Börjeson-Forssman-Lehmann综合征1例

潘 兰桂; 尹 飞; 陈 施梦; 熊 娟; 何 芳; 彭 镜

doi:10.11817/j.issn.1672-7347.2023.220414

. 2023 Feb 28;48(2):294–301. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.220414

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Börjeson-Forssman-Lehmann综合征1例

潘兰桂 ^1,², 尹飞 ^1,^✉, 陈施梦 ¹, 熊娟 ¹, 何芳 ¹, 彭镜 ¹

Editor: 陈丽文

PMCID: PMC10930350 PMID: 36999477

Abstract

Börjeson-Forssman-Lehmann综合征(Börjeson-Forssman-Lehmann syndrome，BFLS)是一种罕见的X连锁智力障碍性疾病，主要临床表现为智力障碍/全面发育落后、特殊面容、手指和足趾异常、性腺功能减退，女性患者多见线状皮肤色素沉着和牙齿异常，男性患者多见肥胖。中南大学湘雅医院儿科收治1例PHF6基因新发突变致BFLS病例。本例为11个月的女性患儿，临床表现为全面发育落后，特殊面容，头发稀疏，眼距增宽，鼻梁低平，耳屏前多毛，上唇薄，牙齿异常，舌系带过短，通贯掌，锥形指，双手小指弯曲，线样皮肤色素沉着斑。二代测序技术结果显示PHF6基因(NM_032458.3)存在新发c.346C>T(p.Arg116*)杂合突变，变异评级为致病性变异。随访期间患儿出现散光、斜视、清醒磨牙症、刻板行为，皮肤色素沉着颜色较前加深。本病目前尚无特异性治疗方法。

Keywords: Börjeson-Forssman-Lehmann综合征, 智力障碍, 发育落后, PHF6基因

Börjeson-Forssman-Lehmann综合征(Börjeson-Forssman-Lehmann syndrome，BFLS)是一种罕见的X连锁智力障碍疾病，以男性多见，主要临床表现为智力障碍、特殊面容、手指及足趾异常、性腺功能减退等。BFLS(OMIM#301900)由Börjeson等^[1]于1962年首次报道，1989年发现其相关染色体区域定位在Xq26-q27^[2-3]，2002年确定该病的致病基因为PHF6 ^[4-5]。迄今已报道90余例患者，其中中国共报道2例BFLS家系病例^[6-7]。现报告就诊于中南大学湘雅医院儿科的1例PHF6基因突变所致BFLS女性患儿，结合文献总结其临床表型，以提高临床医师对该病的认识。

1. 病例资料

1.1. 临床资料

患儿，女，11月龄，因“发育落后11月”于2019年8月22日首次就诊于中南大学湘雅医院儿科门诊。患儿系第1胎，第1产，足月儿，出生体重3.15 kg，经阴道分娩，出生时无产伤及窒息史；其母孕期无特殊疾病情况；出生后混合喂养，无喂养困难。患儿智力发育落后，3个月抬头，8个月翻身，11个月时仍不能独坐、不能叫人、追光追物欠佳。外院智力测验示11月龄相当于4~5月龄儿童水平。自起病以来，患儿一般情况可，饮食正常，睡眠正常，体重逐渐增长。父母均体健，非近亲婚配，否认家族性遗传病史。

体格检查：体重8.9 kg，身高75 cm，头围44 cm，前囟2.0 cm×2.0 cm；运动、智力发育落后；追光追物欠佳；面容特殊(图1)，头发稀疏，耳屏前多毛，眼距增宽，鼻梁低平，上唇薄，牙列不齐，齿距较宽。双肺听诊无异常，心音有力，律齐，未闻及杂音。腹软，肝脾无肿大。通贯掌，锥形指，双手小指弯曲，四肢及躯干皮肤散在线状或条纹状浅褐色色素沉着斑，双脚第2~3趾并趾畸形；四肢肌张力低下，活动可，腱反射可引出，病理征阴性。

**Börjeson-Forssman-Lehmann**综合征患儿11月龄照片

Figure 1 Appearance of a 11-month old child with Börjeson-Forssman-Lehmann syndrome

A: Thin upper lip, irregular dentition, wide interdental distance; B: Sparse hair.

辅助检查：脑电图正常。头颅磁共振成像(magnetic resonance imaging，MRI)：脑内多发异常信号，白质疏松，V-R间隙宽(图2)。染色体未见异常。

11月龄**Börjeson-Forssman-Lehmann** 综合征患儿颅脑磁共振影像**(T₁WI)**

Figure 2 Brain magnetic resonance imaging (T₁WI) of a 11-month old child with Börjeson-Forssman-Lehmann syndrome

A and B: Widening of perivascular space; C: Multiple patchy and spotty hypointense changes in periventricular white matter.

