206 results on '"Dattani MT"'
Search Results
2. Loss-of-function variants in TBC1D32 underlie syndromic hypopituitarism
- Author
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Hietamaki J, Gregory LC, Ayoub S, Iivonen AP, Vaaralahti K, Liu X, Brandstack N, Buckton AJ, Laine T, Kansakoski J, Hero M, Miettinen PJ, Varjosalo M, Wakeling E, Dattani MT, and Raivio T
- Published
- 2020
3. Mutations in the Gene Encoding Fibroblast Growth Factor 8,FGF8,Are Associated with Complex Midline and Hypothalamo-Pituitary Defects.
- Author
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McCabe, MJ, primary, Tziaferi, V, additional, Gaston-Massuet, C, additional, Gregory, LC, additional, Walker, J, additional, Tsai, PS, additional, Pitteloud, N, additional, Martinez-Barbera, JP, additional, and Dattani, MT, additional
- Published
- 2010
- Full Text
- View/download PDF
4. Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland
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Nicholas, AK, Jaleel, S, Lyons, G, Schoenmakers, E, Dattani, MT, Crowne, E, Bernhard, B, Kirk, J, Roche, EF, Chatterjee, VK, Schoenmakers, N, Schoenmakers, Erik [0000-0003-0674-8282], Chatterjee, Krishna [0000-0002-2654-8854], Schoenmakers, Nadia [0000-0002-0847-2884], and Apollo - University of Cambridge Repository
- Subjects
Male ,Heterozygote ,Delayed Diagnosis ,Homozygote ,Infant, Newborn ,Original Articles ,Sequence Analysis, DNA ,Thyrotropin, beta Subunit ,United Kingdom ,Pedigree ,Editor's Choice ,Neonatal Screening ,Hypothyroidism ,Congenital Hypothyroidism ,Humans ,Original Article ,Female ,Ireland - Abstract
Summary Objective Homozygous mutations in the TSH beta subunit gene (TSHB) result in severe, isolated, central congenital hypothyroidism (CCH). This entity evades diagnosis in TSH‐based congenital hypothyroidism (CH) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder. Design, Patients and Measurements Four cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT). Results Two siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4‐kB TSHB deletion (kindred 2, c.1‐4389_417*195delinsCTCA) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth. Conclusions This study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine‐binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.
- Published
- 2016
5. The molecular basis for developmental disorders of the pituitary gland in man
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Dattani Mt and Robinson Ic
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Genetics ,Pituitary gland ,Pituitary disease ,DLX3 ,Homeobox A1 ,Biology ,HNF1B ,medicine.disease ,Phenotype ,medicine.anatomical_structure ,Anterior pituitary ,medicine ,Homeobox ,Genetics (clinical) - Abstract
The development of the anterior pituitary gland is dependent upon a cascade of signalling molecules and developmental genes that function as transcription factors. Many of these genes are homeobox genes which contain a DNA-binding region or homeobox. Animal models have given a valuable insight into human pituitary disease. For example, Pit-1 and Prop1 mutants are known to have deficiencies of growth hormone, prolactin and thyroid-stimulating hormone. Human phenotypes arising as a result of mutations in these genes are similar to the mouse mutants. Mutations in the novel homeobox gene Hesx1/HESX1 are associated with the highly variable phenotype of septo-optic dysplasia in mouse and man. The unravelling of this complex developmental cascade is just commencing.
- Published
- 2000
6. Novel application of luciferase assay for the in vitro functional assessment of KAL1 variants in three females with septo-optic dysplasia (SOD).
- Author
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McCabe, MJ, Hu, Y, Gregory, LC, Gaston-Massuet, C, Alatzoglou, KS, Saldanha, JW, Gualtieri, A, Thankamony, A, Hughes, I, Townshend, S, Martinez-Barbera, JP, Bouloux, PM, Dattani, MT, McCabe, MJ, Hu, Y, Gregory, LC, Gaston-Massuet, C, Alatzoglou, KS, Saldanha, JW, Gualtieri, A, Thankamony, A, Hughes, I, Townshend, S, Martinez-Barbera, JP, Bouloux, PM, and Dattani, MT
- Abstract
KAL1 is implicated in 5% of Kallmann syndrome cases, a disorder which genotypically overlaps with septo-optic dysplasia (SOD). To date, a reporter-based assay to assess the functional consequences of KAL1 mutations is lacking. We aimed to develop a luciferase assay for novel application to functional assessment of rare KAL1 mutations detected in a screen of 422 patients with SOD.Quantitative analysis was performed using L6-myoblasts stably expressing FGFR1, transfected with a luciferase-reporter vector containing elements of the FGF-responsive osteocalcin promoter.The two variants assayed [p.K185N, p.P291T], were detected in three females with SOD (presenting with optic nerve hypoplasia, midline and pituitary defects). Our novel assay revealed significant decreasesin transcriptional activity [p.K185N: 21% (p < 0.01); p.P291T: 40% (p < 0.001)].Our luciferase-reporter assay, developed for assessment of KAL1 mutations, determined that two variants in females with hypopituitarism/SOD are loss-of-function; demonstrating that this assay is suitable for quantitative assessment of mutations in this gene.
- Published
- 2015
7. The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism.
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Gregory, LC, Gaston-Massuet, C, Andoniadou, CL, Carreno, G, Webb, EA, Kelberman, D, McCabe, MJ, Panagiotakopoulos, L, Saldanha, JW, Spoudeas, HA, Torpiano, J, Rossi, M, Raine, J, Canham, N, Martinez-Barbera, JP, Dattani, MT, Gregory, LC, Gaston-Massuet, C, Andoniadou, CL, Carreno, G, Webb, EA, Kelberman, D, McCabe, MJ, Panagiotakopoulos, L, Saldanha, JW, Spoudeas, HA, Torpiano, J, Rossi, M, Raine, J, Canham, N, Martinez-Barbera, JP, and Dattani, MT
- Published
- 2015
8. Chapter 1. Genetic aspects of hypothalamic and pituitary gland development
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McCabe, MJ, Dattani, MT, McCabe, MJ, and Dattani, MT
- Abstract
Hypothalamo-pituitary development during embryogenesis is a highly complex process involving the interaction of a network of spatiotemporally regulated signaling molecules and transcription factors. Mutations in any of the genes encoding these components can lead to congenital hypopituitarism, which is often associated with a wide spectrum of defects affecting craniofacial/midline development. In turn, these defects can be incompatible with life, or lead to disorders encompassing holoprosencephaly (HPE) and cleft palate, and septo-optic dysplasia (SOD). In recent years, there has been increasing evidence of an overlapping genotype between this spectrum of disorders and Kallmann syndrome (KS), defined as the association of hypogonadotropic hypogonadism (HH) and anosmia. This is consistent with the known phenotypic overlap between these disorders and opens a new avenue of identifying novel genetic causes of the hypopituitarism spectrum. This chapter reviews the genetic and molecular events leading to the successful development of the hypothalamo-pituitary axis during embryogenesis, and focuses on genes in which variations/mutations occur, leading to congenital hypopituitarism and associated defects.
