Diagnosis and Long-term Treatment of Suspected Congenital Hypothyroidism in a Pigeon (Columba livia domestica).

An approximately 6-month-old domestic pigeon (Columba livia domestica) was presented for lethargy and an inability to perform its first molt. The pigeon was obese, had anatomical characteristics of a chick, including cere and plumage, and had a ventral coelomic soft tissue mass. Initial blood work was unremarkable. A computed tomographic scan confirmed excessive fat deposition in the coelom and a mass adherent to the liver. A fine-needle aspirate of the mass indicated fat accumulation. A thyroid-stimulating hormone (TSH) test was planned for this pigeon and 3 presumed euthyroid pigeons. Each pigeon was administered 80 µg (∼230 µg/kg) of recombinant human TSH. Blood was drawn at time 0 and 3 and 6 hours after administration of recombinant human TSH. Plasma total thyroxine (TT4) was measured in duplicate with an in-house analyzer and a reference laboratory. After recombinant human TSH administration, healthy pigeons showed a 4- to 21-fold increase in TT4, whereas the hypothyroid pigeon had all values <0.12 µg/dL. The pigeon was prescribed 20 µg of compounded levothyroxine twice daily. In the following months, the pigeon molted and developed adult features. The ventral coelomic soft tissue mass disappeared and repeated computed tomography scans showed a decreased amount of body fat and a reduction in the size of the coelomic mass. Levothyroxine was further adjusted multiple times according to additional TT4 testing to a dose of 2.5 µg once daily. The pigeon has been under treatment with levothyroxine for more than 2 years. Here we present the first reported case of confirmed hypothyroidism in a pigeon. Diagnosis with a TSH stimulation test was unequivocal, even when only considering the results of the in-house analyzer. Levothyroxine treatment resolved clinical signs and could be titrated to an appropriate dose.

Rare case of central congenital hypothyroidism due to a TSHß mutation presenting with macro-orchidism.

A male infant was brought to our paediatric endocrine unit with typical clinical features of congenital hypothyroidism (CH) and striking macro-orchidism. On evaluation, free T3, free T4 and thyroid stimulating hormone (TSH) were found to be low, suggestive of congenital CH. Cortisol was within reference range and prolactin was mildly elevated. No suspicious lesions were encountered on neurosonography. On commencing treatment with thyroxine, clinical features of hypothyroidism showed dramatic improvement with regression of testicular enlargement. Genetic analysis revealed deletion of the TSHß gene.Our case highlights a rare presentation of central CH with macro-orchidism in a genetically proven deletion of TSHß gene. Macro-orchidism has been widely reported in IGSF-1 mutations leading to central CH; however, central CH and macro-orchidism have not been reported in association with TSHß deletions.

[A case of congenital hypothyroidism and Turner syndrome.] / Un caso di ipotiroidismo congenito e sindrome di Turner.

When properly treated, congenital hypothyroidism (CH) allows normal growth. We describe the case of a girl followed-up for CH diagnosed upon newborn screening, with good adherence to L-T4 therapy, who had an impaired linear growth starting from 4 years of age. Diagnostic work-up allowed exclusion of inflammatory diseases and/or malabsorption and led to the diagnosis of Turner syndrome (TS). Recombinant GH (rGH) therapy was undertaken with satisfactory growth recovery. At the age of 8, a condition of autoimmune thyroiditis was detected, due to an increased risk in the context of her syndrome. Except for small adjustments in the dose of L-T4, hypothyroidism remained well-controlled even after starting rGH therapy.

[Cognitive performance of preschoolers with Congenital Hypothyroidism enrolled in a follow-up program]. / Desempeño cognitivo en preescolares con Hipotiroidismo Congénito incorporados en un programa de seguimiento.

