Late-onset dyshormonogenic goitrous hypothyroidism due to a homozygous mutation of the SLC26A7 gene: a case report.

BACKGROUND: In this study, we used targeted next-generation sequencing (NGS) to investigate the genetic basis of congenital hypothyroidism (CH) in a 19-year-old Tunisian man who presented with severe hypothyroidism and goiter. CASE PRESENTATION: The propositus reported the appearance of goiter when he was 18. Importantly, he did not show signs of mental retardation, and his growth was proportionate. A partial organification defect was detected through the perchlorate-induced iodide discharge test. NGS identified a novel homozygous mutation in exon 18 of the SLC26A7 gene (P628Qfs*11), which encodes for a new iodide transporter. This variant is predicted to result in a truncated protein. Notably, the patient's euthyroid brother was heterozygous for the same mutation. No renal acid-base abnormalities were found and the administration of 1 mg of iodine failed to correct hypothyroidism. CONCLUSIONS: We described the first case of goitrous CH due to a homozygous mutation of the SLC26A7 gene diagnosed during late adolescence.

High-resolution melt curve analysis: An approach for variant detection in the TPO gene of congenital hypothyroid patients in Bangladesh.

TPO (Thyroid Peroxidase) is known to be one of the major genes involved in congenital hypothyroid patients with thyroid dyshormonogenesis. The present study aims to validate high-resolution melting (HRM) curve analysis as a substitute method for Sanger sequencing, focusing on the frequently observed non-synonymous mutations c.1117G>T, c.1193G>C, and c.2173A>C in the TPO gene in patients from Bangladesh. We enrolled 36 confirmed cases of congenital hypothyroid patients with dyshormonogenesis to establish the HRM method. Blood specimens were collected, and DNA was extracted followed by PCR and Sanger sequencing. Among the 36 specimens, 20 were pre-sequenced, and variants were characterized through Sanger sequencing. Following pre-sequencing, the 20 pre-sequenced specimens underwent real-time PCR-HRM curve analysis to determine the proper HRM condition for separating the three variations from the wild-type state into heterozygous and homozygous states. Furthermore, 16 unknown specimens were subjected to HRM analysis to validate the method. This method demonstrated a sensitivity and specificity of 100 percent in accurately discerning wild-type alleles from both homozygous and heterozygous states of c.1117G>T (23/36; 63.8%), c.1193G>C (30/36; 83.3%), and c.2173A>C (23/36; 63.8%) variants frequently encountered among 36 Bangladeshi patients. The HRM data was found to be similar to the sequencing result, thus confirming the validity of the HRM approach for TPO gene variant detection. In conclusion, HRM-based molecular technique targeting variants c.1117G>T, c.1193G>C, and c.2173A>C could be used as a high throughput, rapid, reliable, and cost-effective screening approach for the detection of all common mutations in TPO gene in Bangladeshi patients with dyshormonogenesis.

Newborn screening in Colombia: The experience of a private program in Bogotá / Tamizaje neonatal en Colombia: la experiencia de un programa privado en Bogotá.

Introduction. The first neonatal screening program in Colombia ­ PREGEN ­ was set up in the medical private sector of Bogotá in 1988. We report the results from recent years that, given the scarcity of similar information in our country, may help estimate the frequency of the evaluated neonatal disorders and which ones should be included in the neonatal screening programs in our country. Objective. To describe the results of PREGEN´s newborn screening program between 2006 and 2019. Materials and methods. We analyzed databases and other informative documents preserved in PREGEN from the 2006-2019 period. Results. One in every 164 newborns screened in our program had an abnormal hemoglobin variant, and one in every 194 carried some hemoglobin S variant. Glucose-6- phosphate dehydrogenase deficiency and congenital hypothyroidism are next as the more common disorders. Conclusions. Abnormal hemoglobin causes the most frequent monogenic disorder in the world. Glucose-6-phosphate dehydrogenase deficiency is the most common enzymopathy affecting nearly 400 million individuals worldwide. Since both disorders are more common in people of African descent and confer some resistance to malaria, we believe that screening for both disorders may be more relevant in the areas with African ancestry in our country.

