临床特征.

无虹膜症（Aniridia）的特征通常是虹膜完全或部分发育不全(但并不总是)，伴随有隐窝发育不良（foveal hypoplasia），导致早期婴儿的视力减退和眼球震颤。经常伴发的眼部异常(经常发生的)包括白内障、青光眼、角膜浑浊和血管增生。无虹膜症可能只是孤立的眼部异常而没有系统性受累，这是由PAX6基因突变或控制其表达的调控区域缺失引起；或者是Wilms肿瘤-无虹膜症-生殖器异常-智力障碍综合征 (WAGR)的部分表现，患者发生11 p13缺失，涉及PAX6(无虹膜症)位点和相邻WT1(Wilms肿瘤)位点。PAX6和WT1缺失的患者，患Wilms肿瘤的风险可高达50%。
 

诊断/检测.

通过临床检查即可诊断无虹膜症。PAX6基因编码区序列分析的和检测PAX6基因外显子或整个基因的缺失/重复分析被用来确定那些孤立的无虹膜症的致病性变异。高分辨细胞遗传学检测技术用来确定涉及11 p13的缺失、FISH检测技术或PAX6和WT1基因的缺失/重复分析技术则用来确定诊断为WAGR综合症患者的致病机制。
 

处置.

对症治疗：无虹膜症的治疗是矫正屈光不正，配戴彩色或光敏变色的镜片以减少对光的敏感性，遮盖疗法治疗弱视，以及用诸如闭路电视的技术辅助治疗低视力。白内障摘取可以提高致密行白内障患者的视力。青光眼最初是用局部抗青光眼药物治疗的；难治性病例可能需要外科手术(小梁切除术或引流管手术)或cyclodiode治疗。角膜病用润滑剂、粘液溶解剂和

治疗。对于严重的病例，可进行角膜移植手术，但有很高的失败风险，可能需要终生的免疫抑制。罕见的无虹膜性纤维化综合征需要手术治疗的。监测:8岁以下儿童应每4至6个月监测屈光不正和弱视。每年一次的眼科检查可以检测迟发性眼病。终生的每年青光眼筛查包括测量眼压、视盘检查，以及在可能的情况下进行视野评估。

监测：无虹膜纤维化综合征，对前期多次眼内外科手术的患者用裂隙灯进行的检查。对具有WT1缺失的无虹膜患儿，每三个月进行一次肾脏超声检查，直到八岁。对WAGR综合征患者要终身进行肾功能评估，尤其是那些患有双侧Wilms肿瘤的人。对WAGR或孤立的无虹膜症儿童，推荐进行仔细的听力学评价。

避免药物/环境因素：眼内手术可能增加(或加重现有)角膜病的可能性；重复的眼内外科手术治疗会发生罕见但严重的无虹膜性纤维化综合征。

亲属的风险评估：对无虹膜症个体的后代和同胞，建议在婴儿时期进行一次眼科检查，并推荐给患有阿尼里迪亚的人。

遗传咨询.

孤立的无虹膜症的遗传方式为常染色体显性遗传。大多数孤立的无虹膜症患者有受累的父（母）亲；然而，一些人患无虹膜症可能是新生致病性变异的结果，孤立的无虹膜症个体的后代有50%的机会继承PAX6的致病性变异和罹患无虹膜症。因邻近基因缺失所致的WAGR综合征通常是由新生突变引起；由细胞基因可见的缺失引起的WAGR综合症可能是由新生突变，也可能从携带 染色体平衡易位的父母一方传递而来。如果孤立无虹膜症家庭受累成员的致病性变异已被确认，或WAGR综合征先证者的相邻基因缺失或细胞遗传学的可见缺失已经确认，就可能对风险增加的妊娠进行产前检查。
 

临床诊断

无虹膜症的特征是完全或部分的虹膜发育不全（但并不总是）与相关的中心凹注视发育不全，导致视力下降和在婴儿早期出现的眼球震颤。经常伴发出现的眼部异常，通常是晚发性的，包括白内障、青光眼、角膜浑浊和血管化。
 