The age at treatment initiation is decisive for limiting the neurological sequelae of Congenital Hypothyroidism (CH). Incorporating children into follow-up programs could be very helpful. OBJECTIVE: To evaluate the cognitive performance of preschool children with CH incorporated into a follow- up program. PATIENTS AND METHOD: Prospective study of 93 patients with a confirmed diagnosis of CH. Intelligence quotient (IQ) was assessed using the Wechsler Preschool and Primary Intelligence Scale (WPPSI) at 4 and 5 years, and the WISC-R at 6 years of age. Full-Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ) scores were analyzed. RESULTS: The study sample was 80 children. The average age at starting hormonal treatment was 42 ± 18 days; treatment started early in 25 patients (24 ± 6 days) and late in 55 patients (50 ± 16 days). The mean initial dose of Levothyroxine was 13.5 ± 1.5µg/kg/day. Children with athyrosis and late initiation of treatment had lower scores on the VIQ (85 ± 14), the PIQ (89 ± 12), and the FSIQ (86 ± 13) scales at 4 years of age, in comparison with patients with early initiation of treatment. These patients scored within the cut-off point for the normal IQ classification (90-109 points). IQ comparison at 6 years of age revealed differences up to 14 points in the PIQ and 11 points in the FSIQ between children with athyrosis and early initiation of treatment, with and without regular attendance to the follow-up program. DISCUSSION: These results support the importance of early initiation of treatment and the incorporation of children in follow-up programs and early stimulation. The etiology of hypothyroidism and the age at initiation of treatment were the most significant factors that affected cognitive performance.

Hepatomegaly and fatty liver disease secondary to central hypothyroidism in combination with macrosomia as initial presentation of IGSF1 deficiency syndrome.

PURPOSE: IGSF1 deficiency syndrome (immunoglobulin superfamily member 1) is considered the most common sex-linked cause of secondary congenital hypothyroidism and is characterized by a wide variety of other clinical and biochemical features, including hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Congenital central hypothyroidism is a rare disease (1:65,000 births); the detection of which may be delayed and missed by neonatal screening programs since most neonatal screening programs are based on TSH determination in dried blood spots only. Untreated hypothyroidism may cause abnormal liver biochemistry and non-alcoholic fatty liver disease. Our aim is to report a case of secondary hypothyroidism in an infant with an uncommon initial presentation. CASE PRESENTATION (METHODS/RESULTS): A 3-month-old male baby was referred to our hospital due to elevated alpha-fetoprotein levels, hypercholesterolemia, and macrosomia. Initial investigations revealed enlarged fatty liver and central hypothyroidism. Pituitary insufficiency was biochemically excluded and a pituitary MRI showed normal findings. Upon genetic analysis, a hemizygous variant NM_001170961.1:c.2422dup, p.(His808Profs*14), in IGSF1 gene was detected, establishing the diagnosis of the IGSF1 deficiency syndrome. In our patient, no other clinical findings were identified. Treatment with levothyroxine led to the remission of liver disease. CONCLUSION: Liver disease may be the initial presentation of secondary hypothyroidism in neonates and infants. Macrosomia in patients with isolated secondary central hypothyroidism is a strong indicator of IGSF1 syndrome.

Eighteen-years follow-up of congenital hypothyroidism by TSHR gene p.Arg109Gln and p.Arg450His variants.

Congenital hypothyroidism (CH) is a common heterogeneous endocrine disorder. The thyroid-stimulating hormone receptor gene (TSHR) is one of the major candidate genes associated with CH. Studies have investigated the possible correlations between the specific clinical features and the presence of TSHR variants. However, only a few reports have focused on the long-term follow-up of patients with CH. Here we present a case of CH-associated TSHR p.Arg109Gln and p.Arg450His rare compound heterozygous variants, with a follow-up performed until adolescence. The patient had high serum TSH levels during newborn screening. Oral administration of levothyroxine (l-T4) was initiated at 1 month of age. The ultrasonogram revealed normal thyroid morphology and blood flow. Reduced uptake of I-123 and negative perchlorate test was observed. A small amount of l-T4 remained needed although l-T4 could be steadily reduced by puberty. The patient was diagnosed with orthotopic, nongoitrous, and permanent CH. He had no nonclassical TSH resistance. Patients with the TSHR p.Arg109Gln compound heterozygous variant exhibit permanent CH with high TSH levels and normal or slightly lower fT4 levels. In the future, genotype identification could help predict the long-term prognosis and reduce the requirement for detailed examinations. More case studies are needed to determine the relationship between genetic variants and clinical features in CH.

Assessment of Neurodevelopment and Growth in Congenital Hypothyroidism: Serial 6-Year Follow-up Study of 408 Patients.