- Published
- 2014
9. Diagnosis and Evaluation of Hypogonadism
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McCabe, MJ, Bancalari, RE, Dattani, MT, McCabe, MJ, Bancalari, RE, and Dattani, MT
- Abstract
Hypogonadism is defined as defects in gonadal response to gonadotropins or sex hormone biosynthesis. Clinical evaluation and diagnosis of patients is challenging, particularly before puberty. Basal determinations of the gonadotropins luteinizing hormone, follicle-stimulating hormone, the gonadal sex steroids testosterone and/or estrogen and markers of gonadal function including inhibin B and anti-Müllerian hormone are useful, but only at specific ages, thus necessitating combined hormonal tests with meticulous physical examination. GnRH testing can be useful, and may be used in combination with hCG testing to discriminate between isolated hypogonadotropic hypogonadism and constitutional delay of growth and puberty. Urine steroid profiles may be helpful in the diagnosis of androgen biosynthetic defects. Also increasingly important is genotypic screening for genetic or chromosomal abnormalities, together with detailed family and medical histories including antecedent substance abuse, chronic disease, and exposure to chemotherapy or radiotherapy. This chapter explores the diagnosis and evaluation of patients with hypogonadism and reviews the genetic/chromosomal factors involved in the condition.
- Published
- 2014
10. Borjeson-Forssman-Lehmann syndrome: a novel pituitary phenotype due to mutation in a novel gene
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Dattani Mt
- Subjects
Male ,Fibroblast Growth Factor 8 ,Endocrinology, Diabetes and Metabolism ,Physiology ,Gene Expression ,Hypopituitarism ,Growth hormone deficiency ,Novel gene ,Mice ,Endocrinology ,Septo-Optic Dysplasia ,Pituitary Gland, Anterior ,medicine ,Animals ,Humans ,Abnormalities, Multiple ,Genetics ,business.industry ,Börjeson-Forssman-Lehmann syndrome ,Genetic Diseases, X-Linked ,Syndrome ,medicine.disease ,Phenotype ,Fibroblast Growth Factors ,Growth Hormone ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Bone Morphogenetic Proteins ,Mutation ,business ,Signal Transduction ,Transcription Factors - Published
- 2004
11. Structural pituitary abnormalities associated with CHARGE syndrome
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Gregory, LC, Gevers, EF, Baker, J, Kasia, T, Chong, K, Josifova, DJ, Caimari, M, Bilan, F, McCabe, MJ, Dattani, MT, Gregory, LC, Gevers, EF, Baker, J, Kasia, T, Chong, K, Josifova, DJ, Caimari, M, Bilan, F, McCabe, MJ, and Dattani, MT
- Abstract
Introduction: CHARGE syndrome is a multi system disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypopla-sia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. Objective: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia/hypopituitarism. Methods: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism. Results: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features. Conclusion: We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome. Copyright © 2013 by The Endocrine Society.
- Published
- 2013
12. Variations in, But Not, Are Associated With Hypopituitarism and Septo-optic Dysplasia
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McCabe, MJ, Gaston-Massuet, C, Gregory, LC, Alatzoglou, KS, Tziaferi, V, Sbai, O, Rondard, P, Masumoto, K-H, Nagano, M, Shigeyoshi, Y, Pfeifer, M, Hulse, T, Buchanan, CR, Pitteloud, N, Martinez-Barbera, J-P, Dattani, MT, McCabe, MJ, Gaston-Massuet, C, Gregory, LC, Alatzoglou, KS, Tziaferi, V, Sbai, O, Rondard, P, Masumoto, K-H, Nagano, M, Shigeyoshi, Y, Pfeifer, M, Hulse, T, Buchanan, CR, Pitteloud, N, Martinez-Barbera, J-P, and Dattani, MT
- Published
- 2013
13. ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies
- Author
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Webb, EA, Almutair, A, Kelberman, D, Bacchelli, C, Chanudet, E, Lescai, F, Andoniadou, CL, Banyan, A, Alsawaid, A, Alrifai, MT, Alahmesh, MA, Balwi, M, Mousavy-Gharavy, SN, Lukovic, B, Burke, D, McCabe, MJ, Kasia, T, Kleta, R, Stupka, E, Beales, PL, Thompson, DA, Chong, WK, Alkuraya, FS, Martinez-Barbera, JP, Sowden, JC, Dattani, MT, Webb, EA, Almutair, A, Kelberman, D, Bacchelli, C, Chanudet, E, Lescai, F, Andoniadou, CL, Banyan, A, Alsawaid, A, Alrifai, MT, Alahmesh, MA, Balwi, M, Mousavy-Gharavy, SN, Lukovic, B, Burke, D, McCabe, MJ, Kasia, T, Kleta, R, Stupka, E, Beales, PL, Thompson, DA, Chong, WK, Alkuraya, FS, Martinez-Barbera, JP, Sowden, JC, and Dattani, MT
- Abstract
We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373-1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans. © 2013 The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
- Published
- 2013
14. Pituitary Gland Development: An Update
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Mullis, PE, Bancalari, RE, Gregory, LC, McCabe, MJ, Dattani, MT, Mullis, PE, Bancalari, RE, Gregory, LC, McCabe, MJ, and Dattani, MT
- Abstract
The embryonic development of the pituitary gland involves a complex and highly spatio- temporally regulated network of integrating signalling molecules and transcription factors. Genetic mutations in any of these factors can lead to congenital hypopituitarism in association with a wide spectrum of craniofacial/midline defects ranging from incompatibility with life to holoprosencephaly (HPE) and cleft palate and septo- optic dysplasia (SOD). Increasing evidence supports a genotypic overlap with hypogonadotrophic hypogonadal disorders such as Kallmann syndrome, which is consistent with the known overlap in phenotypes between these disorders. This chapter reviews the cascade of events leading up to the successful development of the pituitary gland and to highlight key areas where genetic variations can occur thus leading to congenital hypopituitarism and associated defects.