用于识别无虹膜症眼部畸形的技术

• 裂隙灯检查. 部分或完全的虹膜缺失，虹膜半透明，或异常的结构和瞳孔异常；也可以检测到角膜浑浊和血管化、白内障和青光眼。
• 眼底镜检查（狭缝灯或双目间接检眼镜）。正常的视网膜中央凹的架构的缺失或减少是经常发生的；视神经异常较少见，例如发育不全和残缺等。很少有其他视网膜问题出现。
• 虹膜荧光素的血管造影术可以识别细微的虹膜发育不全，但很少临床应用。
• 光学相干断层摄影术（UBM）.可用于记录中央凹发育不良。虽然在眼球震颤的情况下OCT很难进行，但可以获得有用的图像。眼前节OCT也可以用来描述眼前节结构的详细解剖结构，即使是在角膜浑浊的情况下[Majander et al 2012]。
• 高频超声活组织镜检查(UBM). 在伴发的先天的青光眼所致角膜混浊或严重的角膜水肿的婴儿，高频超声检查眼前节可以证明虹膜发育不全和/或缺失[Nischal 2007]。

无虹膜症可能以下列的一种发生：

• 孤立无虹膜症，无其他系统性受累，是由PAX6突变或控制PAX6表达的调控区域缺失引起。
  
  注意:孤立无虹膜症可能发生在家族病史的个体，符合常染色体显性遗传方式（家族性无虹膜症：70%的无虹膜症患者）,或者没有家族史（单发的无虹膜症,通常被称为“散发性无虹膜症”:30%的无虹膜症患者） [Valenzuela & Cline 2004].
  或
• Wilms肿瘤-无虹膜-生殖器异常发育迟缓（WAGR）综合征。WAGR综合征可能根据以下发现诊断：
  • 细胞遗传学分析可见11p13 缺失
    或
  • FISH或杂合性检测，发现到涉及PAX6 (无虹膜症) 位点和邻近WT1（Wilms肿瘤）位点的亚显微缺失
    或
  • 对无虹膜症个体进行身体检查时发现的一种或更多的WAGR综合症表型。
    
    注：（1）由于Wilms肿瘤、智力残疾和行为异常不太可能在一个患有WAGR综合征的幼儿身上表现出来，因此，在孩子经历了这些症状的风险年龄之前，通常不能确定或排除WAGR综合征的临床诊断。（2）在女性WAGR患者中外生殖器通常是正常的[Fischbach et al 2005].

检测

细胞遗传学检测. 600-650带高分辨细胞遗传学检测，在无家族史的无虹膜症患者中可以检测到20%个体有涉及到11p13缺失。缺失/重复分析通常可检测到这些和更小的缺失，并可以精确地定义断点(表 1).

检测策略

确认/建立孤立的无虹膜症或WAGR的诊断. 为了确定哪些响受累个体的有患Wilms肿瘤的高风险，因此需要启动Wilms肿瘤筛选方案，应该考虑以下测试算法：：
在先证者有下列情况，首先对PAX6和WT1的细胞遗传学检测、FISH和/或缺失/重复分析进行评估：

• 一个患有无虹膜症的婴儿，他是一个单发的病例（例如在家庭中发生的一件事）

• 年龄较大的个体，患有无虹膜症及智力残疾和/或Wilms肿瘤和/或生殖器异常。
  • 通过细胞遗传学研究、FISH测试或缺失/重复分析确定了PAX6和WT1的缺失，证实了WAGR综合征的诊断。细胞遗传学研究发现的缺失，在必要时，可以通过FISH或删除/复制分析得到确认[Crolla & van Heyningen 2002]。

首先使用PAX6序列分析和/或PAX6缺失/重复分析来评估，如果先证者：

• 已知有孤立的无虹膜症（因为他/他已经超过了Wilms肿瘤和智力残疾的风险年龄，或者他/他有一个单纯性无虹膜症阳性家庭史）；
  或
• 没有无虹膜症的家族史，核型正常，通过FISH测试或缺失/重复分析也没有发现WT1缺失。