CONTEXT: The link between congenital hypothyroidism (CH) and neurodevelopment is suggested, yet studies applying quantifiable measures are lacking. Moreover, socioeconomic disparities and subtle variation in timing of approach make the relationship difficult to detect. OBJECTIVE: To evaluate associations between CH and abnormalities in neurodevelopment and growth and determine the critical period for intervention. METHODS: We utilized a nationwide database to conduct a longitudinal analysis of 919 707 children. Exposure to CH was identified using claims-based data. The primary outcome of interest was suspected neurodevelopmental disorder, as measured using the Korean Ages & Stages Questionnaires (K-ASQ) administered annually from 9 to 72 months of age. Secondary outcomes were height and BMI z-scores. After randomly matching cases and controls at a 1:10 ratio, we employed inverse probability of treatment weighting and generalized estimating equation models for our analyses. We conducted subgroup analysis based on the age of treatment initiation. RESULTS: The prevalence of CH in our population was 0.05% (n = 408). Relative to the control group, the CH group had higher risk of suspected neurodevelopmental disorders (propensity score-weighted odds ratio: 4.52; 95% CI: 2.91, 7.02), and significantly increased risk in each of the 5 K-ASQ domains. No time interactions were noted at any rounds for the outcomes according to when the neurodevelopmental assessment was conducted (all P for interaction >.05). The CH group also had higher risk for low height-for-age z-score, but not for elevated BMI-for-age z-score. In subgroup analysis, delayed medication for CH correlated with worse neurodevelopmental outcomes. CONCLUSION: The CH group had worse neurodevelopmental outcomes and reduced height-for-age z-score. Outcomes were worse when onset of treatment was increasingly delayed.

Medical Management of Dental Abnormalities Related to Congenital Hypothyroidism in a Cat.

A 5-month-old intact male domestic shorthair cat presenting for routine vaccinations was diagnosed with congenital hypothyroidism. His primary presenting symptom was incomplete dentition with delayed dental eruption. Congenital hypothyroidism was confirmed by baseline thyroxine (T4), free T4, and thyroid-stimulating hormone testing. The cat was treated with oral thyroid hormone supplementation and 16 weeks after initiation of therapy the cat was clinically normal with age-appropriate dentition. No surgical intervention was necessary to achieve normal dental eruption.

Congenital hypothyroidism in children with eutopic gland or thyroid hemiagenesis: prognostic factors for transient vs. permanent hypothyroidism.

OBJECTIVES: More than one third of children with congenital hypothyroidism (CH) and thyroid gland in situ (or eutopic gland) have transient hypothyroidism. It remains difficult to determine early on whether hypothyroidism will be transient which may cause overtreatment and its complications in these children. Our primary aim was to determine prognostic factors for transient hypothyroidism in children with congenital hypothyroidism and eutopic gland or thyroid hemiagenesis. METHODS: We retrospectively reviewed medical records of 111 children, born between 1996 and 2017, diagnosed with congenital hypothyroidism and eutopic gland or hemiagenesis and treated at the Nancy Regional and University Hospital. RESULTS: Fifty four infants (48.6%) had permanent congenital hypothyroidism (PCH) and 57 (51.4%) transient congenital hypothyroidism (TCH). Prognostic factors for TCH included prematurity, twin pregnancy, low birth weight and Apgar score <7, while low FT3 at diagnosis, maternal levothyroxine treatment, a family history of thyroid dysfunction and TSH ≥10 mUI/L while receiving treatment were associated with PCH. Knee epiphyses on X-ray at diagnosis were absent only in children with PCH. The median levothyroxine dose during follow-up was significantly lower in the TCH group compared to the PCH group. A levothyroxine dose of ≤3.95, ≤2.56, ≤2.19 and ≤2.12 µg/kg/day at 6 months, 1, 2 and 3 years of follow-up, respectively, had the best sensitivity-to-specificity ratio for predicting TCH. CONCLUSIONS: Even though it remains difficult to predict the course of hypothyroidism at diagnosis, we were able to identify several prognostic factors for TCH including perinatal problems and lower levothyroxine requirements that can guide the physician on the evolution of hypothyroidism. Clinical Trial Registration Number: NCT04712760.

Adult Thyroid Outcomes of Congenital Hypothyroidism.