Introducción. En Colombia, el primer programa de tamizaje neonatal, PREGEN, inició labores en el sector privado de Bogotá en 1988. En este artículo se presentan los resultados obtenidos en los últimos años, que, dada la carencia de estos estudios en el país, pueden servir para evaluar la frecuencia de aparición de los trastornos congénitos evaluados y estimar cuáles de ellos deben ser objeto de tamizaje neonatal a nivel nacional. Objetivos. Reportar los resultados del programa de tamizaje PREGEN entre el 2006 y el 2019. Materiales y métodos. Para este análisis se examinaron las bases de datos y otros documentos informativos de PREGEN para el periodo 2006-2019. Resultados. Uno de cada 164 recién nacidos tamizados en el programa PREGEN en Bogotá presentó una variante anormal de la hemoglobina y uno de cada 194 es portador de hemoglobina S. Los siguientes dos trastornos más frecuentes encontrados fueron la deficiencia de la enzima glucosa-6-fosfato deshidrogenasa (frecuencia 1:2.231) y el hipotiroidismo congénito (frecuencia 1:3.915). Conclusiones. Las hemoglobinopatías mostraron ser uno de los desórdenes monogénicos más comunes, seguidos por la deficiencia de glucosa-6-fosfato deshidrogenasa y el hipotiroidismo congénito. Se calcula que cerca de 400 millones de personas en el mundo están afectadas por la deficiencia de glucosa-6-fosfato deshidrogenasa, por lo cual es la enzimopatía más común en el mundo. Como ambos desórdenes son más frecuentes en poblaciones de origen africano y confieren algún grado de resistencia a la malaria, es de prever que su tamizaje debe ser de mayor importancia en las zonas con ancestros africanos en Colombia.

A novel useful marker in the early discrimination of transient hyperthyrotropinemia/hypothyroxinemia and congenital hypothyroidism in preterm infants: thyroid-stimulating hormone/free thyroxine ratio.

OBJECTIVES: Transient hyperthyrotropinemia/transient hypothyroxinaemia and congenital hypothyroidism (CH) have completely different treatment and clinical outcomes. However, a powerful, highly sensitive and cost-effective marker for the differentiation of these clinical entities in the early postnatal period is not available. Therefore, we aimed to test the potential, early predictive, diagnostic power of the thyroid-stimulating hormone (TSH)/free thyroxine (fT4) ratio for differentiation of the two clinical entities in the early period of life. METHODS: TSH and fT4 levels were recorded on the postnatal day 7 of premature infants<32 weeks of gestational age. TSH/fT4 ratio was calculated. The significance degree of TSH/fT4 ratio was analyzed for the differentiation of transient hyperthyrotropinemia or transient hypothyroxinaemia and CH. RESULTS: The study included 1,204 preterm infants<32 weeks of gestational age. Of the 1,204 infants, 978 (81.2 %) had normal thyroid function. Eighty-eight infants (7.3 %) were diagnosed with CH and 138 (11.5 %) with transient hyperthyrotropinemia or transient hypothyroxinemia. Initial TSH/fT4 ratio>4.8 was found to be an early diagnostic warning sign with high power in favor of transient hyperthyrotropinemia or transient hypothyroxinemia (AUC value: 0.947) and TSH/fT4 ratio>12.5 (AUC value: 0.999) was found to be an early diagnostic warning sign with high power in favor of CH (p=0.0001). CONCLUSIONS: We found for the first time that the TSH/fT4 ratio can be used for the early differentiation of transient hyperthyrotropinemia/transient hypothyroxinaemia and CH in preterm infants without additional cost and with high power.

Clinical and magnetic resonance imaging findings in a French bulldog puppy with genetically confirmed congenital hypothyroidism.

A 7-month-old male French bulldog was referred for abnormal mentation and gait. Physical examination revealed a dome shaped calvarium and persistent bregmatic fontanelle. Neurological examination revealed proprioceptive ataxia, pelvic limb paraparesis and strabismus with moderate ventriculomegaly, thinning of the cerebral parenchyma, and widened cerebral sulci on magnetic resonance imaging. Masses were identified in the region of the thyroid, which appeared heterogeneous and hyperintense in T1-weighted and T2-weighted compared with the adjacent muscle signal masses were identified. Radiological diagnosis was hydrocephalus "ex vacuo" and goiter. Blood test revealed abnormally low total thyroxine (TT4), free thyroxine (FT4), and normal thyrotropin concentration. A diagnosis of congenital hypothyroidism was confirmed by positive genetic test for thyroid peroxidase mutation. Thyroxine supplementation treatment rapidly improved clinical signs.

