To compare the effects of liquid and tablet formulations of levothyroxine (L-T4) in 78 newborns with congenital hypothyroidism (CH).
39 patients received liquid L-T4 (group A) and 39 patients ...received tablets (group B). Thyroid-stimulating hormone (TSH) and free thyroxine (fT4) were measured and L-T4 dose recorded at onset of therapy and during the first year of treatment. Developmental quotient (DQ) was assessed by Griffiths' mental development scales at 12 months of age.
Gestational age, birth weight, screening TSH, etiology and severity of CH, age at onset of therapy and median initial L-T4 dose were similar in both groups. fT4 concentration normalized before 10 days of treatment in all patients. Normalization of TSH concentration was achieved after 7-10 days of therapy in 87% of group A patients and in 82% of group B patients. Group A patients had significantly lower TSH values compared with those of group B at 7-10 days (p = 0.05) and 6-8 months (p = 0.043) of treatment, despite similar L-T4 dose and fT4 concentration. Mean DQ scores were within normal range in all patients.
We confirmed the efficacy and safety of both formulations. The TSH inhibition trend when using liquid L-T4 may be linked to a higher absorption in comparison to the tablets.
Analysis of a 2-screen program for congenital hypothyroidism (CH) was performed using differential dried-blood spot thyrotropin (bTSH) cutoffs of 10 mU/L at first screening (all infants) and 5 mU/L ...at second screening (selected infants).
This work aimed to characterize CH infants identified by the second screening and compare infants with bTSH of 5.0 to 9.9 and 10 mU/L or greater on second screening.
Maternal and neonatal clinical features were retrospectively analyzed for 119 CH babies detected on the second screen in the Lombardy region of Italy, 2007 to 2014.
Fifty-two (43.7%) of the 119 CH neonates showed bTSH values ranging from 5.0 to 9.9 mU/L at the second screening (low bTSH group) and 67 (56.3%) bTSH of 10.0 mU/L or greater (high bTSH group). The frequency of thyroid dysgenesis and eutopic gland was similar in both groups, as was the frequency of permanent and transient CH. Moreover, a high frequency of extrathyroidal malformations was found in both groups. The percentage of preterm infants (57.7% vs 23.9%, P < .001) and infants admitted to the neonatal intensive care unit (50.0% vs 17.9%, P < .001) was significantly higher in the low vs the high bTSH group. In addition, maternal treatment with glucocorticoids in pregnancy was significantly more frequent in the low bTSH group than in the high bTSH group (11.5% vs 1.5%, P = .042), as well as maternal hypothyroidism and/or goiter (26.9% vs 10.4%, P = .036).
This study has demonstrated that a lower TSH cutoff at the second screening can detect additional cases of CH and that a second bTSH cutoff of 5.0 mU/L is appropriate for identifying preterm newborns and babies with associated risk factors.
Summary
Objective
Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical ...hypothyroidism (SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long‐term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers.
Design
Observational, retrospective study.
Patients
Thirty four children (age 7 days to 11 years) and 18 adult carriers of TSHR variants.
Measurements
The TSHR gene was sequenced by PCR‐amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density (BMD), and intellectual outcome (IQ) were collected during the long follow‐up (1‐15 years).
Results
Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L‐T4 replacement therapy, in all cases before genetic analysis. After re‐evaluation, six patients resumed L‐T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment (SGA). No adults presented clinical features consistent with impaired thyroid function.
Conclusions
Children carriers of TSHR variants, regardless of L‐T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective Oral solution and tablet formulations of levothyroxine (L-T4) are both used in the treatment of congenital hypothyroidism (CH). However, few studies and with a limited follow-up period have ...been published comparing these two formulations in children. Design The aim of this multicenter study was to compare the effectiveness of L-T4 oral solution (with ethanol as excipient) and tablet formulation in children with CH up to 3 years of age. Methods Children diagnosed with CH between 2006 and 2015 were enrolled and divided into two groups according to the L-T4 formulation used: solution in drops (group D) or tablets (group T). Auxological parameters, thyroid-stimulating hormone (TSH) and free thyroxine (FT4) values and L-T4 dose were collected at diagnosis and at 15 days, 1, 3, 6, 12, 24 and 36 months of treatment. The developmental quotient (DQ) at 1 and 3 years of age was evaluated using Griffiths’ Scale. Results In this study, 254 children were enrolled among which 117 were treated with solution and 137 with tablets. Auxological parameters, dose and thyroid function values at diagnosis, 3, 6, 12, 24, 36 months were not significantly different. TSH at 15 days (P = 0.002) and 1 month (P = 0.009) was significantly reduced in group D. At 2-year follow-up, median TSH was significantly lower in group T (P = 0.03). No statistical difference was detected between the median DQ; however, group D showed lower values in the language subscale at 12 months and in eye–hand coordination at 36 months. Conclusions Both therapeutic strategies are effective in the treatment of CH. A higher risk of overtreatment in the first months of therapy seems to be associated with oral solution L-T4; therefore, a different strategy should be considered when starting and adjusting the dose. No negative effects on cognitive development were observed. The data obtained are encouraging but long-term follow-up is needed.
