Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
Authors: 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 , Sébire 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 S , Vanderver Adeline , Martos-Moreno Gabriel Á , Polychronakos Constantin , Wolf Nicole I , Bernard Geneviève 
Published: October 2020

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.