概述
临床特征.
口-面-指综合征（Oral-facial-digital syndrome type I，OFD1）通常是女性受累，而男性是宫内致死的。OFD1的临床特征如下：
- 口腔（分叉舌，舌结节，硬腭或软腭裂，副齿龈系带，牙发育不全和其他牙齿异常）
- 面部（眼距宽，内眦距过宽，鼻翼发育不良，唇中裂或上唇假唇裂，小颌畸形）
- 指趾（短指，并指，小手指弯曲；大拇趾重复（大脚趾）
- 肾脏（多囊肾）
- 脑（例如，脑内囊肿，胼胝体不发育，小脑的发育不全伴或不伴有Dandy-Walker畸形）
- 智力残疾（约50%的患者）
处置.
治疗临床表现: 外科手术治疗唇腭裂、舌结节、副系带和并趾；拔除副牙和错合齿矫正术；常规治疗肾脏疾病和癫痫。语言治疗和特殊教育是有必要的。监测: 每年进行听力评估和对唇腭裂或腭裂的儿童的语音发展进行评估。对10岁及以上的个体：每年检查血压、测血清肌酸，超声检查肾脏、肝脏、胰腺和卵巢的囊性疾病。
遗传咨询.
OFD1以X-连锁方式遗传，约75%的受累的 个体为单发的 病例（即无OFD1家族史），女性OFD1先证者可能是由于新生致病性变异。新生突变所致的病例的比例尚不清楚。受累女性若是单发纯的个案，其表型正常的母亲生育下一个女性OFD1患者的几率小于1%。理论上，OFD1女性患者生育受累后代的风险是50%；然而，大多数携带致病突变的男性胎儿会自然流产。因此，在分娩时，后代的预期性别比例为:33%为未受累的女性；33%为受累女性；33%为未受累男性。如果家族中基因致病变异已知，可以对风险妊娠孕妇实行产前诊断。产前超声检查可发现结构性的脑畸形和/或大拇趾重复。
Summary
Clinical characteristics.
Oral-facial-digital syndrome type I (OFD1) is usually male lethal during gestation and predominantly affects females. OFD1 is characterized by the following features:
- Oral (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities)
- Facial (widely spaced eyes or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia)
- Digital (brachydactyly, syndactyly, clinodactyly of the fifth finger; duplicated hallux [great toe])
- Kidney (polycystic kidney disease)
- Brain (e.g., intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation)
- Intellectual disability (in ~50% of individuals)
Oral-facial-digital syndrome type I (OFD1)常导致男性胚胎在妊娠期内死亡，因此主要见于女性患者。OFD1具有以下特征：
- 口腔 (分叶舌，舌头结节，硬腭裂或软颚裂，牙龈系带异常，牙齿发育不全，以及其它牙齿异常)
- 面部 (眼距过远或内眦间距过宽, 鼻翼发育不全, 假性上唇正中裂, 小颌畸形)
- 指/趾 (短指（趾）症, 并指（趾）畸形,第五指先天性指侧弯 ; 大拇趾重复)
- 肾 (多囊肾病)
- 大脑 (如：脑囊肿, 胼胝体发育不全, 小脑发育不全伴/不伴Dandy-Walker畸形 )
- 智力残疾 (见于~50%患者)
Diagnosis/testing.
The diagnosis of OFD1 is established in a proband by identification of an OFD1pathogenic variant on molecular genetic testing.
对OFD1的诊断主要是通过分子遗传学方法检测先证者OFD1上的致病突变进行确认.
Management.
Treatment of manifestations: Surgery for cleft lip/palate, tongue nodules, accessory frenulae, and syndactyly; removal of accessory teeth and orthodontia for malocclusion; routine treatment for renal disease and seizures. Speech therapy and special education may be warranted.
对症治疗：手术治疗唇腭裂、舌头结节、系带异常、以及并指畸形；移除多余的牙齿和矫正错颌畸形；常规治疗肾脏疾病和癫痫。必要时给予言语治疗和特殊教育。
Surveillance: Annual audiology evaluation and assessment of speech development in children if cleft lip and/or cleft palate is present. Individuals age ten years and older: annual blood pressure examination, serum creatinine, annual ultrasound examination for renal, hepatic, pancreatic, and ovarian cystic disease.
监护：如果儿童患者患有唇腭裂，每年对其进行听力评估和语言评估。患者年龄到达10岁及以上时：年度评估包括血压，血清肌酐，以及对肾，肝，胰腺和卵巢囊性变的超声检查。
Genetic counseling.
OFD1 is inherited in an X-linked manner. Approximately 75% of affected individuals represent simplex cases (i.e., with no family history of OFD1). A female proband with OFD1 may have the disorder as the result of a de novopathogenic variant; the proportion of cases caused by de novo pathogenic variants is unknown. The risk that the unaffected mother of an affected female who is a simplex case will give birth to another female with OFD1 is less than 1%. At conception, the risk to the offspring of females with OFD1 of inheriting the pathogenic variant is 50%; however, most male conceptuses with the pathogenic variant miscarry. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known. Prenatal ultrasound examination may detect structural brain malformations and/or duplication of the hallux.
OFD1位于X染色体上。大约有75%的感染的患者为孤例 (例如：没有OFD1的家族史)。OFD1女性先证者可能是由于新生突变所导致疾病；新生突变的发生概率目前未知。一位孤例女性患者的未患病母亲，再次生育女儿时，再发概率小于1%。原则上，每个女性OFD1患者的孩子均有50%的可能性遗传到OFD1 的致病突变；然而，大多数携带OFD1 的致病突变的男性胚胎死亡。因此，后代可能性遗传到OFD1 的致病突变的比例为：33% 不患病的女性; 33% 患病的女性; 33% 不患病的男性。如果家庭中已检测到致病突变，可能使怀孕时产前诊断的风险增加。产前超声检查可以对脑畸形、重复拇指畸形进行筛查。
诊断
提示性发现
女性患者若有典型的口-面-指发现、粟丘疹和/或多囊性肾病，应该怀疑患有OFDI型(OFD1)型。在其他的OFDs中也可以见到口-面-指的发现。OFD1的特点是大约50%的患者有肾囊肿性疾病，在家族性病例中为x连锁遗传模式；参见表 2(pdf)。几乎所有的患者都是女性；然而，也有一些受累男性病例报告。在大多数情况下，这些男性为受累女性的畸形胎儿。
口腔的临床特性Clinical Features
- 舌异常（即，分支舌，舌结节，舌系带短缩）
- 腭裂
- 牙槽裂和副齿龈系带
- 牙齿异常(例如，缺牙，额外牙齿)
面部
- 眼相隔较宽，眼距宽，下斜的眼睑
- 鼻翼发育低下
- 唇中裂，上唇假裂
- 小下颌
指趾
- 短指，并指
- 小手指弯曲
- 其他手指的桡骨或尺侧偏移，尤其是中指
- 单侧大拇趾重复（大拇趾）
其他
- 粟丘疹
- 多囊肾（50%）
- 智力残疾
手X射线放射特征
常常显示良好的网状放射物，被描写为骨不规则矿化，有或没有针型的指骨。肾脏超声检查至少50%的人显示肾囊肿。脑MRI 最常见的表现为脑内囊中之物，胼胝体不不发育，以及小脑不发育，伴或不伴Dandy-Walker畸形。确立诊断
目前还没有正式的诊断标准。因为OFD综合征存在广泛的遗传异质性,建议用OFD1基因的分子遗传学检测来确立诊断[Franco & Thauvin-Robinet 2016]。
分子检测方法可以包括单一基因检测，应用表型靶向检测,和更全面的基因组检测。
注：(1)这这个基因包中包括的基因和这个检测对每个基因的敏感性因实验室而异和随着时间的推移而改变。 (2)一些多基因的基因包可能包括与在这个GeneReview中讨论的疾病无关的基因；因此，临床医生需要确定哪个多基因包提供了最好的机会，以最合理的代价来确定这种疾病的遗传原因。(3)用于这个基因包的方法可包括序列分析、缺失/重复分析、和/或其他非测序的测试。- 更全面的基因组检测(如果可以获得)包括外显子组测序 和基因组测序，如果单一基因检测（和/或应用包括OFD1基因的表型靶向检测）不能确认一个具有OFD1特征的个体的诊断，推荐进行更全面的基因组检测。这样的测试可以提供或提示以前没有考虑过的诊断(例如，不同的基因的突变，也产生类似的临床表现）。更多的关于全面的基因组测试的信息请点击这里。
表 1. 用于口-面-指综合征I型的分子遗传学检测
1.关于染色体位点和蛋白质见Table A. Genes and Databases。
2.关于在这个基因所检测到的等位基因变异，见Molecular Genetics。.
