Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
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Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C. / Pelletier, Félixe; Perrier, Stefanie; Cayami, Ferdy K; Mirchi, Amytice; Saikali, Stephan; Tran, Luan T; Ulrick, Nicole; Guerrero, Kether; Rampakakis, Emmanouil; van Spaendonk, Rosalina M L; Naidu, Sakkubai; Pohl, Daniela; Gibson, William T; Demos, Michelle; Goizet, Cyril; Tejera-Martin, Ingrid; Potic, Ana; Fogel, Brent L; Brais, Bernard; Sylvain, Michel; Sebire, Guillaume; Lourenço, Charles Marques; Bonkowsky, Joshua L; Catsman-Berrevoets, Coriene; Pinto, Pedro S; Tirupathi, Sandya; Strømme, Petter; de Grauw, Ton; Gieruszczak-Bialek, Dorota; Krägeloh-Mann, Ingeborg; Mierzewska, Hanna; Philippi, Heike; Rankin, Julia; Atik, Tahir; Banwell, Brenda; Benko, William S; Blaschek, Astrid; Bley, Annette; Boltshauser, Eugen; Bratkovic, Drago; Brozova, Klara; Cimas, Icíar; Clough, Christopher; Corenblum, Bernard; Dinopoulos, Argirios; Dolan, Gail; Faletra, Flavio; Fernandez, Raymond; Fletcher, Janice; Garcia Garcia, Maria Eugenia; Gasparini, Paolo; Gburek-Augustat, Janina; Gonzalez Moron, Dolores; Hamati, Aline; Harting, Inga; Hertzberg, Christoph; Hill, Alan; Hobson, Grace M; Innes, A Micheil; Kauffman, Marcelo; Kirwin, Susan M; Kluger, Gerhard; Kolditz, Petra; Kotzaeridou, Urania; La Piana, Roberta; Liston, Eriskay; McClintock, William; McEntagart, Meriel; McKenzie, Fiona; Melançon, Serge; Misbahuddin, Anjum; Suri, Mohnish; Monton, Fernando I; Moutton, Sebastien; Murphy, Raymond P J; Nickel, Miriam; Onay, Hüseyin; Orcesi, Simona; Özkınay, Ferda; Patzer, Steffi; Pedro, Helio; Pekic, Sandra; Pineda Marfa, Mercedes; Pizzino, Amy; Plecko, Barbara; Poll-The, Bwee Tien; Popovic, Vera; Rating, Dietz; Rioux, Marie-France; Rodriguez Espinosa, Norberto; Ronan, Anne; Ostergaard, John R; Rossignol, Elsa; Sanchez-Carpintero, Rocio; Schossig, Anna; Senbil, Nesrin; Sønderberg Roos, Laura K; Stevens, Cathy A; Synofzik, Matthis; Sztriha, László; Tibussek, Daniel; Timmann, Dagmar; Tonduti, Davide; van de Warrenburg, Bart P; Vázquez-López, Maria; Venkateswaran, Sunita; Wasling, Pontus; Wassmer, Evangeline; Webster, Richard I; Wiegand, Gert; Yoon, Grace; Rotteveel, Joost; Schiffmann, Raphael; van der Knaap, Marjo; Vanderver, Adeline; Martos-Moreno, Gabriel Á; Polychronakos, Constantin; Wolf, Nicole I; Bernard, Geneviève.
