Scientific publications
Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
Félixe Pelletier 1 2 3 4 5 6 , Stefanie Perrier 1 4 , Ferdy K Cayami 7 8 , Amytice Mirchi 1 2 3 4 5 , Stephan Saikali 9 , Luan T Tran 1 2 3 4 , Nicole Ulrick 10 , Kether Guerrero 1 2 3 4 , Emmanouil Rampakakis 2 , Rosalina M L van Spaendonk 11 , Sakkubai Naidu 12 , Daniela Pohl 13 , William T Gibson 14 , Michelle Demos 15 , Cyril Goizet 16 , Ingrid Tejera-Martin 17 , Ana Potic 18 , Brent L Fogel 19 , Bernard Brais 1 3 20 , Michel Sylvain 21 , Guillaume Sébire 2 22 , Charles Marques Lourenço 23 , Joshua L Bonkowsky 24 , Coriene Catsman-Berrevoets 25 , Pedro S Pinto 26 , Sandya Tirupathi 27 , Petter Strømme 28 , Ton de Grauw 29 , Dorota Gieruszczak-Bialek 30 31 , Ingeborg Krägeloh-Mann 32 , Hanna Mierzewska 33 , Heike Philippi 34 , Julia Rankin 35 , Tahir Atik 36 , Brenda Banwell 37 , William S Benko 38 , Astrid Blaschek 39 , Annette Bley 40 , Eugen Boltshauser 41 , Drago Bratkovic 42 , Klara Brozova 43 , Icíar Cimas 44 , Christopher Clough 45 , Bernard Corenblum 46 , Argirios Dinopoulos 47 , Gail Dolan 48 , Flavio Faletra 49 , Raymond Fernandez 50 , Janice Fletcher 51 , Maria Eugenia Garcia Garcia 52 , Paolo Gasparini 53 , Janina Gburek-Augustat 54 , Dolores Gonzalez Moron 55 , Aline Hamati 56 , Inga Harting 57 , Christoph Hertzberg 58 , Alan Hill 59 , Grace M Hobson 60 , A Micheil Innes 61 , Marcelo Kauffman 62 , Susan M Kirwin 63 , Gerhard Kluger 64 , Petra Kolditz 65 , Urania Kotzaeridou 66 , Roberta La Piana 67 , Eriskay Liston 68 , William McClintock 69 70 , Meriel McEntagart 71 , Fiona McKenzie 72 73 , Serge Melançon 74 , Anjum Misbahuddin 75 , Mohnish Suri 76 , Fernando I Monton 17 , Sebastien Moutton 77 , Raymond P J Murphy 78 , Miriam Nickel 79 , Hüseyin Onay 80 , Simona Orcesi 81 , Ferda Özkınay 82 , Steffi Patzer 83 , Helio Pedro 84 , Sandra Pekic 85 , Mercedes Pineda Marfa 86 , Amy Pizzino 87 88 , Barbara Plecko 89 , Bwee Tien Poll-The 90 , Vera Popovic 91 , Dietz Rating 92 , Marie-France Rioux 93 , Norberto Rodriguez Espinosa 17 , Anne Ronan 94 , John R Ostergaard 95 , Elsa Rossignol 96 , Rocio Sanchez-Carpintero 97 , Anna Schossig 98 , Nesrin Senbil 99 , Laura K Sønderberg Roos 100 , Cathy A Stevens 101 , Matthis Synofzik 102 , László Sztriha 103 , Daniel Tibussek 104 , Dagmar Timmann 105 , Davide Tonduti 106 , Bart P van de Warrenburg 107 , Maria Vázquez-López 108 , Sunita Venkateswaran 109 , Pontus Wasling 110 , Evangeline Wassmer 111 , Richard I Webster 112 , Gert Wiegand 113 114 , Grace Yoon 115 , Joost Rotteveel 116 , Raphael Schiffmann 117 , Marjo S van der Knaap 7 118 , Adeline Vanderver 10 119 , Gabriel Á Martos-Moreno 120 121 122 , Constantin Polychronakos 123 , Nicole I Wolf 7 , Geneviève Bernard 1 2 3 4 5
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.
CITATION J Clin Endocrinol Metab. 2021 Jan 23;106(2):e660-e674. doi: 10.1210/clinem/dgaa700
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