3.序列分析发现良性变异、可能良性的、意义不确定、可能致病或致病。致病的变异可能包括小的基因内缺失/插入、错义、无义和剪接位点变异；典型的，不能检测外显子或全-基因缺失/重复。对于需要考虑的序列分析结果解释的问题，点击这里。
4.在序列分析前的PCR扩增无产物，可能提示受累的男性的X 染色体上（多个）外显子和全基因缺失；确认需要额外额外的基因靶向的缺失/重复分析。
5.已经确定了多种致病变异，其中大多数都预示着过早的蛋白质截断。报告的序列分析检出率约为80%[Nowaczyk et al 2003, Thauvin-Robinet et al 2006, Prattichizzo et al 2008]。
6.基因靶向性的缺失/重复分析检测到基因内的缺失或重复。可以使用的方法包括：定量 PCR，长片段PCR，多重链接探针扩增（MLPA），和为检测单一外显子缺失或重复而设计的基因靶向微阵列。
7.一项研究发现，在131个OFD1患者中有6个人有1~14外显子的缺失。没有相同的缺失。在这一组基因测序没有检测到致病性变异的病例中，通过qPCR检测到23%有1个或多个外显子缺失[Thauvin-Robinet et al 2009]。
Suggestive Findings
Oral-facial-digital syndrome type I (OFD1) should be suspected in females with typical oral-facial-digital findings, milia, and/or polycystic kidney disease. The oral-facial-digital findings are also found in other OFDs. OFD1 is characterized by renal cystic disease in approximately 50% of individuals and by the X-linked inheritance pattern in familial cases; see Table 2 (pdf). Almost all individuals with OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by an affected female.
当女性患者有典型的口-面-指指征、粟粒疹和/或多囊肾病时，应怀疑其患有Oral-facial-digital syndrome type I (OFD1)。口-面-指指征也见于在其他类型的OFD中。大约有50%的OFD1患者患有肾囊性疾病并且在家族中为X连锁遗传; 见表2 (pdf)。大多数OFD1患者为女性；然后，也存在少数男性患者。在大多数情况下，这些男性患者主要由OFD1女性患者遗传，并且为畸形胎儿。
Clinical Features
Oral
- Tongue anomalies (e.g., lobulated, nodules, ankyloglossia)
- Cleft palate
- Alveolar clefts and accessory gingival frenulae
- Dental anomalies (e.g., missing teeth, extra teeth)
口腔
- 舌头异常 (例如, 分叶舌, 结节, 舌粘连)
- 腭裂
- 牙槽突裂与牙龈系带异常
- 牙齿异常 (例如, 缺牙, 额外牙)
Facial
- Widely spaced eyes, telecanthus, downslanting palpebral fissures
- Hypoplasia of the alae nasi
- Median cleft lip, pseudocleft upper lip
- Micrognathia
面部
- 眼距过远或内眦间距过宽, 睑裂
- 鼻翼发育不全
- 假性上唇正中裂
- 小颌畸形
Digital
- Brachydactyly, syndactyly
- Clinodactyly of the fifth finger
- Radial or ulnar deviation of the other fingers, particularly the third
- Unilateral duplicated hallux (great toe)
- Digital
- 短指症, 并指畸形
- 第五指先天性指侧弯
- 指尺侧偏斜（特别是第三指）Radial or ulnar deviation of the other fingers, particularly the third
- 重复拇指畸形 [大脚趾]
Other
- Milia
- Polycystic kidney disease (50%)
- Intellectual disability
- X-linked dominant inheritance pattern in familial cases
Other
- 粟粒疹
- 肾囊性疾病 (50%)
- 智力残疾
- 伴X染色体显性遗传疾病
Radiographic Features
Hand x-rays often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges.
肾脏超声结果表明大约50%以上的患者有肾囊肿。
Brain MRI most commonly shows intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation.
颅脑MRI 通常表现为脑囊肿，胼胝体发育不全, 以及小脑发育不全伴随或不伴随Dandy-Walker畸形
Establishing the Diagnosis
No formal diagnostic criteria are available. Because of the extensive genetic heterogeneity observed in OFD syndromes, OFD1molecular genetic testing is recommended to establish the diagnosis [Franco & Thauvin-Robinet 2016].
由于OFD1综合症有广泛的遗传异质性，目前没有正式的诊断标准，推荐运用OFD1分子遗传检测方法进行诊断。[Franco & Thauvin-Robinet 2016].
- Female proband. The diagnosis of OFD1 is established by identification of a heterozygouspathogenic variant in OFD1 by molecular genetic testing (see Table 1).
- 女性先证者。对OFD1的诊断是通过分子遗传检测方法，对其杂合致病突变进行筛查。（见表 1）
- Male proband. The diagnosis of OFD1 is established by identification of a hemizygouspathogenic variant in OFD1 by molecular genetic testing (see Table 1).
- 男性先证者。对OFD1的诊断是通过分子遗传检测方法，对其半合子致病突变进行筛查。（见表 1）
Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensivegenomic testing.
分子检测的方法包括单基因检测，多基因面板，以及更全面的基因组检测。
• Single-gene testing. Sequence analysis of OFD1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
单基因检测。首先对OFD1进行序列分析，如果没有发现致病突变，则进行基因靶向缺失/重复分析。
- A multi-gene panel that includes OFD1 and other genes of interest (see Differential Diagnosis) is recommended if no pathogenic variant is identified on single-gene testing.
- 如果在单基因检测中没有发现致病突变，建议使用包含OFD1及其他感兴趣基因的多基因面板进行分析。
- Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.
- 注意：(1) 基因面板。。。。。（2）一些多基因面板可能包含与GeneReview中讨论的无关的基因；因此，临床医生需要确定哪一个多基因面板能以合理的成本并易于识别疾病的遗传因素。（3）使用的方法可以包括序列分析，删除/重复分析和/或其他非基于测序的研究。
- More comprehensive genomic testing (when available) including whole-exome sequencing (WES) and whole-genome sequencing (WGS) is recommended if serial single-gene testing (and/or use of a multi-gene panel that includes OFD1) fails to confirm a diagnosis in an individual with features of OFD1. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For issues to consider in interpretation of genomic test results, click here.
