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

Félixe Pelletier,Alan Hill,Paolo Gasparini,Barbara Plecko,Argirios Dinopoulos,Eugen Boltshauser,Fiona Mckenzie,Astrid Blaschek,Kether Guerrero,Urania Kotzaeridou,Joost Rotteveel,Bernard Brais,Ingrid Tejera-Martin,Davide Tonduti,Steffi Patzer,Dagmar Timmann,Marie-France Rioux,Michel Sylvain,Evangeline Wassmer,Sakkubai Naidu,Daniel Tibussek,Amy Pizzino,Annette Bley,Adeline Vanderver,Christoph Hertzberg,Ana Potic,Anna Schossig,Icíar Cimas,Pontus Wasling,Gert Wiegand,Simona Orcesi,Bernard Corenblum,Ferda Özkınay,Raymond Fernandez,Charles Marques Lourenço,Constantin Polychronakos,Sunita Venkateswaran,Mohnish Suri,Heike Philippi,Ton De Grauw,Elsa Rossignol,Anne Ronan,Daniela Pohl,Miriam Nickel,Meriel Mcentagart,Roberta La Piana,Michelle Demos,Grace Yoon,Brenda Banwell,Inga Harting,Petra Kolditz,Raphael Schiffmann,Julia Rankin,Anjum Misbahuddin,Eriskay Liston,Guillaume Sébire,Drago Bratkovic,Tahir Atik,Petter Strømme,Nicole Ulrick,Marcelo Kauffman,Flavio Faletra,Hanna Mierzewska,Geneviève Bernard,Sandya Tirupathi,Cyril Goizet,Gail Dolan,Matthis Synofzik,Amytice Mirchi,Gerhard Kluger,Emmanouil Rampakakis,Raymond P Murphy ,László Sztriha ,Pedro Sá Pinto ,M Vázquez-López ,Coriene E Catsman‐Berrevoets ,Rosalina M.l Van Spaendonk ,Sébastien Moutton ,Fernando Montón ,Sylvie Perrier ,Stéphan Saïkali ,Grace M Hobson ,W Mcclintock ,Bart P Van De Warrenburg ,Brent L Fogel ,Vera Popović ,Nesrin Şenbil ,Serge B Melançon ,Chris Clough ,Richard Webster ,A Micheil Innes ,Gabriel Ángel Martos‐Moreno ,Marjo S Van Der Knaap ,Rocı́o Sánchez-Carpintero ,Maria E Garcia ,William Benko ,Hélio Pedro ,John R Østergaard ,Joshua L Bonkowsky ,Ferdy Kurniawan Cayami ,D Rating ,Hüseyin Önay ,Laura Roos ,Luan T Tran ,N Rodríguez-Espinosa ,Cathy A Stevens ,Dorota Gieruszczak‐Białek ,Ingeborg Krägeloh‐Mann ,Janina Gburek‐Augustat ,Nicole I Wolf ,Sandra Pekić ,Klára Brožová ,Mercedes Pineda Marfá ,Janice M Fletcher ,Dolores González Morón ,Susan M Kirwin ,Aline I Hamati ,William T Gibson ,Bwee Tien Poll-Thé

doi:10.1210/clinem/dgaa700

Abstract

Context4H 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.ObjectiveTo systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.DesignAn 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.SettingThis was a multicenter retrospective study using information collected from 3 predominant centers.PatientsA total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.Main Outcome MeasuresVariables 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.ResultsThe 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.ConclusionsOur 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.

Highlights

Corticospinal tracts at the level of the posterior limb of the internal capsule [13, 14]. 4H leukodystrophy has been found to be caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K, each of which encode subunits of the RNA polymerase III (POLR3) complex [15,16,17,18]
This study presents a thorough investigation of the endocrine and growth abnormalities associated with 4H leukodystrophy through an international cross-sectional retrospective study of 150 patients with a molecular confirmation of the diagnosis
Our study confirms that endocrine impairment is frequent in patients with 4H leukodystrophy and limited data were available for the entire cohort of patients, our results reveal notable information regarding abnormalities in the pituitary-gonadotrophic axis

Summary

Introduction

Corticospinal tracts at the level of the posterior limb of the internal capsule [13, 14]. 4H leukodystrophy has been found to be caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K, each of which encode subunits of the POLR3 complex [15,16,17,18]. 4H leukodystrophy has been found to be caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K, each of which encode subunits of the POLR3 complex [15,16,17,18]. As this class of leukodystrophies has been discovered relatively recently, secondary features that are typically associated with this phenotype have not been comprehensively described. This study presents a thorough investigation of the endocrine and growth abnormalities associated with 4H leukodystrophy through an international cross-sectional retrospective study of 150 patients with a molecular confirmation of the diagnosis. This study provides insight on the endocrine disorders associated with this disease, and how some endocrine abnormalities may have an impact on patients’ quality of life, highlighting the importance of considering endocrine therapeutic options and the associated impact on medical care

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