- Published
- 2012
15. Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia
- Author
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Raivio, T, Avbelj, M, McCabe, MJ, Romero, CJ, Dwyer, AA, Tommiska, J, Sykiotis, GP, Gregory, LC, Diaczok, D, Tziaferi, V, Elting, MW, Padidela, R, Plummer, L, Martin, C, Feng, B, Zhang, C, Zhou, QY, Chen, H, Mohammadi, M, Quinton, R, Sidis, Y, Radovick, S, Dattani, MT, Pitteloud, N, Raivio, T, Avbelj, M, McCabe, MJ, Romero, CJ, Dwyer, AA, Tommiska, J, Sykiotis, GP, Gregory, LC, Diaczok, D, Tziaferi, V, Elting, MW, Padidela, R, Plummer, L, Martin, C, Feng, B, Zhang, C, Zhou, QY, Chen, H, Mohammadi, M, Quinton, R, Sidis, Y, Radovick, S, Dattani, MT, and Pitteloud, N
- Abstract
Context: Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain. Objective: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins. Design and Participants: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in gene simplicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro. Results: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in PROKR2 (p.R85G, p.R85H, p.R268C). Conclusions: Mutations in FGFR1/FGF8/PROKR2 contributed to 7.8% of our patients with CPHD/ SOD. These data suggest a significant genetic overlap between conditions affecting the development of anterior midline in the human forebrain. Copyright © 2012 by The Endocrine Society.
- Published
- 2012
16. NovelMutations Associated with Recessive Holoprosencephaly, Craniofacial Defects, and Hypothalamo-Pituitary Dysfunction
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McCabe, MJ, Gaston-Massuet, C, Tziaferi, V, Gregory, LC, Alatzoglou, KS, Signore, M, Puelles, E, Gerrelli, D, Farooqi, IS, Raza, J, Walker, J, Kavanaugh, SI, Tsai, P-S, Pitteloud, N, Martinez-Barbera, J-P, Dattani, MT, McCabe, MJ, Gaston-Massuet, C, Tziaferi, V, Gregory, LC, Alatzoglou, KS, Signore, M, Puelles, E, Gerrelli, D, Farooqi, IS, Raza, J, Walker, J, Kavanaugh, SI, Tsai, P-S, Pitteloud, N, Martinez-Barbera, J-P, and Dattani, MT
- Published
- 2011
17. Septo-optic dysplasia and other midline defects: The role of transcription factors: HESX1 and beyond
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McCabe, MJ, Alatzoglou, KS, Dattani, MT, McCabe, MJ, Alatzoglou, KS, and Dattani, MT
- Abstract
Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising variable phenotypes including midline and forebrain abnormalities, optic nerve and pituitary hypoplasia. Most instances of SOD are sporadic and several aetiologies including drug and alcohol abuse have been suggested to account for the pathogenesis of the condition. However, a number of familial cases have been described with an increasing number of mutations in developmental transcription factors including HESX1, SOX2, SOX3 and OTX2 being implicated in its aetiology. These factors are essential for normal forebrain/pituitary development, and disruptions to these genes could account for the features observed in SOD and other midline disorders. The variable phenotypes observed within the condition are most likely due to the varying contributions of genetic and environmental factors. This review will discuss the current knowledge about SOD. Further study of these and other novel factors may shed light on the complex aetiology of this condition. © 2010 Elsevier Ltd. All rights reserved.
- Published
- 2011
18. Loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1) cause a novel, X-linked syndrome of central hypothyroidism and testicular enlargement
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Schoenmakers, N, primary, Sun, Y, additional, Bak, B, additional, van Trotsenburg, ASP, additional, Oostdijk, W, additional, Voshol, P, additional, Cambridge, E, additional, White, JK, additional, le Tissier, P, additional, Gharavy, SNM, additional, Martinez-Barbera, JP, additional, Stokvis-Brantsma, WH, additional, Vulsma, T, additional, Kempers, MJ, additional, Persani, L, additional, Campi, I, additional, Bonomi, M, additional, Beck-Peccoz, P, additional, Zhu, H, additional, Davis, TME, additional, Hokken-Koelega, ACS, additional, Del Blanco, D Gorbenko, additional, Rangasami, JJ, additional, Ruivenkamp, CAL, additional, Laros, JFJ, additional, Kriek, M, additional, Kant, SG, additional, Bosch, CAJ, additional, Biermasz, NR, additional, Appelman-Dijkstra, NM, additional, Corssmit, EP, additional, Hovens, GCJ, additional, Pereira, AM, additional, den Dunnen, JT, additional, Wade, MG, additional, Breuning, MH, additional, Hennekam, RC, additional, Dattani, MT, additional, Wit, JM, additional, Bernard, DJ, additional, and Chatterjee, K, additional
- Published
- 2013
- Full Text
- View/download PDF
19. Do centimetres matter? Self‐reported versus estimated height measurements in parents
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Gozzi, T, primary, Flück, CE, additional, L’Allemand, D, additional, Dattani, MT, additional, Hindmarsh, PC, additional, and Mullis, PE, additional
- Published
- 2010
- Full Text
- View/download PDF
20. An unusual case of an atypical eating disorder masquerading as a serious multi-systemic illness
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Mehta, A, primary, Viner, R, additional, Christie, D, additional, Newson, T, additional, and Dattani, MT, additional
- Published
- 2004
- Full Text
- View/download PDF
21. Regulation of human GH receptor gene transcription by 20 and 22 kDa GH in a human hepatoma cell line
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Nuoffer, JM, primary, Fluck, C, additional, Deladoey, J, additional, Eble, A, additional, Dattani, MT, additional, and Mullis, PE, additional
- Published
- 2000
- Full Text
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22. HESX1: a novel gene implicated in a familial form of septo-optic dysplasia
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Dattani, MT, primary, Martinez-Barbera, JP, additional, Thomas, PQ, additional, Brickman, JM, additional, Gupta, R, additional, Wales, JKH, additional, Hindmarsh, PC, additional, Beddington, RSP, additional, and Robinson, ICAF, additional
- Published
- 1999
- Full Text
- View/download PDF
23. New growth hormone assays: potential benefits
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Strasburger, CJ, primary and Dattani, MT, additional
- Published
- 1997
- Full Text
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24. Effect of growth hormone deficiency on brain structure, motor function and cognition.
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Webb EA, O'Reilly MA, Clayden JD, Seunarine KK, Chong WK, Dale N, Salt A, Clark CA, and Dattani MT
- Published
- 2012
25. Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland
- Author
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Nicholas, AK, Jaleel, S, Lyons, G, Schoenmakers, E, Dattani, MT, Crowne, E, Bernhard, B, Kirk, J, Roche, EF, Chatterjee, VK, and Schoenmakers, N
- Subjects
Male ,Heterozygote ,Delayed Diagnosis ,Homozygote ,Infant, Newborn ,Sequence Analysis, DNA ,Thyrotropin, beta Subunit ,United Kingdom ,3. Good health ,Pedigree ,Neonatal Screening ,Hypothyroidism ,Congenital Hypothyroidism ,Humans ,Female ,Ireland - Abstract
OBJECTIVE: Homozygous mutations in the TSH beta subunit gene (TSHB) result in severe, isolated, central congenital hypothyroidism (CCH). This entity evades diagnosis in TSH-based congenital hypothyroidism (CH) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder. DESIGN, PATIENTS AND MEASUREMENTS: Four cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT). RESULTS: Two siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4-kB TSHB deletion (kindred 2, c.1-4389_417*195delinsCTCA) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth. CONCLUSIONS: This study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine-binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.
26. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.
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Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, and De Rosa V
- Abstract
Background: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined.Methods: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives.Results: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency.Conclusions: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism. [ABSTRACT FROM AUTHOR]- Published
- 2007
27. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor
- Author
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Wendy Kimber, Stephen O'Rahilly, Anne Grethe Myhre, Oya Ercan, J. A. Edge, Veronica De Rosa, Silvia Fontana, Teresia Wangensteen, Giuseppe Matarese, Dag E. Undlien, Stephan C. Collins, Sheila A. McKenzie, Francesco Perna, Nader Lessan, Maryam Ghodsi, Bill Bottomley, Iván Ferraz-Amaro, Emma Lank, Inês Barroso, Mehul T. Dattani, Judith López-Fernández, I. Sadaf Farooqi, Richard Stanhope, Lars Retterstøl, Julia M. Keogh, Farooqi, I, Wangensteen, T, Collins, S, Kimber, W, Matarese, G, Keogh, Jm, Lank, E, Bottomley, B, LOPEZ FERNANDEZ, J, FERRAZ AMARO, I, Dattani, Mt, Ercan, O, Myhre, Ag, Retterstol, L, Stanhope, R, Edge, Ja, Mckenzie, S, Lessan, N, Ghodsi, M, DE ROSA, V, Perna, Francesco, Fontana, S, Barroso, I, Undlien, De, and O'Rahilly, S.
- Subjects
Delayed puberty ,Adult ,Leptin ,Male ,medicine.medical_specialty ,Genotype ,Receptors, Cell Surface ,Hyperphagia ,Compound heterozygosity ,Article ,Diagnosis, Differential ,Hypogonadotropic hypogonadism ,Internal medicine ,medicine ,Missense mutation ,Humans ,Lymphocyte Count ,Obesity ,Age of Onset ,Child ,Leptin receptor ,business.industry ,Hypogonadism ,digestive, oral, and skin physiology ,Immunologic Deficiency Syndromes ,General Medicine ,medicine.disease ,Pedigree ,Endocrinology ,Phenotype ,Mutation ,Body Composition ,Receptors, Leptin ,Female ,Basal Metabolism ,medicine.symptom ,Age of onset ,business ,hormones, hormone substitutes, and hormone antagonists ,Metabolism, Inborn Errors - Abstract
BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations -- 7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism
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- 2007
28. The molecular basis of hypoprolactinaemia.
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Finn BP and Dattani MT
- Abstract
Hypoprolactinaemia is an endocrinopathy which is typically encountered as part of a combined pituitary hormone deficiency picture. The vast majority of genetic causes identified to date have been in the context of congenital hypopituitarism with multiple co-existent endocrinopathies. This is primarily with its closest hormonal relation, namely growth hormone. Acquired hypoprolactinaemia is generally rare in paediatric patients, and usually occurs together with other hormonal deficiencies. Congenital hypopituitarism occurs with an incidence of 1:4,000-10,000 cases and mutations in the following transcription factors account for the majority of documented genetic causes: PROP-1, POU1F1, LHX3/4 as well as documented case reports for a smaller subset of transcription factors and other molecules implicated in lactotroph development and prolactin secretion. Isolated prolactin deficiency has been described in a number of sporadic case reports in the literature, but no cases of mutations in the gene have been described to date. A range of genetic polymorphisms affecting multiple components of the prolactin signalling pathway have been identified in the literature, ranging from RNA spliceosome mutations (RNPC3) to loss of function mutations in IGSF-1. As paediatricians gain a greater understanding of the long-term ramifications of hypoprolactinaemia in terms of metabolic syndrome, type 2 diabetes mellitus and impaired fertility, the expectation is that clinicians will measure prolactin more frequently over time. Ultimately, we will encounter further reports of hypoprolactinaemia-related clinical presentations with further genetic mutations, in turn leading to a greater insight into the molecular basis of hypoprolactinaemia in terms of signalling pathways and downstream mediators. In the interim, the greatest untapped reserve of genetic causes remains within the phenotypic spectrum of congenital hypopituitarism., (© 2024. Crown.)
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- 2024
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29. Appetite- and Weight-Regulating Neuroendocrine Circuitry in Hypothalamic Obesity.
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Gan HW, Cerbone M, and Dattani MT
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- Humans, Appetite physiology, Neurosecretory Systems physiopathology, Neurosecretory Systems metabolism, Animals, Hypothalamus metabolism, Body Weight physiology, Obesity metabolism, Obesity physiopathology, Hypothalamic Diseases physiopathology, Hypothalamic Diseases metabolism
- Abstract
Since hypothalamic obesity (HyOb) was first described over 120 years ago by Joseph Babinski and Alfred Fröhlich, advances in molecular genetic laboratory techniques have allowed us to elucidate various components of the intricate neurocircuitry governing appetite and weight regulation connecting the hypothalamus, pituitary gland, brainstem, adipose tissue, pancreas, and gastrointestinal tract. On a background of an increasing prevalence of population-level common obesity, the number of survivors of congenital (eg, septo-optic dysplasia, Prader-Willi syndrome) and acquired (eg, central nervous system tumors) hypothalamic disorders is increasing, thanks to earlier diagnosis and management as well as better oncological therapies. Although to date the discovery of several appetite-regulating peptides has led to the development of a range of targeted molecular therapies for monogenic obesity syndromes, outside of these disorders these discoveries have not translated into the development of efficacious treatments for other forms of HyOb. This review aims to summarize our current understanding of the neuroendocrine physiology of appetite and weight regulation, and explore our current understanding of the pathophysiology of HyOb., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2024
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30. Quality of Life in Children and Young People With Congenital Adrenal Hyperplasia-UK Nationwide Multicenter Assessment.
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Lawrence NR, Bacila I, Dawson J, Mahdi S, Alvi S, Cheetham TD, Crowne E, Das U, Dattani MT, Davies JH, Gevers E, Krone RE, Patel L, Randell T, Ryan FJ, Keevil B, Ahmed SF, and Krone NP
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- Child, Humans, Female, Adolescent, Male, Quality of Life psychology, Cross-Sectional Studies, Biomarkers, Steroids, United Kingdom epidemiology, Adrenal Hyperplasia, Congenital drug therapy
- Abstract
Context: Quality of life (QoL) has been inconsistently reported in children and young people (CYP) with congenital adrenal hyperplasia (CAH)., Objective: Assess QoL in CYP with CAH in the UK alongside biometric and androgen profiles., Design: To define the evidence base for health care delivery, we conducted a cross-sectional study in CYP with CAH in the UK. Questionnaire results were compared with normative data and between groups, and modelled for association with sex, height, weight, body mass index, or steroid biomarkers of CAH control., Setting: Tertiary care in 14 UK centers., Patients: Results from 104 patients, 55% female, mean age 12.7 years (SD 3.0), paired responses from parents., Interventions: Strengths and Difficulties questionnaire (SDQ) and pediatric QoL questionnaire., Main Outcome Measure: Total QoL scores as assessed by SDQ and a pediatric QoL questionnaire in comparison to normative data., Results: Total scores were worse in parents than normative data, but similar in patients. Patient QoL was rated better in social functioning but worse in emotional, school, and peer domains by patients, and worse in total scores and domains of peer problems, and psychosocial, emotional, and school functioning by parents. Parents consistently scored QoL of their children lower than their child. Larger height-SD score and lower weight-SD score were associated with better QoL. Girls with lower steroid biomarkers had worse SDQ scores., Conclusions: In CYP with CAH, reduced height, increased weight, and hormonal biomarkers consistent with overtreatment were associated with worse QoL; addressing these problems should be prioritized in clinical management.Clinical Trials Registration Number: SCH/15/088., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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31. Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective.