• 更全面的基因组测试 (有条件时）如果连续单基因检测（和/或使用包括OFD1的多基因检测板）未能确认具有OFD1特征的个体的诊断，推荐进行更全面的基因组测试包括全外显子组测序（WES）和全基因组测序（WGS），这类测试可以提供之前没有考虑过的诊断（例如导致相似临床表现的不同基因的突变）。有关解释基因组测试结果的问题，请点击这里。
Table 1.
Molecular Genetic Testing Used in Oral-Facial-Digital Syndrome Type I
Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
OFD1 | Sequence analysis 3, 4 | 80% 5 |
Gene-targeted deletion/duplication analysis 6 | 5% 7 |
1.
See Table A. Genes and Databases for chromosomelocus and protein.
见表A 染色体位点和蛋白质的基因和数据库
2.
See Molecular Genetics for information on allelic variants detected in this gene.
请参见分子遗传学有关该基因检测的等位变异的信息。
3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
序列分析检测良性，不明意义的，可能致病的，或致病的变异。致病突变可能包括小的基因缺失/插入和错义，无意突变和剪接位点变体；通常，未检测到外显子或全基因缺失/重复，要解决序列分析结果时要考虑的问题，请点击这里。
4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-genedeletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
在序列分析之前，PCR扩增缺失可以表明受影响男性在X染色体上存在一个假定的（多）外显子或整个基因缺失。确认需要通过额外进行基因靶向删除/重复分析。
5.
A variety of pathogenic variants have been identified, the majority of which predict premature protein truncation. The reported detection rate with sequence analysis is about 80% [Nowaczyk et al 2003, Thauvin-Robinet et al 2006, Prattichizzo et al 2008].
已经鉴定了各种致病突变，大多数预测过早的蛋白截短。序列分析报告的检出率约为80% [Nowaczyk et al 2003, Thauvin-Robinet et al 2006, Prattichizzo et al 2008]。
6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
基因靶向删除/重复分析检测基因缺失或重复。可以使用的方法可以包括：定量PCR，长距离PCR，多重连接依赖性探针扩增（MLPA），以及基因打靶芯片检测单个外显子缺失或重复。
7.
One study found that six of 131 individuals with OFD1 had a deletion ranging in size from one to 14 exons. None had the same deletion. Within this group, 23% of those who did not have a pathogenic variant identified on gene sequencing were found on qPCR to have an exon or multiexon deletion [Thauvin-Robinet et al 2009].
一项研究发现，131名患有OFD1患有中有6位患者包含1到14个外显子的缺失，并且没有相同缺失。在这项研究里，23%位患者在qPCR检测中发现外显子或multiexon缺失，但没有在基因测序鉴定中发现致病突变。
临床特征
临床描述
根据口腔-面部和指趾的异常，在一些婴儿出生时就诊断出口-面-指趾综合征I型(OFD1)；在其他情况下，只有在儿童晚期或成年后发现多囊性肾病之后，才有可能怀疑是OFD1。几乎所有的OFD1受累者都是女性；只有少数受累男性被报告。在大多数情况下，这些男性被描述为畸形的胎儿，其母亲为OFD1女性。
口腔表现.为分成小叶的舌头，有舌结节，通常是错构瘤或脂肪瘤，至少有1/3的OFD1患者会出现。舌系带短缩属常见，是由于舌系带缩短所致。50%以上的受累个体有硬腭裂或软腭列、黏膜下腭裂或高腭弓。亦有三裂软腭的报道[al-Qattan 1998]。牙槽和副齿龈系带很常见。这些纤维带是增生的系带，由口腔黏膜延伸到牙槽嵴，形成了下陷的牙槽嵴。牙齿异常包括牙齿缺失(最常见的)、额外的牙齿、牙釉质发育不良和咬合不良。
面部特征.33%受累个体有眼距宽或内眦距过宽、鼻翼发育不良、唇中裂或上唇假裂是常见的。小颌畸形和眼裂下斜也很常见。
指趾异常.短指、不同程度的并指和小手指弯曲常见。其他手指，尤其是第三个手指(即:中指)可以显示不同程度的桡侧或尺侧偏移。不到50%的受累个体有大拇趾重复(大脚趾)，而且通常是单侧的。1%-2%的受累个体有手的轴前或轴后多指。手的放射学经常表现出精细的网状放射状，被描述为骨骼不规则的矿化，伴或不伴指骨针状物形成[al-Qattan & Hassanain 1997]。
粟丘疹.小的角质化囊肿，发生在至少10%患者，而且可能更多，最常见的是出现在头皮、耳廓、面部和手背上。粟丘疹通常在婴儿时期就出现，然后就会消失，但会留下疤痕。
肾脏.肾囊肿可发生在肾小管和肾小球。通常在成年期发病，但在2岁以下儿童也有肾囊肿报道。虽然产前检查已见到肾囊肿[Nishimura et al 1999]，但在这些病例中，诊断是值得怀疑的。在18岁以后，严重的肾脏疾病的风险似乎超过了60%[Prattichizzo et al 2008, Saal et al 2010]。在年龄11到70岁受累的女孩和妇女中已经报道了终末期肾病。
智力残疾.据估计，有多达50%的OFD1个体有一定程度的智力障碍或学习障碍。智力障碍在一定程度上取决于大脑是否存在异常，但并没有一致的相关性。如果存在智力残疾，智力障碍通常是轻微的。在没有大脑畸形的情况下，严重的智力障碍似乎是罕见的[Del Giudice et al 2014]。
脑畸形.多达65%的OFD1患者会出现脑结构性异常[Thauvin-Robinet et al 2006, Macca & Franco 2009, Bisschoff et al 2013, Del Giudice et al 2014]。最常见的异常包括脑内囊肿、胼胝体不发育和小脑不发育，伴或不伴有Dandy-Walker畸形。其他报告的异常包括孔洞脑2型(裂脑性孔洞脑)、巨脑回和heterotopias、脑积水、大脑或小脑萎缩、下丘脑错构瘤、berry aneurysms，每一种只有少数几例受累个体的报道。大脑的结构异常可能伴随着癫痫和共济失调，尤其是那些有小脑萎缩症的人。
其他.已有复发性中耳炎导致听力损失的报道，经常与腭裂伴发。有时，说话和咀嚼也会受到影响。头发通常被描述成干燥的、粗糙的、易碎的。脱发通常是部分的，是偶尔的发现。也有描述说脱发following the lines of Blaschko[Boente et al 1999]。可以见到肝、胰腺和卵巢囊肿，但也只能在有肾囊肿的患者中观察到。据报道，矮个子、后鼻孔闭锁和胫骨的假关节也有报道。受累女性的表型变异性经常见到，可能是随机的X-染色体失活 的结果 [Morleo & Franco 2008]。
Clinical Description
The diagnosis of oral-facial-digital syndrome type I (OFD1) is established at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood. Almost all affected individuals with OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by a female with OFD1.
oral-facial-digital syndrome type I (OFD1)的通过对新生儿的口腔，面部以及digital anomalies来诊断；其他情况下，在儿童期后期或成年期时，发生肾囊性疾病也可能推测患有OFD1。大多数OFD1患者为女性；然而，也发现有少数男性患有疾病。在大多数情况下，这些男性主要为畸形胎儿并由OFD1女性患者遗传。
Oral manifestations. The tongue is lobulated. Tongue nodules, which are usually hamartomas or lipomas, also occur in at least one third of individuals with OFD1. Ankyloglossia attributable to a short lingual frenulum is common. Cleft hard or soft palate, submucous cleft palate, or highly arched palate occurs in more than 50% of affected individuals. Trifurcation of the soft palate has been reported [al-Qattan 1998]. Alveolar clefts and accessory gingival frenulae are common. These fibrous bands are hyperplastic frenulae extending from the buccal mucous membrane to the alveolar ridge, resulting in notching of the alveolar ridges. Dental abnormalities include missing teeth (most common), extra teeth, enamel dysplasia, and malocclusion.