1.2. 基因检测

经家属签字同意后抽取患儿及其父母静脉血 3 mL置于乙二胺四乙酸(ethylene diamine tetraacetic acid，EDTA)抗凝管，送至北京赛福基因公司行DNA拷贝数变异及全外显子测序基因检查。采用低倍基因组检测方法，未检测到可以明确解释患者表型的致病性或疑似致病性拷贝数变异。采用二代基因测序技术，检测到可以解释患者表型的PHF6基因变异，再用Sanger测序技术对患儿及其父母的PHF6基因突变进行验证。患儿PHF6基因存在c.346C>T(p.Arg116*)的杂合变异(转录本NM_032458.3)，染色体位置在chrX:134393606，位于第4外显子，编码区第346号核苷酸由C变为T，该变异导致编译第116号Arg的密码子变为终止密码子，从而使肽链合成提前终止，为无义突变，该变异已有文献^[8]报道。Sanger测序验证该变异来源，结果提示患儿父母该位点无变异(图3)，考虑为新生变异，在该家庭符合共分离特征，符合X连锁遗传致病模式。根据《2015年美国医学遗传学和基因组学学会(The American College of Medical Genetics and Genomics，ACMG)序列变异解读标准与指南》^[9]对该变异进行分析：1)该突变为无义变异(PVS1)；2)该突变为新发变异(不排除父母生殖腺存在嵌合可能)(PS2)；3)该突变在ExAC、gnomAD、千人基因组亚洲人群数据库中的发生频率没有被收录(PM2)。PHF6基因与BFLS相关联，该病为X连锁隐性遗传，考虑X染色体非随机失活，杂合变异可致病。综上所述，根据ACMG遗传变异分类联合标准规则，PHF6基因c.346C>T突变为致病变异。

患儿家系 ***PHF6*** 基因**c.346C>T Sanger**测序结果

Figure 3 Results of c.346C>T Sanger sequencing of *PHF6* gene in the whole family

本研究通过中南大学湘雅医院医学伦理委员会审批(审批号：201605585)，患儿监护人知情同意，并签署知情同意书。

1.3. 治疗及随访

患儿自10月龄开始进行康复治疗，共1年2个月，2岁时可独走。患儿4岁时，身高106 cm，体重15 kg；头发稀疏；双眼有散光及斜视；牙齿小而异常，门牙形状不规则，清醒时磨牙；有刻板行为；四肢及躯干散在条纹状色素沉着斑无增多，但颜色较前更深(图4)；可上下楼梯、跑步；语言差，最多说5字，发音不准，在外院就诊时发现舌系带过短(已手术治疗)。

**Börjeson-Forssman-Lehmann**综合征患儿4岁时照片

Figure 4 Photos of the child with Börjeson-Forssman-Lehmann syndrome at the 4 years old

A: Abnormal teeth; B: Syndactyly of digits 2-3 of both feet; C: Linear skin pigmentation of thigh; D: Tapering fingers and curved digitus V of both hands. Red arrows represent linear skin pigmentation.

2. 讨论

目前共报道38种PHF6基因致病突变，突变类型包括错义突变、无义突变、移码突变、剪接突变、重复、插入和缺失，其中以错义突变最常见^{[5, 8, 10-13]}。PHF6基因位于染色体Xq26.2，包含11个外显子，编码365个氨基酸的PHD指蛋白6(PHD finger protein 6，PHF6)。PHF6具有2个核定位序列、1个核仁定位序列和2个PHD锌指结构域(PHD1和PHD2)，在发育中的中枢神经系统中高度表达且表达水平随着发育进展下降^[14]，参与转录调控、神经元发育和神经元迁移等过程^{[10, 15-18]}。PHF6通过与血小板活化因子1转录延伸复合物结合促进大脑皮层中的神经元迁移，PHF6基因敲除小鼠的神经元迁移停滞并形成神经元过度兴奋的白质异位^[15-16]，1例BFLS患者的病理结果也显示皮质异位^[19]，这可能与BFLS癫痫和智力障碍相关。PHF6的突变还与白血病有关，PHF6蛋白通过染色质修饰参与转录调控。已在各种血液系统恶性肿瘤中发现PHF6突变，突变类型以移码和无义突变多见^[20-21]。研究^[22-23]报道1例男性BFLS患者在7岁时被诊断为急性T淋巴细胞白血病，男1例男性BFLS患者在16岁时被诊断为霍奇金淋巴瘤。因此需警惕PHF6基因突变患者合并血液系统恶性肿瘤的可能^[20]。