Background: More than 40 years have passed since the introduction of newborn screening (NBS) for congenital hypothyroidism (CH), and many early diagnosed patients have reached adulthood. Their thyroid morphology and function have been little studied. This cross-sectional, observational study was conducted to characterize the thyroid morphology and function of adult CH patients diagnosed in the framework of NBS for CH. Methods: A total of 103 adult CH patients born after 1979 were enrolled at Ito Hospital, Tokyo, Japan, and were classified into Goiter, Normal gland, and Dysgenesis groups based on ultrasonographic findings. For 60 patients, genetic analysis was performed. Thyroid function test results and the proportion of patients with thyroid nodules were compared among the three groups and between 56 female CH patients and 168 non-CH women matched for thyrotropin levels. Results: A significantly low serum free triiodothyronine/free thyroxine ratio (0.22) was observed in the Dysgenesis group. Thyroid nodules were detected in 14.3% (8/56) of female CH patients, more frequently than in non-CH women. Thyroid nodules were detected most frequently in the Goiter group (71%, 10/14). Genetic defects were identified in 89% (8/9) of patients belonging to the Goiter group, including thyroglobulin defect (33%, 3/9), thyroid peroxidase defect (33%, 3/9), and dual oxidase 2 defect (22%, 2/9). Conclusions: Our results suggest that adults with thyroid dysgenesis on levothyroxine replacement therapy have relative triiodothyronine deficiency. Most adults with goitrous CH have genetic dyshormonogenesis. They are at high risk of developing thyroid nodules. Our findings support the current guideline recommendation that CH patients with dyshormonogenesis should undergo periodic thyroid ultrasonography.

Different FT3/TSH correlation in acquired and congenital hypothyroid patients reveals a different hypothalamic set-point.

OBJECTIVE: To understand differences in thyroid hormone replacement therapy with levo-thyroxine (l-T4) between acquired and congenital hypothyroid (CH) patients. DESIGN: We compared biochemical thyroid parameters between euthyroid subjects (EU) and both CH adult patients and thyroidectomized patients (TP) under replacement therapy. PATIENTS AND MEASUREMENTS: A retrospective analysis was performed on a series of 98 consecutive adult CH patients (27 males and 71 females) with a median age of 24 years (range 18-58). Serum TSH, FT3, FT4, l-T4 dose and body weight were assessed. For comparison purposes, large series of 461 TP for thyroid cancer and 1852 EU followed at our Thyroid Clinic were used as control groups. RESULTS: The daily weight-based l-T4 dose was significantly higher in CH than TP group (1.9 vs. 1.7 mcg/kg, p = .03). FT3/FT4 ratio was significantly higher in the EU group, intermediate in CH and lower in TP groups (0.32, 0.28 and 0.24, respectively). Linear regression analysis displayed an inverse correlation between FT4 and TSH in all the groups. An inverse correlation between FT3 and TSH was observed in the TP group, but not in the EU and CH group suggesting that CH patients, under replacement therapy, display biochemical thyroid parameters similar to EU subjects. CONCLUSIONS: Adult CH patients require a higher daily l-T4 dose than adult TP. However, the different correlation of TSH and FT3 values between CH and TP patients suggests an adaptive and different hypothalamic-pituitary-thyroid axis regulation that may depend on the early timing of the onset of hypothyroidism in CH.

Clinical survey of current practice regarding treatment of children with borderline thyroid abnormalities.

AIM: Recently, there has been debate about reducing newborn screening (NBS) thyroid-stimulating hormone (TSH) cut-offs to identify children with mild, but potentially clinically significant, thyroid deficiency. Once identified by NBS, these children will be referred to paediatric endocrinologists for further testing and possible treatment; however, variation in current clinical practice is not known. The aim of this study is to survey Paediatric Endocrinologists in Australia and New Zealand to gain insight into clinical practice for the treatment of mild thyroid deficiency. METHODS: A piloted questionnaire was sent to members of the Australasian Paediatric Endocrinologist Group. The survey asked the Australasian Paediatric Endocrinologist Group members about the investigations performed, treatment and follow-up for infants with different confirmatory serum TSH levels. RESULTS: There were 42 completed surveys, a response rate of 34%. When presented with four case studies, 7% of clinicians would treat a child with confirmatory serum TSH of 8.7 mU/L with thyroxine, 69% would treat a child with confirmatory serum TSH 21.4 mU/L, 76% would treat a child with confirmatory serum TSH 24.3 mU/L and 95% would treat a child with confirmatory serum TSH 44.7 mU/L. CONCLUSION: This contemporary survey of clinicians regarding the treatment of mild thyroid deficiency in children has shown that clinical practice varies extensively. International and national guidelines on the treatment of congenital hypothyroidism should be updated to incorporate new evidence and ensure consistency across clinical practice.

