【初稿】 致死性骨发育不全

Thanatophoric Dysplasia

英文原文链接

Author Information

翻译者：郭奕斌

Initial Posting: 2017-12-02 11:15:46; Last Update: .

概要

临床表现：致死性骨发育不全(TD)是一种短肢侏儒症综合征，通常导致围产期死亡。TDⅠ型，特征为具有弯曲股骨的短肢畸形，以及不常见的不同严重程度的分叶状颅。TDⅡ型，其特征为具有直股骨的短肢畸形和普遍存在中至重度分叶状颅。Ⅰ型和Ⅱ型常见的其他特征包括：短肋，胸廓狭窄，巨头畸形，特殊的面部特征，短指畸形，张力减退和沿着四肢的多余皮肤褶皱。大多数受影响的婴儿在出生后不久就会死于呼吸功能不全。据报告有罕见的长期存活者。
诊断：TD的诊断基于临床检查和（或）产前超声检查和放射检测。还存在特征组织病理学改变。 FGFR3突变是已知导致TD的唯一基因。高达99％的突变导致TDⅠ型和超过99％的突变导致TDⅡ型，因此可以通过FGFR3基因的分子遗传检测来鉴定。
疾病管理：对症治疗：管理侧重于父母为新生儿提供舒适护理的愿望。新生儿需要呼吸支持（气管插管和通气）才能生存。麻醉管理可包括：用柔性纤维镜观察插管，颈椎处于中性位置;在程序中使用诱发电位监测和避免可能干扰诱发电位记录的挥发性麻醉剂和肌肉松弛剂。其他治疗措施可包括：用于控制癫痫发作的抗癫痫药，脑积水分流，用于缓解颅颈交界收缩的枕下减压术，以及助听器。

监测：长期幸存者需要神经学，矫形外科和听力学评估，CT监测颅颈收缩和EEG监测癫痫发作活动。

妊娠管理：当TD在出生前被诊断时，治疗目标是避免潜在的妊娠并发症，包括早产，羊水过多，胎位不正性难产。以及大头畸形和/或弯曲和僵硬颈部的分娩并发症;头颅穿刺术和剖腹产可以被考虑用于避免产妇并发症的发生。

遗传咨询：TD以常染色体显性方式遗传的，大多数先证者具有FGFR3的新生突变。生育有一个患胎的父母的再次生育的再发风险相对于一般人群没有显著增加。健康父母的生殖腺嵌合现象虽然过去没有报道，但理论上仍可能存在。产前诊断可以使用超声检查和分子遗传检测。
 

诊断

临床诊断

致死性骨发育不全（TD）是一种短肢侏儒症。当显着的长骨短小和胸廓狭窄在孕期或新生儿期被检测到，特别是当围产期死亡发生时要高度怀疑。

产前超声检测 [De Biasio et al 2000, Chen et al 2001, Ferreira et al 2004, De Biasio et al 2005, Tonni et al 2010, Khalil et al 2011, Martínez-Frias et al 2011] 在妊娠期包括以下发现

  • 孕早期
    • 长骨缩短，可早在孕12-14周可见
    • 颈部透明层厚度增加
    • 静脉导管中的逆流（一例病例报告），可能是狭窄的胸廓压缩血流的结果
  • 孕中晚期
    • 肢体长度生长缺陷，低于5%可在孕20周被发现识别
    • 脊椎和头骨良好
    • 扁平椎
    • 心室肥大
    • 胸腔狭窄与短肋骨
    • 羊水过多
    • 股骨弯曲（TDⅠ型）
    • 脑膨出（不常见，其他大脑异常也被描述）
    • 分叶状颅（Kleeblattschädel）（通常为TD Ⅱ型，偶尔在TD I型发现）和/或相对的畸形巨头

注意：尽管在妊娠中期鉴定致死性骨发育不全通常是直接可行的，但建立特异性诊断可能是困难的。  [Parilla et al 2003, Krakow et al 2008, Schramm et al 2009]通过OB/遗传学家的超声检查或薄膜超声检查可能是产前诊断中最有用的特异诊断方法。三维超声检查也可以帮助可视化面部特征和TD的其他软组织检测 [Chen et al 2001].

