0000000000143208
AUTHOR
Joachim Pohlenz
Novel Mutations in the NKX2.1 gene and the PAX8 gene in a Boy with Brain-Lung-Thyroid Syndrome
Abstract 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 NKX2.1 (p.A329GfsX108). In vitro studies were performed to functionally characterize these mutations. Congenital hypothyroidism (CH) was identified by neonatal screening associated with a hypoplastic thyroid gland. Postpartum he developed a brain-lung-thyroid syndrome with severe respiratory failure, symptomatic epilepsy and a considerable psychomotor retardation. The DNA-bi…
Mutations in the NKX2.1 and the PAX8 genes in a boy with thyroid dysgenesis, respiratory and neurological disorders
s of the 51st Workshop for Pediatric Research 51st Workshop for Pediatric Research Gottingen, Germany
Mutations in the PDS Gene in German Families with Pendred’s Syndrome: V138F Is a Founder Mutation
Pendred's syndrome, an autosomal-recessive condition characterized by congenital sensorineural hearing loss and goiter, is caused by mutations in the PDS gene. Located on chromosome 7q22-q31, it encodes a chloride-iodide transporter expressed in the thyroid, inner ear, and kidney. We investigated the PDS gene of six affected individuals from four unrelated families with Pendred's syndrome by direct sequencing. PDS mutations were identified in homozygous or compound heterozygous state in all six cases. A homozygous missense mutation leading to the amino acid substitution S133T was detected in a family of Turkish origin. The mutations found in the other affected individuals, who originate fro…
Manifestation of Diabetes Mellitus Type 1: A Questionnaire to Evaluate the Acceptance of Initial Intravenous Therapy
For families suddenly confronted with the diagnosis of a lifelong chronic disease, implementing a continuous iv. infusion represents restriction of movement and possibly also a psychological burden. We designed a questionnaire to evaluate the perception of pediatric patients and their parents for this treatment as part of a diabetes manifestation. Patients and their parents treated in the diabetes outpatient clinic at children’s university hospital in Mainz were asked for their opinion about “iv. infusion” and “frequency of blood taking” during their first stay in the hospital upon manifestation of diabetes. They assigned scores from 1 to 10 for the following parameters: “delivery of diagno…
Intrathyroidal Thymic Tissue Surrounding an Intrathyroidal Parathyroid Gland, the Cause of a Solitary Thyroid Nodule in a 6-Year-Old Boy
Ectopic intrathyroidal thymic tissue is a rare occurrence; parathyroid glands sometimes occur in an intrathyroidal location, but this is uncommon. We report a 6-year-old boy who was noted to have a solitary thyroid nodule on ultrasound. A hemithyroidectomy was performed, and histological investigation revealed that the nodule consisted of ectopic intrathyroidal thymus tissue surrounding a well-defined parathyroidal gland. This condition is an exceedingly rare cause of a thyroid nodule, but intrathyroidal thymic tissue should probably be included in the differential diagnosis of solitary thyroid nodules.
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
Background: 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. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation system, describing both the strength of recommendations and the quali…
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
<b><i>Background:</i></b> Isolated central congenital hypothyroidism (ICCH) is rare but important. Most ICCH patients are diagnosed later, which results in severe growth failure and intellectual disability. <b><i>Objective:</i></b> We describe a boy with ICCH due to a large homozygous <i>TSHβ </i>gene deletion. <b><i>Results:</i></b> A 51-day-old male Turkish infant, whose parents were first cousins, was admitted for evaluation of prolonged jaundice. His clinical appearance was compatible with hypothyroidism. Venous thyrotropin (TSH) was undetectably low, with a subsequent low free T4 and a low free T3, sugg…
Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene.
AbstractPendred syndrome (PS) is the most common cause of syndromic deafness, accounting for more than 5% of all autosomal-recessive hearing loss cases. It is characterized by bilateral sensorineural hearing loss and by goiter with or without hypothyroidism. Mutations in the SLC26A4 gene cause both classical PS and deafness associated with an enlarged vestibular aqueduct without goiter.To investigate a possible genotype-phenotype correlation in PS, we performed a detailed clinical and genetic study in three adult German sibs with typical PS caused by a common homozygous SLC26A4 mutation, T416P. An audiological long-term follow-up of 23 yr showed that the mutation T416P is associated with a …
Differenzierung zwischen prämaturer Thelarche und Pubertas praecox anhand klinischer, hormoneller und radiologischer Befunde
In a retrospective study of 39 girls (aged 10 months to 7 10/12 years) with premature breast development criteria for distinguishing between premature thelarche and precocious puberty were analysed. Serum estradiol levels and bone age were determined and a test with luteinizing hormone-releasing hormone (LHRH) performed (inclusion criteria). On the basis of the LHRH test and bone age, premature thelarche was diagnosed in 29 patients and precocious puberty in ten: while those with premature thelarche had a follicle-stimulating hormone (FSH) pattern of rise, in those with precocious puberty the rise in gonadotropin was of the LH type. The LH/FSH ratio 30 min after stimulation was 1 (median 2.…
Elevated serum triiodothyronine and intellectual and motor disability with paroxysmal dyskinesia caused by a monocarboxylate transporter 8 gene mutation.
