Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Félixe Pelletier; Stefanie Perrier; Ferdy K. Cayami; Amytice Mirchi; Stephan Saikali; Luan T. Tran; Nicole Ulrick; Kether Guerrero; Emmanouil Rampakakis; Rosalina M.L. Van Spaendonk; Sakkubai Naidu; Daniela Pohl; William T. Gibson; Michelle Demos; Cyril Goizet; Ingrid Tejera-Martin; Ana Potic; Brent L. Fogel; Bernard Brais; Michel Sylvain; Guillaume Sébire; Charles Marques Lourenço; Joshua L. Bonkowsky; Coriene Catsman-Berrevoets; Pedro S. Pinto; Sandya Tirupathi; Petter Strømme; Ton De Grauw; Dorota Gieruszczak-Bialek; Ingeborg Krägeloh-Mann; Hanna Mierzewska; Heike Philippi; Julia Rankin; Tahir Atik; Brenda Banwell; William S. Benko; Astrid Blaschek; Annette Bley; Eugen Boltshauser; Drago Bratkovic; Klara Brozova; Icíar Cimas; Christopher Clough; Bernard Corenblum; Argirios Dinopoulos; Gail Dolan; Flavio Faletra; Raymond Fernandez; Janice Fletcher; Maria Eugenia Garcia Garcia; Paolo Gasparini; Janina Gburek-Augustat; Dolores Gonzalez Moron; Aline Hamati; Inga Harting; Christoph Hertzberg; Alan Hill; Grace M. Hobson; A. Micheil Innes; Marcelo Kauffman; Susan M. Kirwin; Gerhard Kluger; Petra Kolditz; Urania Kotzaeridou; Roberta La Piana; Eriskay Liston; William McClintock; Meriel McEntagart; Fiona McKenzie; Serge Melançon; Anjum Misbahuddin; Mohnish Suri; Fernando I. Monton; Sebastien Moutton; Raymond P.J. Murphy; Miriam Nickel; Hüseyin Onay; Simona Orcesi; Ferda Özklnay; Steffi Patzer; Helio Pedro; Sandra Pekic; Mercedes Pineda Marfa; Amy Pizzino; Barbara Plecko; Bwee Tien Poll-The; Vera Popovic; Dietz Rating; Marie France Rioux; Norberto Rodriguez Espinosa; Anne Ronan; John R. Ostergaard; Elsa Rossignol; Rocio Sanchez-Carpintero; Anna Schossig; Nesrin Senbil; Laura K. Sønderberg Roos; Cathy A. Stevens; Matthis Synofzik; László Sztriha; Daniel Tibussek; Dagmar Timmann; Davide Tonduti; Bart P. Van De Warrenburg; Maria Vázquez-López; Sunita Venkateswaran; Pontus Wasling; Evangeline Wassmer; Richard I. Webster; Gert Wiegand; Grace Yoon; Joost Rotteveel; Raphael Schiffmann; Marjo S. Van Der Knaap; Adeline Vanderver; Gabriel Martos-Moreno; Constantin Polychronakos; Nicole I. Wolf; Geneviève Bernard

doi:10.1210/clinem/dgaa700

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Félixe Pelletier
, Stefanie Perrier
, Ferdy K. Cayami
, Amytice Mirchi
, Stephan Saikali
, Luan T. Tran
, Nicole Ulrick
, Kether Guerrero
, Emmanouil Rampakakis
, Rosalina M.L. Van Spaendonk
, Sakkubai Naidu
, Daniela Pohl
, William T. Gibson
, Michelle Demos
, Cyril Goizet
, Ingrid Tejera-Martin
, Ana Potic
, Brent L. Fogel
, Bernard Brais
, Michel Sylvain

