Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update-An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology.

An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH.

Determination of thyroid volume in infants with suspected congenital hypothyroidism-the limitations of both subjective and objective evaluation.

Objective: To compare two methods of assessing gland size on thyroid ultrasound in newborn infants with suspected congenital hypothyroidism (CH).

Methods: Images from infants with eutopic glands referred between 2007 and 2013 were evaluated blind by two sets of observers. Subjective gland size was categorised as small, borderline-small, normal, borderline-large and large.

Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS.

Patients diagnosed with pseudohypoparathyroidism type Ia (PHP Ia) suffer from hormonal resistance and abnormal postural features, in a condition classified as Albright hereditary osteodystrophy (AHO) syndrome. This syndrome is linked to a maternally inherited mutation in the GNAS complex locus, encoding for the GTPase subunit Gsα. Here, we investigated how platelet phenotype and omics analysis can assist in the often difficult diagnosis.

A Novel Homozygous Mutation in the Solute Carrier Family 26 Member 7 Gene Causes Thyroid Dyshormonogenesis in a Girl with Congenital Hypothyroidism.

We investigated the genetic cause of thyroid dyshormonogenesis in a girl with congenital hypothyroidism. Genetic analysis showed that she was homozygous for a hitherto not described mutation (c.1432_1433delGT, p.

Thyroid surgery in children and young adults: potential overtreatment and complications.

Purpose: Thyroid nodules in the pediatric population are more frequently associated with malignant thyroid disease than in adult cohorts. Yet, there is a potential risk of surgical overtreatment. With this single center study, an analysis of potential overtreatment for suspected malignant thyroid disease in children and young adults was aimed for.

Identification of Transient Receptor Potential Channel 4-Associated Protein as a Novel Candidate Gene Causing Congenital Primary Hypothyroidism.

Background: Congenital primary hypothyroidism (CH) is the most common endocrine disorder in neonates.

Methods: To identify novel genes, we performed whole exome sequencing (WES) in 6 patients with CH due to thyroid dysgenesis (TD). The potential effects of the most relevant variants were analyzed using in silico prediction tools.

Novel Mutations in the NKX2.1 gene and the PAX8 gene in a Boy with Brain-Lung-Thyroid Syndrome.

Objective: To elucidate the molecular mechanism which causes thyroid dysgenesis (TD) in a boy with brain-lung-thyroid syndrome.

Design, Patients, Measurements: We describe a patient with TD, respiratory disease and cerebral palsy who is heterozygous for mutations in two different genes, the PAX8 (p.E234K) and the NKX2.

A further case of brain-lung-thyroid syndrome with deletion proximal to NKX2-1.

Brain-lung-thyroid syndrome (OMIM #610978) is associated with mutations in the NK2 homeobox 1 (NKX2-1) gene, a transcription factor important in development. 50% of patients are affected by the full triad, comprising congenital hypothyroidism, benign hereditary chorea and infant respiratory distress syndrome. Four cases have previously been reported where a patient has features consistent with brain-lung-thyroid syndrome and a chromosome 14q13 deletion adjacent to, but not disrupting, NKX2-1.

Familial Central Hypothyroidism Caused by a Novel IGSF1 Gene Mutation.

Background: Congenital hypothyroidism of central origin (CH-C) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin stimulation of a normal thyroid gland. A recently described syndrome of isolated CH-C and macroorchidism was attributed to loss-of-function mutations of the immunoglobulin superfamily, member 1 gene (IGSF1).

Patients And Methods: CH-C was diagnosed in three siblings.

A novel deletion in the thyrotropin Beta-subunit gene identified by array comparative genomic hybridization analysis causes central congenital hypothyroidism in a boy originating from Turkey.

Background: Isolated central congenital hypothyroidism (ICCH) is rare but important. Most ICCH patients are diagnosed later, which results in severe growth failure and intellectual disability.

Objective: We describe a boy with ICCH due to a large homozygous TSHβ gene deletion.

A new mutation in the promoter region of the PAX8 gene causes true congenital hypothyroidism with thyroid hypoplasia in a girl with Down's syndrome.

Background: Thyroid dysfunction is common in newborn infants with Down's syndrome (DS), but defects causing classic thyroid dysgenesis (TD) with permanent congenital hypothyroidism (CH) have not been described.

Objective: We studied a girl with DS and CH who had a mutation in the promoter sequence of the PAX8 gene.

Results: A female infant was found to have trisomy 21 and CH, with a venous thyrotropin (TSH) of >150 mU/L and a free thyroxine (fT4) of 15.

Diagnostic and predictive value of ultrasound and isotope thyroid scanning, alone and in combination, in infants referred with thyroid-stimulating hormone elevation on newborn screening.

Objective: To determine the diagnostic and predictive value of ultrasound and radioisotope scans of the thyroid, alone and in combination, during a single visit after initial referral by the screening laboratory with thyroid-stimulating hormone (TSH) elevation.

Study Design: Retrospective blind review of ultrasound and radioisotope images followed by final diagnosis based on clinical features, biochemistry, imaging, and molecular genetic study.

Results: Infants (n = 97; 61 female) with median birthweight 3.

A new PAX8 mutation causing congenital hypothyroidism in three generations of a family is associated with abnormalities in the urogenital tract.

Background: Although thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH), its molecular basis remains largely elusive. Indeed, in only a minority of cases with thyroid dysgenesis (2%-3%) was it possible to identify an underlying genetic defect. The objective of this study was to screen the PAX8 gene and the PAX2 gene in a family with six cases of CH spanning three generations and presenting urogenital malformations.