Treatment of Congenital Hypothyroidism: Impact of Secular Changes in Levothyroxine Initial Dose on Early Growth.

INTRODUCTION: Newborn screening of congenital hypothyroidism (CH) has enabled early treatment with levothyroxine (LT4), ensuring normal growth and development. The initial LT4 dose recommendation has increased over decades. We evaluated whether the increased LT4 dosing influenced thyroid-stimulating hormone (TSH) and thyroxine (fT4) concentrations, growth, or treatment-related symptoms. METHODS: LT4 doses, TSH, fT4, anthropometrics, and treatment-related symptoms until age 2 years were evaluated in 172 Finnish CH patients born between 1980 and 2018. The patients were grouped according to birth decade: 1980s (n = 19, mean LT4 starting dose 6.8 µg/kg/day), 1990s (n = 50, 7.4 µg/kg/day), 2000s (n = 59, 9.7 µg/kg/day), and 2010s (n = 44, 10.8 µg/kg/day). RESULTS: TSH concentrations were higher during the first 2 years of life in children born in the 1980s compared to children born later. TSH concentrations were often subnormal in children receiving higher LT4 doses (children born in the 2000s and 2010s). However, symptoms of overtreatment were uncommon. Linear or head growth showed no differences between the groups during the first 2 years of life. Although growth was within the normal spectrum, children in all groups were shorter than their target length at 2 years and their weight-for-length was above the mean through the first 2 years of life. DISCUSSION: Current treatment practice with higher LT4 dose normalizes TSH rapidly without significant increase in side effects. However, irrespective of initial LT4 dose, children were shorter than expected at 2 years of age. Effects of different initial LT4 dose on cognitive development urges further investigation.

Clinical and genetic investigation in patients with permanent congenital hypothyroidism.

BACKGROUND: Permanent congenital hypothyroidism (CH) is usually a more severe type of CH. However, the molecular etiology and clinical features of permanent CH remain unclear. METHODS: We recruited 42 patients who were diagnosed with CH and followed-up after diagnosis. Demographic information and data at diagnosis and treatment were recorded. Genetic analyses were performed using whole exome sequencing. Based on the presence or absence of variants and differences in clinical features, we grouped the study participants and analyzed their characteristics. RESULTS: A total of 29 patients (69.0 %) were identified as having variants potentially related to their disease. Among the 24 patients with normal-sized thyroid gland-in-situ (GIS) or goiter, 23 (95.8 %, P < 0.001) had variants. This is compared to 18 patients with thyroid dysgenesis (TD), of which six (33.3 %) had genetic variants. We detected 55 variants in six genes, the most frequently mutated gene being DUOX2 (70.9 %). Biallelic DUOX2 variants were detected in 14 of 24 (58.3 %) GIS or goiter patients. Compared to the cases with variants, the L-T4 dose at 2 and 3 years of age and current dose were higher in the unmutated cases. At 2 years of age, patients with TD required higher doses of L-T4 supplementation. Patients with DUOX2 variants showed lower doses of L-T4 being required at 2 and 3 years of age and current. Furthermore, patients with GIS or goiter with DUOX2 variants showed lower doses of L-T4. CONCLUSIONS: Patients with CH, whether TD or GIS or goiter, are at risk of developing a permanent condition. Compared with patients with TD, the detection of variants was higher in patients with GIS or goiter. The most frequently mutated gene was DUOX2, with a biallelic type. Patients with TD required higher doses of L-T4 supplementation with age, whereas those patients with the DUOX2 variant required relatively lower doses.

Clinical features and outcomes of 31 children with congenital hypothyroidism missed by neonatal screening.