以“PHF6”和“Börjeson-Forssman-Lehmann syndrome”为检索词，分别在中国知网(CNKI)数据库、万方数据库和PubMed数据库(建库至2022年7月)进行检索，排除内容不相符、重复研究、无法获取全文的文献后，对24篇文献^{[1, 4-8, 12-13, 21, 24-38]}报道的90例BFLS患者和本例患儿的临床表现进行总结。男性63例，女性28例，年龄分布从10月龄到62岁。主要临床表现(表1)：1)智力障碍，女性多表现为轻-中度智力障碍，男性则多为中-重度智力障碍。2)特殊面容，典型面容特征表现为颞部狭窄、眉弓及颧骨突出、眼窝深陷、大耳、短鼻、头发稀疏，其他表现还有球形鼻尖、连眉、拱形眉、薄上唇、低发际线、眼距宽、耳屏有毛发等。3)手指及足趾异常，包括斜指、弯曲指、锥形指、短指/趾、并趾、第1~2趾宽间隙、指/趾甲发育不良。4)肥胖和身材矮小，以男性多见。5)性腺功能减退或外生殖器异常，男性多见乳房发育、小阴茎和小睾丸等表现，女性则表现为月经稀发。6)牙齿异常，表现为小齿、牙齿形状不规则、牙发育不良、缺牙、牙列不齐、齿距宽、出牙延迟、牙根异常；男性少见牙齿异常报道。7)线状皮肤色素沉着，表现为线状浅褐色斑，分布部位有腋窝、腹股沟、臀部、腿部、躯干等；男性未见此表型报道。8)癫痫，部分患者在抗癫痫治疗下能达到完全控制，但也有难治性癫痫表型。9)行为异常，表现为焦虑、多动、攻击性行为、强迫性行为等。10)眼异常，表现为眼球震颤、近视、远视、散光、斜视、视网膜色素脱失、视网膜营养不良和黄斑病变等。其他还包括小头畸形或大头畸形、肌张力减退、听力障碍、反复耳部感染、垂体功能减退、肾脏异常、喂养困难、睡眠困难、多毛症、脊柱侧弯、腭裂等。

表1.

PHF6 基因突变导致BFLS的临床表现

Table 1 Clinical manifestations of PHF6 gene mutation leading to BFLS

性别	智力障碍	行为异常	癫痫	特殊面容	牙齿异常	眼异常
合计	80	20	9	72	20	17
女性	25/28	7/16	5/24	24/26	19/21	14/16
男性	55/55	13/34	4/42	48/48	1/1	3/5

性别	手指异常	足趾异常	肥胖	身材矮小	性腺功能减退/外生殖器异常	线状皮肤色素沉着
合计	42	44	49	12	55	18
女性	25/26	22/26	5/26	2/24	10/10	18/26
男性	17/23	22/23	44/49	10/22	45/46	NA

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相关表型无详细描述者未统计入分母。PHF6：PHD指蛋白；BFLS：Börjeson-Forssman-Lehmann综合征；NA：未在已发表的研究中单独陈述或报告。

BFLS女性患者与男性患者表型重叠，但女性表型更轻微，也可出现与男性患者显著不同的表型^{[8, 13]}。值得注意的是，BFLS女性患者中常见的线状皮肤色素沉着表型，在男性患者中却未见报道^{[8, 12, 37]}。手指和脚趾异常在男性患者中以锥形指和短趾最常见，女性患者的异常表现则更为多样化^{[8, 12]}。男性较女性多见身材矮小、肥胖和生殖器异常，女性患者常见牙齿异常^{[8, 12-13]}。在同等高水平的X染色体失活偏斜的女性患者中，表型从不典型到典型均有，表明X染色体失活水平检测可能无法可靠地预测PHF6基因突变携带者的BFLS特征的外显率^{[7, 11]}。本例患儿为女性，临床表现为全面发育落后、特殊面容(头发稀疏、耳屏前多毛、鼻梁低平、薄上唇)、牙齿异常、锥形指、双手小指弯曲、通贯掌、并趾畸形和皮肤色素沉着斑。在末次随访时，患儿头发仍稀疏，皮肤色素沉着颜色较前加深，出现散光、斜视、刻板动作、清醒磨牙症。该患儿临床表现及病程发展与已报道的BFLS女性患者相似。其中清醒磨牙症和舌系带过短表型目前未见报道，耳屏前多毛为BFLS少见的临床表型，仅1例相关报道^[27]。

BFLS患者在不同年龄阶段可呈现不同的临床特点。患儿出生时通常具有正常或接近正常的生长参数；婴儿期临床特点为发育迟缓、肌张力低下、喂养困难、小阴茎及睾丸、大耳、手指及足趾畸形；随着年龄增长可出现智力障碍、小头畸形或大头畸形、牙齿异常、身材矮小、性腺功能减退、垂体功能减退、癫痫和行为问题等；儿童晚期特点为向心性肥胖、青春期乳房发育等；成年期的面容特征变得显著，表现为额部狭窄、眉弓突出、颧骨突出、眼睛深陷、大耳等^{[11, 13, 16, 24]}。

BFLS需与Coffin-Lowry综合征、Coffin-Siris综合征、Prader-Willi综合征等疾病相鉴别^[24]。BFLS与Coffin-Lowry综合征(OMIM#303600)的重叠表型包括锥形手指、类似的面容特征、身材矮小和听力缺陷，鉴别点为Coffin-Lowry综合征常见漏斗胸和进行性脊柱侧弯，可出现刺激诱发的跌倒发作、进行性痉挛等表现；而在BFLS中脊柱侧弯很少见，并且没有跌倒发作和进行性痉挛^[38]。婴儿期BFLS女性患者与Coffin-Siris综合征患者之间存在显著的重叠表型，表现为头发稀疏、牙齿异常和远端指骨或指(趾)甲发育不良^{[12, 27]}，但大部分BFLS女性患者都存在线状皮肤色素沉着^[13]。Prader-Willi综合征(OMIM#176270)与BFLS相比，其新生儿肌张力减退、喂养困难及向心性肥胖程度更严重，且肥胖出现的年龄较BFLS患者更小，为婴儿后期或儿童早期^{[11, 39]}。

