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

被引：28

作者：

Pelletier, Felixe ^{[1
,2
,3
,4
,5
,6
]}

Perrier, Stefanie ^{[1
,4
]}

Cayami, Ferdy K. ^{[7
,8
,9
]}

Mirchi, Amytice ^{[1
,2
,3
,4
,5
]}

Saikali, Stephan ^{[10
]}

Tran, Luan T. ^{[1
,2
,3
,4
]}

Ulrick, Nicole ^{[11
]}

Guerrero, Kether ^{[1
,2
,3
,4
]}

Rampakakis, Emmanouil ^{[2
]}

van Spaendonk, Rosalina M. L. ^{[12
]}

Naidu, Sakkubai ^{[13
]}

Pohl, Daniela ^{[14
]}

Gibson, William T. ^{[15
]}

Demos, Michelle ^{[16
]}

Goizet, Cyril ^{[17
,18
]}

Tejera-Martin, Ingrid ^{[19
]}

Potic, Ana ^{[20
]}

Fogel, Brent L. ^{[21
]}

Brais, Bernard ^{[1
,3
,22
]}

Sylvain, Michel ^{[23
]}

Sebire, Guillaume ^{[2
,24
]}

Lourenco, Charles Marques ^{[25
]}

Bonkowsky, Joshua L. ^{[26
]}

Catsman-Berrevoets, Coriene ^{[27
]}

Pinto, Pedro S. ^{[28
]}

Tirupathi, Sandya ^{[29
]}

Stromme, Petter ^{[30
,31
]}

de Grauw, Ton ^{[32
]}

Gieruszczak-Bialek, Dorota ^{[33
,34
]}

Kraegeloh-Mann, Ingeborg ^{[35
]}

Mierzewska, Hanna ^{[36
]}

Philippi, Heike ^{[37
]}

Rankin, Julia ^{[38
]}

Atik, Tahir ^{[39
]}

Banwell, Brenda ^{[40
]}

Benko, William S. ^{[41
]}

Blaschek, Astrid ^{[42
]}

Bley, Annette ^{[43
]}

Boltshauser, Eugen ^{[44
]}

Bratkovic, Drago ^{[45
]}

Brozova, Klara ^{[46
]}

Cimas, Iciar ^{[47
]}

Clough, Christopher ^{[48
]}

Corenblum, Bernard ^{[49
]}

Dinopoulos, Argirios ^{[50
]}

Dolan, Gail ^{[51
]}

Faletra, Flavio ^{[52
]}

Fernandez, Raymond ^{[53
]}

Fletcher, Janice ^{[54
]}

Garcia, Maria Eugenia Garcia ^{[55
]}

机构：

[1] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 0G4, Canada

[2] McGill Univ, Dept Pediat, Montreal, PQ H3A 0G4, Canada

[3] McGill Univ, Dept Human Genet, Montreal, PQ H3A 0G4, Canada

[4] McGill Univ, Child Hlth & Human Dev Program, Res Inst, Hlth Ctr, Montreal, PQ H4A 3J1, Canada

[5] McGill Univ, Dept Specialized Med, Div Med Genet, Hlth Ctr, Montreal, PQ H4A 3J1, Canada

[6] Univ Montreal, Dept Pediat, Div Child Neurol, CHU St Justine, Montreal, PQ H3T 1C5, Canada

[7] Vrije Univ Amsterdam, Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Child Neurol,Amsterdam Leukodystrophy Ctr, NL-1081 Amsterdam, Netherlands

[8] Vrije Univ Amsterdam, Amsterdam Neurosci, NL-1081 Amsterdam, Netherlands

[9] Diponegoro Univ, Fac Med, Ctr Biomed Res, Semarang 50275, Indonesia

[10] Ctr Hosp Univ Quebec, Dept Pathol, Quebec City, PQ G1R 2J6, Canada

[11] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA

[12] Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam UMC, NL-1081 Amsterdam, Netherlands

[13] Johns Hopkins Med Inst, Kennedy Krieger Inst, Dept Neurogenet, Baltimore, MD 21205 USA

[14] Univ Ottawa, Childrens Hosp Eastern Ontario, Div Neurol, Ottawa, ON K1H 8L1, Canada

[15] Univ British Columbia, BC Childrens Hosp, Dept Med Genet, Res Inst, Vancouver, BC V6T 1Z4, Canada

[16] Univ British Columbia, BC Childrens Hosp, Dept Pediat, Div Neurol, Vancouver, BC V6T 1Z4, Canada