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Backeljauw PF, Andrews M, Bang P, Dalle Molle L, Deal CL, Harvey J, Langham S, Petriczko E, Polak M, Storr HL, and Dattani MT
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- Humans, Insulin-Like Growth Factor I therapeutic use, Quality of Life, Growth Disorders, Laron Syndrome diagnosis, Laron Syndrome drug therapy, Laron Syndrome genetics, Dwarfism drug therapy
- Abstract
Background: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care., Objective: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally., Methods: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD., Results: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing., Conclusions: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)
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- 2023
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32. Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders.
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Gregory LC, Cionna C, Cerbone M, and Dattani MT
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- Humans, Mutation, Transcription Factors genetics, Phenotype, Genes, Homeobox, Hypopituitarism genetics
- Abstract
Purpose: Congenital hypopituitarism (CH) disorders are phenotypically variable. Variants in multiple genes are associated with these disorders, with variable penetrance and inheritance., Methods: We screened a large cohort (N = 1765) of patients with or at risk of CH using Sanger sequencing, selected according to phenotype, and conducted next-generation sequencing (NGS) in 51 families within our cohort. We report the clinical, hormonal, and neuroradiological phenotypes of patients with variants in known genes associated with CH., Results: We identified variants in 178 patients: GH1/GHRHR (51 patients of 414 screened), PROP1 (17 of 253), POU1F1 (15 of 139), SOX2 (13 of 59), GLI2 (7 of 106), LHX3/LHX4 (8 of 110), HESX1 (8 of 724), SOX3 (9 of 354), OTX2 (5 of 59), SHH (2 of 64), and TCF7L1, KAL1, FGFR1, and FGF8 (2 of 585, respectively). NGS identified 26 novel variants in 35 patients (from 24 families). Magnetic resonance imaging showed prevalent hypothalamo-pituitary abnormalities, present in all patients with PROP1, GLI2, SOX3, HESX1, OTX2, LHX3, and LHX4 variants. Normal hypothalamo-pituitary anatomy was reported in 24 of 121, predominantly those with GH1, GHRHR, POU1F1, and SOX2 variants., Conclusion: We identified variants in 10% (178 of 1765) of our CH cohort. NGS has revolutionized variant identification, and careful phenotypic patient characterization has improved our understanding of CH. We have constructed a flow chart to guide genetic analysis in these patients, which will evolve upon novel gene discoveries., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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33. Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism.
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Aung Y, Kokotsis V, Yin KN, Banerjee K, Butler G, Dattani MT, Dimitri P, Dunkel L, Hughes C, McGuigan M, Korbonits M, Paltoglou G, Sakka S, Shah P, Storr HL, Willemsen RH, and Howard SR
- Subjects
- Adolescent, Humans, Male, Adult, Female, Retrospective Studies, Testosterone, Puberty, Delayed diagnosis, Hypogonadism diagnosis
- Abstract
Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development., Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed., Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay., Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment. ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aung, Kokotsis, Yin, Banerjee, Butler, Dattani, Dimitri, Dunkel, Hughes, McGuigan, Korbonits, Paltoglou, Sakka, Shah, Storr, Willemsen and Howard.)
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- 2023
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34. Mosaic PRKACA duplication causing a novel and distinct phenotype of early-onset Cushing's syndrome and acral cutaneous mucinosis.
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McGlacken-Byrne SM, Abdelmaksoud A, Haini M, Palm L, Ashworth M, Li J, Wang W, Wang X, Wang J, Callaghan B, Kinsler VA, Faravelli F, and Dattani MT
- Subjects
- Humans, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits genetics, Phenotype, Infant, Adrenal Hyperplasia, Congenital genetics, Cushing Syndrome diagnosis, Mucinoses complications
- Abstract
Significance Statement: We describe a mosaic PRKACA duplication in a young infant who presented with a Carney-like complex: bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing's syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens the extra-adrenal phenotype of PRKACA-associated Cushing's syndrome. Our data suggest that Cushing's syndrome phenotypes arising from somatic and germline PRKACA abnormalities can exist on a spectrum. We emphasise the value of ascertaining a genetic diagnosis for PRKACA-mediated adrenal and extra-adrenal disease to guide individualised and targeted care., (© 2022 European Society of Endocrinology.)
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- 2022
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35. A Single-Center, Observational Study of 607 Children and Young People Presenting With Differences of Sex Development (DSD).
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Man E, Mushtaq I, Barnicoat A, Carmichael P, Hughes CR, Davies K, Aitkenhead H, Amin R, Buchanan CR, Cherian A, Costa NJ, Creighton SM, Duffy PG, Hewson E, Hindmarsh PC, Monzani LC, Peters CJ, Ransley PG, Smeulders N, Spoudeas HA, Wood D, Hughes IA, Katugampola H, Brain CE, Dattani MT, and Achermann JC
- Abstract
Context: Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important., Objective: We aimed to better understand the presentation and prevalence of pediatric DSD., Methods: A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence., Results: Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood., Conclusion: DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2022
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36. Health status of children and young persons with congenital adrenal hyperplasia in the UK (CAH-UK): a cross-sectional multi-centre study.