临床描述
 

无虹膜症是一种眼病，影响角膜、虹膜、眼内压、晶状体、中心凹和视神经。在家庭内和家庭间个体表型有差别；然而，受累的个体两只眼睛之间的差异通常很小。无虹膜症个体表现为眼球震颤、视力受损（通常为20/100-20/200），以及小的发育不全。轻型无虹膜症只有轻度的虹膜结构变化，视觉良好，中心凹结构正常[Hingorani et al 2009]。其他的异常包括角膜病变、青光眼、白内障、晶状体脱位、斜视、视神经乳头瘤和发育不全，偶尔还会出现小眼症。
 

视觉精度的下降主要是由中心凹发育不良引起的，但白内障、青光眼和角膜浑浊导致视力逐渐下降。大多数患有无虹膜症的儿童在出生时都有明显的虹膜或瞳孔异常，或者在婴儿时期出现眼眼球震颤（通常在六周大时出现）。
先天性青光眼很少发生在无虹膜症；在这种情况下，角膜直径大和角膜水肿可能是其表现。尽管有许多眼部问题，但大多数患有无虹膜症的个体可以通过适当的眼科处理而保留有用的视力。
 

虹膜.最明显的眼部异常是虹膜发育不全。症状的严重程度有差异，从几乎正常的虹膜到几乎完全缺失虹膜，在goni透视，前段，10月，或 前房角镜、眼前节OCT或生物显微学检查可见一小块残余的虹膜组织[Okamoto et al 2004]。 
某些不太极端的病例，瞳孔大小可能是正常的，但是虹膜表面的结构可能会失去或者透明的虹膜[Hingorani et al 2009].
虹膜的其他变化包括虹膜部分缺陷（类似缺损）或瞳孔偏斜或畸形及虹膜外翻[Nelson et al 1984, Willcock et al 2006]。
晶状体. 先天性晶状体混浊（尤其是极性）是常见的[Gramer et al 2012]。通常，前晶状体囊（晶状体血管膜

）或皮膜残体瞳孔前膜的残余。晶状体混浊很少密集到在婴儿期需要晶体摘除

,但50% -85%患者的晶状体混浊最终发展为妨碍视觉,通常在青少年或成年早期。镜头的半脱位或脱位会发生，但并不常见。
眼内压.当眼压升高与视网膜神经节细胞丧失有关，导致视野损失和视神经cupping，诊断为青光眼。无虹膜症患者常见眼内压升高和青光眼，并且可能三分之二的个体最终会发生 [Gramer et al 2012]。青光眼的发作通常在儿童后期或成年期；婴儿时期的青光眼是罕见的[Gramer et al 2012]。

角膜. Keratopathy (corneal degeneration) is a relatively late manifestation with 多因素的 causes including limbal stem cell abnormalities and abnormal wound healing [Ramaesh et al 2005]. Changes vary from mild peripheral vascularization to pan corneal vascularization, opacification, and keratinization. Inadequate tear production is common and exacerbates the ocular surface problems. Central corneal thickness is increased – a finding of uncertain clinical relevance, but which may result in undermeasurement of intraocular pressure on tonometry [Brandt et al 2004, Whitson et al 2005]. Rarely, those with aniridia may have microcornea and, extremely rarely, megalocornea [Lipsky & Salim 2011, Wang et al 2012].
 

中心凹. Foveal hypoplasia is usually (but not always) present. Findings include reduced foveal reflex, macular hypopigmentation, and crossing of the usual foveal avascular zone by retinal vessels. OCT images can clearly delineate the absence of normal foveal architecture.
 

视神经. Optic nerve hypoplasia (i.e., the optic nerve head appears abnormally small) may occur in up to 10% and there may be optic nerve colobomata [McCulley et al 2005].
 

无虹膜纤维化综合征. Individuals with aniridia who have a history of multiple ocular procedures (penetrating keratoplasty, intraocular lenses [IOLs], and drainage tube insertion) may rarely develop aniridic fibrosis syndrome in which a fibrotic retrolenticular and retrocorneal membrane arises from the root of the rudimentary iris tissue. This membrane may cause forward displacement of the IOLs, IOL entrapment, and corneal decompensation [Tsai et al 2005].
 