Clinical and molecular analyses of isolated central congenital hypothyroidism based on a survey conducted in Japan.

Central congenital hypothyroidism (CH) can occur as an isolated deficiency or as part of combined pituitary hormone deficiency. Unlike primary CH, central CH cannot be detected by newborn screening (NBS) using dry filter paper blood TSH levels, and early diagnosis remains challenging. In this study, the clinical and genetic backgrounds of patients with isolated central CH were determined through a questionnaire-based survey among members of the Japanese Society for Pediatric Endocrinology. The known causes of isolated central CH were studied in 14 patients, including six with previously reported patient data. The results revealed IGSF1 and TBL1X pathogenic variants in nine and one patient, respectively. All six patients with low free thyroxine (FT4) levels detected in NBS carried IGSF1 pathogenic variants. Five patients with isolated central CH diagnosed after 3 months of age were variant-negative, except for one female patient with a heterozygous IGSF1 variant. Two of the four variant-negative patients and a variant-positive patient were diagnosed with pituitary hypoplasia. One and two patients with IGSF1 variant had obesity and intellectual disability, respectively. Left amblyopia was identified in the patient with a TBL1X variant. The study revalidated that IGSF1 variants comprise the most frequent pathogenic variant in patients with isolated central CH in Japan. The neonatal period is the optimal time for the diagnosis of central CH, particularly IGSF1 abnormalities, and the introduction of T4 screening should be considered in the future, taking cost-effectiveness into consideration.

TSHR Variant Screening and Phenotype Analysis in 367 Chinese Patients With Congenital Hypothyroidism.

Background: Genetic defects in the human thyroid-stimulating hormone (TSH) receptor (TSHR) gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype-phenotype relationships for most TSHR variants associated with CH remain unexplored. We aimed to identify TSHR variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships between TSHR genotypes and clinical phenotypes. Methods: In total, 367 patients with CH were recruited for TSHR variant screening using whole-exome sequencing. The effects of the variants were evaluated by in-silico programs such as SIFT and polyphen2. Furthermore, these variants were transfected into 293T cells to detect their Gs/cyclic AMP and Gq/11 signaling activity. Results: Among the 367 patients with CH, 17 TSHR variants, including three novel variants, were identified in 45 patients, and 18 patients carried biallelic TSHR variants. In vitro experiments showed that 10 variants were associated with Gs/cyclic AMP and Gq/11 signaling pathway impairment to varying degrees. Patients with TSHR biallelic variants had lower serum TSH levels and higher free triiodothyronine and thyroxine levels at diagnosis than those with DUOX2 biallelic variants. Conclusions: We found a high frequency of TSHR variants in Chinese patients with CH (12.3%), and 4.9% of cases were caused by TSHR biallelic variants. Ten variants were identified as loss-of-function variants. The data suggest that the clinical phenotype of CH patients caused by TSHR biallelic variants is relatively mild. Our study expands the TSHR variant spectrum and provides further evidence for the elucidation of the genetic etiology of CH.

Screening for Delayed Thyroid Stimulation Hormone Rise and Atypical Congenital Hypothyroidism in Infants Born Very Preterm and Infants with Very Low Birth Weight.