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Bacila I, Lawrence NR, Mahdi S, Alvi S, Cheetham TD, Crowne E, Das U, Dattani MT, Davies JH, Gevers E, Krone RE, Kyriakou A, Patel L, Randell T, Ryan FJ, Keevil B, Ahmed SF, and Krone NP
- Subjects
- Biomarkers, Child, Cholesterol, Cross-Sectional Studies, Glucocorticoids, Health Status, Humans, Quality of Life, Triglycerides, United Kingdom epidemiology, Adrenal Hyperplasia, Congenital epidemiology, Adrenal Hyperplasia, Congenital metabolism
- Abstract
Objective: There is limited knowledge on the onset of comorbidities in congenital adrenal hyperplasia (CAH) during childhood. We aimed to establish the health status of children with CAH in the UK., Design and Methods: This cross-sectional multicentre study involved 14 tertiary endocrine UK units, recruiting 101 patients aged 8-18 years with classic 21-hydroxylase deficiency and 83 controls. We analysed demographic, clinical and metabolic data, as well as psychological questionnaires (Strengths and Difficulties (SDQ), Paediatric Quality of Life (PedsQL))., Results: Patient height SDS in relation to mid-parental height decreased with age, indicating the discrepancy between height achieved and genetic potential height. Bone age was advanced in 40.5% patients, with a mean difference from the chronological age of 1.8 (±2.3) years. Patients were more frequently overweight (27%) or obese (22%) compared to controls (10.8% and 10.8%, respectively, P < 0.001). No consistent relationship between glucocorticoid dose and anthropometric measurements or hormonal biomarkers was detected. A small number of patients had raised total cholesterol (3.0%), low HDL (3.0%), raised LDL (7.0%) and triglycerides (5.0%). SDQ scores were within the 'high' and 'very high' categories of concern for 16.3% of patients. 'School functioning' was the lowest PedsQL scoring dimension with a median (interquartile range) of 70 (55-80), followed by 'emotional functioning' with a median of 75 (65-85)., Conclusions: Our results show an increased prevalence of problems with growth and weight gain in CAH children and suggest reduced quality of life. This highlights the urgent need to optimise management and monitoring strategies to improve long-term health outcomes.
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- 2022
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37. Treatment Burden of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Randomized Study.
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Maniatis AK, Carakushansky M, Galcheva S, Prakasam G, Fox LA, Dankovcikova A, Loftus J, Palladino AA, de Los Angeles Resa M, Turich Taylor C, Dattani MT, and Lebl J
- Abstract
Context: Somatrogon is a long-acting recombinant human growth hormone treatment developed as a once-weekly treatment for pediatric patients with growth hormone deficiency (GHD)., Objective: Evaluate patient and caregiver perceptions of the treatment burden associated with the once-weekly somatrogon injection regimen vs a once-daily Somatropin injection regimen., Methods: Pediatric patients (≥3 to <18 years) with GHD receiving once-daily somatropin at enrollment were randomized 1:1 to Sequence 1 (12 weeks of once-daily Somatropin, then 12 weeks of once-weekly somatrogon) or Sequence 2 (12 weeks of once-weekly somatrogon, then 12 weeks of once-daily Somatropin). Treatment burden was assessed using validated questionnaires completed by patients and caregivers. The primary endpoint was the difference in mean overall life interference (LI) total scores after each 12-week treatment period (somatrogon vs Somatropin), as assessed by questionnaires., Results: Of 87 patients randomized to Sequence 1 (n = 43) or 2 (n = 44), 85 completed the study. Once-weekly somatrogon had a significantly lower treatment burden than once-daily Somatropin, based on mean overall LI total scores after somatrogon (8.63) vs Somatropin (24.13) treatment (mean difference -15.49; 2-sided 95% CI -19.71, -11.27; P < .0001). Once-weekly somatrogon was associated with greater convenience, higher satisfaction with treatment experience, and less LI. The incidence of treatment-emergent adverse events (TEAEs) for Somatropin and somatrogon was 44.2% and 54.0%, respectively. No severe or serious AEs were reported., Conclusion: In pediatric patients with GHD, once-weekly somatrogon had a lower treatment burden and was associated with a more favorable treatment experience than once-daily Somatropin., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2022
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38. Approach to the Patient: Management of Pituitary Hormone Replacement Through Transition.
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Cerbone M, Katugampola H, Simpson HL, and Dattani MT
- Subjects
- Adolescent, Humans, Pituitary Gland, Puberty, Young Adult, Hormone Replacement Therapy methods, Hypopituitarism diagnosis, Hypopituitarism drug therapy, Pituitary Hormones therapeutic use
- Abstract
Hypopituitarism in childhood is a rare, complex disorder that can present with highly variable phenotypes, which may continue into adult life. Pituitary deficits can evolve over time, with unpredictable patterns resulting in significant morbidity and mortality. Hypopituitarism and hypothalamic dysfunction may be associated with challenging comorbidities such as obesity, learning difficulties, behavioral issues, sleep disturbance, and visual impairment. Transition is the purposeful planned movement of adolescents and young adults with chronic conditions from child-centered to adult-oriented health care systems with a shift from parent- to patient-focused care. To achieve effective transition within a health care setting, the inherent challenges involved in the evolution from a dependent child to an independent adult must be recognized. Transition is a critical time medically for patients with hypopituitarism. Complex issues with respect to puberty, attainment of optimal stature, adherence to treatment, and acceptance of the need for life-sustaining medications need to be addressed. For health care professionals, transition is an opportunity for reassessment of the pituitary deficits and the need for lifelong replacement therapies, often against a background of complex psychological issues. We present 4 illustrative cases of hypopituitarism of differing etiologies with diverse clinical presentations. Diagnostic and management processes from clinical presentation to young adulthood are discussed, with a particular focus on needs and outcomes through transition., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2022
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39. Corrigendum to 'Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes' [Surgery 171 (2021) 77-87].
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Shariq OA, Lines KE, English KA, Jafar-Mohammadi B, Prentice P, Casey R, Challis BG, Selberherr A, Boon H, Cranston T, Ryan FJ, Mihai R, Healy U, Kurzawinski T, Dattani MT, Bancos I, Dy BM, Lyden ML, Young WF Jr, McKenzie TJ, Richards D, and Thakker RV
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- 2022
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40. Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency.
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McGlacken-Byrne SM, Del Valle I, Quesne Stabej PL, Bellutti L, Garcia-Alonso L, Ocaka LA, Ishida M, Suntharalingham JP, Gagunashvili A, Ogunbiyi OK, Mistry T, Buonocore F, Crespo B, Moreno N, Niola P, Brooks T, Brain CE, Dattani MT, Kelberman D, Vento-Tormo R, Lagos CF, Livera G, Conway GS, and Achermann JC
- Subjects
- Adenosine analogs & derivatives, Adenosine genetics, Adenosine metabolism, Female, Humans, Meiosis, Primary Ovarian Insufficiency genetics, RNA Helicases genetics
- Abstract
Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: c. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosis-associated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377* variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI.
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- 2022
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41. Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency.