Prompt initiation of L-thyroxine therapy in neonates with congenital hypothyroidism (CH) often prevents the performance of functional studies. Aetiological diagnosis is thus postponed until after ...infancy, when the required investigations are performed after L-thyroxine withdrawal. The aim of this study was to verify the efficacy and safety of new protocols for rhTSH (Thyrogen) testing during L-thyroxine replacement in the differential diagnosis of CH.
Ten CH patients (15-144 months old) were studied. Seven had neonatal evidence of gland in situ at the ultrasound examination performed at enrolment and received two rhTSH injections (4 microg/kg daily, i.m.) with 123I scintigraphy and perchlorate test on day 3. Three patients with an ultrasound diagnosis of thyroid dysgenesis received three rhTSH injections with 123I scintigraphy on days 3 and 4. TSH and thyroglobulin (Tg) determinations were performed on days 1, 3 and 4, and neck ultrasound on day 1.
rhTSH stimulation caused Tg levels to increase in eight cases. Blunted Tg responses were seen in two patients with ectopia and hypoplasia. Interestingly, in two cases the association of different developmental defects was demonstrated. Perchlorate test revealed a total iodide organification defect in two patients, including one with a neonatal diagnosis of Pendred's syndrome, who were subsequently found to harbour TPO mutations. rhTSH did not cause notable side-effects.
These new rhTSH protocols always resulted in accurate disease characterisation, allowing specific management and targeted genetic analyses. Thus, rhTSH represents a valid and safe alternative to L: -thyroxine withdrawal in the differential diagnosis of CH in paediatric patients.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Context:
Over the years lower TSH cutoffs have been adopted in some screening programs for congenital hypothyroidism (CH) worldwide. This has resulted in a progressive increase in detecting ...additional mild forms of the disease, essentially with normally located and shaped thyroid. However, the question of whether such additional mild CH cases can benefit from detection by newborn screening and early thyroid hormone treatment is still open.
Objective:
The aim of this study was to estimate the frequency of cases with mild increase of TSH at screening in the Italian population of babies with permanent CH and to characterize these babies in terms of diagnosis classification and neonatal features.
Methods:
Data recorded in the Italian National Registry of infants with CH were analyzed.
Results:
Between 2000 and 2006, 17 of the 25 Italian screening centers adopted a TSH cutoff at screening of <15.0 μU/mL. It was found that 21.6% of babies with permanent CH had TSH at screening of 15.0 μU/mL or less, whereas this percentage was 54% in infants with transient hypothyroidism. Among the babies with permanent CH and mild increase of TSH at screening (≤15 μU/mL), 19.6% had thyroid dysgenesis with serum TSH levels at confirmation of the diagnosis ranging from 9.9 to 708 μU/mL. These babies would have been missed at screening if the cutoff had been higher.
Conclusions:
Lowering TSH cutoff in our country has enabled us to detect additional cases of permanent CH, a number of which had defects of thyroid development and severe hypothyroidism at confirmation of the diagnosis.
A 72-year-old woman was admitted to our Department for syncopes, diarrhoea, and weight loss. We suspected the diagnosis of systemic amyloidosis after the detection of macroglossia and periorbital ...purpura, despite the biopsy of the previous year, that resulted negative for amyloid substance. We confirmed the diagnosis after the histological evidence of deposits of amyloid in bone marrow and the clinical evidence of pneumatosis of bladder wall. Chemotherapy improved only temporarily clinical condition.