Guillaume Sébire, Charles Marques Lourenço, Joshua L. Bonkowsky, Coriene Catsman-Berrevoets, Pedro S. Pinto, Sandya Tirupathi, Petter Strømme, Ton De Grauw, Dorota Gieruszczak-Bialek, Ingeborg Krägeloh-Mann, Hanna Mierzewska, Heike Philippi, Julia Rankin, Tahir Atik, Brenda Banwell, William S. Benko, Astrid Blaschek, Annette Bley, Eugen Boltshauser, Drago Bratkovic, Klara Brozova, Icíar Cimas, Christopher Clough, Bernard Corenblum, Argirios Dinopoulos, Gail Dolan, Flavio Faletra, Raymond Fernandez, Janice Fletcher, Maria Eugenia Garcia Garcia, Paolo Gasparini, Janina Gburek-Augustat, Dolores Gonzalez Moron, Aline Hamati, Inga Harting, Christoph Hertzberg, Alan Hill, Grace M. Hobson, A. Micheil Innes, Marcelo Kauffman, Susan M. Kirwin, Gerhard Kluger, Petra Kolditz, Urania Kotzaeridou, Roberta La Piana, Eriskay Liston, William McClintock, Meriel McEntagart, Fiona McKenzie, Serge Melançon, Anjum Misbahuddin, Mohnish Suri, Fernando I. Monton, Sebastien Moutton, Raymond P.J. Murphy, Miriam Nickel, Hüseyin Onay, Simona Orcesi, Ferda Özklnay, Steffi Patzer, Helio Pedro, Sandra Pekic, Mercedes Pineda Marfa, Amy Pizzino, Barbara Plecko, Bwee Tien Poll-The, Vera Popovic, Dietz Rating, Marie France Rioux, Norberto Rodriguez Espinosa, Anne Ronan, John R. Ostergaard, Elsa Rossignol, Rocio Sanchez-Carpintero, Anna Schossig, Nesrin Senbil, Laura K. Sønderberg Roos, Cathy A. Stevens, Matthis Synofzik, László Sztriha, Daniel Tibussek, Dagmar Timmann, Davide Tonduti, Bart P. Van De Warrenburg, Maria Vázquez-López, Sunita Venkateswaran, Pontus Wasling, Evangeline Wassmer, Richard I. Webster, Gert Wiegand, Grace Yoon, Joost Rotteveel, Raphael Schiffmann, Marjo S. Van Der Knaap, Adeline Vanderver, Gabriel Martos-Moreno, Constantin Polychronakos, Nicole I. Wolf, Geneviève Bernard

McGill University
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University of Amsterdam
Universitas Diponegoro
Université Laval
The Children's Hospital of Philadelphia
Vrije Universiteit Amsterdam
Johns Hopkins University
University of Ottawa
University of British Columbia
Centre Hospitalier Universitaire de Bordeaux
Hospital Universitario Nuestra Senora de Candelaria
University of Belgrade
University of California at Los Angeles
Université de Sherbrooke
Centro Universitario Estácio de Ribeirão Preto
University of Utah
Erasmus University Rotterdam
University Hospital Center of Santo António
Belfast Health and Social Care Trust
University of Oslo
Emory University
Children's Memorial Health Institute
Medical University of Warsaw
University of Tübingen
Institute of Mother and Child
Center of Developmental Neurology (SPZ Frankfurt Mitte)
Royal Devon & Exeter NHS Foundation Trust
Ege University
University of California at Davis
Ludwig Maximilian University of Munich
University of Hamburg
University of Zurich
Women's and Children's Hospital Adelaide
Thomayers Hospital
Povisa Hospital
King's College London
University of Calgary
National and Kapodistrian University of Athens
Bristow Pediatrics
IRCCS Ospedale Infantile Burlo Garofolo - Trieste
Pediatric Neurology Associates
Royal London Hospital
Leipzig University
Hospital General de Agudos José María Ramos Mejía
Indiana University-Purdue University Indianapolis
Heidelberg University
Vivantes Klinikum Neukolln
Alfred I. duPont Hospital for Children
Schön Klinik Vogtareuth
Kantonsspital Luzern
University of Toronto
Pediatric Specialists of Virginia
Children's National Medical Center
St George's Hospital
Genetic Services of Western Australia
University of Western Australia
Barking, Havering and Redbridge University Hospitals NHS Trust
Nottingham University Hospitals NHS Trust
Tallaght University Hospital
IRCCS Fondazione Istituto Neurologico Casimiro Mondino - Pavia
Martin Luther University Halle-Wittenberg
Rutgers - The State University of New Jersey, Newark
SJD Barcelona Children's Hospital
The MetroHealth System
Medical University of Graz
University of Newcastle
Aarhus University
University of Navarra
Innsbruck Medical University
Klrlkkale University
University of Copenhagen
University of Tennessee, Chattanooga
University of Szeged
Heinrich Heine University Düsseldorf
University of Duisburg-Essen
Ospedale dei Bambini Vittore Buzzi
Radboud University Nijmegen
Sección Neuropediatría. Hospital Maternoinfantil Gregorio Marañón
University of Gothenburg
Birmingham Women's and Children's NHS Foundation Trust
The Children's Hospital at Westmead
Kiel University
Asklepios Clinic Hamburg Nord-Heidberg
Baylor Scott & White Health
University of Pennsylvania
Hospital Universitario de la Princesa
Universidad Autónoma de Madrid
Instituto de Salud Carlos III