OBJECTIVE: To investigate the clinical features and outcomes of children with congenital hypothyroidism (CH) missed by neonatal screening. METHODS: The clinical and laboratory date of 31 children with CH missed by neonatal screening from February 2015 to February 2022 in Guangzhou Women and Children's Medical Center were retrospectively analyzed. Whole-exome high-throughput sequencing analysis was performed in 17 patients. RESULTS: Among the 31 patients, 19 cases (61.3%) were preterm, 12 cases (38.7%) were term neonates. The median value of gestation age was 36 (26-40) weeks, birth weight was 2.35 (0.75-3.70) kg, diagnosed age was 20 d (7 d-4 years), dry blood spot thyrotropin was 4.18 (0.34-8.97) mU/L. Nine cases (29.0%) were same-sex twins and 4 cases (12.9%) had a family history of hypothyroidism. The initial clinical symptoms were growth retardation in 11 cases (35.5%), prolonged jaundice in 7 cases (22.6%), short stature, abdominal distension, fetal edema and goiter in 1 case (3.2%), respectively. Genetic analysis of the 17 children showed that DUOX2 gene mutations were detected in 10 cases (6 cases with biallelic mutations and 4 cases with monoallelic mutations), of whom 3 had a family history of hypothyroidism. A total of 22 patients were reevaluated at the age of 2-3 years, of whom 17 cases (77.3%) were transient CH and 5 cases (22.7%) were permanent CH. Among the 10 cases with DUOX2 gene mutations, 6 cases were transient CH, 1 case was permanent CH, and 3 cases (< 3 years old) were still under treatment with L-thyroxine. CONCLUSIONS: False negative results on neonatal screening for CH often occurs in preterm birth, low birth weight, same-sex twins, family history of hypothyroidism, and DUOX2 defects are the common molecular pathogenesis, most of whom are transient CH. Thyroid function should be evaluated in time for children with unexplained slow growth and delayed jaundice regression.

Effect of initial levothyroxine dose on neurodevelopmental and growth outcomes in children with congenital hypothyroidism.

Objectives: We designed a multicentre open prospective randomized trial to evaluate the risk-benefit profile of two different initial treatment schemes with levothyroxine (L-T4), 10-12.5 µg/kg/day vs 12.6-15 µg/kg/day, on growth and neurodevelopmental outcomes in children with congenital hypothyroidism (CH) detected by neonatal screening to identify the best range dose to achieve optimal neurocognitive development. Design patients and methods: Children detected by neonatal screening were randomly assigned to receive an initial L-T4 dose of 10-12.5 µg/kg/day (Low) or 12.6-15 µg/kg/day (High). All patients underwent periodical clinical examination with measurement of growth parameters and measurement of TSH and FT4. Neurocognitive development was evaluated at the age of 24 months using Griffiths Mental Development Scales (GMDS) and cognitive and behavioral assessment was performed at 48 months of age using Wechsler Preschool and Primary scale of Intelligence (WIPPSI-III). The study was registered with clinicaltrials.gov (NCT05371262). Results: Treatment schemes below or above 12.5 µg/kg/day were both associated with rapid normalization of TSH and thyroid hormone levels in most patients with no differences in the risk of over- and under-treatment episodes in the first months of life. Growth parameters were normal and comparable between the two groups. Developmental quotients at 24 months of age were normal in both groups (Low 100.6 ± 15.5 vs High 96.9 ± 16.6). Likewise, at 4 years of age IQ and subtest scores were comparable between patients from Low and High (Total IQ 104.2 ± 11.4 vs 101.0 ± 20.3, Verbal IQ 103.9 ± 11.5 vs 98.7 ± 15.1, Performance IQ 105.3 ± 10.4 vs 100.3 ± 19.8). 6/45 CH patients (13.3%) showed a total IQ below 85 (73.7 ± 5.9) regardless of age at diagnosis, L-T4 starting dose, time of FT4 and TSH normalization and episodes of over and undertreatment. Worse socioeconomic status and delayed bone age at diagnosis were the only predictors of an increased risk of having suboptimal IQ at 24 and IQ at 48 months. Conclusions: Our results indicate that initial treatment with L-T4, 10-12.5 µg/kg/day vs 12.6-15 µg/kg/day, are both associated with normal growth and neurodevelopmental outcomes in children with CH detected by neonatal screening. Further studies with a long-term follow-up on a larger number of patients are needed to confirm these results. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT05371262?term=NCT05371262&draw=2&rank=1 identifer NCT05371262.

Primary Congenital Hypothyroidism in Children Below 3 Years Old - Etiology and Treatment With Overtreatment and Undertreatment Risks, a 5-Year Single Centre Experience.