Abstract
It is unclear whether patients with Hashimoto thyroiditis (HT) are predisposed to develop thyroid nodules and/or thyroid cancer. The objective of our study was therefore to assess the ...prevalence of thyroid nodules and/or cancer in patients with HT and to look for possible prognostic factors. A retrospective survey of 904 children/adolescents with HT (709 females, 195 males) regularly followed in nine Italian centers of pediatric endocrinology was performed. Median period of follow-up was 4.5 years (1.2 to 12.8 years). We evaluated free T4, TSH, thyroid peroxidase antibody (TPOAb), thyroglobulin antibodies, and thyroid ultrasound yearly. One hundred seventy-four nodules were detected, with an annual incidence rate of 3.5%. Ten nodules were malignant (8 papillary and 2 papillary follicular variant), giving a 5.7% prevalence of cancer among patients with nodules. The severity of hypoechogenity at ultrasound, TPOAb, and free T4 serum concentrations were predictive for the appearance of new nodules. Furthermore, a positive correlation was observed between TPOAb titer and the development of thyroid cancer. In conclusion, HT seems to influence the development of thyroid nodules, but not cancer in children and adolescents.
Context:
Heterozygous mutations in the TSH receptor gene (TSHR) are associated with partial TSH resistance, characterized by isolated nonautoimmune hyperthyrotropinemia (NAHT). The prevalence and ...management of this condition is controversial.
Objective:
Our objective was to investigate the prevalence and clinical impact of TSHR alterations in a large series of pediatric patients with NAHT and to dissect their mechanism of action.
Design and Setting:
For this prospective multicenter study, clinical data and samples were collected in the clinical units and conveyed to a centralized laboratory for analysis.
Patients:
Subjects included 153 unrelated patients with NAHT aged <18 yr. Exclusion criteria included thyroid dysgenesis or major associated congenital defects.
Main Outcome Measures:
Parameters of thyroid function, TSHR gene analysis, and TSHR functional assays were evaluated.
Results:
The frequency of heterozygous nonpolymorphic TSHR variations was 11.8%. We identified seven previously unknown variations: a frameshift (p.Q33PfsX46), one intronic (g.IVS4+2A→G), and five novel missense (p.P162L, p.Y466C, p.I583T, p.I607T, and p.R609Q) variations. The missense variations variably affected TSHR membrane expression and Gs and/or Gq/11 signaling. Several variations cosegregated with NAHT in the affected families. Parameters of thyroid function were similar between affected and unaffected family members.
Conclusions:
Nonpolymorphic alterations in the TSHR gene are commonly associated with isolated NAHT in young patients, thus configuring partial TSH resistance as the most frequent inheritable cause of isolated NAHT. The identification of TSHR defects may thus be helpful for a tailored management of subclinical hypothyroidism. We provide further evidence that besides the well-known defects in Gs signaling, TSHR genetic alternations found in NAHT may frequently impair the Gq/11 pathway.
The aim of the replacement therapy with levothyroxine in congenital hypothyroidism (CH) is to correct hypothyroidism and ensure normal growth and neuropsychological development. Few data are ...available about the appropriate dose during childhood and early adolescence; therefore, we performed a multicenter observational study in a large population of patients with CH to assess the required levothyroxine dose to obtain euthyroidism. We recruited 216 patients with permanent CH classified into three groups (agenesia, ectopia, and in situ gland) on the basis of the thyroid imaging. The levothyroxine dose was recorded at 6 and 12 months and then yearly until 12 years of age. The daily levothyroxine requirement progressively decreased during the follow-up, irrespective of etiology. It was significantly lower in patients with in situ gland than in patients with athyreosis during the entire study period and with ectopic gland from the age of 1 year. The levothyroxine requirement at 6 months of age was correlated with the requirement at each later time-point. The daily dose was modified less frequently in patients with in situ thyroid (36 %) than in patients with ectopic gland (41.4 %) or with athyreosis (43.6 %). Patients with in situ gland required a lower dose than the other two subgroups. The dose at 6 months seems predictive of the requirement until 12 years of age. Euthyroidism may be achieved in pre-school and in-school patients by 3–4 and 2–3 µg/kg/day (70–90 and 60–80 µg/m
2
/day) of levothyroxine, respectively.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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