Oral manifestations口腔.分叶舌。舌头结节，通常表现为错构瘤或脂肪瘤，至少发生于三分之一的OFD1患者中。常见舌粘连导致的舌系带短。硬腭裂或软颚裂，粘膜下腭裂或高弓颚发生在超过50%以上的患者中。Trifurcation of 软腭已有相关报道[al-Qattan 1998]。常见牙槽突裂以及相关手术治疗。从颊粘膜到牙槽嵴系带增生,导致牙槽嵴凹陷，牙齿异常包括缺牙（较常见），多牙，釉质发育不全，以及错颌畸形。
Facial features. Widely spaced eyes or telecanthus occurs in at least 33% of affected individuals. Hypoplasia of the alae nasi, median cleft lip, or pseudocleft upper lip is common. Micrognathia and downslanting palpebral fissures are common.
Facial features.面部特征。眼距过远或内眦间距过宽至少发生在33%的患者中。常见鼻翼发育不全，假性上唇正中裂。小颌畸形与睑裂在患者中普遍存在。
Digital anomalies. Brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger are common. The other fingers, particularly the third (i.e., middle finger) may show variable radial or ulnar deviation. Duplicated hallux (great toe) occurs in fewer than 50% of affected individuals, and if present is usually unilateral. Preaxial or postaxial polydactyly of the hands occurs in 1%-2% of affected individuals. Radiographs of the hands often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges [al-Qattan & Hassanain 1997].
Digital anomalies. 常见不同程度上的短指症, 并指畸形，和第五指先天性指侧弯。其他的手指，尤其是第三根手指（即，中指）易发生 radial或指尺侧偏斜。重复拇指畸形 [大脚趾]出现在不到50%的患者中，如果出现一般为单侧。大约有1%－2%的患者出现轴前型多指或轴后型多指。手部的放射照片通常表现出良好的网状透亮影像, 表示骨骼的不规则矿化, 伴随或不伴随指骨骨刺的形成 [al-Qattan & Hassanain 1997].
Milia, small keratinizing cysts, occur in at least 10%, and likely more, most often appearing on the scalp, ear pinnae, face, and dorsa of the hands. Milia are usually present in infancy and then resolve, but can leave pitting scars.
粟粒疹，角化囊肿的发生率至少为10%，大多出现在头皮，耳廓，脸部以及手背。粟粒疹通常在婴儿时期发生然后痊愈，但会留下凹陷性疤痕。
Kidney. Renal cysts can develop from both tubules and glomeruli. The age of onset is most often in adulthood, but renal cysts in children as young as age two years have been described. Although renal cysts have been reported as a prenatal finding [Nishimura et al 1999], the diagnosis is doubtful in these cases. The risk for significant renal disease appears to be higher than 60% after age 18 years [Prattichizzo et al 2008, Saal et al 2010]. End-stage renal disease has been reported in affected girls and women ranging in age from 11 to 70 years.
肾.肾囊肿可以从肾小管与肾小球中形成，绝大多数在成年发生，但在两岁的孩子中也发现肾囊肿。尽管肾囊肿作为产前检查的一项 [Nishimura et al 1999], 但诊断结果仍持怀疑态度。在18岁之后肾病发生率达到60%以上 [Prattichizzo et al 2008, Saal et al 2010]。终末期肾脏疾病在11岁到70岁之间的女性患者中存在。
Intellectual disability. It is estimated that as many as 50% of individuals with OFD1 have some degree of intellectual disability or learning disability. Intellectual disability depends in part on the presence of brain abnormalities, but no consistent correlation exists. When present, intellectual disability is usually mild. Severe intellectual disability in the absence of brain malformations appears to be rare [Del Giudice et al 2014].
智力残疾.据统计大约有50%的OFD1患者有不同程度的智力残疾或学习障碍。智力残疾与大脑的部分异常有关，但不存在相关性。当存在时，通常为轻度智力残疾。少见有在不发生脑部畸形的重度智力残疾。[Del Giudice et al 2014].
Brain malformations. Structural brain abnormalities may occur in as many as 65% of individuals with OFD1 [Thauvin-Robinet et al 2006, Macca & Franco 2009, Bisschoff et al 2013, Del Giudice et al 2014]. Anomalies most commonly include intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation. Other reported anomalies include type 2 porencephaly (schizencephalic porencephaly), pachygyria and heterotopias, hydrocephalus, cerebral or cerebellar atrophy, hypothalamic hamartomas, and berry aneurysms, each of which has been described in a few affected individuals.
Structural brain abnormalities may be accompanied by seizures and ataxia, especially in those with cerebellar atrophy.
脑部结构. 多达65％的OFD患者可能发生脑结构异常，[Thauvin-Robinet et al 2006, Macca & Franco 2009, Bisschoff et al 2013, Del Giudice et al 2014]. 常见的症状包括：脑囊肿, 胼胝体发育不全, 小脑发育不全伴随或不伴随Dandy-Walker畸形。其他症状在少数患者中也有发生，包括：2型脑穿通畸形（脑膜炎），巨脑回畸形与灰质异位，脑积水，大脑萎缩或小脑萎缩，下丘脑错构瘤，与颅内小动脉瘤。
Other
Hearing loss from recurrent otitis media, usually associated with cleft palate, has been reported. On occasion, speech and mastication can be affected.
The hair is often described as dry, coarse, and brittle. Alopecia, usually partial, is an occasional finding. Alopecia following the lines of Blaschko has been described [Boente et al 1999].
Liver, pancreatic, and ovarian cysts may be observed, but only in those who have renal cysts as well.
Short stature, choanal atresia, and tibial pseudarthrosis have been reported.
Phenotypic variability is often seen in affected females, possibly as a result of random X-chromosome inactivation [Morleo & Franco 2008].
其它
中耳炎反复发作导致听力丧失，已报道通常与腭裂有关。不定期会影响语言和咀嚼能力。
头发通常干燥，粗糙和脆性。偶尔发现头发部分脱落。沿Blaschko线脱发现象已有报道。[Boente et al 1999].
患有肾囊肿的患者可能在其他部位如：肝脏，胰腺和卵巢有囊肿的发生。
身材矮小，胆囊闭锁，以及先天性胫骨假关节已有报道。
女性患者经常存在表型变异，可能与X染色体随即失活有关。
Genotype-Phenotype Correlations
No convincing genotype-phenotype correlations have been reported. The majority of OFD1 pathogenic variants are localized within exon 16 of the OFD1 transcript.
目前没有基因型 - 表型相关性的报道。OFD1主要的治病突变位于其转录本的第16个外显子上。
Penetrance
OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females [McLaughlin et al 2000].
OFD1似乎有较高的渗透性，尽管表达多义性。在一些报道里，女性患者唯一明显的症状为肾囊肿。
Nomenclature
OFD1 was previously called Papillon-Léage-Psaume syndrome.
OFD1 之前被称为Papillon-Léage-Psaume综合症。
Prevalence
Prevalence estimates range from 1:250,000 to 1:50,000.