产后体检 [Lemyre et al 1999, Passos-Bueno et al 1999, De Biasio et al 2000]:

  • 畸形巨头
  • 前囟增大
  • 前额突出，鼻梁扁平塌陷，眼球突出
  • 显著四肢缩短（短肢）
  • 短指伴三叉手
  • 冗余皮肤褶皱
  • 狭窄的钟形胸伴短肋骨和突出的腹部
  • 相对正常的躯干长度
  • 全身性肌张力降低
  • 股骨弯曲（TDⅠ型）
  • 分叶状颅（Kleeblattschädel）（通常为TD Ⅱ型，偶尔在TD I型发现）

射线照片/其他图像研究 [Wilcox et al 1998, Lemyre et al 1999]:

  • 长骨根部缩短
  • 长骨干骺端不规则
  • 扁平椎
  • 枕骨打孔过小、脑干受压
  • CNS异常包括颞叶畸形，脑积水，脑干发育不全，神经元迁移异常
  • 股骨弯曲（TDⅠ型）
  • 分叶状颅（Kleeblattschädel）（通常为TD Ⅱ型，偶尔在TD I型发现）

其他报告 心脏缺陷（动脉导管未闭和房间隔缺损）和肾脏异常。

分子遗传学检测

基因. FGFR3基因突变是已知导致TDⅠ型和Ⅱ型的唯一基因。已经在所有患有TDⅡ型的个体中检测到FGFR3基因p.Lys650Glu突变[Bellus et al 2000].

临床诊断

  • 整个FGFR3基因编码区的测序分析  序列分析在临床上没有针对TD的指示，因为检测的特异性没有增加。并且由于发现不确定临床意义的新变体，检测特异性还可能降低

表1

TD的分子遗传学诊断

View in own window

基因 1诊断方法检测到的突变 2检测方法和表型的突变检出频率3
TDⅠ型TDⅡ型
FGFR3FGFR3靶向突变分析，特定区域的序列分析已报道的突变 4, 5达99%NA
p.Lys650GluNA>99%
整个编码区的序列分析  6, 7FGFR3序列存在突变>99%>99%
 

NA = 不适用

 

1. 参见表A.染色体基因座和蛋白质的基因数据库.

 

2. 有关等位基因变的信息，请参见分子遗传学。.

 

3. 用于检测指定基因中存在的突变的测试方法的检出能力

 

4. 一些实验室不检测p.Lys650Met。这种突变引起严重的软骨发育不全与发育迟缓和黑棘皮病（SADDAN）和致死性骨发育不全I型 [Bellus et al 2000].

 

5.突变和突变检测率可能因实验室而存在差异。先前报道的选择的FGFR3外显子突变检测：对于TDⅠ型，FGFR3的7,10,15和19号外显子;对于TDⅡ型，FGFR3的15号外显子。

 

6. 没有临床指征。参见分子遗传学诊断，整个FGFR3基因编码区的测序分析。.

 

7.通过序列分析检测的突变的实例可以包括小的基因内缺失/插入和错义、无义和剪接位点突变。通常，外显子或整个基因的缺失/重复不会被检测到。这些都是解释序列分析结果时需要考虑的问题。

诊断策略

根据产前或产后检查结果确诊或疑似TD

  • 如果是基于直股骨和分叶状颅疑似的TDⅡ型，对于p.Lys650Glu突变的靶向检测可能是诊断中的最适当的第一步。
  • 另外，可以考虑选择部分外显子做序列分析。如果没有鉴定出致病突变，则做整个基因的测序分析。

产前诊断：对于高危怀孕的孕妇需要事先鉴定家族中引起疾病的突变。

注意：一些以前有确诊儿童的家庭可以优先选择分子遗传检测（即使复发风险没有显着升高，超声检查可以在妊娠早期检测到TD）。

临床症状与特点

临床症状描述

致死性骨发育不良（TD）Ⅰ型和Ⅱ型在出生前或在新生儿期被确诊。两种亚型都被认为是致死性骨骼发育不良。大多数受影响的婴儿在生命的最初几小时或几天内死于呼吸功能不全。呼吸功能不全可能继发于胸腔狭窄和肺发育不全，枕骨大孔过小导致的脑干受压或两者均有。一些受影响的儿童通过积极的通气支持存活至童年。

长期存活者

临床发现来源于两个孩子（最后一次随访时的男孩为4.75岁，女孩为3.7岁）。两个小孩都有出生长度和重量低于3%，头围在第97百分位。两个小孩，十个月龄生长停滞。:

  • 男孩在出生时需要通气支持，并在三个月时进行气管切开术。其他临床发现包括：短肢，多余的皮肤褶皱，在两个月时诊断的脑积水，三个月时的癫痫发作活动，在15个月时诊断的由于枕骨大孔过小导致的脑干受压以及在20个月后发育基本停滞。对应地，弓形管状骨和张开的肋骨被放射线记录。头部CT显示大脑白质和灰质的异常分化。
  • 女孩从两个月开始需要通气支持。在两个月时诊断出由于枕骨大孔过小导致的脑干受压，并且在4个月时诊断为脑积水。在年龄为3.7岁时观察到双侧听力损失和尾骨成骨。她会很少的发音，知道一些手语动作。