Monocarboxylate transporter 8 (MCT8 or SLC16A2) is important for the neuronal uptake of triiodothyronine (T3) in its function as a specific and active transporter of thyroid hormones across the cell membrane, thus being essential for human brain development. We report on a German male with Allan-Herndon-Dudley syndrome presenting with severe intellectual and motor disability, paroxysmal dyskinesia combined with truncal muscular hypotonia, and peripheral muscular hypertonia at his current age of 9 years. Additionally, the patient has a lesion in the left putamen region revealed by magnetic resonance imaging and elevated serum T3 levels. The male appeared to have a hemizygous mutation (R271H)…
Two novel mutations in the human thyroid peroxidase (TPO) gene: genetics and clinical findings in four children
UNLABELLED We report four children originating from two unrelated German families with congenital hypothyroidism (CH) due to mutations in the thyroid peroxidase (TPO) gene. Three female siblings (family 1) were found to be compound heterozygous for two mutations, a known mutation in exon 9 (W527C), and a mutation in exon 8 (Q446H), which has not been described before. In the second family we identified a boy with goitrous CH, who had a novel homozygous mutation in the TPO gene in exon 16 (W873X). All children of family 1 were diagnosed postnatally by newborn screening. The case of the boy of family 2 has already been reported for the in utero treatment of a goiter with hypothyroidism. CONCL…
Goitrous Congenital Hypothyroidism and Hearing Impairment Associated with Mutations in the TPO and SLC26A4/PDS Genes
Abstract Context: Pendred syndrome (PS) and thyroid peroxidase (TPO) deficiency are autosomal-recessive disorders that result in thyroid dyshormonogenesis. They share congenital hypothyroidism, goiter, and an iodide organification defect as common features. Whereas the hallmark of PS is sensorineural deafness, other forms of congenital hypothyroidism may also lead to hearing impairment. Therefore, a definite diagnosis may be difficult and require molecular genetic analyses. Case Report: The propositus presented at birth with primary hypothyroidism and goiter. He also had congenital bilateral moderate hearing loss, and PS was suspected. Methods: We sequenced the SLC26A4/PDS and TPO genes in …
A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene as a cause for congenital hypothyroidism in Albright's hereditary osteodystrophy.
OBJECTIVE: To identify the molecular defect by which psychomotor retardation is caused in two brothers with congenital hypothyroidism who received adequate treatment with l-thyroxine. CASE REPORT: A six-year-old boy presented with psychomotor retardation and congenital primary hypothyroidism (CH). The patient had a normal blood thyrotrophin (TSH) level on neonatal screening, but low total serum thyroxine and triiodothyronine concentrations prompting thyroid hormone substitution shortly after birth. Nevertheless, psychomotor development was retarded and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO) such as round face, obesity, and…
Clinical and genetic characteristics of congenital hypothyroidism due to mutations in the thyroid peroxidase (TPO) gene in Israelis
Summary Objectives Iodide organification defect (IOD) is characterized by a reduced ability of the thyroid gland to retain iodide and results in hypothyroidism. Mutations in the thyroid peroxidase (TPO) gene are a frequent cause of IOD. While TPO mutations have been identified in various populations, none have been reported in Israeli patients with IOD. The objectives of this study were to characterize the molecular basis of IOD in an Israeli Arab-Muslim population and to analyse the clinical, neurological and imaging data of patients with TPO mutations followed for up to 29 years. Patients Twenty-two patients from six core families with congenital hypothyroidism (CH) and IOD living in th…
Phenotypic variability in patients with generalised resistance to thyroid hormone.