Worldwide neonatal screening for congenital hypothyroidism (CH) is a gold standard of active surveillance in newborns. Prompt diagnosis, subsequent timely treatment implementation, and proper dosage of levothyroxine (L-T4) are crucial for normal growth and development, especially of the central nervous system. However, overtreatment may have a potential negative impact on further neurodevelopment. We retrospectively analysed data of 99 newborns with CH diagnosis, referred to the Endocrinology Outpatient Clinic of the Institute of Mother and Child in Warsaw, Poland from the CH screening program from 2017 to 2021. We evaluated the diagnostic process and treatment up to the age of 3 years. We compared groups of children from the first and the second screening groups (FSG, SSG) in the neonatal screening with an evaluation of ultrasound examination (thyroid dysgenesis vs. gland in situ, GIS). The overtreatment and undertreatment risks were assessed and an analysis of the new TSH thresholds was performed. Treatment was implemented at a median of 9 days of life (3 - 27); 8 days (3 - 17) in FSG and 19 (6 - 27) in SSG. The dose of L-T4 differed between FSG and SSG at all three analysed time points (start of the therapy, 12 months, and 3 years) with significantly higher doses in FSG. The same was observed for the patients with thyroid dysgenesis vs. GIS. Screening TSH level was ≥ 28mIU/l in 91.7% of patients with thyroid dysgenesis in comparison to 74.0% of patients with GIS (p= 0.038). The optimally treated group (fT4 in the upper half of the reference range, according to the guidelines) was up to 58.0% of the children during the follow-up. The risk for overtreatment was present in 1/5 of the study group after 12 months and 1/4 after 3 years of L-T4 therapy. Analysis of new TSH thresholds showed an increased prevalence of mild hypothyroidism, GIS, and either euthyroid state or overtreatment while treating with lower L-T4 doses in comparison to the rest of the cohort. The study confirmed the general efficacy of the CH diagnostic pathway and the timely implemented L-T4 therapy. The suspected overtreatment after the first 12 months of L-T4 therapy requires consideration of the earlier diagnosis re-evaluation.

An Overview on Different L-Thyroxine (l-T4) Formulations and Factors Potentially Influencing the Treatment of Congenital Hypothyroidism During the First 3 Years of Life.

Congenital hypothyroidism (CH) is a relatively frequent congenital endocrine disorder, caused by defective production of thyroid hormones (THs) at birth. Because THs are essential for the development of normal neuronal networks, CH is also a common preventable cause of irreversible intellectual disability (ID) in children. Prolonged hypothyroidism, particularly during the THs-dependent processes of brain development in the first years of life, due to delays in diagnosis, inadequate timing and dosing of levothyroxine (l-thyroxine or l-T4), the non-compliance of families, incorrect follow-up and the interference of foods, drugs and medications affecting the absorption of l-T4, may be responsible for more severe ID. In this review we evaluate the main factors influencing levels of THs and the absorption of l-T4 in order to provide a practical guide, based on the existing literature, to allow optimal follow-up for these patients.

Levothyroxine treatment for congenital hypothyroidism based on thyroid function: a 10-year clinical retrospective study.

OBJECTIVE: To explore the appropriate dosage of levothyroxine treatment for congenital hypothyroidism patients with different thyroid stimulating hormone (TSH) levels. METHODS: A total of 116 patients, who were regularly followed-up in our endocrine clinic from January 2010 to December 2020, were divided into four groups based on their thyroid function (group A: TSH ≥ 100 mIU/L, group B: TSH ≥ 20, and < 100, group C: TSH > 4.6 mIU/L and < 20 mIU/L with free thyroxine (FT4) < 6.6 pmol/L, and group D: TSH > 4.6 mIU/L and < 20 mIU/L with FT4 > 6.6 pmol/L). The initial dosage of levothyroxine was individualized for each patient based on their TSH level and then adjusted according to their thyroid function at every follow-up time point. The levothyroxine dosage at each time point was compared between the groups, and thyroid function and physical and neurological development after treatment were also compared. RESULTS: After individualized dosage adjustment, all patients achieved normal thyroid function. Although there were statistical differences in neurological development between the four groups (p < 0.05), development was within the normal range for all groups. CONCLUSION: An individualized levothyroxine dosage can provide the same therapeutic effect compared to the recommended dosage. This strategy may also reduce the risk of a drug overdose.