一位具有常见TDⅠ型突变p.Arg248Cys的9岁男性。出生体重在50％（正常生长图表），出生长度大于4SD在平均值以下（软骨发育不全增长图表）。他需要气管造口术和通气支持。在三岁时，他表现出稳定的巨脑室，颅缝早闭和四肢增长迟缓。到8岁时，他有癫痫发作，双侧听力损失，脊柱后凸畸形，以及关节过度活动和关节痉挛。 9岁时，四肢几乎不再增长，并且放射学检查结果与TD中预期的相似。存在广泛的棘皮症。他有严重的发育迟缓，没有语言。最终身高估计值为80-90cm（32-35英寸）。

Thompson et al [2011]报道了一位11个月（出版时）幸存者，由于阵挛而在婴儿期行枕下减压术。由于枕骨大孔过小继发肢体运动减少。

 体  一位47岁常见TD I型突变p.Arg248Cys体女性具有长度不对称的四肢，双侧先天性髋关节脱位，骨骼弯曲病灶，“S”形肱骨，广泛黑棘皮症，沿四肢的冗余皮肤褶皱，膝盖和肘的弯曲畸形[Hyland et al 2003]。她还是一个孩子的时候病程发展却是延缓的。学术成就低于健康的兄弟姐妹，但她能够阅读和写作，并被雇为工厂工人。她唯一的男性小孩在30孕周死产，这个死产男婴带有短肢骨骼发育不良和肺发育不良。

Takagi et al [2012] 描述了具有p.Arg248Cys体的个体（突变通常导致典型的TDⅠ型），其呈现非典型软骨发育不全的特征。

与表现型的关联

TDⅠ型和Ⅱ型不共享共同的FGFR3突变 [Wilcox et al 1998, Brodie et al 1999, Camera et al 2001].

在TDⅠ型和TDⅡ型内都不存在FGFR3突变的显著与表现型的相关性。TD的多样性在之前已经被描述，除了在长骨中软骨膜干扰的严重程度方面提出的突变依赖性差异外[Bellus et al 2000]，都不是突变特异性的。

 [Pannier et al 2009, Marquis-Nicholson et al 2013]报道了由 cis中的两个FGFR3突变引起的TD的病例。在这两个病例中，一个突变在先前报道与致死性骨发育不全有关，另一个是一个新的突变。

     其他临床病症很少涉及以前在TD个体中鉴定的FGFR3突变（参见Genetically Related Disorders）。

    FGFR3中突变的为100％。

预期

     没有观察到预期。

命名与术语

     TD最初被描述为致死性侏儒症，这一术语已不再使用。

     虽然被认为是原发性致死性骨骼发育不良之一，但是与特定亚型（圣地亚哥，卢顿或托兰斯）一起使用的术语PLSD将被认为是来自Ⅰ型和Ⅱ型TD的单独的临床实体。由于其临床相似性，PLSD有时被称作“TD变异型”。

流行

    TD的发病率最初估计为1：20,000至1：50,000的新生儿[Wilcox et al 1998, Baitner et al 2000, Chen et al 2001]。最近的研究表明，在具有优化确定的群体中，发病率实际上更接近1：20,000 [Barbosa-Buck et al 2012] 或更高（北爱尔兰1：12,000）[Donnelly et al 2010]。

 

遗传相关（等位基因）异常

已经在具有高度可变表型的几种异常中鉴定了FGFR3突变：

鉴别诊断

在致死性骨发育不良（TD）的鉴别诊断中要考虑的疾病 [Passos-Bueno et al 1999, De Biasio et al 2000, Lee et al 2002, Neumann et al 2003]:

管理

初步诊断后的评估

 

   为了确定被诊断为致病性发育不良（TD）新生儿的疾病程度和需求，建议进行以下评估：

  • 通过呼吸频率和皮肤颜色评估呼吸状态;动脉血气监控可能有助于在出生后幸存的婴儿。
  • 通过CT或MRI评估脑积水或其他中枢神经系统异常的是否存在。
  • 医学遗传科会诊和遗传咨询

对症治疗  

   管理方面的关注只能限于父母对新生儿提供生命支持措施和安慰服务的愿望。

   新生儿需要呼吸支持（气管造口术和通气）才能存活。

   麻醉管理问题由Thompson et al [2011]等人描述，包括：

  • 使用柔性光纤镜在颈椎中间部位插管
  • 在手术期间使用诱发电位监测（体感诱发电位[SEPs]和运动诱发电位[MEPs]）来评价术中操作期间的安全性
  •  避免可能影响诱发电位记录的挥发性麻醉剂和肌肉松弛剂的干扰

其他措施：

  • 通过药物治疗控制癫痫发作，同一般患者
  • 脑积水发生时进行分流
  • 枕下减压术用于缓解颅颈交界处的收缩
  • 当听力出现损伤时，使用助听器协助听力

监控

    以下方式是合适（适当）的：

  • 体格检查时对神经系统状况进行常规评估
  • 对关节挛缩或关节过度活动的发展进行骨科评估 [Wilcox et al 1998]
  • 听力评估
  • CT评估长期存活者的颅颈收缩状况，如果发生呼吸功能不全可能是颅颈交界区脑干挤压导致
  • EEG用于癫痫发作