Genetic linkage of generalised resistance to thyroid hormone (GRTH) to the human thyroid receptor beta 1 gene has been identified. To date 38 different mutations in several kindreds have been documented. We report on a family with GRTH displaying an adenine for guanine substitution at nucleotide 1234 resulting in a threonine for alanine substitution at codon 317 of exon 9. This mutation has been described for different phenotypes, suggesting that the heterogeneity in GRTH may be the result of multiple genetic factors.
Clinical and metabolic findings in a 6-year-old boy with a Leydig cell tumour
Aim: To analyse the urinary steroid metabolome in a boy who had true precocious puberty after a Leydig cell tumour. Method: Case report and detailed description of clinical and metabolic findings in a 7-year-old-boy with a Leydig cell tumour. Results: Before surgery, the urinary steroid metabolome showed an activation of an alternative route to gonadal androgens independent of dehydroepiandrosterone (DHEA). After surgery, the boy entered true precocious puberty. Under leuprolide acetate treatment, clinical and laboratory findings normalized. Conclusion: Central precocious puberty after precocious pseudopuberty may be more common than expected and should be considered in children with pe…
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
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.We studied a girl with DS and CH who had a mutation in the promoter sequence of the PAX8 gene.A female infant was found to have trisomy 21 and CH, with a venous thyrotropin (TSH) of150 mU/L and a free thyroxine (fT4) of 15.1 pmol/L (day 12). Thyroid peroxidase antibodies and thyroglobulin antibodies were elevated. Scintigraphy showed normal uptake, but ultrasound identified a small gland with heterogenous echotexture and cystic changes. Sequence analysis of the PAX8 gene revealed a new heterozygo…
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. Objective gland volume, calculated as the sum of each lobe using the prolate ellipsoid formula (length x width x depth x π/6), was put into corresponding categories: <0.8, 0.81–1.0, 1.1– <2.2, 2.2–2.4 and >2.4 ml, derived from normative Scottish data. Results: Of 36 infants, permanent CH was present in 17, transie…
Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA-Binding Region: In Vitro Studies Reveal Different Pathogenic Mechanisms
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). We performed in vitro studies to functionally characterize these mutations.Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)- an…
Developmental Abnormalities of the Thyroid
Developmental anomalies of the thyroid gland (thyroid dysgenesis) underlie the majority of cases of congenital hypothyroidism. Only a small number of monogenic defects have been shown to result in athyreosis or orthotopic thyroid hyperplasia, whereas the commonest developmental anomaly, thyroid ectopy, remains unexplained. Ectopy may result from multiple genetic or epigenetic hits in the germline and/or at the somatic level. This chapter gives a brief overview of the monogenic defects in candidate genes that have been identified so far and of the syndromes that are known to be associated with thyroid dysgenesis. In addition, we discuss gain-of-function mutations of the thyroid hormone stimu…
Pseudodominant inheritance of goitrous congenital hypothyroidism caused by TPO mutations: molecular and in silico studies.
CONTEXT AND OBJECTIVE: Most cases of goitrous congenital hypothyroidism (CH) from thyroid dyshormonogenesis 1) follow a recessive mode of inheritance and 2) are due to mutations in the thyroid peroxidase gene (TPO). We report the genetic mechanism underlying the apparently dominant inheritance of goitrous CH in a nonconsanguineous family of French Canadian origin. DESIGN, SETTING, AND PARTICIPANTS: Two brothers identified by newborn TSH screening had severe hypothyroidism and a goiter with increased (99m)Tc uptake. The mother was euthyroid, but the father and two paternal uncles had also been diagnosed with goitrous CH. After having excluded PAX8 gene mutations, we hypothesized that the und…
Congenital hypothyroidism in a child with unsuspected familial dysalbuminemic hyperthyroxinemia caused by a mutation (R218H) in the human albumin gene
We found familial dysalbuminemic hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T4) and higher than normal total triiodothyronine (T3) levels. Thyroid hormone substitution began at 5 weeks of age when T4 and T3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was al…
Congenital secondary hypothyroidism caused by exon skipping due to a homozygous donor splice site mutation in the TSHbeta-subunit gene.
Isolated TSH deficiency as a cause for congenital hypothyroidism is relatively uncommon. Even more rare is the identification of mutations in the TSHβ gene, only four of which have been identified. We here report a 4-month-old girl with isolated TSH deficiency born to consanguineous parents. Sequencing of the TSHβ-subunit gene revealed a homozygous G to A transition at position +5 of the donor splice site of intron 2. TSHβ gene transcript could not be obtained from fibroblasts or white blood cells by illegitimate amplification. Thus, to investigate further the mechanism leading to TSH deficiency in this patient, we used an in vitro exon-trapping system. The mutation at position +5 of the do…
Treatment of pituitary resistance to thyroid hormone (PRTH) in an 8-year-old boy.