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	E660-E674
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	106
Issue number	2
DOIs	https://doi.org/10.1210/clinem/dgaa700
State	Published - 1 Feb 2021
Externally published	Yes

Keywords

4H leukodystrophy
POLR3-related leukodystrophy
hypogonadotropic hypogonadism
hypomyelination

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10.1210/clinem/dgaa700

Cite this

Pelletier, F., Perrier, S., Cayami, F. K., Mirchi, A., Saikali, S., Tran, L. T., Ulrick, N., Guerrero, K., Rampakakis, E., Van Spaendonk, R. M. L., Naidu, S., Pohl, D., Gibson, W. T., Demos, M., Goizet, C., Tejera-Martin, I., Potic, A., Fogel, B. L., Brais, B., ... Bernard, G. (2021). Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C. Journal of Clinical Endocrinology and Metabolism, 106(2), E660-E674. https://doi.org/10.1210/clinem/dgaa700

@article{d115f8079a2c4e69a4db45bb7b4fba31,

title = "Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C",

abstract = "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.",

keywords = "4H leukodystrophy, POLR3-related leukodystrophy, hypogonadotropic hypogonadism, hypomyelination",

author = "F{\'e}lixe Pelletier and Stefanie Perrier and Cayami, \{Ferdy K.\} and Amytice Mirchi and Stephan Saikali and Tran, \{Luan T.\} and Nicole Ulrick and Kether Guerrero and Emmanouil Rampakakis and \{Van Spaendonk\}, \{Rosalina M.L.\} and Sakkubai Naidu and Daniela Pohl and Gibson, \{William T.\} and Michelle Demos and Cyril Goizet and Ingrid Tejera-Martin and Ana Potic and Fogel, \{Brent L.\} and Bernard Brais and Michel Sylvain and Guillaume S{\'e}bire and Louren{\c c}o, \{Charles Marques\} and Bonkowsky, \{Joshua L.\} and Coriene Catsman-Berrevoets and Pinto, \{Pedro S.\} and Sandya Tirupathi and Petter Str{\o}mme and \{De Grauw\}, Ton and Dorota Gieruszczak-Bialek and Ingeborg Kr{\"a}geloh-Mann and Hanna Mierzewska and Heike Philippi and Julia Rankin and Tahir Atik and Brenda Banwell and Benko, \{William S.\} and Astrid Blaschek and Annette Bley and Eugen Boltshauser and Drago Bratkovic and Klara Brozova and Ic{\'i}ar Cimas and Christopher Clough and Bernard Corenblum and Argirios Dinopoulos and Gail Dolan and Flavio Faletra and Raymond Fernandez and Janice Fletcher and \{Garcia Garcia\}, \{Maria Eugenia\} and Paolo Gasparini and Janina Gburek-Augustat and \{Gonzalez Moron\}, Dolores and Aline Hamati and Inga Harting and Christoph Hertzberg and Alan Hill and Hobson, \{Grace M.\} and Innes, \{A. Micheil\} and Marcelo Kauffman and Kirwin, \{Susan M.\} and Gerhard Kluger and Petra Kolditz and Urania Kotzaeridou and \{La Piana\}, Roberta and Eriskay Liston and William McClintock and Meriel McEntagart and Fiona McKenzie and Serge Melan{\c c}on and Anjum Misbahuddin and Mohnish Suri and Monton, \{Fernando I.\} and Sebastien Moutton and Murphy, \{Raymond P.J.\} and Miriam Nickel and H{\"u}seyin Onay and Simona Orcesi and Ferda {\"O}zklnay and Steffi Patzer and Helio Pedro and Sandra Pekic and \{Pineda Marfa\}, Mercedes and Amy Pizzino and Barbara Plecko and Poll-The, \{Bwee Tien\} and Vera Popovic and Dietz Rating and Rioux, \{Marie France\} and \{Rodriguez Espinosa\}, Norberto and Anne Ronan and Ostergaard, \{John R.\} and Elsa Rossignol and Rocio Sanchez-Carpintero and Anna Schossig and Nesrin Senbil and \{S{\o}nderberg Roos\}, \{Laura K.\} and Stevens, \{Cathy A.\} and Matthis Synofzik and L{\'a}szl{\'o} Sztriha and Daniel Tibussek and Dagmar Timmann and Davide Tonduti and \{Van De Warrenburg\}, \{Bart P.\} and Maria V{\'a}zquez-L{\'o}pez and Sunita Venkateswaran and Pontus Wasling and Evangeline Wassmer and Webster, \{Richard I.\} and Gert Wiegand and Grace Yoon and Joost Rotteveel and Raphael Schiffmann and \{Van Der Knaap\}, \{Marjo S.\} and Adeline Vanderver and Gabriel Martos-Moreno and Constantin Polychronakos and Wolf, \{Nicole I.\} and Genevi{\`e}ve Bernard",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.",

