8 results on '"Schoenmakers N"'
Search Results
2. IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction.
- Author
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Joustra SD, Roelfsema F, van Trotsenburg ASP, Schneider HJ, Kosilek RP, Kroon HM, Logan JG, Butterfield NC, Zhou X, Toufaily C, Bak B, Turgeon MO, Brûlé E, Steyn FJ, Gurnell M, Koulouri O, Le Tissier P, Fontanaud P, Duncan Bassett JH, Williams GR, Oostdijk W, Wit JM, Pereira AM, Biermasz NR, Bernard DJ, and Schoenmakers N
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Growth Hormone biosynthesis, Humans, Immunoglobulins deficiency, Insulin-Like Growth Factor I analysis, Intercellular Signaling Peptides and Proteins deficiency, Male, Membrane Proteins deficiency, Mice, Middle Aged, Immunoglobulins physiology, Intercellular Signaling Peptides and Proteins physiology, Membrane Proteins physiology, Neurosecretion physiology, Somatotrophs physiology
- Abstract
Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition., Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function., Patients, Design, and Setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting., Main Outcome Measures: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates., Results: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels., Conclusions: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure., (© Endocrine Society 2019.)
- Published
- 2020
- Full Text
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3. DUOX2 / DUOXA2 Mutations Frequently Cause Congenital Hypothyroidism that Evades Detection on Newborn Screening in the United Kingdom.
- Author
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Peters C, Nicholas AK, Schoenmakers E, Lyons G, Langham S, Serra EG, Sebire NJ, Muzza M, Fugazzola L, and Schoenmakers N
- Subjects
- Cross-Sectional Studies, Female, Humans, Infant, Newborn, Male, Mutation, Neonatal Screening, United Kingdom, Congenital Hypothyroidism diagnosis, Congenital Hypothyroidism genetics, Dual Oxidases genetics, Membrane Proteins genetics
- Abstract
Background: The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 ( DUOX2 ) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both DUOX2 and its accessory protein DUOXA2 may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort. Methods: A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. DUOX2 was sequenced in 52 patients with a bsTSH of 6-19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland in situ . DUOXA2 was sequenced in DUOX2 mutation-negative cases, and novel DUOXA2 mutations were functionally characterized. Results: A total of 26 (50%) patients harbored likely pathogenic mutations in DUOX2 ( n = 20; 38%) or DUOXA2 ( n = 6; 12%), including novel gene variants ( DUOX2 , n = 3; DUOXA2 , n = 7). Two recurrent DUOX2 mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range ( M = 9.3 pmol/L, range <3.9-15.8 pmol/L), Conclusions: Targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring DUOX2 / DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.
- Published
- 2019
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4. A novel IGSF1 mutation in a large Irish kindred highlights the need for familial screening in the IGSF1 deficiency syndrome.
- Author
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Roche EF, McGowan A, Koulouri O, Turgeon MO, Nicholas AK, Heffernan E, El-Khairi R, Abid N, Lyons G, Halsall D, Bonomi M, Persani L, Dattani MT, Gurnell M, Bernard DJ, and Schoenmakers N
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Congenital Hypothyroidism blood, Congenital Hypothyroidism diagnosis, Female, Humans, Infant, Ireland, Male, Middle Aged, Thyroxine blood, Triiodothyronine blood, Young Adult, Congenital Hypothyroidism genetics, Immunoglobulins genetics, Membrane Proteins genetics, Mutation genetics
- Abstract
Objective: Loss-of-function mutations in IGSF1 result in X-linked central congenital hypothyroidism (CeCH), occurring in isolation or associated with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred., Design, Patients and Measurements: A novel hemizygous IGSF1 mutation was identified by direct sequencing in two brothers with CeCH, and its functional consequences were characterized in vitro. Genotype-phenotype correlations were investigated in the wider kindred., Results: The mutant IGSF1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a TSH-based CH screening programme, which does not detect CeCH; therefore, genetic ascertainment preceded biochemical diagnosis of moderate CH in five of seven boys as well as their 75-year-old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (FT3) and low/low normal reverse T3 (rT3) concentrations suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed., Conclusions: As observed with other IGSF1 mutations, p.L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasize the need for multi-generation genetic ascertainment in affected families, especially where TSH-based CH screening programmes may fail to detect CeCH at birth., (© 2018 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)
- Published
- 2018
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5. IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.
- Author
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Joustra SD, Heinen CA, Schoenmakers N, Bonomi M, Ballieux BE, Turgeon MO, Bernard DJ, Fliers E, van Trotsenburg AS, Losekoot M, Persani L, Wit JM, Biermasz NR, Pereira AM, and Oostdijk W
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Attention Deficit Disorder with Hyperactivity genetics, Child, Child, Preschool, Female, Genetic Diseases, X-Linked genetics, Humans, Hypothyroidism genetics, Immunoglobulins genetics, Infant, Male, Membrane Proteins genetics, Middle Aged, Neuropsychological Tests, Quality of Life, Syndrome, Young Adult, Attention Deficit Disorder with Hyperactivity drug therapy, Genetic Diseases, X-Linked drug therapy, Hypothyroidism drug therapy, Immunoglobulins deficiency, Membrane Proteins deficiency, Practice Guidelines as Topic standards, Thyroxine therapeutic use
- Abstract
Context: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations., Objective: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management., Methods: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases., Results: Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters., Conclusion: IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.