In: J CLIN ENDOCR METAB, Vol. 106, No. 2, 23.01.2021, p. e660-e674.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
AU - Pelletier, Félixe
AU - Perrier, Stefanie
AU - Cayami, Ferdy K
AU - Mirchi, Amytice
AU - Saikali, Stephan
AU - Tran, Luan T
AU - Ulrick, Nicole
AU - Guerrero, Kether
AU - Rampakakis, Emmanouil
AU - van Spaendonk, Rosalina M L
AU - Naidu, Sakkubai
AU - Pohl, Daniela
AU - Gibson, William T
AU - Demos, Michelle
AU - Goizet, Cyril
AU - Tejera-Martin, Ingrid
AU - Potic, Ana
AU - Fogel, Brent L
AU - Brais, Bernard
AU - Sylvain, Michel
AU - Sebire, Guillaume
AU - Lourenço, Charles Marques
AU - Bonkowsky, Joshua L
AU - Catsman-Berrevoets, Coriene
AU - Pinto, Pedro S
AU - Tirupathi, Sandya
AU - Strømme, Petter
AU - de Grauw, Ton
AU - Gieruszczak-Bialek, Dorota
AU - Krägeloh-Mann, Ingeborg
AU - Mierzewska, Hanna
AU - Philippi, Heike
AU - Rankin, Julia
AU - Atik, Tahir
AU - Banwell, Brenda
AU - Benko, William S
AU - Blaschek, Astrid
AU - Bley, Annette
AU - Boltshauser, Eugen
AU - Bratkovic, Drago
AU - Brozova, Klara
AU - Cimas, Icíar
AU - Clough, Christopher
AU - Corenblum, Bernard
AU - Dinopoulos, Argirios
AU - Dolan, Gail
AU - Faletra, Flavio
AU - Fernandez, Raymond
AU - Fletcher, Janice
AU - Garcia Garcia, Maria Eugenia
AU - Gasparini, Paolo
AU - Gburek-Augustat, Janina
AU - Gonzalez Moron, Dolores
AU - Hamati, Aline
AU - Harting, Inga
AU - Hertzberg, Christoph
AU - Hill, Alan
AU - Hobson, Grace M
AU - Innes, A Micheil
AU - Kauffman, Marcelo
AU - Kirwin, Susan M
AU - Kluger, Gerhard
AU - Kolditz, Petra
AU - Kotzaeridou, Urania
AU - La Piana, Roberta
AU - Liston, Eriskay
AU - McClintock, William
AU - McEntagart, Meriel
AU - McKenzie, Fiona
AU - Melançon, Serge
AU - Misbahuddin, Anjum
AU - Suri, Mohnish
AU - Monton, Fernando I
AU - Moutton, Sebastien
AU - Murphy, Raymond P J
AU - Nickel, Miriam
AU - Onay, Hüseyin
AU - Orcesi, Simona
AU - Özkınay, Ferda
AU - Patzer, Steffi
AU - Pedro, Helio
AU - Pekic, Sandra
AU - Pineda Marfa, Mercedes
AU - Pizzino, Amy
AU - Plecko, Barbara
AU - Poll-The, Bwee Tien
AU - Popovic, Vera
AU - Rating, Dietz
AU - Rioux, Marie-France
AU - Rodriguez Espinosa, Norberto
AU - Ronan, Anne
AU - Ostergaard, John R
AU - Rossignol, Elsa
AU - Sanchez-Carpintero, Rocio
AU - Schossig, Anna
AU - Senbil, Nesrin
AU - Sønderberg Roos, Laura K
AU - Stevens, Cathy A
AU - Synofzik, Matthis
AU - Sztriha, László
AU - Tibussek, Daniel
AU - Timmann, Dagmar
AU - Tonduti, Davide
AU - van de Warrenburg, Bart P
AU - Vázquez-López, Maria
AU - Venkateswaran, Sunita
AU - Wasling, Pontus
AU - Wassmer, Evangeline
AU - Webster, Richard I
AU - Wiegand, Gert
AU - Yoon, Grace
AU - Rotteveel, Joost
AU - Schiffmann, Raphael
AU - van der Knaap, Marjo
AU - Vanderver, Adeline
AU - Martos-Moreno, Gabriel Á
AU - Polychronakos, Constantin
AU - Wolf, Nicole I
AU - Bernard, Geneviève
N1 - © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.
PY - 2021/1/23
Y1 - 2021/1/23
N2 - CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers.PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
AB - CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers.PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
U2 - 10.1210/clinem/dgaa700
DO - 10.1210/clinem/dgaa700
M3 - SCORING: Journal article
C2 - 33005949
VL - 106
SP - e660-e674
JO - J CLIN ENDOCR METAB
JF - J CLIN ENDOCR METAB
SN - 0021-972X
IS - 2
ER -