Severe Neurodevelopmental Phenotype, Diagnostic and Treatment Challenges in Patients with SECISBP2 Deficiency.

PURPOSE: Defects in the gene encoding selenocysteine insertion sequence binding protein 2, SECISBP2, result in global impaired selenoprotein synthesis manifesting a complex syndrome with characteristic serum thyroid function tests due to impaired thyroid hormone metabolism. Knowledge about this multisystemic defect remains limited. METHODS: Genetic and laboratory investigations were performed in affected members from six families presenting with short stature, failure to thrive. RESULTS: Four probands presented a complex neurodevelopmental profile, including absent speech, autistic features, and seizures. Pediatric neurological evaluation prompted genetic investigations leading to the identification of SECISBP2 variants before knowing the characteristic thyroid tests in two cases. Thyroid hormone treatment improved motor development, while speech and intellectual impairments persisted. This defect poses great diagnostic and treatment challenges for clinicians, as illustrated by a case that escaped detection for 20years, as SECISBP2 was not included in the neurodevelopmental genetic panel, and his complex thyroid status prompted anti-thyroid treatment instead. CONCLUSION: This syndrome uncovers the role of selenoproteins in humans. The severe neurodevelopmental disabilities manifested in four patients with SECISBP2 deficiency highlight an additional phenotype in this multisystem disorder. Early diagnosis and treatment are required, and long-term evaluation will determine the full spectrum of manifestations and the impact of therapy.

Borealin/CDCA8 deficiency alters thyroid development and results in papillary tumor-like structures.

Background: BOREALIN/CDCA8 mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although BOREALIN mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid. Methods: We characterized thyroid development and function in Borealin-deficient (Borealin +/-) mice using histology, transcriptomic analysis, and quantitative PCR. Results: Thyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult Borealin +/- mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. Borealin +/- aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of Braf-like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, Borealin +/- thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a BOREALIN mutation, suggesting a role in thyroid tumor susceptibility. Conclusion: These findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying BOREALIN mutations.

Resolved Severe Primary Hypothyroidism in Sensenbrenner Syndrome Post Hepatorenal Transplantation: A Case Report.

INTRODUCTION: Sensenbrenner syndrome, or cranioectodermal dysplasia (OMIM #218330), is a rare genetic condition inherited as an autosomal recessive with less than 70 reported cases worldwide. It results in multiorgan abnormalities along with ectodermal structural defects. No previous reported cases demonstrated primary hypothyroidism in a matter of Sensenbrenner syndrome. CASE PRESENTATION: Herein, we report a 6-year-old girl who suffered from progressive liver failure and end-stage renal disease secondary to Sensenbrenner syndrome, which was associated with severe primary hypothyroidism that completely recovered after a combined renal and liver transplant. CONCLUSION: For the first time in the literature, we report an association of Sensenbrenner syndrome with hypothyroidism that resolved after a combined renal and liver transplant. Such findings expand the clinical spectrum of this syndrome. However, a larger cohort is needed to confirm or exclude such an association. Our case highlights the importance of thyroid function monitoring in any patient with renal and liver failure prior to and after a hepatorenal transplant.

Approach to the Patient With Congenital Hypothyroidism.

Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and the most common preventable cause of development delay and growth failure if diagnosed and treated early. The thyroid is the first endocrine gland to develop during embryonic life and to be recognizable in humans. Thyroid development and maturation can be divided into 2 phases: a first phase of embryogenesis and a second phase of folliculogenesis and differentiation with thyroid hormone production at the final steps. Regulation of the thyroid function requires normal development of the hypothalamic-pituitary-thyroid axis, which occurs during the embryonic and neonatal period. Defects in any of steps of thyroid development, differentiation, and regulation lead to permanent CH. Newborn screening programs, established in only one-third of countries worldwide, detect CH and are cost-effective and highly sensitive and specific. During the last decade, epidemiology of CH has changed with increased frequency of thyroid in situ in primary CH. Advances in molecular testing have expanded knowledge and understanding of thyroid development and function. However, a molecular cause is identified in only 5% of CH due to thyroid dysgenesis. The purpose of this article is to describe the clinical approach to the child with CH, focusing on diagnostic work-up and future challenges on optimizing thyroid replacement therapy and regenerative medicine. The review is written from the perspective of the case of 2 girls referred for CH after newborn screening and diagnosed with thyroid ectopy. The genetic work-up revealed novel mutations in TUBB1 gene, associated with large platelets and abnormal platelet physiology.