发病率在1:250,000 to 1:50,000之间。
Genetically Related (Allelic) Disorders
OFD7, which includes unilateral cleft lip and hydronephrosis, has only been described in one mother-daughter pair, who were later found to have a pathogenic variant in OFD1; thus, this condition is either allelic to oral-facial-digital syndrome type I (OFD1) or demonstrates variable expression of OFD1 [Nowaczyk et al 2003]. Similarly, in a family in which males had a lethal congenital malformation syndrome characterized by oral, facial, digital, cerebral, and renal anomalies and in utero lethality, disease was found to be caused by a novel splicing variant (c.2388+1G>C) in intron 17 of OFD1. Heterozygous females were described to have hyperplastic frenulae and tooth anomalies only [Tsurusaki et al 2013].
OFD7，主要特征为单侧唇裂与肾积水，只在一对母女中发生，并且之后发现有OFD1致病突变；因此，这表明oral-facial-digital syndrome type I (OFD1)的等位基因或OFD1的表达多义性[Nowaczyk et al 2003]. 同样的，在一个家族有先天性致死综合症的男性，其特征为口腔，面部，digital，颅内与肾发育异常并且在宫内死亡，发现由OFD1第17号内含子发生剪切突变所引起(c.2388+1G>C) 。杂合女性只存在口腔系带增生和牙齿异常。 [Tsurusaki et al 2013].
Pathogenic variants in OFD1 have been reported in several individuals with Joubert syndrome [Coene et al 2009, Field et al 2012, Juric-Sekhar et al 2012].
OFD1的治病突变在一些Joubert syndrome患者中发现[Coene et al 2009, Field et al 2012, Juric-Sekhar et al 2012].
An X-linked syndrome (OMIM) associated with cognitive impairment, macrocephaly, and ciliary dysfunction is associated with a four-nucleotide duplication within OFD1, which led to a premature stop codon in exon 16 [Budny et al 2006].
一种X-linked syndrome伴随认知障碍，大头畸形与纤毛功能障碍与OFD1的四核苷酸重复相关，使其第16号外显子终止密码自提前。[Budny et al 2006].
Males with retinitis pigmentosa and an intronicpathogenic variant (IVS9+706A.G) in OFD1 have been described [Webb et al 2012].
色素性视网膜炎的男性，OFD1的内含子发生致病突变(IVS9+706A.G)[Webb et al 2012].
Differential Diagnosis
The differential diagnosis includes the other oral-facial-digital syndromes and disorders, including cystic renal disease.
其它 oral-facial-digital 综合症的诊断，包括肾囊肿疾病。
Oral-facial-digital (OFD)syndromes. See also Table 2 (pdf).
- OFD2 (Mohr syndrome; OMIM) is primarily distinguished by polydactyly. Other manifestations include bifid nasal tip. Affected individuals do not have milia or polycystic kidney disease.
- OFD2 (Mohr syndrome; OMIM) 主要有多指来区分，其它症状包括鼻间裂，患者没有粟丘疹或多囊肾病。
- OFD3 (OMIM) is characterized by seesaw winking (alternate winking of the eyes) and polydactyly. Myoclonic jerks, profound intellectual disability, bulbous nose, and apparently low-set ears also occur.
- OFD3 (OMIM) 主要特征为：seesaw winking（交替眨眼），多指，肌阵挛，重度智力残疾，球状鼻与明显的低耳廓。
- OFD4 (OMIM) has tibial involvement and polydactyly as the primary manifestations. Other findings include pectus excavatum and short stature.
- OFD4 (OMIM) 主要症状表现为tibial involvement与多指。其他症状表现为漏斗孔和身材矮小。
- OFD5 (OMIM) includes polydactyly and median cleft lip only. Hyperplastic frenula have been reported in one affected individual.
- OFD5 (OMIM) 主要症状为多指与唇正中裂。系带增生在一例患者中有报道。
- OFD6 (OMIM) is distinguished by polydactyly (particularly central) and cerebellar malformations. Renal agenesis and dysplasia have been described. Brain MRI may show a molar tooth sign leading some to consider OFD6 a Joubert syndrome-related disorder.
- OFD6 (OMIM) 通过多指（特别是中心）与小脑畸形来诊断。肾发育不全与发育不良已被报道。脑MRI可能从臼齿观察出OFD6是与Joubert综合征相关疾病。
- OFD8 (OMIM), apparently inherited as an X-linked trait, is characterized by the combination of polydactyly, tibial and radial defects, and epiglottal abnormalities, none of which are seen in the classic form of OFD1.
- OFD8 (OMIM)，伴X染色体显性遗传疾病，特征为多指，胫骨和桡骨缺损，会厌功能异常，没有患者出现典型OFD1特征。
- OFD9 (OMIM) includes retinal abnormalities and non-median cleft lip.
- OFD9 (OMIM)包括视网膜异常与唇裂(非正中)。
- OFD10 (OMIM) includes short limbs with bilateral radial shortening and fibular agenesis.
- OFD10 (OMIM)包括双侧桡骨短缩的四肢短小与腓骨发育不全。
- OFD11 (OMIM) includes odontoid and vertebral abnormalities.
- OFD11 (OMIM)包括牙齿以及骨骼发育异常。
- OFD12 is described in only one individual with brain malformations, myelomeningocele, short tibiae and central Y-shaped metacarpal [Gurrieri et al 2007].
- OFD12 只在一位患者中发现，其特征为脑畸形，脊髓脊膜膨出，短胫骨与中央Y形掌骨 [Gurrieri et al 2007].
- OFD13 is described in only one individual with neuropsychiatric disturbances and leukokaraiosis [Gurrieri et al 2007].
- OFD13只在一位患者中发现，其特征为神经精神障碍与脑白质疏松症 [Gurrieri et al 2007].
- OFD14 (OMIM) includes severe microcephaly and intellectual disability. Brain MRI shows vermis hypoplasia and molar tooth sign.
- OFD14 (OMIM)包括严重的小头畸形症和智力障碍。Brain MRI 严重的小脑蚓部发育不全和智力障碍and molar tooth sign。
Cystic renal disease
- Autosomal dominant polycystic kidney disease(ADPKD). The diagnosis of ADPKD has been made in some individuals who later were found to have OFD1 [Scolari et al 1997]. In ADPKD, cysts develop from tubules, whereas in OFD1 cysts develop from both tubules and glomeruli; however, imaging studies cannot always distinguish the renal cystic disease of OFD1 from that of ADPKD and other cystic renal disorders. The cysts are said to be smaller and more uniform in size in OFD1 than in ADPKD, and the kidneys are not as enlarged or malformed in OFD1. Hepatic cysts and berry aneurysms have been observed in OFD1. Other distinguishing features are mode of inheritance and the absence of oral, facial, digital, or brain abnormalities in ADPKD. The two genes in which pathogenic variants are known to cause ADPKD are PKD1 and PKD2.
- Autosomal dominant polycystic kidney disease(ADPKD).在一些ADPKD的患者中后来也出现了OFD1的症状[Scolari et al 1997].在ADPKD的患者中，囊肿从肾小管形成，而OFD1患者的囊肿从肾小球与肾小管形成；然而，影像学研究不能很好的将OFD1与ADPKD患者和其他肾囊性疾病区分，囊肿在OFD1患者中普遍比ADPKD患者更小，更均匀。OFD1患者的肾脏未见扩大与畸形，但见肝囊肿与颅内动脉瘤的发生。其它可以区分的特征是遗传模式与 ADPKD患者中没有口腔，面部，digital或脑异常。PKD1与PKD2的致病突变可以导致 ADPKD发生。
- Meckel-Gruber syndrome is characterized by CNS malformation (posterior encephalocele, cerebral and cerebellar hypoplasia), polycystic or hypoplastic kidneys, preaxial or postaxial polydactyly, and early demise. Additional findings include cleft lip and palate, ambiguous genitalia, microcephaly, and microphthalmia. Ocular histopathology reveals retinal dysplasia, coloboma, cataract, and corneal dysgenesis. Inheritance is autosomal recessive. See Meckel Syndrome: OMIM Phenotypic Series for associated genes.