We report on an 8-year-old boy with pituitary resistance to thyroid hormone (PRTH) having a cysteine for arginine substitution at codon 320 in the TR-beta gene who was presented because of thyrotoxicosis. Due to its suppressive effect on the pituitary thyrotropin secretion, treatment with D-thyroxine (D-T4) was started. After a few days, clinical euthyroidism was achieved but thyroid stimulating hormone secretion was not suppressed. Symptoms of thyrotoxicosis relapsed when therapy was interrupted so that therapy with D-T4 was reinstituted and continued to date. Symptoms did not recur, and the psychomotor development proceeded normally. D-T4 should therefore be considered in the treatment of…
Congenital goitrous primary hypothyroidism in two German families caused by novel thyroid peroxidase (TPO) gene mutations.
Congenital hypothyroidism occurs with a prevalence of approximately 1:3 500. Defects in thyroid hormone synthesis which lead to goitrous hypothyroidism account for 10-15% of these cases. Several genetic defects have been characterized and mutations in the thyroid peroxidase (TPO) gene are the most common cause for dyshormonogenesis.So far, more than 80 mutations in the TPO gene have been described, resulting in a variable decrease in TPO bioactivity. Clinically TPO defects manifest with congenital primary goitrous hypothyroidism.We here present 2 children with congenital primary hypothyroidism, who were identified to have compound heterozygous TPO mutations. They both shared the same novel …
New point mutation (R243W) in the hormone binding domain of the c‐erbA β1 gene in a family with generalized resistance to thyroid hormone
Two years after the first mutation on exon 7 in the carboxy-terminal part of the hinge domain (D) was reported (Behr and Loos 1992), we have identified the second mutation on exon 7 in patients with GRTH. Interestingly, our mutation it is not located in the two previously described "hot spot regions", but instead very close to the hinge domain (D) of the receptor protein that is essential for the function of the hormone binding domain (E) (Lin et al., 1991). Confirming the observation that the majority of single base substitutions causing human genetic diseases or DNA polymorphisms follow the hot spot mutation rule of CG to TG and CG to CA transition (Barker et al., 1984), an additional CpG…
Missense mutations of dual oxidase 2 (DUOX2) implicated in congenital hypothyroidism have impaired trafficking in cells reconstituted with DUOX2 maturation factor.
Abstract Dual oxidase 2 (DUOX2), a reduced NAD phosphate:O2 oxidoreductase flavoprotein, is a component of the thyrocyte H2O2 generator required for hormone synthesis at the apical plasma membrane. We recently identified a specific DUOX2 maturation factor (DUOXA2) that is necessary and sufficient for expression of functional DUOX2 in mammalian cell lines. We have now used a DUOXA2 reconstituted system to provide the first characterization of natural DUOX2 missense variants (Q36H, R376W, D506N) at the molecular level, analyzing their impact on H2O2 generation, trafficking, stability, folding, and DUOXA2 interaction. The Q36H and R376W mutations completely prevent routing of DUOX2 to the cell…
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.V478KfsX11) in the solute carrier family 26 member 7 (SLC26A7) gene. SLC26A7 is proposed to be an anion transporter in the thyroid gland. The mutation leads to a frameshift and a premature stop codon. The predicted protein is truncated and very likely to be nonfunctional if it was expressed at all. In addition, in silico studies predict the mutation to be pathogenic.
Four new cases of congenital secondary hypothyroidism due to a splice site mutation in the thyrotropin-beta gene: Phenotypic variability and founder effect
WOS: 000223072400081 PubMed ID: 15292359 Isolated TSH deficiency is a rare cause of congenital hypothyroidism. We here report four children from two consanguineous Turkish families with isolated TSH deficiency. Affected children who were screened at newborn age had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. All affected children carried an identical homozygous splice site mutation (IVS2 + 5 Gdouble right arrowA) in the TSHbeta gene. This mutation leads to skipping of exon 2 and a loss of the translational start codon without ability to produce a TSH-like protein. However, using specific monoclonal antibodies, we …
Familial Central Hypothyroidism Caused by a Novel IGSF1 Gene Mutation.
