Publicaciones científicas

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

23-ene-2021 | Revista: The Journal of Clinical Endocrinology and Metabolism

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.

CITA DEL ARTÍCULO  J Clin Endocrinol Metab. 2021 Jan 23;106(2):e660-e674. doi: 10.1210/clinem/dgaa700

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