视网膜. Retinal detachment may occur, probably as a consequence of a high myopia or previous intraocular surgery. Very rarely, primary retinal manifestations such as an exudative vascular retinopathy or chorioretinal degeneration may occur [Hingorani et al 2009, Aggarwal et al 2011].
 

其他眼部表现. Affected individuals may have significant refractive errors and may develop a secondary strabismus (squint, eye misalignment).

中枢神经系统. Individuals with 孤立的 aniridia may show reduced olfaction and cognition, behavioral problems, or developmental delay. Central nervous system abnormalities (including absence or hypoplasia of the anterior commissure; abnormalities of grey matter in the anterior cingulate cortex, cerebellum, and temporal and occipital lobes; white matter deficits in and reduced volume of the corpus callosum; absence of the pineal gland; and occasionally olfactory bulb hypoplasia) can be demonstrated on MRI [Sisodiya et al 2001, Free et al 2003, Mitchell et al 2003, Ellison-Wright et al 2004, Valenzuela & Cline 2004, Bamiou et al 2007, Abouzeid et al 2009].
 

听力. Central auditory processing difficulties (from abnormal interhemispheric transfer) present in some individuals may cause hearing difficulties. This finding is particularly important in the context of associated visual impairment [Bamiou et al 2007].
 

WAGR综合征. Individuals with cytogenetically visible deletions of 11p13 or cryptic deletions of PAX6 and WT1 may develop WAGR syndrome: Wilms tumor-aniridia-genital anomalies-retardation syndrome [Fischbach et al 2005]:

• Wilms肿瘤 risk for individuals with a cytogenetically visible 缺失 of 11p13 or a submicroscopic deletion that involves PAX6 and WT1 is probably as high as 50%. Individuals with WAGR syndrome are more likely than those with 孤立的 Wilms tumor to develop bilateral tumors and have an earlier age of diagnosis and a more favorable tumor histology with better prognosis [Halim et al 2012].
• 无虹膜症 is almost universally present in individuals with such a 缺失 and typically is severe. However, WAGR without aniridia has been described.
• 泌尿生殖器异常 include cryptorchidism (most commonly, in 60% of males), uterine abnormalities, hypospadias, ambiguous genitalia, streak ovaries, urethral strictures, ureteric abnormalities, and gonadoblastoma.
• 智力障碍和行为异常. in WAGR syndrome are highly variable:
  • Seventy percent of individuals with WAGR syndrome have intellectual disability (defined as IQ <74); other individuals with WAGR syndrome can have normal intellect without behavior problems.
  • Behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, anxiety, depression, and obsessive compulsive disorder.
• 神经系统异常 occur in up to one third of individuals with WAGR syndrome. Findings include hypertonia or hypotonia, epilepsy, enlarged ventricles, corpus callosum agenesis, and microcephaly.
• 终末期肾病(ESRD). The risk of later ESRD is significant, relating to Wilms tumor and its surgery, focal segmental glomerulosclerosis, and occasionally renal malformation. The rate of ESRD is 36% with unilateral Wilms tumor and 90% with bilateral Wilms tumor. Approximately 25% of individuals with WAGR syndrome have proteinuria ranging from minimal to overt nephritic syndrome [Breslow et al 2005, Fischbach et al 2005].
• 肥胖. The association of obesity in the WAGR spectrum, for which the acronym WAGRO has been suggested, has been confirmed [Brémond-Gignac et al 2005a].

Affected individuals may also show craniofacial dysmorphism, hemihypertrophy, growth retardation, scoliosis, and kyphosis. Other anomalies reported on occasion include polydactyly and 先天的 diaphragmatic hernia [Nelson et al 1984, Brémond-Gignac et al 2005b, Manoukian et al 2005, Scott et al 2005] (see Congenital Diaphragmatic Hernia Overview).