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).CH-C was diagnosed in three siblings. The TRH, TRHR, and TSHB genes were sequenced followed by whole-exome sequencing in the proband. A mutation identified in IGSF1 was analyzed by direct PCR sequencing in family members. The effects of the mutation were assessed by in vitro studies in HEK293 cells.The index case was negative for mutations in TRH,…
Developmental Abnormalities of the Thyroid
Publisher Summary This chapter explores the abnormalities in the development of the thyroid gland during organogenesis referred to as thyroid dysgenesis. Permanent primary congenital hypothyroidism (CH) is mentioned to be the most common congenital endocrine disorder as estimated from systematic biochemical screening of newborns. The functional disorders of the thyroid gland are known as thyroid dyshormonogenesis and this disorder is typically inherited in an autosomal recessive manner and common in populations with a high degree of consanguinity. It briefly reviews the single gene disorders that cause CH from thyroid dysgenesis, and mutations that activate the thyrotropin receptor (TSH) re…
A novel mutation in the PAX8 promoter region causes permanent congenital hypothyroidism in a patient with Down’s Syndrome
Thyroid dysfunction is common in newborn infants with Down’s syndrome (DS) but defects in organogenesis have not been described. A female infant was diagnosed to have trisomy 21, atrio-ventricular septal defect and patent ductus. Newborn screening showed capillary TSH 43.8 mU/L(day 5), venous TSH >150 mU/l and free T4 15.1 pmol/L (day 12). Thyroid ultrasound showed a small gland with heterogenous echotexture and cystic changes. Scintigraphy showed normal uptake into an eutopic gland. The infant was treated with thyroxine and underwent cardiac repair at 69 days. Sequencing analysis of candidate genes involved in thyroid development revealed a new heterozygous mutation close to the transcript…
Mutations in the NKX2.5 Gene and the PAX8 Promoter in a Girl with Thyroid Dysgenesis
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).We studied a girl with TD who had mutations in two transcription factors involved in thyroid development.Sequencing analysis of candidate genes involved in thyroid gland development revealed a new paternally inherited heterozygous mutation in the NKX2.5 gene (S265R) and a new maternally inherited heterozygous mutation in the PAX8 promoter region (-456CT). Both parents and a brother, who was also heterozygous for both mutations, were phenotypically normal. Immunofluorescence microscopy showed a correct nucl…
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. Heterozygous inactivating Gs alpha (GNAS) gene mutations have been identified in these patients. Methods We studied a boy with PHP Ia. During follow-up the patient developed elevated liver enzyme serum levels and abd…
Simultaneous stimulation of growth hormone, adrenocorticotropin and cortisol with L‐dopa/L‐carbidopa and propranolol in children of short stature
In 59 otherwise healthy children of short stature, the simultaneous response of growth hormone, cortisol and plasma adrenocorticotropin (ACTH) to L-dopa/L-carbidopa and propranolol at 45 and 90 min after administration were investigated. A growth hormone response of 10 microg/l or higher was considered positive. The definition of a positive cortisol response included either a hormone increase of at least 193 nmol/l or a peak hormone level of at least 497 nmol/l. The ACTH increase had to be fourfold above 11 pmol/l to be considered positive. In the 59 investigated children, the median basal growth hormone levels increased from 1.35 microg/l to 18.05 microg/l and 10.15 microg/l at 45 and 90 m…
Intrauterine therapy of goitrous hypothyroidism in a boy with a new compound heterozygous mutation (Y453D and C800R) in the thyroid peroxidase gene. A long-term follow-up.
We report the results of intrauterine L-thyroxine therapy, and the long-term follow-up in a fetus who presented at 32 weeks' gestation with goitrous hypothyroidism, hyperextension of the neck, and polyhydramnios. Spontaneous delivery was possible and hypothyroidism improved. Molecular analysis revealed a new compound heterozygous mutation (Y453D/C800R) in the TPO gene.
Non-Immune Goiter and Hypothyroidism in a 19-Week Fetus: A Plea for Conservative Treatment
Hypothyroidism was documented by cordocentesis at 19 weeks in a fetus with non-immune goiter. Intra-amniotic thyroxine was injected at 25 weeks when amniotic fluid volume increased. Psychomotor outcome was normal. We argue that intra-amniotic thyroxine should not be used to treat the hypothyroidism but only to correct the development of polyhydramnios.
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
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.We now report an infant with transient CH due to a complex genetic alteration of the DUOX/DUOXA system.Our patient was born to euthyroid nonconsanguineous parents and presented with an elevated TSH…
Resistance to thyroid hormone in a family caused by a new point mutation L330S in the thyroid receptor (TR) beta gene.