BFLS患者临床表现多样，在生长发育过程中逐渐出现多个器官、系统受累症状，需要神经、内分泌、生殖、血液、骨骼、口腔、眼和皮肤等多学科合作，定期进行医疗评估。该综合征目前尚无有效治疗方法，需要积极对症治疗，及时处理并发症。既往报道苯巴比妥、拉莫三嗪可有效控制癫痫^[25]，但也有多药难以控制的难治性癫痫病例^[25]；性腺功能减退或生长激素缺乏症可行替代治疗^{[3, 11]}；部分患者容易长龋齿^{[26, 34]}，需要注意保持口腔清洁，或因为牙齿缺损而需要补牙^[27]；少数患者可出现听力障碍，需尽早干预治疗；患儿喂养困难时应及时行鼻饲喂养；发育迟缓或智力障碍患者可进行康复训练和特殊教育。

综上所述，对于不明原因X连锁智力障碍合并特殊面容、锥形指、短趾、性腺功能减退和肥胖的男性患者，以及表现为智力障碍、特殊面容、手指及足趾异常、牙齿异常和线状皮肤色素沉着的女性患者需要考虑BFLS可能，应尽早完善基因学检查，以便于明确病情、判断预后，对确诊的受累家庭再生育提供遗传学咨询。

本研究不足之处：为单样本病例，缺乏功能学研究，缺乏X染色体失活、家系验证等结果。

基金资助

国家自然科学基金(81771408)。

This work was supported by the National Natural Science Foundation of China (817714081).

利益冲突声明

作者声称无任何利益冲突。

作者贡献

潘兰桂研究设计与实施，论文撰写与修改；尹飞研究指导，对论文的知识性内容进行批评性审阅；陈施梦、熊娟数据采集；何芳数据分析、解释；彭镜对论文的知识性内容进行批评性审阅。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202302294.pdf