OBJECTIVE: To determine among infants born very preterm (VPT) or with very low birth weight (VLBW) the incidence of alterations in thyroid function and associated comorbidities; the incidence of atypical congenital hypothyroidism (CH) requiring thyroxine therapy; and reference ranges for rescreening at 1 month of age. STUDY DESIGN: A retrospective review of infants born VPT or with VLBW and admitted to UC Irvine Medical Center between January 1, 2012, and December 31, 2020. Repeat thyroid screening was obtained at 1 month of life (+10 days). Infants with thyroid-stimulating hormone (TSH) >5 µIU/mL or free thyroxine <0.8 ng/dL underwent follow-up testing and endocrinology consultation. Initial newborn screening (NBS) and repeat thyroid screening data were collected via chart review. Demographic data and short-term outcomes were abstracted from the California Perinatal Quality Care Collaborative database. RESULTS: In total, 430 patients were included; 64 of 429 patients (14.9%) had TSH >5 µIU/mL and 20 of 421 patients (4.8%) had free thyroxine <0.8 ng/dL. Logistic regression analysis identified small for gestational age (P = .044), patent ductus arteriosus (P = .013), and late-onset sepsis (P = .026) as risk factors associated with delayed TSH rise. Atypical CH requiring treatment through neonatal intensive care unit discharge was diagnosed in 6 patients (incidence of 1.4%); none were identified by NBS. The 90th percentile TSH for infants with extremely low birth weight (<1000 g) was 7.2 µIU/mL, and the 95th percentile for those with birth weight of 1000-1500 g was 6.1 µIU/mL; using these cutoff values identified all infants diagnosed with atypical CH with 100% sensitivity and 90%-95% specificity. CONCLUSIONS: Abnormal thyroid function is common in infants born preterm. Those infants, including some with atypical CH, are missed by NBS. We recommend repeat thyroid screening with TSH at 1 month of age in infants born VPT or infants with VLBW to identify CH that may require therapy.

A literature review on the redundancy of additional thyroid function tests in neonates of mothers with hypothyroidism.

AIM: Newborn thyroid screening tests are carried out during the first days after birth in many parts of the world. The aim of this review was to assess whether additional thyroid function tests of neonates born to mothers with hypothyroidism are necessary to diagnose newborns with congenital hypothyroidism (CH) missed by the usual screening test. METHODS: A search in PubMed and Google Scholar databases was conducted for pertinent studies, using relevant keywords. All studies that were published in any language from 1 January 2000 to 30 June 2023 were included. Observational cohort studies were included in the analysis, while case reports and studies not referring to neonates were excluded. RESULTS: Thirteen studies were identified comprising more than 4400 infants with CH. Studies with the larger study populations recommended against additional testing in healthy infants of hypothyroid mothers. Similar were the results of some smaller retrospective studies. Few studies identified in total 16 infants with CH that were missed on neonatal screening without, though, a definite causative link between the mother's and the infant's thyroid dysfunction. CONCLUSION: Based on available data, additional thyroid function tests seem redundant in identifying undiagnosed cases of CH. Larger studies are needed to reach a definite conclusion.

Hoffmann's syndrome in subclinical hypothyroidism.

Hypothyroidism is an endocrine disorder which occurs due to a deficiency of thyroid hormones. Hoffmann's syndrome is a rare complication of hypothyroidism - presenting as hypothyroid myopathy. We describe the case of a 20-year-old lactating female, known to have hypothyroidism (diagnosed during her pregnancy and having discontinued treatment following delivery), presenting with complaints of pain, swelling of bilateral calf muscles with cramps in bilateral lower limbs. Symptoms of muscle pseudohypertrophy with muscle stiffness are relatively rare in subclinical hypothyroidism and it is important to identify and diagnose this rare condition, and initiate appropriate treatment.

Evaluation of patients diagnosed with congenital hypothyroidism by newborn screening between 2011-2019 in Diyarbakir, Turkey.

This study aimed to determine the incidence of congenital hypothyroidism in Turkey's Diyarbakir Province and assess the development and growth conditions of people with congenital hypothyroidism. Patients born between 2011-2019 and diagnosed with congenital hypothyroidism within the scope of the newborn screening program were included. The medical records of these patients were retrospectively reviewed. The length and weight for age, weight for length, and body mass index standard deviation scores were calculated. We investigated the treatment status of the patients, whether their relatives had a similar disorder, and the presence of consanguinity between parents. Blood samples were collected from 380,592 newborns. As a result of further tests, 498 newborns were diagnosed with congenital hypothyroidism (incidence: 1/764). Demographic and anthropometric data of 241 patients were analyzed. The patients comprised 46.9% (n = 113) females and 53.1% (n = 128) males. It was determined that 44.4% of the individuals had transient congenital hypothyroidism and 53.6% had permanent congenital hypothyroidism. The parents of 29.8% of the individuals diagnosed with transient congenital hypothyroidism and 44.2% of the individuals diagnosed with permanent congenital hypothyroidism were consanguineous (P = .02). According to the latest anthropometric assessment, 6.8% of individuals diagnosed with congenital hypothyroidism had a weight z-score below -2 SD and 16.9% had a length z-score below -2 SD. The incidence of congenital hypothyroidism was higher in our region. The ratio of consanguinity between parents was higher in patients diagnosed with permanent congenital hypothyroidism than in those diagnosed with transient congenital hypothyroidism. According to the most recent follow-up, weight and age were found to be similar in patients with transient and permanent congenital hypothyroidism.