亲属风险评估

    关于遗传咨询中高危亲属测试的相关问题，请参见遗传咨询。

妊娠管理

    当TD在孕期被诊断，潜在的孕期并发症包括早产，羊水过多，胎位不正性难产和由脑积水引起的巨头与弯曲僵硬的脖子导致的头盆不称。头颅穿刺术和剖腹产可以考虑用于避免或减轻孕妇并发症。

    受影响孕妇的孕期管理由父母对施救措施的意愿强烈程度作为指导。它可以在三个层面上处理：

  • 孕妇（母亲）头盆不称，羊水过多和/或早产的监测以避免紧急剖腹产中胎儿呼吸窘迫
  •  胎儿  胎位不正的监测，周期性的产前超声监测头围，MRI监测胎儿肺容积和/或胎儿压力测试 
  • 家庭（家族）建立用于评估、护理的围产期计划，和/或在分娩后撤销

在研究阶段的治疗方式

    搜索ClinicalTrials.gov获取更加广泛的关于疾病和症状的临床研究信息。注意：这种疾病可能还没有临床试验。

遗传咨询

遗传咨询是向个人和家庭提供关于遗传疾病的致病实质，遗传性和基因异常情况的相关信息，以帮助他们获得充分的医疗知情和对疾病的情况做出各种个人决定过程。以下部分涉及遗传风险评估，家族史和遗传诊断的应用，以阐明家庭成员的遗传状况。本节不是为了解决个人可能面临的所有个人、文化或伦理问题，或代替与遗传学专业人士的咨询。 —ED.

遗传模式

致死性骨发育不良（TD）是以常染色体显性方式遗传的，大多数的先证者都是散发的新生突变。

家庭成员风险

    先证者父母

  •  TD几乎总是由FGFR3的新生突变引起的
  • 先证者的父母不受影响

  • 在受影响（患病）的个体中已经报道了在FGFR3（p.Arg248Cys）中包括生殖腺突变的体细胞嵌合体 [Hyland et al 2003]，这个个体的唯一后代患有致死性的骨骼发育不良。当前的诊断技术还不能检测到导致TD的FGFR3的嵌合体突变模式。

  • 年长父亲的年龄效应被报道[Lemyre et al 1999, Donnelly et al 2010].

先证者同胞

  • 先证者同胞的风险取决于先证者父母的遗传（基因）状况
  • 由于TD通常由新发突变所导致的，因此先证者同胞的再发风险很小
  • 虽然在文献中没有报道在不存在骨骼发育不良迹象的个体中生殖腺嵌合的情况，但这在理论上仍然是一种可能性

先证者后代

  • 患有TD的个体不能繁衍后代

  • 在FGFR3（p.Arg248Cys）突变中的生殖腺和体细胞嵌合体的受影响（患病）的个体已被报道 [Hyland et al 2003]，这个个体的后代存在致死性 的骨骼发育不良

先证者的其他亲属   先证者家族中的其他成员的再发风险不会提高

遗传咨询的相关问题

    家庭计划   确定遗传风险和讨论产前诊断有效性的最佳时间是怀孕前

    DNA银行 用于DNA（通常从白细胞中提取）的储存，以备将来使用。因为诊断方法和我们对基因，等位基因突变和疾病的理解可能会在未来得到提升，所以应该考虑对受影响个体的DNA进行储存。

产前诊断

    高风险妊娠 如果在受影响的家庭成员中鉴定出致病突变，则可以通过临床实验室或提供定制产前诊断的实验室给予妊娠风险提高了的孕妇实施产前诊断。

     低风险妊娠 常规产前超声检查可以识别未知风险胎儿中TD的疑似诊断，骨骼异常（例如，分叶状颅，四肢短小，胸廓狭窄）。一旦致死性骨骼发育不良在孕期被诊断，通常很难再做出具体的确切诊断。在这种情况下考虑对FGFR3基因突变进行分子遗传检测是合适的。

     植入前遗传学诊断 可能是一些已经明确得知致病性突变家庭的选择

资源

GeneReviews的工作人员选择了以下特定疾病和/或相关工作组织和/或为患有此障碍的个人及其家人的利益的一些注册机构。GeneReviews不对其他组织提供的信息负责。有关选择标准的信息，请单击此处here。

  • National Library of Medicine Genetics Home Reference
  • Compassionate Friends
    Supporting Family After a Child Dies
    PO Box 3696
    Oak Brook IL 60522
    Phone: 877-969-0010 (toll free); 630-990-0010
    Fax: 630-990-0246
    Email: nationaloffice@compassionatefriends.org
  • Helping After Neonatal Death (HAND) - Support Groups
    PO Box 341
    Los Gatos CA 95031
    Phone: 888-908-4263
    Email: info@handonline.org
  • Medline Plus
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

分子遗传学

分子遗传学部分和OMIM表格中的信息可能与GeneReview中的其他地方不同，表格可能包含更多更新信息-. —ED.