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Akin L, Rizzoti K, Gregory LC, Corredor B, Le Quesne Stabej P, Williams H, Buonocore F, Mouilleron S, Capra V, McGlacken-Byrne SM, Martos-Moreno GÁ, Azmanov DN, Kendirci M, Kurtoglu S, Suntharalingham JP, Galichet C, Gustincich S, Tasic V, Achermann JC, Accogli A, Filipovska A, Tuilpakov A, Maghnie M, Gucev Z, Gonen ZB, Pérez-Jurado LA, Robinson I, Lovell-Badge R, Argente J, and Dattani MT
- Subjects
- Animals, Female, Humans, Male, Mice, Nuclear Proteins genetics, Pedigree, Phenotype, Prolactin genetics, RNA-Binding Proteins genetics, Hypopituitarism genetics, Primary Ovarian Insufficiency genetics
- Abstract
Purpose: We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency., Methods: We used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain., Results: We described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain, including the hypothalamus and Rathke's pouch. Female Rnpc3 mutant mice displayed a reduction in pituitary GH content but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype., Conclusion: Our findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function., Competing Interests: Conflict of Interest All authors declare that they have no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)
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- 2022
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42. ZSWIM7 Is Associated With Human Female Meiosis and Familial Primary Ovarian Insufficiency.
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McGlacken-Byrne SM, Le Quesne Stabej P, Del Valle I, Ocaka L, Gagunashvili A, Crespo B, Moreno N, James C, Bacchelli C, Dattani MT, Williams HJ, Kelberman D, Achermann JC, and Conway GS
- Subjects
- Adolescent, Amenorrhea diagnosis, Child, DNA Mutational Analysis, Female, Humans, Loss of Function Mutation, Ovary growth & development, Pedigree, Point Mutation, Primary Ovarian Insufficiency complications, Primary Ovarian Insufficiency diagnosis, RNA-Seq, Zinc Fingers, Amenorrhea genetics, DNA-Binding Proteins genetics, Meiosis genetics, Oogenesis genetics, Primary Ovarian Insufficiency genetics
- Abstract
Background: Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development., Objective: We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree., Methods: Genome sequencing and variant filtering using an autosomal recessive model was performed in the 2 affected sisters and their unaffected family members. Quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage 22/23, 9 weeks post conception (wpc), 11 wpc, 15/16 wpc, 19/20 wpc) and in adult tissue., Results: Only 1 homozygous variant cosegregating with the POI phenotype was found: a single nucleotide substitution in zinc finger SWIM-type containing 7 (ZSWIM7), NM_001042697.2: c.173C > G; resulting in predicted loss-of-function p.(Ser58*). qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16 wpc ovary compared with testis, corresponding to peak meiosis in the fetal ovary. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes., Main Conclusions: Disruption of ZSWIM7 is associated with POI in humans. ZSWIM7 is likely to be important for human homologous recombination; these findings expand the range of genes associated with POI in women., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2022
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43. Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes.
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Shariq OA, Lines KE, English KA, Jafar-Mohammadi B, Prentice P, Casey R, Challis BG, Selberherr A, Boon H, Cranston T, Ryan FJ, Mihai R, Healy U, Kurzawinski T, Dattani MT, Bancos I, Dy BM, Lyden ML, Young WF Jr, McKenzie TJ, Richards D, and Thakker RV
- Subjects
- Adolescent, Child, Duodenal Neoplasms genetics, Duodenal Neoplasms surgery, Female, Humans, Hyperparathyroidism, Primary genetics, Hyperparathyroidism, Primary surgery, Male, Multiple Endocrine Neoplasia Type 1 genetics, Multiple Endocrine Neoplasia Type 1 surgery, Pancreatic Neoplasms genetics, Pancreatic Neoplasms surgery, Parathyroid Neoplasms genetics, Parathyroid Neoplasms surgery, Parathyroidectomy statistics & numerical data, Retrospective Studies, Duodenal Neoplasms epidemiology, Hyperparathyroidism, Primary epidemiology, Multiple Endocrine Neoplasia Type 1 complications, Pancreatic Neoplasms epidemiology, Parathyroid Neoplasms epidemiology
- Abstract
Background: Clinical manifestations and treatment outcomes in children and adolescents with multiple endocrine neoplasia type 1 are not well characterized., Methods: We conducted a retrospective cohort study of 80 patients with multiple endocrine neoplasia type 1 who commenced tumor surveillance at ≤18 years of age., Results: Fifty-six patients (70%) developed an endocrine tumor by age ≤18 years (median age = 14 years, range = 6-18 years). Primary hyperparathyroidism occurred in >80% of patients, with >70% undergoing parathyroidectomy, in which less-than-subtotal (<3-gland) resection resulted in decreased disease-free outcomes versus subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months versus not reached; P = .005). Pancreaticoduodenal neuroendocrine tumors developed in ∼35% of patients, of whom >70% had nonfunctioning tumors, >35% had insulinomas, and <5% had gastrinomas, with ∼15% having metastases and >55% undergoing surgery. Pituitary tumors developed in >30% of patients, and ∼35% were macroprolactinomas. Tumor occurrence in male patients and female patients was not significantly different. Genetic analyses revealed 38 germline MEN1 mutations, of which 3 were novel., Conclusion: Seventy percent of children aged ≤18 years with multiple endocrine neoplasia type 1 develop endocrine tumors, which include parathyroid tumors for which less-than-subtotal parathyroidectomy should be avoided; pancreaticoduodenal neuroendocrine tumors that may metastasize; and pituitary macroprolactinomas., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
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44. A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia.
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Whittaker DE, Oleari R, Gregory LC, Le Quesne-Stabej P, Williams HJ, Torpiano JG, Formosa N, Cachia MJ, Field D, Lettieri A, Ocaka LA, Paganoni AJ, Rajabali SH, Riegman KL, De Martini LB, Chaya T, Robinson IC, Furukawa T, Cariboni A, Basson MA, and Dattani MT
- Subjects
- Animals, Cerebellum enzymology, Developmental Disabilities enzymology, Developmental Disabilities genetics, Disease Models, Animal, Humans, Mice, Mice, Mutant Strains, Neurons enzymology, Cerebellum abnormalities, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Hypogonadism enzymology, Hypogonadism genetics, Hypothalamus enzymology, Mutation, Nervous System Malformations enzymology, Nervous System Malformations genetics, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.
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- 2021
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45. Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty.
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Saengkaew T, Patel HR, Banerjee K, Butler G, Dattani MT, McGuigan M, Storr HL, Willemsen RH, Dunkel L, and Howard SR
- Subjects
- Adolescent, Cohort Studies, Computational Biology, Computer Simulation, Diagnosis, Differential, Exome genetics, Female, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Hypogonadism genetics, Male, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Exome Sequencing, Puberty, Delayed diagnosis, Puberty, Delayed genetics
- Abstract
Context: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents., Objective: To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients., Design: Retrospective study., Methods: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed., Results: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP., Conclusion: This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.
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- 2021
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46. The phenotypic spectrum associated with OTX2 mutations in humans.