参考文献

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2. Mathews KD, Ardinger HH, Nishimura DY, et al. Linkage localization of Börjeson-forssman-Lehmann syndrome[J]. Am J Med Genet, 1989, 34(4): 470-474. 10.1002/ajmg.1320340403. [DOI] [PubMed] [Google Scholar]
3. Turner G, Gedeon A, Mulley J, et al. Börjeson-Forssman-Lehmann syndrome: clinical manifestations and gene localization to Xq26-27[J]. Am J Med Genet, 1989, 34(4): 463-469. 10.1002/ajmg.1320340402. [DOI] [PubMed] [Google Scholar]
4. Lower KM, Turner G, Kerr BA, et al. Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome[J]. Nat Genet, 2002, 32(4): 661-665. 10.1038/ng1040. [DOI] [PubMed] [Google Scholar]
5. Ernst A, Le VQ, Højland AT, et al. The PHF6 mutation c.1A>G; pM1V causes Börjeson-Forsman-Lehmann syndrome in a family with four affected young boys[J]. Mol Syndromol, 2015, 6(4): 181-186. 10.1159/000441047. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. 阙勇祥, 李培, 胡恕香. PHF6基因变异致Börjeson-Forssman-Lehmann综合征一例[J]. 中华儿科杂志, 2021, 59(5): 414-416. 10.3760/cma.j.cn112140-20201015-00944. [DOI] [PubMed] [Google Scholar]; QUE Yongxiang, LI Pei, HU Xuxiang. A case of Börjeson-Forssman-Lehmann syndrome caused by PHF6 gene mutation[J]. Chinese Journal of Pediatrics, 2021, 59(5): 414-416. 10.3760/cma.j.cn112140-20201015-00944. [DOI] [PubMed] [Google Scholar]
7. Zhang X, Fan YJ, Liu XM, et al. A novel nonsense mutation of PHF6 in a female with extended phenotypes of Borjeson-Forssman-Lehmann syndrome[J]. J Clin Res Pediatr Endocrinol, 2019, 11(4): 419-425. 10.4274/jcrpe.galenos.2019.2018.0220. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Gerber CB, Fliedner A, Bartsch O, et al. Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6[J]. Clin Genet, 2022, 102(3): 182-190. 10.1111/cge.14173. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. 10.1038/gim.2015.30. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Ahmed R, Sarwar S, Hu J, et al. Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann syndrome[J]. Hum Mol Genet, 2021, 30(7): 575-594. 10.1093/hmg/ddab081. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Gécz J, Turner G, Nelson J, et al. The Börjeson-Forssman-Lehman syndrome (BFLS, MIM #301900)[J]. Eur J Hum Genet, 2006, 14(12): 1233-1237. 10.1038/sj.ejhg.5201639. [DOI] [PubMed] [Google Scholar]
12. Zweier C, Rittinger O, Bader I, et al. Females with de novo aberrations in PHF6: clinical overlap of Borjeson-Forssman-Lehmann with Coffin-Siris syndrome[J]. Am J Med Genet C Semin Med Genet, 2014, 166C(3): 290-301. 10.1002/ajmg.c.31408. [DOI] [PubMed] [Google Scholar]
13. Garcia-Melendo C, Roé E, Rodríguez-Santiago B, et al. A case report of PHF6 mosaicism: beyond the classic Börjeson-Forssman-Lehmann syndrome[J]. Pediatr Dermatol, 2021, 38(4): 919-925. 10.1111/pde.14636. [DOI] [PubMed] [Google Scholar]
14. Voss AK, Gamble R, Collin C, et al. Protein and gene expression analysis of Phf6, the gene mutated in the Börjeson-Forssman-Lehmann syndrome of intellectual disability and obesity[J]. Gene Expr Patterns, 2007, 7(8): 858-871. 10.1016/j.modgep.2007.06.007. [DOI] [PubMed] [Google Scholar]
15. Zhang C, Mejia LA, Huang J, et al. The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain[J]. Neuron, 2013, 78(6): 986-993. 10.1016/j.neuron.2013.04.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Jahani-Asl A, Cheng C, Zhang C, et al. Pathogenesis of Börjeson-forssman-Lehmann syndrome: insights from PHF6 function[J]. Neurobiol Dis, 2016, 96: 227-235. 10.1016/j.nbd.2016.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Wang JD, Leung JW, Gong ZH, et al. PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis[J]. J Biol Chem, 2013, 288(5): 3174-3183. 10.1074/jbc.M112.414839. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Fliedner A, Gregor A, Ferrazzi F, et al. Loss of PHF6 leads to aberrant development of human neuron-like cells[J]. Sci Rep, 2020, 10(1): 19030. 10.1038/s41598-020-75999-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Brun A, Börjeson M, Forssman H. An inherited syndrome with mental deficiency and endocrine disorder. A patho-anatomical study[J]. J Ment Defic Res, 1974, 18(4): 317-325. 10.1111/j.1365-2788.1974.tb01243.x. [DOI] [PubMed] [Google Scholar]
20. Eisa YA, Guo Y, Yang FC. The role of PHF6 in hematopoiesis and hematologic malignancies[J]. Stem Cell Rev Rep, 2023, 19(1): 67-75. 10.1007/s12015-022-10447-4. [DOI] [PubMed] [Google Scholar]
21. Carter MT, Picketts DJ, Hunter AG, et al. Further clinical delineation of the Börjeson-Forssman-Lehmann syndrome in patients with PHF6 mutations[J]. Am J Med Genet A, 2009, 149A(2): 246-250. 10.1002/ajmg.a.32624. [DOI] [PubMed] [Google Scholar]
22. Chao MM, Todd MA, Kontny U, et al. T-cell acute lymphoblastic leukemia in association with Börjeson-Forssman-Lehmann syndrome due to a mutation in PHF6[J]. Pediatr Blood Cancer, 2010, 55(4): 722-724. 10.1002/pbc.22574. [DOI] [PMC free article] [PubMed] [Google Scholar]
23. Trowbridge JJ. Context-specific tumor suppression by PHF6[J]. Blood, 2019, 133(16): 1698-1700. 10.1182/blood-2019-03-900829. [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Bellad A, Bandari AK, Pandey A, et al. A novel missense variant in PHF6 gene causing Börjeson-forssman-Lehman syndrome[J]. J Mol Neurosci, 2020, 70(9): 1403-1409. 10.1007/s12031-020-01560-5. [DOI] [PubMed] [Google Scholar]
25. Kasper BS, Dörfler A, di Donato N, et al. Central nervous system anomalies in two females with Borjeson-Forssman-Lehmann syndrome[J]. Epilepsy Behav, 2017, 69: 104-109. 10.1016/j.yebeh.2017.01.022. [DOI] [PubMed] [Google Scholar]
26. di Donato N, Isidor B, Lopez Cazaux S, et al. Distinct phenotype of PHF6 deletions in females[J]. Eur J Med Genet, 2014, 57(2/3): 85-89. 10.1016/j.ejmg.2013.12.003. [DOI] [PubMed] [Google Scholar]
27. Zweier C, Kraus C, Brueton L, et al. A new face of Borjeson-Forssman-Lehmann syndrome? De novo mutations in PHF6 in seven females with a distinct phenotype[J]. J Med Genet, 2013, 50(12): 838-847. 10.1136/jmedgenet-2013-101918. [DOI] [PubMed] [Google Scholar]
28. Berland S, Alme K, Brendehaug A, et al. PHF6 deletions may cause Borjeson-Forssman-Lehmann syndrome in females[J]. Mol Syndromol, 2011, 1(6): 294-300. 10.1159/000330111. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Mangelsdorf M, Chevrier E, Mustonen A, et al. Börjeson-Forssman-Lehmann syndrome due to a novel plant homeodomain zinc finger mutation in the PHF6 gene[J]. J Child Neurol, 2009, 24(5): 610-614. 10.1177/0883073808327830. [DOI] [PubMed] [Google Scholar]
30. Baumstark A, Lower KM, Sinkus A, et al. Novel PHF6 mutation p.D333del causes Börjeson-Forssman-Lehmann syndrome[J]. J Med Genet, 2003, 40(4): e50 [2022-07-01]. 10.1136/jmg.40.4.e50. [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Lower KM, Solders G, Bondeson ML, et al. 1024C> T (R342X) is a recurrent PHF6 mutation also found in the original Börjeson-Forssman-Lehmann syndrome family[J]. Eur J Hum Genet, 2004, 12(10): 787-789. 10.1038/sj.ejhg.5201228. [DOI] [PubMed] [Google Scholar]
32. Crawford J, Lower KM, Hennekam RM, et al. Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient[J]. J Med Genet, 2006, 43(3): 238-243. 10.1136/jmg.2005.033084. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. de Winter CF, van Dijk F, Stolker JJ, et al. Behavioural phenotype in Börjeson-forssman-Lehmann syndrome[J]. J Intellect Disabil Res, 2009, 53(4): 319-328. 10.1111/j.1365-2788.2009.01156.x. [DOI] [PubMed] [Google Scholar]
34. Wieczorek D, Bögershausen N, Beleggia F, et al. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling[J]. Hum Mol Genet, 2013, 22(25): 5121-5135. 10.1093/hmg/DDT366. [DOI] [PubMed] [Google Scholar]
35. Turner G, Lower KM, White SM, et al. The clinical picture of the Börjeson-Forssman-Lehmann syndrome in males and heterozygous females with PHF6 mutations[J]. Clin Genet, 2004, 65(3): 226-232. 10.1111/j.0009-9163.2004.00215.x. [DOI] [PubMed] [Google Scholar]
36. Vallée D, Chevrier E, Graham GE, et al. A novel PHF6 mutation results in enhanced exon skipping and mild Börjeson-Forssman-Lehmann syndrome[J]. J Med Genet, 2004, 41(10): 778-783. 10.1136/jmg.2004.020370. [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Happle R. An unusual linear hypermelanosis reflecting lyonization in women with Börjeson-Forssman-Lehmann syndrome[J]. J Eur Acad Dermatol Venereol, 2016, 30(2): 323-324. 10.1111/jdv.12717. [DOI] [PubMed] [Google Scholar]
38. Pereira PM, Schneider A, Pannetier S, et al. Coffin-Lowry syndrome[J]. Eur J Hum Genet, 2010, 18(6): 627-633. 10.1038/ejhg.2009.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Cassidy SB, Schwartz S, Miller JL, et al. Prader-willi syndrome[J]. Genet Med, 2012, 14(1): 10-26. 10.1038/gim.0b013e31822bead0. [DOI] [PubMed] [Google Scholar]