表 A.

致死性骨发育不全：基因和数据库信息

View in own window

基因染色体定位蛋白质位点特异性HGMD
FGFR34p16​.3Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3
 

数据来自以下标准的参考文献：来自HGNC的基因信息; 染色体位点、基因座名称，临界区，互补群信息来源于OMIM; 蛋白来自UniProt。有关提供链接的数据库（Locus Specific，HGMD）的描述，请单击此处here

表 B.

在OMIM中有关致死性骨发育不全的词目 (View All in OMIM)

View in own window

134934成纤维细胞生长因子受体3；FGFR3
187600致死性骨发育不全，I 型；TD1
187601致死性骨发育不全，II 型；TD2

Gene structure.FGFR3 is 17 exons in length with transcription initiation located in 2. For a detailed summary of and protein information, see Table A, Gene.

Benign allelic variants. See Table 2 for known normal variants.

Pathogenic allelic variants

  • TD type I.FGFR3 mutations responsible for the TD type I can be divided into two categories:
    • Missense mutations [Passos-Bueno et al 1999]. Most of these mutations create new, unpaired cysteine residues in the protein. The two common mutations p.Arg248Cys and p.Tyr373Cys probably account for 60%-80% of TD type I (see Table 2).
    • Stop codon mutations. These mutations cause a read-through of the native stop codon, adding a highly hydrophobic alpha helix-containing to the C terminus of the protein. Mutations that obliterate the stop codon represent 10% or more of TD type I mutations (see Table 2).
  • TD type II. A single FGFR3 mutation (p.Lys650Glu) has been identified in all cases of TD type II [Bellus et al 2000]. The lysine residue at position 650 plays a role in stabilizing the activation loop of the tyrosine kinase in an inactive state. Mutations of this residue destabilize the loop, allowing ligand-independent activation of the tyrosine kinase domain, likely without the need for receptor dimerization at the cell surface [Bellus et al 2000]. Other mutations at this position give rise to different phenotypes: p.Lys650Met has been identified in TD type I, and p.Lys650Gln is seen in SADDAN (see Table 2).

Table 2.

Selected FGFR3 Allelic Variants

View in own window

PhenotypeClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)		Reference Sequences
Not applicableBenignc.882C>Tp.(=) 2
(N294N)		NM_000142​.3
NP_000133​.1
c.1953A>Gp.(=)
(T651T)
TD type IPathogenicc.742C>Tp.Arg248Cys 3
c.746C>Gp.Ser249Cys
c.1108G>Tp.Gly370Cys
c.1111A>Tp.Ser371Cys
c.1118A>Gp.Tyr373Cys 3
c.1949A>Tp.Lys650Met
c.2420G>Tp.Ter807LeuextTer101
c.2419T>Gp.Ter807GlyextTer101
c.2419T>Cp.Ter807ArgextTer101
c.2419T>Ap.Ter807ArgextTer101
c.2421A>Tp.Ter807CysextTer101
c.2421A>Cp.Ter807CysextTer101
c.2421A>Gp.Ter807TrpextTer101
TD type IIc.1948A>Gp.Lys650Glu
 

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

 

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

 

1. Variant designation that does not conform to current naming conventions

 

2. p.(=) indicates that the protein has not been analyzed but no change is expected.

 

3. Two most common mutations

Normal .FGFR3 encodes one of four known fibroblast growth factor receptors (FGFRs). All FGFRs share considerable amino acid homology, and the organization is nearly identical to that seen in mice. FGFRs are proteoglycans that function as tyrosine kinases upon binding of a ligand — usually one of more than 20 fibroblast growth factors (FGFs) plus proteoglycans containing heparan sulfate [McIntosh et al 2000, Torley et al 2002, Lievens & Liboi 2003]. Once a ligand binds, the FGFRs form homo- or heterodimers and undergo phosphorylation of the tyrosine residues in the tyrosine kinase . This is followed by a conformational change that frees intracellular binding sites. Intracellular proteins bind and initiate a signal cascade that usually influences protein activation or gene expression [Cohen 2002, Torley et al 2002]. Multiple pathways have been implicated, including ras/MAPK/ERK, P13/Akt, PLC-γ, and STAT1 [Cohen 2002, Torley et al 2002]. After activation, the complex is internalized for signal downregulation. This is accomplished via one of two pathways [Lievens et al 2006]: ubiquitination and degradation of the activated FGFR or feedback from the end targets (namely ERK) through the docking protein FRS2α.