Meckel-Gruber syndrome 主要特征为CNS畸形（后脑膨出，脑和小脑发育不全），多囊肾或肾发育不全，轴前或轴后多指与早期死亡。其他特征表现为唇裂和腭裂，两性生殖器，小头畸形与小眼症。眼组织病理学显示有视网膜发育不良，眼组织残缺，白内障和角膜发育不全，遗传模式为常染色体隐形遗传。见梅克尔综合征：OMIM表型系列的相关基因。
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with oral-facial-digital syndrome type I (OFD1), the following evaluations are recommended:
为了对oral-facial-digital syndrome type I (OFD1)患者进行正确诊断，推荐进行以下检查。
- Examination of the face, especially the mouth, and the hands for characteristic anomalies
- Formal, age-appropriate assessment of development and behavior
- Evaluation of CNS involvement
- Blood pressure and serum creatinine concentration
- Urinalysis, serum chemistries, and ultrasound examination of the kidneys, liver, ovary and pancreas for cysts if the individual is age ten years or older
- Audiology evaluation if cleft palate is present
- Consultation with a clinical geneticist and/or genetic counselor
- 检查患者脸部，尤其口腔，手部是否出现异常。
- 对其发育生长与行为进行适当的年龄评估。
- 评估CNS。
- 血压及血肌酐浓度。
- 如果患者年龄在十岁及以上，建议进行尿液、血清检测，和超声检测肾脏，肝脏，卵巢和胰腺是否形成囊肿。
- 腭裂患者听力损失的评估。
- 向临床遗传学家和/或遗传咨询师咨询。
Treatment of Manifestations
The following are appropriate:
建议进行以下治疗：
- Cosmetic or reconstructive surgery for clefts of the lip and/or palate, tongue nodules, and accessory frenulae; treatment as for isolated cleft palate, including speech therapy and assessment for and aggressive treatment of otitis media
- Removal of accessory teeth
- Orthodontia for malocclusion
- Surgery to repair syndactyly, if present
- Routine management of renal disease, which may require hemodialysis or peritoneal dialysis and renal transplantation
- Routine management of seizures
- Special educational evaluation and input to address learning disabilities and other cognitive impairments
- 对于患有唇裂或腭裂，舌头结节，accessory frenulae的患者采用重建外科或整形手术治疗；对于单纯腭裂，采用言语治疗并对中耳炎进行评估与治疗。
- 移除多余牙齿。
- 对畸形牙齿采用矫正治疗。
- 如果患有并指畸形则采用手术治疗。
- 肾病采用常规治疗方法，可能需要血液透析，腹膜透析与肾移植等治疗方法。
- 对癫痫患者采用常规治疗方法。
- 对患有学习障碍和其他认知障碍的患者进行评估和特殊教育的方法治疗。
- Surveillance
Surveillance includes the following:
- Annual audiology evaluation and assessment of speech development and frequency of ear infections in children if cleft lip and/or cleft palate is present
- Annual blood pressure examination and serum creatinine concentration to monitor renal function in individuals age ten years or older
- Annual ultrasound examination for renal, hepatic, pancreatic, and ovarian cystic disease in individuals age ten years and older
- 如果儿童患有唇裂或腭裂，每年进行其言语发展和frequency of ear infections的听力学评估。
- 年龄在10岁及以上的患者，每年进行血压检查和血肌酐浓度监测肾功能。
- 年龄在10岁及以上的患者，每年对其肾脏，肝脏，胰腺和卵巢囊性疾病进行超声检查。
Evaluation of Relatives at Risk
If an OFD1pathogenic variant has been identified in an affected family member, it is appropriate to evaluate apparently asymptomatic female relatives (even in the absence of oral, facial, and digital anomalies) to determine if they are at risk for renal disease.
如果OFD1的治病突变已在已有感染的家族中发现，建议对患有肾病但无明显症状（如：口腔，面部，与digital anomalies）的女性进行检查。
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Affected pregnant women should undergo careful monitoring of their blood pressure and renal function during pregnancy.
女性患者在怀孕期间应仔细监测血压和肾功能。
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
搜索ClinicalTrials.gov获取关于各种疾病和病症的临床研究的信息。注意：这种疾病可能没有临床试验。
Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
遗传咨询是向个人和家庭提供关于遗传疾病的nature，遗传和影响的相关信息，以帮助他们做出informed medical 和个人决定。遗传风险评估主要是主要是利用家族历史和基因检测来阐明家族成员的遗传情况。This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Oral-facial-digital syndrome type I (OFD1) is inherited in an X-linked manner. Almost all affected individuals are female. A few affected males have been reported; in most cases, these males are described as malformed fetuses delivered by females with OFD1.
Oral-facial-digital syndrome type I (OFD1) 是伴X染色体遗传。几乎大多数的患者都为女性。少数的男性患者也有报道；大多数情况下，男性患者为畸形胎儿并母亲为OFD1患者。
Risk to Family Members
Parents of a female proband
女性先证者的父母
- Approximately 25% of females diagnosed with OFD1 have an affected mother.
- Approximately 75% of affected females are simplex cases (i.e., occurrence of OFD1 in a single family member) and have a de novopathogenic variant [Feather et al 1997, Macca & Franco 2009].
- Recommendations for the evaluation of the mother of a proband with an apparent de novopathogenic variant include clinical evaluation and molecular genetic testing if the pathogenic variant in the proband has been identified. If the mother meets the diagnostic criteria for OFD1 or if she has another affected relative, she is an obligate heterozygote.
- 大约25%的女性患者其母亲也患有OFD1疾病。
- 大约75%的女性患者为simplex cases（即，作为家族中仅有的OFD1患者）并且有de novo治病突变[Feather et al 1997, Macca & Franco 2009].
- 建议将有新生突变治病突变的母亲作为先证者，新生突变治病突变通过
- Sibs of a female proband
- 女先证者的兄弟
- The risk to sibs depends on the genetic status of the mother.
- When the mother of an affected female is also affected, the risk to sibs of inheriting the disease-causing OFD1allele at conception is 50%; however, most male conceptuses with the OFD1pathogenic variant miscarry [Macca & Franco 2009]. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males.
- If the proband represents a simplex case (i.e., a single occurrence in a family) and if the OFD1pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. Although germline mosaicism has not been reported, it remains a possibility.
- 其兄弟患病的风险取决于母亲的遗传情况。
- 当女性患者的母亲也患病时，其兄弟携带OFD1致病基因的概率为50%；然而，由于大多数携带OFD1治病突变的男性在胎儿期死亡 [Macca & Franco 2009].因此，患病的比率为：33% 不患病的女性; 33% 患病的女性; 33% 不患病的男性。
- 如果先证者代表simplex case（即，作为家族中仅有的OFD1患者），并且OFD1治病突变不能在其母亲白细胞的DNA中检测到，其兄弟的患病率高于一般人群（虽然<1%），是由于母亲可能为生殖系嵌合体，尽管生殖系嵌合体还没有相关报道，但也存在这种可能。
Offspring of a female proband. At conception, the risk that the OFD1pathogenic variant will be transmitted is 50%; however, the risk to the offspring of females with OFD1 must take into consideration the presumed lethality to affected males during gestation (most male conceptuses with an OFD1 pathogenic variant miscarry). Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males.