A clinically euthyroid child with a large goiter due to a thyroglobulin gene defect: clinical features and genetic studies.

A 10-year old child born to consanguineous parents presented with an extremely large goiter, a low free T4 level and free T4 index, and normal TSH concentration. The findings of undetectable thyroglobulin (TG) and low free T4, and an elevated free T3/free T4 ratio suggested the possibility of a defect in TG synthesis. Noteworthy aspects of this case were the extremely elevated thyroidal radioiodide uptake despite a normal TSH concentration and the fact that the reduction in the size of her goiter only occurred when her TSH was suppressed below the normal range.

Novel heterozygous thyrotropin receptor mutation presenting with neonatal hyperthyrotropinaemia, mild thyroid hypoplasia and absent uptake on radioisotope scan.

Hyperthyrotropinaemia [mildly elevated thyrotropin (TSH) with normal thyroxine (T4) levels] demands a full assessment, including clinical examination, thyroid imaging and, where indicated, molecular genetic investigations. A male infant, both of whose parents were on T4 treatment, was referred at age 57 days with mild but persistent TSH elevation (12.7 mU/L) and normal free T4 (19.

Two cases of thyroid dysgenesis caused by different novel PAX8 mutations in the DNA-binding region: in vitro studies reveal different pathogenic mechanisms.

Background: Mutations in PAX8, a transcription factor gene, cause thyroid dysgenesis (TD). The extreme variability of the thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q).

A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations.

Background: Pompe disease (Glycogen storage disease type II, GSD II, acid alpha-glucosidase deficiency, acid maltase deficiency, OMIM # 232300) is an autosomal-recessive lysosomal storage disorder due to a deficiency of acid alpha-glucosidase (GAA, acid maltase, EC 3.2.1.

Minimally invasive follicular thyroid carcinoma developed in dyshormonogenetic multinodular goiter due to thyroid peroxidase gene mutation.

Background: The occurrence of thyroid carcinoma in patients with congenital hypothyroidism (CH) caused by dyshormonogenesis is very rare, and has only been reported in one patient harboring mutations in the thyroid peroxidase (TPO) gene.

Patient Findings: We report on a 29-year follow-up of two consanguineous siblings with CH due to total iodide organification defect who also had sensorineural hearing loss. Molecular analysis revealed a novel biallelic mutation of the TPO gene in which phenylalanine substitutes serine at codon 292 (c.

A new heterozygous mutation (D196N) in the Gs alpha gene as a cause for pseudohypoparathyroidism type IA in a boy who had gallstones.

Background: Pseudohypoparathyroidism (PHP) is characterized by hypocalcemia and hyperphosphatemia in association with an increased secretion of parathyroid hormone (PTH) due to decreased target tissue responsiveness to PTH. Patients with PHP type Ia are not only resistant to PTH, but also to other hormones that bind to receptors coupled to stimulatory G protein (Gsalpha). PHP Ia and Albright hereditary osteodystrophy (AHO) are caused by a reduced activity of the Gsalpha protein.

Mutations in the NKX2.5 gene and the PAX8 promoter in a girl with thyroid dysgenesis.

Context: Screening of the known candidate genes involved in thyroid organogenesis has revealed mutations in a small subset of patients with congenital hypothyroidism due to thyroid dysgenesis (TD).

Objective: We studied a girl with TD who had mutations in two transcription factors involved in thyroid development.

Results: Sequencing analysis of candidate genes involved in thyroid gland development revealed a new paternally inherited heterozygous mutation in the NKX2.

A single copy of the recently identified dual oxidase maturation factor (DUOXA) 1 gene produces only mild transient hypothyroidism in a patient with a novel biallelic DUOXA2 mutation and monoallelic DUOXA1 deletion.

Context: Dual oxidases (DUOX1 and DUOX2) play a crucial role in the generation of hydrogen peroxide required in the oxidation of iodide and the synthesis of thyroid hormone. Heterodimerization with specific maturation factors (DUOXA1 and DUOXA2) is essential for the maturation and function of the DUOX enzyme complexes. Biallelic loss-of-function mutations of DUOX2 result in congenital hypothyroidism (CH), whereas a single reported case of homozygous DUOXA2 mutation (Y246X) has been associated with mild CH.

Congenital Central Hypothyroidism due to a Homozygous Mutation in the TSHβ Subunit Gene.

Congenital central hypothyroidism (CCH) is a rare condition occurring in 1 : 20000 to 1 : 50000 newborns. As TSH plasma levels are low, CCH is usually not detected by TSH-based neonatal screening for hypothyroidism, and, as a result, diagnosis is often delayed putting affected children at risk for developmental delay and growth failure. We report on a girl with isolated central hypothyroidism due to a homozygous one-base pair deletion (T313del) in exon 3 of the TSHβ subunit gene.

Detection of papillary thyroid carcinoma by analysis of BRAF and RET/PTC1 mutations in fine-needle aspiration biopsies of thyroid nodules.

Background: Activating mutations of the oncogene BRAF or rearrangements of the tyrosine kinase receptor RET are observed in up to 80% of papillary thyroid carcinomas (PTCs). The predominant BRAF V600E mutation has not been detected in benign thyroid tissue so far, so consequently, this assumedly pathognomonic alteration is qualified to improve the preoperative diagnosis of PTC.

Methods: Two hundred ninety preoperatively harvested fine-needle aspiration biopsies (FNABs) underwent routine cytologic assessment.