Genetics of congenital hypothyroidism: Modern concepts.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.

[Genetic of congenital hypothyroidism]. / Génétique de l'hypothyroïdie congénitale.

Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). DH accounts for about 35% of CH and a genetic cause is identified in 50% of patients. However, TD accounts for about 65% of CH, and a genetic cause is identified in less than 5% of patients. The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development and function. We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.

Title: Génétique de l'hypothyroïdie congénitale. Abstract: L'hypothyroïdie congénitale (HC) est la maladie endocrinienne néonatale la plus fréquente. Elle peut être due à des défauts de développement ou de la fonction de la thyroïde (HC primaire ou périphérique) ou d'origine hypothalamo-hypophysaire (HC centrale). L'HC primaire est causée dans la majorité des cas par une anomalie du développement de la glande (dysgénésie thyroïdienne, DT) ou par un défaut de synthèse des hormones thyroïdiennes (dyshormonogenèse, DH). Une origine génétique est identifiée chez 50 % des patients présentant une HCDH mais dans moins de 5 % des patients présentant une HCDT. Cette revue fait le point sur l'ensemble des causes génétiques des HC et sur les différents modes de transmission. L'HC n'est plus simplement une maladie dominante pour les dysgénésies thyroïdiennes et récessive pour les dyshormonogenèses, mais est devenue une maladie plus complexe.

New genetics in congenital hypothyroidism.

INTRODUCTION: Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and one of the most common preventable forms of mental retardation worldwide. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). TD accounts for about 65% of CH, however a genetic cause is identified in less than 5% of patients. PURPOSE: The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development, function and pathways. RESULTS AND CONCLUSION: We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.

First case of fetal goitrous hypothyroidism due to SLC5A5/NIS mutations.

BACKGROUND: Among patients with congenital hypothyroidism, 35% have dyshormonogenesis (DH) with thyroid gland in situ with or without goiter. The majority of DH cases are due to mutations in genes involved in thyroid hormone production as TG, TPO, SLC5A5/NIS, SLC26A4/PDS, IYD/DEHAL1, DUOX2, and DUOXA2, and are usually inherited on an autosomal recessive basis. Most previously reported cases of fetal hypothyroidism and goiter were related to TG or TPO mutations and recently DUOXA2. PATIENT: In a male patient with antenatal goiter treated with intraamniotic levothyroxine injections, whose long-term follow-up is described in detail, two novel NIS mutations were detected. Mutations of NIS were located in exon 1 (c.52G>A, p.G18R) and exon 13 (c.1546C>T, p.R516X), each mutation was inherited from parents, who are healthy carriers. The p.G18R mutation affecting the first transmembrane domain of the protein can be responsible for deficient iodide uptake. However, the second is a nonsense mutation leading probably to mRNA degradation. In addition, the patient has undergone a thyroidectomy and we have studied the thyroid tissue. The thyroid histology showed heterogeneity with large follicles, epithelial hyperplasia and many areas of fibrosis. Immunohistochemistry with NIS specific antibody showed NIS staining at the basolateral plasma membrane of the thyrocytes. CONCLUSIONS: We report the first case of fetal goitrous hypothyroidism due to two novel NIS mutations with access to thyroid tissue of the patient, specific histology studies and long-term follow-up. This case expands our knowledge and provides further insights on molecular causes of fetal goiter in humans.

Ex vivo model for elucidating the functional and structural differentiation of the embryonic mouse thyroid.

Terminal thyroid gland differentiation - the last developmental step needed to enable thyroid hormone (T4) synthesis - involves profound structural and biochemical changes in the thyroid follicular cells (TFCs). We aimed to develop an ex vivo thyroid model of embryonic mouse thyroid that would replicate the in vivo TFC differentiation program. E13.5 thyroid explants were cultured ex vivo in chemically defined medium for 7 days. Immunostaining and qPCR of thyroid explants showed thyroglobulin production onset, follicle formation, and T4 synthesis onset in 1-, 3-, and 5-day-old cultures, respectively. Differentiation was maintained and follicular growth continued throughout the 7-day culture period. Pharmacological approaches to culture inhibition were performed successfully in the ex vivo thyroids. Our robust and well described ex vivo thyroid culture model replicates the sequence of thyroid differentiation to T4 synthesis seen in vivo. This model can be used to test the effects of pharmacological inhibitors on thyroid hormone production.

High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis.

Objective: To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS). Study design: We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature. Results: TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis. Conclusions: In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.