Results of neonatal screening for congenital hypothyroidism and hyperphenylalaninemia in Zhejiang province from 1999 to 2022. / 浙江省1200ä¸‡ä¾‹æ–°ç”Ÿå„¿å ˆå¤©æ€§ç”²çŠ¶è ºåŠŸèƒ½å‡é€€ç—‡ã€é«˜è‹¯ä¸™æ°¨é ¸è¡€ç—‡ç­›æŸ¥ç»“æžœåˆ†æž.

OBJECTIVES: To analyze the results of neonatal screening for congenital hypothyroidism (CH) and hyperphenylalaninemia (HPA) in Zhejiang province from 1999 to 2022. METHODS: A total of 11 922 318 newborns were screened from September 1999 and December 2022 in Zhejiang province. The blood thyroid stimulating hormone (TSH) levels were measured by a fluorescence method and blood phenylalanine (Phe) levels were measured by fluorescence method or tandem mass spectrometry. TSH≥9 µIU/mL was considered positive for CH, while Phe>120 µmol/L and/or Phe/Tyr ratio>2.0 were considered positive for HPA. The positive newborns in screening were recalled, and the gene variations were detected by high-throughput sequencing and MassARRAY tests. RESULTS: The overall neonatal screening rate during 1999-2022 was 89.41% (11 922 318/13 333 929) and the screening rate was increased from 6.46% in 1999 to 100.0% in 2022. A total of 8924 cases of CH were diagnosed among screened newborns with an incidence rate of 1/1336. A total of 563 cases of HPA were diagnosed, including 508 cases of classic phenylketonuria (cPKU) and 55 cases of tetrahydrobiopterin deficiency (BH4D), with an incidence rate of 1/21 176. Ninety-seven out of 8924 cases of CH underwent genetic analysis. Gene mutations were detected in 9 CH related genes, the highest frequency mutations were found in DUOX2 gene (69.0%) with c.3329G>A (p.R1110Q) (18.2%) and c.1588A>T (p.K530X) (17.3%) as the hotspot mutations. There were 81 PAH gene variants detected in a total of 250 cases of cPKU, and c728G>A (p.R243Q) (24.4%), c.721C>T (p.R241C) (15.0%) were the hotspot mutations. Meanwhile 7 novel variants in PAH gene were detected: c.107C>A (p.S36*), c.137G>T (p.G46V), c.148A>G(p.K50E), c.285C>T (p.I95I), c.843-10delTTCC, exon4-7del and c.1066-2A>G. There were 12 PTS gene variants detected in 36 cases of BH4D, and c.259C>T (p.P87S) (31.9%) was the hotspot mutation. CONCLUSIONS: The incident of CH has increased from 1999 to 2022 in Zhejiang province, and it is higher than that of national and global levels; while the incidence of HPA is similar to the national average. DUOX2 gene variation is the most common in CH patients; c.728G>A (p.R243Q) is the hotspot mutation in cPKU patients, while c.259C>T (p.P87S) is the hotspot mutation in BH4D patients.

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.

Homozygous Mutations in Thyroid Peroxidase (TPO) in Hypothyroidism with Intellectual Disability, Developmental Delay, and Hearing and Ocular Anomalies in Two Families: Severe Manifestation of Untreated TPO-deficiency Poses a Diagnostic Dilemma.