FGFR3 consists of an extracellular signal peptide, three immunoglobulin-like domains (IgI, IgII, and IgIII) with an acid box between IgI and IgII, a transmembrane , and a split intracellular tyrosine kinase domain [Hyland et al 2003]. Ligand binding occurs between IgII and IgIII [McIntosh et al 2000]. The normal function of FGFR3 is to serve as a negative regulator of bone growth during ossification [Legeai-Mallet et al 1998, Cohen 2002]. Mice with knockout mutations of Fgfr3 are overgrown with elongated vertebrae and long femurs and tails. The growth plates of the long bones are expanded [McIntosh et al 2000, Cohen 2002]. Alternative of exons 8 and 9 has been documented, with such diversity conferring the capacity for differential expression and binding of multiple ligands [Cohen 2002]. Three reported of FGFR3 include: the native protein, an intermediate intracellular membrane-associated glycoprotein, and a mature glycoprotein [Lievens & Liboi 2003].

FGFR3 is expressed in a spatial- and temporal-specific pattern during embryogenesis [McIntosh et al 2000]. The highest levels of expression occur in cartilage and the central nervous system [Cohen 2002]. FGFR3 is also expressed in the dermis and epidermis [McIntosh et al 2000, Torley et al 2002].

The FGFR3 signaling pathway is activated in several cancers, including bladder and cervical cancer and multiple myeloma. Meyer et al [2004] identified FGFR3 in complex with Pyk2, a focal adhesion kinase known to regulate apoptosis in multiple myeloma cells and to activate Stat5B. FGFR3 phosphorylates Pyk2 and activates a signaling pathway without recruitment of proteins from the Src family (which are normally recruited by Pyk2 in the absence of FGFR3). Hyperactivated FGFR3 (i.e., mutations similar to those causing TD) causes hyperphosphorylation of Pyk2. FGFR3 may also sequester Pyk2 from Shp2, which normally functions to decrease Pyk2 phosphorylation and downregulate Pyk2 signaling. Both FGFR3 and Pyk2 may work in concert to maximally activate Stat5B [Meyer et al 2004].

Abnormal . Mutations in FGFR3 are mutations that produce a constitutively active protein capable of initiating intracellular signal pathways in the absence of ligand binding [Baitner et al 2000, Cohen 2002]. This activation leads to premature differentiation of proliferative chondrocytes into pre-hypertrophic chondrocytes and, ultimately, to premature maturation of the bone [Cohen 2002, Legeai-Mallet et al 2004]. The mechanism for other clinical findings in TD type I and TD type II (CNS and dermal abnormalities) is less clear. All reported mutations cause constitutive activation through the creation of new, unpaired cysteine residues that induce ligand-independent dimerization [Cohen 2002], activation of the tyrosine kinase loop [Tavormina et al 1999, Cohen 2002], or creation of an elongated protein through destruction of the native stop codon.

Studies have shown that the level of ligand-independent tyrosine kinase activity conferred by different FGFR3 mutations is correlated with the severity of disorganization of endochondral ossification and, therefore, with the skeletal [Bellus et al 1999, Bellus et al 2000].

The p.Lys650Glu mutation causing thanatophoric dysplasia type II has been shown to cause accumulation of intermediate, activated forms of FGFR3 in the endoplasmic reticulum [Lievens & Liboi 2003]. This immature, cellular FGFR3 is able to signal through an FRS2α-independent pathway (via the JAK/STAT pathway) that is then not subject to FRS2α-mediated downregulation [Lievens et al 2006].