女性先证者的子女。概念上，OFD1致病基因的的遗传风险为50%；然而，OFD1女性患者的后代的患病率，必须考虑到在妊娠期间对感染男婴的假定的致死率（大多数患有OFD1男性在胎儿期死亡）。因此，患病的比率为：33% 不患病的女性; 33% 患病的女性; 33% 不患病的男性。
Other family members. The risk to other family members depends on the status of the proband's mother: if the mother is affected, her family members could be at risk.
其他家庭成员。其它家庭成员的患病率取决于先证者母亲，如果其母亲患病，她的家庭成员可能患病。
Related Genetic Counseling Issues
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
See Management, 对患者其家属进行危险评估是为了早的诊断和治疗。
Specific risk issues. Males described as having OFD1 have been reported. As virtually all are simplex cases (i.e., a single occurrence in a family), the certainty of the diagnosis is unknown. It is theoretically possible for an affected male to be born alive, though this would be exceedingly rare.
具体风险问题。已发现患者OFD1的男性患者，几乎全部为simplex cases（即，作为家族中仅有的OFD1患者），目前尚未确切诊断，虽然非常罕见，但在理论上男性患者可以生存。
Family planning
家庭计划
- The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.
- 在怀孕之前确定遗传风险和进行产前检测。
- 对患者或有风险患病的人进行适当遗传咨询（包括后代患病的风险以及生育选择）
Ascertainment of affected individuals. Often, mildly affected female relatives are diagnosed only after the identification of a severely affected individual [Thauvin-Robinet et al 2001].
确定患者，通常, 只有在确定病情严重的患者后，才能诊断出轻度受影响的女性亲属 [Thauvin-Robinet et al 2001].
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
DNA banking是存储DNA（通常从白细胞中提取）以备日后使用， Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, 应考虑将患者的DNA存储在DNA banking 中.
Prenatal Testing and Preimplantation Genetic Diagnosis
Molecular genetic testing. Once the OFD1pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.
分子遗传学检测。一旦在患者的家庭成员中鉴定了OFD1致病突变，prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options。
Ultrasound examination
- High-risk pregnancies. In pregnancies of a female with OFD1, which are at 50% risk, prenatal ultrasound examination may detect structural brain malformations (e.g., porencephaly) [Shipp et al 2000, Thauvin-Robinet et al 2001] and/or duplicated hallux.
- Low-risk pregnancies. In pregnancies not known to be at increased risk for OFD1, the findings of structural brain anomalies and unilateral polydactyly of the great toe (duplicated hallux) should lead to consideration of OFD1. In such instances, it is appropriate to evaluate the mother for manifestations of OFD1.
超声检查
• 高风险怀孕. OFD1的女性患者在怀孕时，会有50％的风险，产前超声检查可能会检测胎儿结构性脑部畸形（例如，小脑畸形）[Shipp et al 2000, Thauvin-Robinet et al 2001] 和/或重复的拇指。
• 低风险怀孕.在怀孕，不知道有OFD1风险增加，发现结构性脑部异常与单脚多趾的大拇指（重复的趾）时，胎儿可能患有OFD1，在这种情况下，对母亲进行OFD1表现评估是合适的。
Genetic counseling is the process ofproviding individuals and families with information on the nature, inheritance,and implications of genetic disorders to help them make informed medical andpersonal decisions. The following section deals with genetic risk assessment andthe use of family history and genetic testing to clarify genetic status forfamily members. This section is not meant to address all personal, cultural, orethical issues that individuals may face or to substitute for consultation witha genetics professional. —ED.
Mode of Inheritance
Oral-facial-digital syndrome type I (OFD1) is inherited in an X-linked manner. Almost all 受累的 individuals are female. A few affected males have been reported; in most cases, these males are described as malformed fetuses delivered by females with OFD1.
Risk to Family Members
Parents of a female 先证者
- Approximately 25% of females diagnosed with OFD1 have an 受累的 mother.
- Approximately 75% of 受累的 females are 单发的 cases (i.e., occurrence of OFD1 in a single family member) and have a de novo致病性变异 [Feather et al 1997, Macca & Franco 2009].
Sibs of a female 先证者
- The risk to sibs depends on the genetic status of the mother.
- When the mother of an 受累的 female is also affected, the risk to sibs of inheriting the disease-causing OFD1等位基因 at conception is 50%; however, most male conceptuses with the OFD1致病性变异 miscarry [Macca & Franco 2009]. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males.
- If the 先证者 represents a 单发的 case (i.e., a single occurrence in a family) and if the OFD1致病性变异 cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal 胚系嵌合. Although germline mosaicism has not been reported, it remains a possibility.
Offspring of a female 先证者. At conception, the risk that the OFD1致病性变异 will be transmitted is 50%; however, the risk to the offspring of females with OFD1 must take into consideration the presumed lethality to 受累的 males during gestation (most male conceptuses with an OFD1 pathogenic variant miscarry). Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males.
Other family members. The risk to other family members depends on the status of the 先证者's mother: if the mother is 受累的, her family members could be at risk.
Related Genetic Counseling Issues
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
Specific risk issues. Males described as having OFD1 have been reported. As virtually all are 单发的 cases (i.e., a single occurrence in a family), the certainty of the diagnosis is unknown. It is theoretically possible for an 受累的 male to be born alive, though this would be exceedingly rare.
Family planning
- The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
Ascertainment of 受累的 individuals. Often, mildly affected female relatives are diagnosed only after the identification of a severely affected individual [Thauvin-Robinet et al 2001].
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of 受累的 individuals.
Prenatal Testing and Preimplantation Genetic Diagnosis
Molecular genetic testing. Once the OFD1致病性变异 has been identified in an 受累的 family member, prenatal testing for a pregnancy at increased risk and 植入前遗传诊断 are possible options.
Ultrasound examination
- High-risk pregnancies. In pregnancies of a female with OFD1, which are at 50% risk, prenatal ultrasound examination may detect structural brain malformations (e.g., porencephaly) [Shipp et al 2000, Thauvin-Robinet et al 2001] and/or duplicated hallux.
- Low-risk pregnancies. In pregnancies not known to be at increased risk for OFD1, the findings of structural brain anomalies and unilateral polydactyly of the great toe (duplicated hallux) should lead to consideration of OFD1. In such instances, it is appropriate to evaluate the mother for manifestations of OFD1.
Resources
GeneReviews staff has selected the following disease-specific and/orumbrella support organizations and/or registries for the benefit of individualswith this disorder and their families. GeneReviews is not responsible for theinformation provided by other organizations. For information on selectioncriteria, click here.