Intellectual disability (ID) involves compromised intellectual, learning and cognitive skills, and behavioral capabilities with reduced psychomotor skills. One of the preventable causes of ID is congenital hypothyroidism (CH), which may be due to biallelic mutations in thyroid peroxidase (TPO). In low- and middle-income countries with no newborn screening programs, CH poses a great risk of ID and long-term morbidity. We report two large Pakistani families with a total of 16 patients afflicted with CH. Detailed clinical and behavioral assessments, SNP-based homozygosity mapping, linkage analysis, and exome sequencing were performed. Initially, affected individuals were referred as suffering ID (in 11 of 16 patients) and developmental delay (in 14). Secondary/associated features were verbal apraxia (in 13), goiter (in 12), short stature (in 11), limb hypotonia (in 14), no pubertal onset (five of 10 of age ≥14 years), high myopia (in eight), muscle cramps (in six), and in some, variable microcephaly and enuresis/encopresis, fits, chronic fatigue, and other behavioral symptoms, which are not characteristics of CH. Molecular genetic analyses led to the discovery of homozygous variants in TPO: novel missense variant c.719A>G (p.Asp240Gly) in family 1 and rare c.2315A>G (p.Tyr772Cys) in family 2. In low-resource countries where neonatal screening programs do not include a CH test, the burden of neurodevelopmental disorders is likely to be increased due to untreated CH. Secondly, in the background of the high prevalence of recessive disorders due to high parental consanguinity, the severe manifestation of TPO-deficiency mimics a wide range of neurological and other presentations posing a diagnostic dilemma.

Two Cases of Congenital Hypothyroidism Revealing Thyroid Agenesis.

Congenital hypothyroidism (CH) may have major detrimental effects on growth and neurological development, but early intervention leads to excellent outcomes. CH is classified as transient or permanent, primary or secondary, with primary CH being the most common neonatal endocrine disorder. Most patients with CH do not present any typical signs and symptoms of hypothyroidism shortly after birth, partly due to transplacental maternal thyroid hormone transfer and residual neonatal thyroid function. This paper reports on two CH cases. During the initial Neonatal Intensive Care Unit (NICU) admission phase, CH was not suspected due to nonspecific signs. The distinct characteristics of our cases are as follows: both infants were admitted to the NICU for respiratory distress syndrome, requiring invasive mechanical ventilation, and both were born to diabetic mothers. Following extubation, they both showed similar neurological issues, including reduced muscle tone and feeding difficulties. Initially, those symptoms were attributed to delayed clearance of analgesic and sedative medication. However, symptoms progressively worsened over time. Subsequent tests revealed both meeting CH diagnostic criteria: an unusual ultrasound indicating thyroid agenesis and abnormal hormone levels. Guided by the pediatric endocrinology team, prompt hormonal treatment was started with improvements in neurocognitive function and feeding. Usually, CH screening involves blood samples from healthy newborns at 2-3 days of life. Abnormal results require confirmation, prompting treatment within two weeks. Certain NICU-admitted infants face higher diagnosis delays, as seen in those two cases where CH screening was postponed. Thus, for all neonates with persistent pathologies unresponsive to standard etiological treatment, conducting a comprehensive anamnestic evaluation of the medical history, along with maternal preconceptional and prenatal nutrition, is recommended.

Optimizing the Dutch newborn screening for congenital hypothyroidism by incorporating amino acids and acylcarnitines in a machine learning-based model.

Objective: Congenital hypothyroidism (CH) is an inborn thyroid hormone (TH) deficiency mostly caused by thyroidal (primary CH) or hypothalamic/pituitary (central CH) disturbances. Most CH newborn screening (NBS) programs are thyroid-stimulating-hormone (TSH) based, thereby only detecting primary CH. The Dutch NBS is based on measuring total thyroxine (T4) from dried blood spots, aiming to detect primary and central CH at the cost of more false-positive referrals (FPRs) (positive predictive value (PPV) of 21% in 2007-2017). An artificial PPV of 26% was yielded when using a machine learning-based model on the adjusted dataset described based on the Dutch CH NBS. Recently, amino acids (AAs) and acylcarnitines (ACs) have been shown to be associated with TH concentration. We therefore aimed to investigate whether AAs and ACs measured during NBS can contribute to better performance of the CH screening in the Netherlands by using a revised machine learning-based model. Methods: Dutch NBS data between 2007 and 2017 (CH screening results, AAs and ACs) from 1079 FPRs, 515 newborns with primary (431) and central CH (84) and data from 1842 healthy controls were used. A random forest model including these data was developed. Results: The random forest model with an artificial sensitivity of 100% yielded a PPV of 48% and AUROC of 0.99. Besides T4 and TSH, tyrosine, and succinylacetone were the main parameters contributing to the model's performance. Conclusions: The PPV improved significantly (26-48%) by adding several AAs and ACs to our machine learning-based model, suggesting that adding these parameters benefits the current algorithm.

[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.