References

Literature Cited

  • Arikawa-Hirasawa E, Wilcox WR, Yamada Y. Dyssegmental dysplasia, Silverman-Handmaker type: unexpected role of perlecan in cartilage development. Am J Med Genet. 2001;106:254–7. [PubMed: 11891676]
  • Baitner AC, Maurer SG, Gruen MB, Di Cesare PE. The genetic basis of the osteochondrodysplasias. J Pediatr Orthop. 2000;20:594–605. [PubMed: 11008738]
  • Barbosa-Buck CO, Orioli IM, Dutra MG, Lopez-Camelo J, Castilla EE, Cavalcanti DP. Clinical epidemiology of skeletal dysplasias in South America. Am J Med Genet Part A. 2012;158A:1038–45. [PubMed: 22407836]
  • Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko O, Jabs EW, Curry CJ, Wilcox WR, Lachman RS, Rimoin DL, Francomano CA. Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Am J Med Genet. 1999;85:53–65. [PubMed: 10377013]
  • Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000;67:1411–21. [PMC free article: PMC1287918] [PubMed: 11055896]
  • Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet. 1999;84:476–80. [PubMed: 10360402]
  • Camera G, Baldi M, Strisciuglio G, Concolino D, Mastroiacovo P, Baffico M. Occurrence of thanatophoric dysplasia type I (R248C) and hypochondroplasia (N540K) mutations in two patients with achondroplasia phenotype. Am J Med Genet. 2001;104:277–81. [PubMed: 11754059]
  • Chen CP, Chern SR, Shih JC, Wang W, Yeh LF, Chang TY, Tzen CY. Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn. 2001;21:89–95. [PubMed: 11241532]
  • Cohen MM Jr. Some chondrodysplasias with short limbs: molecular perspectives. Am J Med Genet. 2002;112:304–13. [PubMed: 12357475]
  • De Biasio P, Ichim IB, Scarso E, Baldi M, Barban A, Venturini PL. Thanatophoric dysplasia type I presenting with increased nuchal translucency in the first trimester. Prenat Diagn. 2005;25:426–8. [PubMed: 15906417]
  • De Biasio P, Prefumo F, Baffico M, Baldi M, Priolo M, Lerone M, Toma P, Venturini PL. Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation. Prenat Diagn. 2000;20:835–7. [PubMed: 11038465]
  • Donnelly DE, McConnell V, Paterson A, Morrison PJ. The prevalence of thanatophoric dysplasia and lethal osteogenesis imperfecta type II in Northern Ireland - a complete population study. Ulster Med J. 2010;79:114–8. [PMC free article: PMC3284715] [PubMed: 22375084]
  • Ferreira A, Matias A, Brandao O, Montenegro N. Nuchal translucency and ductus venosus blood flow as early sonographic markers of thanatophoric dysplasia. A case report. Fetal Diagn Ther. 2004;19:241–5. [PubMed: 15067234]
  • Hyland VJ, Robertson SP, Flanagan S, Savarirayan R, Roscioli T, Masel J, Hayes M, Glass IA. Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia. Am J Med Genet A. 2003;120A:157–68. [PubMed: 12833394]
  • Khalil A, Pajkrt E, Chitty LS. Early prenatal diagnosis of skeletal anomalies. Prenat Diagn. 2011;31:115–24. [PubMed: 21210484]
  • Krakow D, Alanay Y, Rimoin LP, Lin V, Wilcox WR, Lachman RS, Rimoin DL. Evaluation of prenatal-onset osteochondrodysplasias by ultrasonography: a retrospective and prospective analysis. Am J Med Genet A. 2008;146A:1917–24. [PMC free article: PMC2713784] [PubMed: 18627037]
  • Lee SH, Cho JY, Song MJ, Min JY, Han BH, Lee YH, Cho BJ, Kim SH. Fetal musculoskeletal malformations with a poor outcome: ultrasonographic, pathologic, and radiographic findings. Korean J Radiol. 2002;3:113–24. [PMC free article: PMC2713834] [PubMed: 12087201]
  • Legeai-Mallet L, Benoist-Lasselin C, Delezoide AL, Munnich A, Bonaventure J. Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. J Biol Chem. 1998;273:13007–14. [PubMed: 9582336]
  • Legeai-Mallet L, Benoist-Lasselin C, Munnich A, Bonaventure J. Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias. Bone. 2004;34:26–36. [PubMed: 14751560]
  • Lemyre E, Azouz EM, Teebi AS, Glanc P, Chen MF. Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: review and update. Can Assoc Radiol J. 1999;50:185–97. [PubMed: 10405653]
  • Lievens PM, Liboi E. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. J Biol Chem. 2003;278:17344–9. [PubMed: 12624096]
  • Lievens PM, Roncador A, Liboi E. K644E/M FGFR3 mutants activate Erk1/2 from the endoplasmic reticulum through FRS2 alpha and PLC gamma-independent pathways. J Mol Biol. 2006;357:783–92. [PubMed: 16476447]
  • MacDonald IM, Hunter AG, MacLeod PM, MacMurray SB. Growth and development in thanatophoric dysplasia. Am J Med Genet. 1989;33:508–12. [PubMed: 2596513]
  • Mansour S, Hall CM, Pembrey ME, Young ID. A clinical and genetic study of campomelic dysplasia. J Med Genet. 1995;32:415–20. [PMC free article: PMC1050480] [PubMed: 7666392]
  • Marquis-Nicholson R, Aftimos S, Love DR. Molecular Analysis of a Case of Thanatophoric Dysplasia Reveals Two de novo FGFR3 Missense Mutations located in cis. Sultan Qaboos Univ Med J. 2013;13:80–7. [PMC free article: PMC3616804] [PubMed: 23573386]