- Published
- 2016
- Full Text
- View/download PDF
6. The IGSF1 deficiency syndrome: characteristics of male and female patients.
- Author
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Joustra SD, Schoenmakers N, Persani L, Campi I, Bonomi M, Radetti G, Beck-Peccoz P, Zhu H, Davis TM, Sun Y, Corssmit EP, Appelman-Dijkstra NM, Heinen CA, Pereira AM, Varewijck AJ, Janssen JA, Endert E, Hennekam RC, Lombardi MP, Mannens MM, Bak B, Bernard DJ, Breuning MH, Chatterjee K, Dattani MT, Oostdijk W, Biermasz NR, Wit JM, and van Trotsenburg AS
- Subjects
- Adult, Aged, 80 and over, Child, Congenital Hypothyroidism genetics, Congenital Hypothyroidism immunology, Congenital Hypothyroidism pathology, Family Health, Female, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked immunology, Genetic Diseases, X-Linked pathology, Heterozygote, Human Growth Hormone blood, Human Growth Hormone deficiency, Humans, Immunoglobulins genetics, Infant, Male, Membrane Proteins genetics, Metabolic Syndrome etiology, Organ Size, Prolactin blood, Puberty, Delayed etiology, Testicular Diseases genetics, Testicular Diseases immunology, Testicular Diseases pathology, X Chromosome Inactivation, Aging, Congenital Hypothyroidism physiopathology, Genetic Diseases, X-Linked physiopathology, Immunoglobulins deficiency, Membrane Proteins deficiency, Testicular Diseases physiopathology
- Abstract
Context: Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce., Objective: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes., Methods: All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory., Results: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases., Conclusion: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.
- Published
- 2013
- Full Text
- View/download PDF
7. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement.
- Author
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Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, Cambridge E, White JK, le Tissier P, Gharavy SN, Martinez-Barbera JP, Stokvis-Brantsma WH, Vulsma T, Kempers MJ, Persani L, Campi I, Bonomi M, Beck-Peccoz P, Zhu H, Davis TM, Hokken-Koelega AC, Del Blanco DG, Rangasami JJ, Ruivenkamp CA, Laros JF, Kriek M, Kant SG, Bosch CA, Biermasz NR, Appelman-Dijkstra NM, Corssmit EP, Hovens GC, Pereira AM, den Dunnen JT, Wade MG, Breuning MH, Hennekam RC, Chatterjee K, Dattani MT, Wit JM, and Bernard DJ
- Subjects
- Adolescent, Adult, Aged, Animals, Base Sequence, Child, Child, Preschool, Exome, Ferrous Compounds, Humans, Infant, Male, Metallocenes, Mice, Middle Aged, Pituitary Gland metabolism, Pituitary Gland pathology, Prolactin blood, Receptors, Thyrotropin-Releasing Hormone biosynthesis, Sequence Analysis, DNA, Syndrome, Testis anatomy & histology, Testis pathology, Thyrotropin blood, Triiodothyronine analysis, Young Adult, Congenital Hypothyroidism genetics, Genetic Diseases, X-Linked genetics, Immunoglobulins genetics, Membrane Proteins genetics, Mutation, Testicular Diseases genetics
- Abstract
Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.
- Published
- 2012
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8. IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management
- Author
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Joustra, S.D., Heinen, C.A., Schoenmakers, N., Bonomi, M., Ballieux, B.E.P.B., Turgeon, M.O., Bernard, D.J., Fliers, E., Trotsenburg, A.S.P. van, Losekoot, M., Persani, L., Wit, J.M., Biermasz, N.R., Pereira, A.M., Oostdijk, W., IGSF Clinical Care Grp, Schoenmakers, Nadia [0000-0002-0847-2884], and Apollo - University of Cambridge Repository
- Subjects
Adult ,Aged, 80 and over ,Male ,Adolescent ,Immunoglobulins ,Infant ,Membrane Proteins ,Genetic Diseases, X-Linked ,Syndrome ,Middle Aged ,Neuropsychological Tests ,Thyroxine ,Young Adult ,Hypothyroidism ,Attention Deficit Disorder with Hyperactivity ,Child, Preschool ,Practice Guidelines as Topic ,Quality of Life ,Humans ,Female ,Child ,Aged - Abstract
CONTEXT: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. OBJECTIVE: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. METHODS: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. RESULTS: Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. CONCLUSION: IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.
- Published
- 2016
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