[r1] 1. Borjeson M, Forssman H, Lehmann O. An X-linked, recessively inherited syndrome characterized by grave mental deficiency, epilepsy, and endocrine disorder[J]. Acta Med Scand, 1962, 171: 13-21. 10.1111/j.0954-6820.1962.tb04162.x. [DOI] [PubMed] [Google Scholar]

[r2] 2. Mathews KD, Ardinger HH, Nishimura DY, et al. Linkage localization of Börjeson-forssman-Lehmann syndrome[J]. Am J Med Genet, 1989, 34(4): 470-474. 10.1002/ajmg.1320340403. [DOI] [PubMed] [Google Scholar]

[r3] 3. Turner G, Gedeon A, Mulley J, et al. Börjeson-Forssman-Lehmann syndrome: clinical manifestations and gene localization to Xq26-27[J]. Am J Med Genet, 1989, 34(4): 463-469. 10.1002/ajmg.1320340402. [DOI] [PubMed] [Google Scholar]

[r4] 4. Lower KM, Turner G, Kerr BA, et al. Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome[J]. Nat Genet, 2002, 32(4): 661-665. 10.1038/ng1040. [DOI] [PubMed] [Google Scholar]

[r5] 5. Ernst A, Le VQ, Højland AT, et al. The PHF6 mutation c.1A>G; pM1V causes Börjeson-Forsman-Lehmann syndrome in a family with four affected young boys[J]. Mol Syndromol, 2015, 6(4): 181-186. 10.1159/000441047. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r6] 6. 阙勇祥, 李培, 胡恕香. PHF6基因变异致Börjeson-Forssman-Lehmann综合征一例[J]. 中华儿科杂志, 2021, 59(5): 414-416. 10.3760/cma.j.cn112140-20201015-00944. [DOI] [PubMed] [Google Scholar]; QUE Yongxiang, LI Pei, HU Xuxiang. A case of Börjeson-Forssman-Lehmann syndrome caused by PHF6 gene mutation[J]. Chinese Journal of Pediatrics, 2021, 59(5): 414-416. 10.3760/cma.j.cn112140-20201015-00944. [DOI] [PubMed] [Google Scholar]