Early studies recognized that 30% of individuals with aniridia who had no family history of aniridia developed Wilms tumor within the first five years of life; subsequent studies revealed that the risk may be lower [Grønskov et al 2001]. It is now known that these individuals have WAGR syndrome caused by a 邻近基因缺失 encompassing both PAX6 and the nearby Wilms tumor suppressor gene (WT1). Absence of one WT1等位基因 in the 胚系 in these individuals leads to a high risk (~45%) of Wilms tumor occurring through somatic mutation that results in 杂合性丢失 (LOH) in a single differentiating kidney cell.

基因型-表型相关性

单纯性无虹膜症. Haploinsufficiency (loss of protein function of one 等位基因) of PAX6 can be identified in approximately 90% of individuals with aniridia, with intragenic 功能丧失性 variants (often premature termination codons) accounting for two thirds and deletions or 染色体 rearrangements in PAX6 or regulatory elements for one third of cases [Grønskov et al 2001, Robinson et al 2008]. PAX6单倍剂量不足 produces classic and severe aniridia with a high incidence of sight-reducing pathology such as optic nerve malformations, glaucoma, cataract and corneal changes [Kleinjan & van Heyningen 1998, Prosser & van Heyningen 1998, Grønskov et al 1999, Hanson et al 1999, Lauderdale et al 2000, van Heyningen & Williamson 2002, Chao et al 2003, Tzoulaki et al 2005, Dansault et al 2007, Hingorani et al 2009].

PAX6 pathogenic 错义 variants, particularly those which are in the paired 结构域 and therefore likely to significantly reduce the DNA binding ability, tend to produce atypical/milder or variable-表型 aniridia with better vision, more residual iris tissue and a lower frequency of sight reducing malformations and complications [Hingorani et al 2009]. Pathogenic missense variants may also result in related disorders (see Table 2) such as foveal hypoplasia, 常染色体显性遗传 keratitis, developmental abnormalities of the optic nerve, and Peters anomaly, sometimes associated with neurodevelopmental abnormalities.

C-terminal extension (CTE) pathogenic variants, which generate a longer protein product, are associated with a moderately severe aniridic 表型 with poor vision, keratopathy, and cataracts; however, individuals with CTE pathogenic variants are less likely to have glaucoma and are more likely to have preservation of iris tissue than individuals who have pathogenic 无效 variants [Hingorani et al 2009, Aggarwal et al 2011]. The rare reports of significant non-foveal retinal abnormalities (exudative retinopathy, chorioretinal degeneration) are all associated with CTE pathogenic variants, for reasons which are not clear [Hingorani et al 2009, Aggarwal et al 2011].

Although the 表型 can be variable within a family, individuals usually show little difference between the two eyes. The causes for this variation in phenotype among individuals with the same 致病性变异 are unknown [Negishi et al 1999].
 

WAGR综合征是由细胞遗传学上不可见或可见的缺失引起，缺失涉及11p区域不同长度的片段，包括11p13中PAX6和邻近基因。WT1的缺失产生泌尿和肾功能异常，易诱发Wilms肿瘤，系杂合性丢失(LOH)所致。PAX6杂合性缺失导致无虹膜症。
与智力障碍相关的确切基因损失尚未确定[Fischbach et al 2005]，但表型谱是由基因的 缺失有关,更严重的智力障碍通常与更大的缺失相关联[Fischbach et al 2005, Xu et al 2008].

外显率

外显率为100%。

患病率

无虹膜症的发病率为1:40,000 to 1:100,000. 没有种族或性别差异。WAGR综合征的发病率大约为1:500,000。

Evaluation Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with aniridia, the following are recommended:

• Evaluation of visual acuity (not easily performed in infants), the degree of iris tissue deficiency, and the presence of foveal and optic nerve hypoplasia in order to predict future visual function
• Evaluation for the presence and degree of corneal involvement, cataract, and glaucoma, as they are potentially treatable causes of further visual reduction; however, they may not appear until later in life.
• Clinical genetics consultation

Treatment of Manifestations

Aniridia. Simple measures are often the most important:

• Regular eye examinations and correction of refractive errors. Refractive errors range from high myopia through emmetropia to high hypermetropia. Spectacle correction of refractive errors is usually recommended as use of contact lenses can be difficult in the presence of keratopathy and reduced tear production.
• Tinted or photochromic lenses to reduce light sensitivity associated with the large pupillary aperture. Colored, tinted or artificial pupil contact lenses may reduce light sensitivity or restore a more normal appearance to the eye but, as above, may be difficult to wear because of a poor ocular surface and tear film.
• Occlusion therapy for anisometropic amblyopia or strabismic amblyopia in childhood
• Optical low-vision aids and other devices such as closed-circuit television systems to help adults and children of school age
• Advice and help with schooling
• Social support

Note: Corrective surgery for strabismus can be undertaken but is usually only for cosmetic rather than visual purposes.