[17] Univ Bordeaux, Bordeaux Univ Hosp, Ctr Reference Neurogenet, Serv Genet Med, F-33076 Bordeaux, France

[18] Univ Bordeaux, INSERM U1211, Lab MRGM, F-33076 Bordeaux, France

[19] Hosp Univ Nuestra Senora de Candelaria, Dept Neurol, Santa Cruz De Tenerife 38010, Canary Islands, Spain

[20] Univ Belgrade, Dept Neurol, Clin Child Neurol & Psychiat, Med Fac, Belgrade 11000, Serbia

[21] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[22] Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada

[23] CHU Quebec, Ctr Mere Enfant, Quebec City, PQ G1V 4G2, Canada

[24] Univ Sherbrooke, Dept Pediat, Sherbrooke, PQ J1K 2R1, Canada

[25] Ctr Univ Estacio Ribeirao Preto, Fac Med, BR-14096160 Ribeirao Preto, SP, Brazil

[26] Univ Utah, Dept Pediat, Sch Med, Salt Lake City, UT 84132 USA

[27] Erasmus Univ Hosp, Dept Paediat Neurol, Sophia Childrens Hosp, NL-3015 CN Rotterdam, Netherlands

[28] Ctr Hosp Porto, Neuroradiol Dept, P-4099001 Porto, Portugal

[29] Royal Belfast Hosp Sick Children, Dept Paediat Neurol, Belfast BT12 6BA, Antrim, North Ireland

[30] Oslo Univ Hosp, Div Pediat & Adolescent Med, N-0450 Oslo, Norway

[31] Univ Oslo, N-0315 Oslo, Norway

[32] Emory Sch Med, Dept Pediat, Atlanta, GA 30322 USA

[33] Childrens Mem Hlth Inst, Dept Med Genet, PL-04730 Warsaw, Poland

[34] Med Univ Warsaw, Dept Pediat, PL-02091 Warsaw, Poland

[35] Univ Childrens Hosp Tubingen, Dept Child Neurol, D-72076 Tubingen, Germany

[36] Inst Mother & Child Hlth, Dept Child & Adolescent Neurol, PL-01211 Warsaw, Poland

[37] Ctr Dev Neurol SPZ Frankfurt Mitte, D-60316 Frankfurt, Germany

[38] Royal Devon & Exeter NHS Fdn Trust, Peninsula Clin Genet Serv, Exeter EX2 5DW, Devon, England

[39] Ege Univ, Sch Med, Dept Pediat, Div Genet, TR-35040 Izmir, Turkey

[40] Childrens Hosp Philadelphia, Dept Pediat, Div Neurol, Philadelphia, PA 19104 USA

[41] UC Davis Hlth Syst, Div Pediat Neurol, Dept Neurol, Sacramento, CA 95817 USA

[42] Ludwig Maximilians Univ Munchen, Dr V Hauner Childrens Hosp, Dept Pediat Neurol & Dev Med, Univ Hosp, D-80337 Munich, Germany

[43] Univ Med Ctr Hamburg Eppendorf, Univ Childrens Hosp, D-20251 Hamburg, Germany

[44] Univ Childrens Hosp Zurich, Dept Child Neurol, CH-8032 Zurich, Switzerland

[45] Womens & Childrens Hosp, Metab Clin, Adelaide, SA 5006, Australia

[46] Thomayers Hosp, Dept Child Neurol, Prague 14059, Czech Republic

[47] Povisa Hosp, Dept Neurol, Vigo 36211, Spain

[48] Kings Coll Hosp London, Dept Neurol, London SE5 9RS, England

[49] Univ Calgary, Dept Med, Div Endocrinol & Metab, Calgary, AB T2n 1n4, Canada

[50] Natl & Kapodistrian Univ Athens, Attikon Hosp, Dept Pediat 3, Athens 15772, Greece

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2021年 / 106卷 / 02期

基金：

加拿大健康研究院;

关键词：

POLR3-related leukodystrophy; 4H leukodystrophy; hypomyelination; hypogonadotropic hypogonadism; DIFFUSE HYPOMYELINATION; PATTERN-RECOGNITION; RECESSIVE MUTATIONS; HORMONE DEFICIENCY; SUBUNIT; CLASSIFICATION; DIAGNOSIS;

D O I：

10.1210/clinem/dgaa700

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：E660 / E674

页数：15

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