  • Martínez-Frías ML, Egüés X, Puras A, Hualde J, de Frutos CA, Bermejo E, Nieto MA, Martínez S. Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis. Am J Med Genet A. 2011;155A:197–202. [PubMed: 21204232]
  • McIntosh I, Bellus GA, Jab EW. The pleiotropic effects of fibroblast growth factor receptors in mammalian development. Cell Struct Funct. 2000;25:85–96. [PubMed: 10885578]
  • Meyer AN, Gastwirt RF, Schlaepfer DD, Donoghue DJ. The cytoplasmic tyrosine kinase Pyk2 as a novel effector of fibroblast growth factor receptor 3 activation. J Biol Chem. 2004;279:28450–7. [PubMed: 15105428]
  • Neumann L, Kunze J, Uhl M, Stover B, Zabel B, Spranger J. Survival to adulthood and dominant inheritance of platyspondylic skeletal dysplasia, Torrance-Luton type. Pediatr Radiol. 2003;33:786–90. [PubMed: 12961049]
  • Nishimura G, Nakashima E, Mabuchi A, Shimamoto K, Shimamoto T, Shimao Y, Nagai T, Yamaguchi T, Kosaki R, Ohashi H, Makita Y, Ikegawa S. Identification of COL2A1 mutations in platyspondylic skeletal dysplasia, Torrance type. J Med Genet. 2004;41:75–9. [PMC free article: PMC1757240] [PubMed: 14729840]
  • Pannier S, Martinovic J, Heuertz S, Delezoide AL, Munnich A, Schibler L, Serre V, Legeai-Mallet L. Thanatophoric dysplasia caused by double missense FGFR3 mutations. Am J Med Genet A. 2009;149A:1296–301. [PubMed: 19449430]
  • Parilla BV, Leeth EA, Kambich MP, Chillis P, MacGregor SN. Antenatal detection of skeletal dysplasias. J Ultrasound Med. 2003;22:255–8. [PubMed: 12636325]
  • Passos-Bueno MR, Wilcox WR, Jabs EW, Sertie AL, Alonso LG, Kitoh H. Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat. 1999;14:115–25. [PubMed: 10425034]
  • Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nurnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, Becker C, Lehnerdt K, Cremers CW, Yuksel-Apak M, Nurnberg P, Kubisch C, Schlessinger J, van Bokhoven H, Wollnik B. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006;38:414–7. [PubMed: 16501574]
  • Schramm T, Gloning KP, Minderer S, Daumer-Haas C, Hörtnagel K, Nerlich A, Tutschek B. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol. 2009;34:160–70. [PubMed: 19548204]
  • Takagi M, Kaneko-Schmitt S, Suzumori N, Nishimura G, Hasegawa T. Atypical achondroplasia due to somatic mosaicism for the common thanatophoric dysplasia mutation R248C. Am J Med Genet Part A. 2012;158A:247–50. [PubMed: 22106050]
  • Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano CA. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet. 1999;64:722–31. [PMC free article: PMC1377789] [PubMed: 10053006]
  • Thompson DR, Browd SR, Sangaré Y, Rowell JC, Slimp JC, Haberkern CM. Anesthetic management of an infant with thanatophoric dysplasia for suboccipital decompression. Paediatr Anaesth. 2011;21:92–4. [PubMed: 21155935]
  • Tonni G, Azzoni D, Ventura A, Ferrari B, Felice CD, Baldi M. Thanatophoric dysplasia type I associated with increased nuchal translucency in the first trimester: Early prenatal diagnosis using combined ultrasonography and molecular biology. Fetal Pediatr Pathol. 2010;29:314–22. [PubMed: 20704477]
  • Torley D, Bellus GA, Munro CS. Genes, growth factors and acanthosis nigricans. Br J Dermatol. 2002;147:1096–101. [PubMed: 12452857]
  • Wilcox WR, Tavormina PL, Krakow D, Kitoh H, Lachman RS, Wasmuth JJ, Thompson LM, Rimoin DL. Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet. 1998;78:274–81. [PubMed: 9677066]
  • Zankl A, Neumann L, Ignatius J, Nikkels P, Schrander-Stumpel C, Mortier G, Omran H, Wright M, Hilbert K, Bonafé L, Spranger J, Zabel B, Superti-Furga A. Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within type 2 collagenopathies. Am J Med Genet A. 2005;133A:61–7. [PubMed: 15643621]

Suggested Reading

  • Bonaventure J, Horne WC, Baron R. The localization of FGFR3 mutations causing thanatophoric dysplasia type I differently affects phosphorylation, processing and ubiquitylation of the receptor. FEBS J. 2007;274:3078–93. [PubMed: 17509076]
  • You M, Spangler J, Li E, Han X, Ghosh P, Hristova K. Effect of pathogenic cysteine mutations on FGFR3 transmembrane domain dimerization in detergents and lipid bylayers. Biochemistry. 2007;46:11039–46. [PubMed: 17845056]

Chapter Notes

Acknowledgments

The authors wish to thank Julie Hoover-Fong MD, Clinical Director of the Greenberg Center for Skeletal Dysplasias at Johns Hopkins University, for her clinical insight.

Revision History

  • 12 September 2013 (me) Comprehensive update posted live
  • 30 September 2008 (cg) Comprehensive update posted live
  • 7 July 2006 (me) Comprehensive update posted live
  • 21 May 2004 (me) Review posted live
  • 27 February 2004 (bk, gc) Original submission