- AboutFace International123 Edward StreetSuite 1003Toronto Ontario M5G 1E2CanadaPhone: 800-665-3223 (toll-free); 416-597-2229Fax: 416-597-8494Email: info@aboutfaceinternational.org
- Children's Craniofacial Association (CCA)13140 Coit RoadSuite 517Dallas TX 75240Phone: 800-535-3643 (toll-free); 214-570-9099Fax: 214-570-8811Email: contactCCA@ccakids.com
- Cleft Palate Foundation (CPF)1504 East Franklin StreetSuite 102Chapel Hill NC 27514-2820Phone: 800-242-5338 (toll-free); 919-933-9044Fax: 919-933-9604Email: info@cleftline.org
- Friendly FacesEmail: smile@friendlyfaces.org
- Kidney Foundation of Canada310-5160 Decarie Blvd.Montreal Ontario H3X 2H9CanadaPhone: 800-361-7494 (toll-free); 514-369-4806Fax: 514-369-2472Email: info@kidney.ca
- National Kidney Foundation (NKF)30 East 33rd StreetNew York NY 10016Phone: 800-622-9010 (toll-free); 212-889-2210Email: info@kidney.org
- National Renal Resource CentreSydney Dialysis Centre37 Darling Point roadDarling Point New South Wales 2027AustraliaPhone: 61 2 9362 3995; 61 2 9362 3121; 1 800 257 189 (toll-free)Fax: 61 2 9362 4354Email: renalresource@nsccahs.health.nsw.gov.au
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. -ED.
Table A.
Oral-Facial-Digital Syndrome Type I: Genes and Databases
| Gene | Chromosome Locus | Protein | Locus-Specific Databases | HGMD | ClinVar |
|---|---|---|---|---|---|
| OFD1 | Xp22-.2 | Oral-facial-digital syndrome 1 protein | OFD1 @ LOVD | OFD1 | OFD1 |
Table B.
OMIM Entries for Oral-Facial-Digital Syndrome Type I (View All in OMIM)
Gene structure.OFD1 has 23 exons (reference sequence NM_003611.2) and is located on a region of the X chromosome where transcripts frequently escape X-chromosome inactivation. See Table 3 (pdf) for benign allelic variants. See Table A, Gene for a detailed summary of gene and protein information.
基因结构 OFD1拥有23个外显子（参考序列NM_003611.2），并且位于X染色体上，其转录本逃避X染色体失活，见Table 3 (pdf) 良性等位基因变体. 见Table A, 基因和蛋白质信息的详细总结.
Pathogenic allelic variants. To date, more than 120 different pathogenic variants (including large genomic rearrangements) have been identified [Ferrante et al 2001, Rakkolainen et al 2002, Stoll & Sauvage 2002, Romio et al 2003, Morisawa et al 2004, Thauvin-Robinet et al 2006, Prattichizzo et al 2008, Thauvin-Robinet et al 2009, Bisschoff et al 2013, Franco & Thauvin-Robinet 2016]. See Table 3.
致病性基因突变，至今超过120种致病突变已经被发现（包括大型基因重组） [Ferrante et al 2001, Rakkolainen et al 2002, Stoll & Sauvage 2002, Romio et al 2003, Morisawa et al 2004, Thauvin-Robinet et al 2006, Prattichizzo et al 2008, Thauvin-Robinet et al 2009, Bisschoff et al 2013, Franco & Thauvin-Robinet 2016]. See Table 3.
Both exonic and intronic pathogenic allelic variants have been described throughout the gene. Nucleotide variants in exons include single base-pair changes, frameshifts, and deletions [Macca & Franco 2009, Bisschoff et al 2013].
内含子以及外显子的致病等位基因突变在整个基因上已经描述，外显子中的核苷酸变体包括单碱基对变化，移码和缺失[Macca & Franco 2009, Bisschoff et al 2013].
Nine different genomic deletions involving exons 1 through 23 or the entire transcript have been reported [Thauvin-Robinet et al 2009, Bisschoff et al 2013].
已经报道了涉及外显子1至23或整个转录本的九种不同的基因组缺失 [Thauvin-Robinet et al 2009, Bisschoff et al 2013].
Normal gene product. Oral-facial-digital syndrome 1 protein occurs in two forms, OFD1-1 (Cxorf5-1) and OFD1-2 (Cxorf5-2), which are differentiated by the use of an alternative splice site. OFD1-1 is a 1012-amino acid protein (reference sequence NP_003602.1); OFD1-2 is a 367-amino acid protein. The two proteins share the first 351 amino acids; OFD1-2 then has a C-terminal region of 16 amino acids. OFD1 was expressed in all adult tissues that were examined by de Conciliis et al [1998]. However, during early development, expression is exclusively in the genital ridges, soon followed by expression in craniofacial structures and nervous system [Ferrante et al 2001]. The function of the protein is as yet unknown, although characterization of a mouse model bearing ubiquitous inactivation of the Ofd1 transcript from early stages of development demonstrated that Ofd1 is required for formation of primary cilia and determination of left-right asymmetry [Ferrante et al 2006]. In vitro studies demonstrate that Ofd1 regulates the length and distal structures of centrioles [Singla et al 2010].
正常基因产物。 Oral-facial-digital syndrome 1 蛋白有两种亚型，OFD1-1 (Cxorf5-1) 和OFD1-2 (Cxorf5-2), 通过其可变剪切位点来区分。OFD1-1有1012个氨基酸组成 (参考序列。NP_003602.1); OFD1-2由367个氨基酸组成，两种蛋白的351个氨基酸相同，OFD1-2的C末端含有16个氨基酸，de Conciliis et al [1998]发现OFD1在成人的各个组织中均有表达，然而，在早期发育中，主要在生殖脊中表达，随后在颅面结构和神经系统中表达[Ferrante et al 2001]。蛋白的功能至今还不清楚，尽管在携带Ofd1转录本ubiquitous失活的小鼠的早期发育中，显示Ofd1为原位纤毛的形成和左右不对称性产生所需要[Ferrante et al 2006]。体外实验证明OFD1调控中心粒的长度和远端结构。
Abnormal gene product. Most of the pathogenic variants predict a premature truncation of the protein and apparent loss of function, which is further supported by the OFD1 intragenic deletion alleles. Since OFD1 is on the portion of the X chromosome that escapes X-chromosome inactivation, the truncated protein may theoretically interact with the wild-type product to produce a dominant-negative effect.
异常的基因产物。大多数致病突变意味着蛋白翻译提前终止并且功能丧失，主要由于OFD1等位基因的缺失所造成的。因为OFD1是在X染色体上逃避X染色体失活的部分，理论上截短的蛋白质可以与野生型产物相互作用，通过显性负性效应的方式致病。
References
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Suggested Reading
- Franco B. The molecular basis of oral-facial-digital type 1 (OFD1) syndrome. In: Epstein JC, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. 2 ed. Vol 1. New York, NY: Oxford University Press; 2008:1379-86.
- Odent S, Le Marec B, Toutain A, David A, Vigneron J, Treguier C, Jouan H, Milon J, Fryns JP, Verloes A. Central nervous system malformations and early end-stage renal disease in oro-facio-digital syndrome type I: a review. Am J Med Genet. 1998;75:389鈥�94. [PubMed: 9482645]
Chapter Notes
Author History
Ange-Line Bruel, PhD (2016-present)
Brunella Franco, MD (2010-present)
Danilo Moretti-Ferreira, PhD; São Paulo State University, Brazil (2002-2010)
Izolda Nunes Guimaraes, PhD; São Paulo State University, Brazil (2002-2010)
Christel Thauvin-Robinet, MD, PhD (2016-present)
Helga V Toriello, PhD (2002-present)
Revision History
- 4 August 2016 (sw) Comprehensive update posted live
- 28 February 2013 (me) Comprehensive update posted live
- 14 October 2010 (me) Comprehensive update posted live
- 14 August 2006 (me) Comprehensive update posted to live Web site
- 29 June 2004 (me) Comprehensive update posted to live Web site
- 24 July 2002 (me) Review posted to live Web site
- 27 February 2002 (ht) Original submission