Aim of this commentary is to analyze the current views about the phenotypic features of Hashimoto's thyroiditis (HT) and Graves' disease (GD) in Turner syndrome (TS) girls, in terms of epidemiology, clinical and biochemical presentation, long-term course and metamorphic autoimmunity evolution. In TS GD course is not atypical, whereas HT course is characterized by both a mild presenting picture and a severe long-term evolution of thyroid function tests. Furthermore, TS girls seem to have an increased risk of switching over time from HT to GD. On the light of these findings, it may be concluded that TS girls with HT need a careful monitoring of thyroid status over time. CONCLUSIONS: 1) In children the association with TS is able to condition a peculiar phenotypic expression of HT in terms of epidemiology, presentation course and long-term metamorphic autoimmunity; 2) by contrast, children with TS do not exhibit an atypical clinical and biochemical course of GD, but only a significantly higher prevalence of this disease.

Epidemiological and clinical aspects of autoimmune thyroid diseases in children with Down's syndrome.

Aim of this commentary is to report the main peculiarities that have been found to characterize the phenotypic expression of autoimmune thyroid diseases (AITDs) in children with Down's syndrome (DS). According to recent reports, DS children are, per se, more exposed to the risk of both Hashimoto's thyroiditis (HT) and Graves' disease (GD), irrespective of other concomitant risk factors, such as female gender and family antecedents for AITDs. In the context of extra-thyroidal autoimmune disorders, the ones that preferentially aggregate with AITDs in DS children are alopecia areata and vitiligo. Another peculiar aspect, in DS children, is that HT presents with a more severe biochemical picture, which furtherly deteriorates over time. By contrast, GD does not demonstrate a more severe clinical and biochemical picture with respect to that generally observed in patients without DS. Finally, DS children might be at higher risk of progressing from HT toward GD over time.

FTL c.-168G>C Mutation in Hereditary Hyperferritinemia Cataract Syndrome: A New Italian Family.

We describe a new Italian family with 7 members affected by hereditary hyperferritinemia cataract syndrome (HHCS), an uncommon autosomal dominant disease caused by mutations of the iron-responsive element (IRE) of the ferritin light chain (FTL) gene determining its overexpression. The family diagnosis of HHCS took place after finding high ferritin levels in a 6-year-old girl. Seven members of the family had bilateral and symmetrical cataracts, normal iron, and hematological parameters except for high serum ferritin levels. About 160 families/unrelated cases with HHCS are known worldwide. This report documents a second Italian family, with a c.-168G>C mutation that is located in the highly conserved 3-nucleotide bulge structure of the FTL in the 5' untranslated region. This case shows how important the family history is in reaching a correct diagnosis and avoiding unnecessary and invasive analysis. HHCS should be considered in the differential diagnosis of childhood hyperferritinemia, especially in the presence of normal transferrin saturation.

Differentiated thyroid carcinoma presentation may be more aggressive in children and adolescents than in young adults.

BACKGROUND: The available studies concerning the influence of age on the phenotypical expression of differentiated thyroid carcinoma (DTC) have hitherto compared DTC presentation either between pre-pubertal and pubertal children or between pediatric patients and aged adults; aim of this study was to ascertain for the first time whether presentation of DTC may significantly vary according to age, even within a peculiar study population covering only young patients aged less than 30 years. METHODS: The main clinical, biochemical and pathologic data at DTC diagnosis were retrospectively recorded in 2 selected cohorts including, respectively, 18 children and adolescents aged less than 18 years (Group A) or 45 young adults aged between 20 and 29.8 years (Group B). RESULTS: The statistical distribution of DTC cases in the different age ranges was found to progressively increase with increasing age; furthermore, the patients of Group A exhibited at diagnosis a more severe clinical involvement and a higher rate of extra-regional metastases; finally, also the association with both autoimmune thyroid diseases (AITDs) and a biochemical hypothyroid pattern was more common in Group A patients. CONCLUSIONS: In a study population younger than 30 years: a) the risk of developing DTC increases with age, achieving its zenith during the 3rd decade of life; b) clinical presentation is more severe in children and adolescents younger than 18 years than in the patients aged between 20 and 30; c) in the cohort of children and adolescents DTC is more often associated with AITDs, which might play some role in conditioning the more aggressive phenotypical presentation of DTC in this patient group.

Thyroid function test evolution in children with Hashimoto's thyroiditis is closely conditioned by the biochemical picture at diagnosis.

ᅟ: Aim of this commentary is to summarize the salient literature views on the relationships between presentation and evolution patterns of thyroid function in children with Hashimoto's thyroiditis (HT). According to the most recent reports, children with HT and subclinical hypothyroidism (SH) are more prone to the risk of developing severe thyroid dysfunctions over time, if compared to those presenting with euthyroidism. In contrast, children presenting with HT and either overt or subclinical hyperthyroidism are incline to exhibit a definitive resolution of the hyperthyroid phase within some months, although there is a wide variability between the different individuals. The natural history of frank hypothyroidism in the children with HT has never been investigated so far, since in these cases an immediate onset of replacement treatment is mandatory. CONCLUSIONS: 1) a deterioration of thyroid status over time may be observed especially in the children presenting with SH, but also in those presenting with euthyroidism; 2) a definitive resolution of the hyperthyroid phase is generally observed in those presenting with either overt or subclinical hyperthyroidism.