[r7] 7. Zhang X, Fan YJ, Liu XM, et al. A novel nonsense mutation of PHF6 in a female with extended phenotypes of Borjeson-Forssman-Lehmann syndrome[J]. J Clin Res Pediatr Endocrinol, 2019, 11(4): 419-425. 10.4274/jcrpe.galenos.2019.2018.0220. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r8] 8. Gerber CB, Fliedner A, Bartsch O, et al. Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6[J]. Clin Genet, 2022, 102(3): 182-190. 10.1111/cge.14173. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r9] 9. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. 10.1038/gim.2015.30. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r10] 10. Ahmed R, Sarwar S, Hu J, et al. Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann syndrome[J]. Hum Mol Genet, 2021, 30(7): 575-594. 10.1093/hmg/ddab081. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r11] 11. Gécz J, Turner G, Nelson J, et al. The Börjeson-Forssman-Lehman syndrome (BFLS, MIM #301900)[J]. Eur J Hum Genet, 2006, 14(12): 1233-1237. 10.1038/sj.ejhg.5201639. [DOI] [PubMed] [Google Scholar]

[r12] 12. Zweier C, Rittinger O, Bader I, et al. Females with de novo aberrations in PHF6: clinical overlap of Borjeson-Forssman-Lehmann with Coffin-Siris syndrome[J]. Am J Med Genet C Semin Med Genet, 2014, 166C(3): 290-301. 10.1002/ajmg.c.31408. [DOI] [PubMed] [Google Scholar]

[r13] 13. Garcia-Melendo C, Roé E, Rodríguez-Santiago B, et al. A case report of PHF6 mosaicism: beyond the classic Börjeson-Forssman-Lehmann syndrome[J]. Pediatr Dermatol, 2021, 38(4): 919-925. 10.1111/pde.14636. [DOI] [PubMed] [Google Scholar]

[r14] 14. Voss AK, Gamble R, Collin C, et al. Protein and gene expression analysis of Phf6, the gene mutated in the Börjeson-Forssman-Lehmann syndrome of intellectual disability and obesity[J]. Gene Expr Patterns, 2007, 7(8): 858-871. 10.1016/j.modgep.2007.06.007. [DOI] [PubMed] [Google Scholar]

[r15] 15. Zhang C, Mejia LA, Huang J, et al. The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain[J]. Neuron, 2013, 78(6): 986-993. 10.1016/j.neuron.2013.04.021. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r16] 16. Jahani-Asl A, Cheng C, Zhang C, et al. Pathogenesis of Börjeson-forssman-Lehmann syndrome: insights from PHF6 function[J]. Neurobiol Dis, 2016, 96: 227-235. 10.1016/j.nbd.2016.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r17] 17. Wang JD, Leung JW, Gong ZH, et al. PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis[J]. J Biol Chem, 2013, 288(5): 3174-3183. 10.1074/jbc.M112.414839. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r18] 18. Fliedner A, Gregor A, Ferrazzi F, et al. Loss of PHF6 leads to aberrant development of human neuron-like cells[J]. Sci Rep, 2020, 10(1): 19030. 10.1038/s41598-020-75999-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r19] 19. Brun A, Börjeson M, Forssman H. An inherited syndrome with mental deficiency and endocrine disorder. A patho-anatomical study[J]. J Ment Defic Res, 1974, 18(4): 317-325. 10.1111/j.1365-2788.1974.tb01243.x. [DOI] [PubMed] [Google Scholar]

[r20] 20. Eisa YA, Guo Y, Yang FC. The role of PHF6 in hematopoiesis and hematologic malignancies[J]. Stem Cell Rev Rep, 2023, 19(1): 67-75. 10.1007/s12015-022-10447-4. [DOI] [PubMed] [Google Scholar]

[r21] 21. Carter MT, Picketts DJ, Hunter AG, et al. Further clinical delineation of the Börjeson-Forssman-Lehmann syndrome in patients with PHF6 mutations[J]. Am J Med Genet A, 2009, 149A(2): 246-250. 10.1002/ajmg.a.32624. [DOI] [PubMed] [Google Scholar]

[r22] 22. Chao MM, Todd MA, Kontny U, et al. T-cell acute lymphoblastic leukemia in association with Börjeson-Forssman-Lehmann syndrome due to a mutation in PHF6[J]. Pediatr Blood Cancer, 2010, 55(4): 722-724. 10.1002/pbc.22574. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r23] 23. Trowbridge JJ. Context-specific tumor suppression by PHF6[J]. Blood, 2019, 133(16): 1698-1700. 10.1182/blood-2019-03-900829. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r24] 24. Bellad A, Bandari AK, Pandey A, et al. A novel missense variant in PHF6 gene causing Börjeson-forssman-Lehman syndrome[J]. J Mol Neurosci, 2020, 70(9): 1403-1409. 10.1007/s12031-020-01560-5. [DOI] [PubMed] [Google Scholar]