Resistance to thyroid hormone (RTH) is an inherited defect manifesting as variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TR beta) gene. Up to now 78 mutations in this gene have been identified, mostly clustered in two regions located in exon 9 and 10. We describe a new point mutation replacing the normal thymidine-1274 with a cytosine that results in the substitution of the normal leucine-330 with a serine (L330S) in the receptor protein. This mutation was identified in an 11-year-old boy who presented with symptoms and signs suggestive of both hyperthyroidism and hypothyroidism. Interestingly a mutation in the same c…
Congenital primary hypothyroidism with subsequent adenomatous goiter in a Turkish patient caused by a homozygous 10-bp deletion in the thyroid peroxidase (TPO) gene
Summary Objective Congenital primary hypothyroidism occurs in 1 of 4000 births. Whereas the majority of the cases are due to developmental defects of the thyroid gland, 20% carry a defect in thyroid hormonogenesis. We report a Turkish boy who had goitrous hypothyroidism due to a mutation in the thyroid peroxidase (TPO) gene. Design The TPO gene was sequenced directly from genomic DNA and cDNA which was transcribed from three RNA samples harvested from different parts of the patient's excised thyroid gland. Patient The boy was thyroidectomized because of continuing growth of his thyroid gland and development of multiple nodes suspected of malignancy by ultrasound examination. Histopatholo…
Krankheiten der Schilddrüse
Schilddrusenhormone spielen nicht nur im Energiestoffwechsel eine zentrale Rolle. Sie sind vor allem fur das normale Wachstum und die normale korperliche und geistige Entwicklung des Kindes unentbehrlich. Ihre Wirkung wird durch spezifische Schilddrusenhormonrezeptoren vermittelt die sich im Zellkern befinden und die Transkription der vom Schilddrusenhormon abhangigen Gene regulieren. Unter Kontrolle der hypothalamisch-hypophysaren-thyreoidalen Achse besteht normalerweise eine euthyreote Stoffwechselsituation. Storungen dieses Regelkreises konnen die optimale Entwicklung des Kindes gefahrden und sollten deswegen fruhzeitig erkannt und behandelt werden. Meist handelt es sich um eine Uber- od…
Subclinical hyperthyroidism due to a thyrotropin receptor (TSHR) gene mutation (S505R).
Aim: To identify the molecular defect by which non-autoimmune subclinical hyperthyroidism was caused in a 6-mo-old infant who presented with weight loss. Methods: Congenital non-autoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin receptor (TSHR) gene. Therefore, the TSHR gene was sequenced directly from the patient's genomic DNA. Results: Molecular analysis revealed a heterozygous point mutation (S505R) in the TSHR gene as the underlying defect. Conclusion: A constitutively activating mutation in the TSHR gene has to be considered not only in patients with severe congenital non-autoimmune hyperthyroidism, but also in children with subclinical non-autoimm…
Congenital hypothyroidism caused by new mutations in the thyroid oxidase 2 (THOX2) gene
Summary Objective Congenital primary hypothyroidism (CH) occurs in one of 4000 births and in 20% of the cases CH is due to a defect in thyroid hormonogenesis. Candidate genes were examined to determine the precise aetiology of suspected dyshormonogenesis in CH. Design The genes that code for thyroid peroxidase (TPO), pendrin (PDS), sodium iodide symporter (NIS) and thyroid oxidase 2 (THOX2) were sequenced directly from genomic DNA. Patients Two girls found to have CH in the neonatal screening programme and suspected of having thyroid dyshormonogenesis were investigated to identify their molecular defect. Results Patient A had a novel heterozygous 1 bp insertion in the THOX2 gene (ins602…
Effect of oestrogen/gestagen replacement therapy on liver enzymes in patients with Ullrich-Turner syndrome.
The absence of breast development and the prevention of osteoporosis in Ullrich-Turner syndrome (UTS) require oestrogen/gestagen substitution therapy. In 8 out of 35 (23%) patients with UTS treated with conjugated equine oestrogens and cyclically with norethisterone acetate, the serum liver enzymes increased to conspicuous levels (AST 35; 20-73 U/l, ALT 92; 37-141 U/l, GGT 77; 25-227 U/l, [median; min-max]). These findings were compared with those in 41 tall girls who received a six-fold larger dose of conjugated equine oestrogens for the reduction of final height. None of these 41 girls showed abnormal serum liver enzyme levels. The conspicuous rise in serum liver enzyme levels occurred in…