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Gregory LC, Gergics P, Nakaguma M, Bando H, Patti G, McCabe MJ, Fang Q, Ma Q, Ozel AB, Li JZ, Poina MM, Jorge AAL, Benedetti AFF, Lerario AM, Arnhold IJP, Mendonca BB, Maghnie M, Camper SA, Carvalho LRS, and Dattani MT
- Subjects
- Adolescent, Animals, Animals, Genetically Modified, Brazil, Cell Line, Child, Child, Preschool, Cohort Studies, Female, Humans, Hypopituitarism embryology, Hypopituitarism genetics, Hypothalamus cytology, Infant, Male, Mice, Microphthalmos embryology, Microphthalmos genetics, Mutation, Neurons pathology, Pedigree, Pituitary Gland embryology, Pituitary Gland pathology, Septo-Optic Dysplasia embryology, Septo-Optic Dysplasia genetics, United Kingdom, Hypopituitarism physiopathology, Microphthalmos physiopathology, Neurons physiology, Otx Transcription Factors genetics, Pituitary Gland physiopathology, Septo-Optic Dysplasia physiopathology
- Abstract
Objective: The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development., Design: We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action., Methods: We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants., Results: Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary., Conclusions: OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.
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- 2021
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47. Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.
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Buonocore F, Maharaj A, Qamar Y, Koehler K, Suntharalingham JP, Chan LF, Ferraz-de-Souza B, Hughes CR, Lin L, Prasad R, Allgrove J, Andrews ET, Buchanan CR, Cheetham TD, Crowne EC, Davies JH, Gregory JW, Hindmarsh PC, Hulse T, Krone NP, Shah P, Shaikh MG, Roberts C, Clayton PE, Dattani MT, Thomas NS, Huebner A, Clark AJ, Metherell LA, and Achermann JC
- Abstract
Context: Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood., Objective: We investigated genetic causes of PAI in children and young people over a 25 year period., Design Setting and Participants: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers., Intervention and Outcome Measurements: Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018)., Results: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1 /steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause., Conclusions: PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2021
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48. Impact of short stature on quality of life: A systematic literature review.
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Backeljauw P, Cappa M, Kiess W, Law L, Cookson C, Sert C, Whalen J, and Dattani MT
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- Achondroplasia physiopathology, Achondroplasia psychology, Adult, Body Height, Child, Growth Disorders etiology, Growth Disorders psychology, Humans, Infant, Small for Gestational Age, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic physiopathology, beta-Thalassemia complications, beta-Thalassemia physiopathology, Caregiver Burden, Cost of Illness, Growth Disorders physiopathology, Human Growth Hormone deficiency, Parents, Quality of Life
- Abstract
Objective: We sought to obtain a better understanding of the burden of short stature using a systematic literature review., Methods: Studies of the burden of short stature, of any cause in adults and children, were searched using Embase, MEDLINE and Cochrane databases in April 2020, capturing publications from 2008 onwards. Case series and populations with adult-onset growth hormone deficiency (GHD) were excluded., Results: Of 1684 publications identified, 41 studies (33 in children, 8 in adults) were included. All studies assessed human burden. Most study populations in children included short stature due to GHD, idiopathic short stature (ISS) and short stature after being born small for gestational age (SGA). In these populations, four studies showed that quality of life (QoL) in children with short stature was significantly worse than in children with normal stature. A significant association between QoL and short stature was observed in children with chronic kidney disease (CKD) (3 studies), achondroplasia (1 study) and transfusion-dependent β-thalassaemia (1 study), and in samples with mixed causes of short stature (3 studies). Three studies (one in GHD/ISS/SGA and two in CKD) found no significant association between short stature and QoL, and several studies did not report statistical significance. Approximately half of adult studies showed that QoL was reduced with short stature, and the other half showed no association. Two studies, one in adults with Prader-Willi syndrome and one in children with GHD, suggested a potential association between short stature and poorer cognitive outcomes. Three studies demonstrated an increased caregiver burden in parents of children with short stature., Conclusions: Evidence suggests that, compared with those with normal stature, children and adults with short stature of any cause may experience poorer QoL. Further research could extend our understanding of the human burden in this field., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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49. Congenital growth hormone deficiency associated with hip dysplasia and Legg-Calve-Perthes disease.
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Lamback EB, Chiarini S, Roposch A, and Dattani MT
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- Adolescent, Child, Humans, Retrospective Studies, Dwarfism, Pituitary, Hip Dislocation, Human Growth Hormone deficiency, Legg-Calve-Perthes Disease
- Abstract
Objective: Growth hormone deficiency (GHD) is usually treated with recombinant human GH (rhGH), and this has been rarely associated with hip disorders. We analysed the clinical data of patients with congenital GHD receiving rhGH who had associated hip dysplasia or Legg-Calve-Perthes disease (LCPD), with a view to determining whether the hip dysplasia was associated with the underlying disease or with rhGH treatment., Design: We performed a retrospective analysis of paediatric and adolescent patients seen between 1992-2018 with congenital GHD and hip disorders. Data were collected through a review of the patients' medical records and included demographics, clinical and imaging data, and the time frame between the onset of the symptoms related to the hip disorders and the onset of GH treatment., Results: Of the 13 patients with hip disorders, hip dysplasia was present in ten patients and LCPD in three. Hip dysplasia was diagnosed before rhGH was initiated in 50% of cases. These patients had bilateral hip dysplasia and isolated GHD. LCPD was diagnosed in one patient before rhGH was commenced and did not progress. In two patients, LCPD was diagnosed after rhGH was started and did temporarily progress in one of them, but rhGH was not discontinued because LCPD did not seem to be related to rhGH treatment., Conclusions: This study suggests that hip dysplasia could be a manifestation of an underlying GHD. Additionally, rhGH treatment may not necessarily be causative of LCPD., (© 2020 John Wiley & Sons Ltd.)
- Published
- 2021
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50. Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans.
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Gualtieri A, Kyprianou N, Gregory LC, Vignola ML, Nicholson JG, Tan R, Inoue SI, Scagliotti V, Casado P, Blackburn J, Abollo-Jimenez F, Marinelli E, Besser REJ, Högler W, Karen Temple I, Davies JH, Gagunashvili A, Robinson ICAF, Camper SA, Davis SW, Cutillas PR, Gevers EF, Aoki Y, Dattani MT, and Gaston-Massuet C
- Subjects
- Animals, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cells, Cultured, Child, Child, Preschool, Corticotrophs cytology, Corticotrophs metabolism, Ectodermal Dysplasia genetics, Facies, Failure to Thrive genetics, HEK293 Cells, Heart Defects, Congenital genetics, Humans, Infant, MAP Kinase Signaling System genetics, Melanotrophs cytology, Melanotrophs metabolism, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins B-raf metabolism, Exome Sequencing methods, Mice, Gain of Function Mutation, Hypopituitarism genetics, Hypothalamus metabolism, Pituitary Gland metabolism, Proto-Oncogene Proteins B-raf genetics
- Abstract
Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the Braf
V600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.- Published
- 2021
- Full Text
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