[r25] 25. Kasper BS, Dörfler A, di Donato N, et al. Central nervous system anomalies in two females with Borjeson-Forssman-Lehmann syndrome[J]. Epilepsy Behav, 2017, 69: 104-109. 10.1016/j.yebeh.2017.01.022. [DOI] [PubMed] [Google Scholar]

[r26] 26. di Donato N, Isidor B, Lopez Cazaux S, et al. Distinct phenotype of PHF6 deletions in females[J]. Eur J Med Genet, 2014, 57(2/3): 85-89. 10.1016/j.ejmg.2013.12.003. [DOI] [PubMed] [Google Scholar]

[r27] 27. Zweier C, Kraus C, Brueton L, et al. A new face of Borjeson-Forssman-Lehmann syndrome? De novo mutations in PHF6 in seven females with a distinct phenotype[J]. J Med Genet, 2013, 50(12): 838-847. 10.1136/jmedgenet-2013-101918. [DOI] [PubMed] [Google Scholar]

[r28] 28. Berland S, Alme K, Brendehaug A, et al. PHF6 deletions may cause Borjeson-Forssman-Lehmann syndrome in females[J]. Mol Syndromol, 2011, 1(6): 294-300. 10.1159/000330111. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r29] 29. Mangelsdorf M, Chevrier E, Mustonen A, et al. Börjeson-Forssman-Lehmann syndrome due to a novel plant homeodomain zinc finger mutation in the PHF6 gene[J]. J Child Neurol, 2009, 24(5): 610-614. 10.1177/0883073808327830. [DOI] [PubMed] [Google Scholar]

[r30] 30. Baumstark A, Lower KM, Sinkus A, et al. Novel PHF6 mutation p.D333del causes Börjeson-Forssman-Lehmann syndrome[J]. J Med Genet, 2003, 40(4): e50 [2022-07-01]. 10.1136/jmg.40.4.e50. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r31] 31. Lower KM, Solders G, Bondeson ML, et al. 1024C> T (R342X) is a recurrent PHF6 mutation also found in the original Börjeson-Forssman-Lehmann syndrome family[J]. Eur J Hum Genet, 2004, 12(10): 787-789. 10.1038/sj.ejhg.5201228. [DOI] [PubMed] [Google Scholar]

[r32] 32. Crawford J, Lower KM, Hennekam RM, et al. Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient[J]. J Med Genet, 2006, 43(3): 238-243. 10.1136/jmg.2005.033084. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r33] 33. de Winter CF, van Dijk F, Stolker JJ, et al. Behavioural phenotype in Börjeson-forssman-Lehmann syndrome[J]. J Intellect Disabil Res, 2009, 53(4): 319-328. 10.1111/j.1365-2788.2009.01156.x. [DOI] [PubMed] [Google Scholar]

[r34] 34. Wieczorek D, Bögershausen N, Beleggia F, et al. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling[J]. Hum Mol Genet, 2013, 22(25): 5121-5135. 10.1093/hmg/DDT366. [DOI] [PubMed] [Google Scholar]

[r35] 35. Turner G, Lower KM, White SM, et al. The clinical picture of the Börjeson-Forssman-Lehmann syndrome in males and heterozygous females with PHF6 mutations[J]. Clin Genet, 2004, 65(3): 226-232. 10.1111/j.0009-9163.2004.00215.x. [DOI] [PubMed] [Google Scholar]

[r36] 36. Vallée D, Chevrier E, Graham GE, et al. A novel PHF6 mutation results in enhanced exon skipping and mild Börjeson-Forssman-Lehmann syndrome[J]. J Med Genet, 2004, 41(10): 778-783. 10.1136/jmg.2004.020370. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r37] 37. Happle R. An unusual linear hypermelanosis reflecting lyonization in women with Börjeson-Forssman-Lehmann syndrome[J]. J Eur Acad Dermatol Venereol, 2016, 30(2): 323-324. 10.1111/jdv.12717. [DOI] [PubMed] [Google Scholar]

[r38] 38. Pereira PM, Schneider A, Pannetier S, et al. Coffin-Lowry syndrome[J]. Eur J Hum Genet, 2010, 18(6): 627-633. 10.1038/ejhg.2009.189. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r39] 39. Cassidy SB, Schwartz S, Miller JL, et al. Prader-willi syndrome[J]. Genet Med, 2012, 14(1): 10-26. 10.1038/gim.0b013e31822bead0. [DOI] [PubMed] [Google Scholar]

PERMALINK

Börjeson-Forssman-Lehmann综合征1例

Börjeson-Forssman-Lehmann syndrome: A case report

潘兰桂

尹飞

陈施梦

熊娟

何芳

彭镜

Abstract

Abstract