year = "2021",

month = feb,

day = "1",

doi = "10.1210/clinem/dgaa700",

language = "English",

volume = "106",

pages = "E660--E674",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "2",

}

Pelletier, F, Perrier, S, Cayami, FK, Mirchi, A, Saikali, S, Tran, LT, Ulrick, N, Guerrero, K, Rampakakis, E, Van Spaendonk, RML, Naidu, S, Pohl, D, Gibson, WT, Demos, M, Goizet, C, Tejera-Martin, I, Potic, A, Fogel, BL, Brais, B, Sylvain, M, Sébire, G, Lourenço, CM, Bonkowsky, JL, Catsman-Berrevoets, C, Pinto, PS, Tirupathi, S, Strømme, P, De Grauw, T, Gieruszczak-Bialek, D, Krägeloh-Mann, I, Mierzewska, H, Philippi, H, Rankin, J, Atik, T, Banwell, B, Benko, WS, Blaschek, A, Bley, A, Boltshauser, E, Bratkovic, D, Brozova, K, Cimas, I, Clough, C, Corenblum, B, Dinopoulos, A, Dolan, G, Faletra, F, Fernandez, R, Fletcher, J, Garcia Garcia, ME, Gasparini, P, Gburek-Augustat, J, Gonzalez Moron, D, Hamati, A, Harting, I, Hertzberg, C, Hill, A, Hobson, GM, Innes, AM, Kauffman, M, Kirwin, SM, Kluger, G, Kolditz, P, Kotzaeridou, U, La Piana, R, Liston, E, McClintock, W, McEntagart, M, McKenzie, F, Melançon, S, Misbahuddin, A, Suri, M, Monton, FI, Moutton, S, Murphy, RPJ, Nickel, M, Onay, H, Orcesi, S, Özklnay, F, Patzer, S, Pedro, H, Pekic, S, Pineda Marfa, M, Pizzino, A, Plecko, B, Poll-The, BT, Popovic, V, Rating, D, Rioux, MF, Rodriguez Espinosa, N, Ronan, A, Ostergaard, JR, Rossignol, E, Sanchez-Carpintero, R, Schossig, A, Senbil, N, Sønderberg Roos, LK, Stevens, CA, Synofzik, M, Sztriha, L, Tibussek, D, Timmann, D, Tonduti, D, Van De Warrenburg, BP, Vázquez-López, M, Venkateswaran, S, Wasling, P, Wassmer, E, Webster, RI, Wiegand, G, Yoon, G, Rotteveel, J, Schiffmann, R, Van Der Knaap, MS, Vanderver, A, Martos-Moreno, G, Polychronakos, C, Wolf, NI & Bernard, G 2021, 'Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C', Journal of Clinical Endocrinology and Metabolism, vol. 106, no. 2, pp. E660-E674. https://doi.org/10.1210/clinem/dgaa700

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 - Sébire, 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 - Özklnay, 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 S.

AU - Vanderver, Adeline

AU - Martos-Moreno, Gabriel

AU - Polychronakos, Constantin

AU - Wolf, Nicole I.

AU - Bernard, Geneviève

PY - 2021/2/1

Y1 - 2021/2/1

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.

KW - 4H leukodystrophy

KW - POLR3-related leukodystrophy

KW - hypogonadotropic hypogonadism

KW - hypomyelination

UR - https://www.scopus.com/pages/publications/85097520880

U2 - 10.1210/clinem/dgaa700

DO - 10.1210/clinem/dgaa700

M3 - Article

C2 - 33005949

AN - SCOPUS:85097520880

SN - 0021-972X

VL - 106

SP - E660-E674

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 2

ER -

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

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