Lens. Cataract extraction can significantly improve visual acuity in those with severe lens opacities. It should be remembered that in aniridia visual improvement after surgery is limited by foveal hypoplasia; thus, mild to moderate lens opacities may not require surgery:

• Children rarely require surgery (lens aspiration or lensectomy).
• In adults, phacoemulsification can be successful.

Note: (1) A significant number of individuals with aniridia have poor zonular stability, which increases the risk for intraoperative complications and influences the choice of surgical technique and options for IOL implantation [Schneider et al 2003]. (2) The use of various types of black diaphragm aniridic IOLs may reduce glare or light sensitivity but may be associated with a higher rate of surgical complications [Reinhard et al 2000, Menezo et al 2005, Pozdeyeva et al 2005].

Intraocular pressure

• Glaucoma is usually initially treated with topical anti-glaucoma medication.
• Surgery is reserved for eyes that do not respond to medical therapy:
  • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in patients with primary glaucoma who undergo the same treatment.
  • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases, although this treatment is increasingly being undertaken as a primary procedure [Khaw 2002, Kirwan et al 2002, Arroyave et al 2003, Lee et al 2010].

Note: (1) Glaucoma presenting in infancy is more difficult to treat. Medical treatment is generally ineffective and surgery is required. Goniotomy and trabeculotomy have a low success rate, but trabeculectomy with or without antimetabolites is often successful [Nelson et al 1984, Okada et al 2000, Khaw 2002]. (2) While goniosurgery has been suggested as a preventive measure, glaucoma never develops in a significant proportion of those with aniridia [Swanner et al 2004].

Cornea

• Ocular surface disease can be treated medically using lubricants, mucolytics, and punctal occlusion. Note: Drops without preservatives are often required to avoid preservative-related ocular surface toxicity.
• When corneal opacification causes significant visual reduction, penetrating keratoplasty (PK) may be considered; however, in the presence of the significant limbal stem cell deficiency observed in aniridia, PK alone has a poor prognosis [Tiller et al 2003].
• Limbal stem cell transplantation alone, preceding or concurrent with keratoplasty may be undertaken, but requires an allograft as both eyes are usually 受累的. This may take the form of a cultured stem cell sheet or a limbal tissue transplant [Lee et al 2008, Pauklin et al 2010]. However, this therapy is associated with a high risk of failure and lifelong systemic immunosuppression may be required to prevent rejection. Whether the use of cultured oral mucous membrane cells may have a beneficial role is as yet uncertain.

Aniridic fibrosis syndrome. Surgical intervention is recommended at the first sign of aniridic fibrosis syndrome [Tsai et al 2005].

Wilms tumor. See Wilms Tumor Overview.

Prevention of Secondary Complications

Detection of high refractive errors and amblyopia in children will allow therapy to protect or restore the vision

Early detection of ocular hypertension and glaucoma will allow the instigation of therapy to prevent the further loss of visual function.

Protection of the ocular surface with lubricants and lacrimal punctual obstruction may help slow the progression of sight-threatening corneal changes.

Surveillance

Amblyopia and refractive error. Children younger than age eight years should be monitored every four to six months for refractive errors and detection and treatment of incipient or actual amblyopia (strabismic, refractive, or sensory). Glasses and other visual aids should be provided to be able to best access educational materials.

Detection of later-onset eye pathology. Individuals with aniridia should have an annual ophthalmology review to detect problems such as corneal changes and cataracts.

Glaucoma. Individuals with aniridia should undergo annual glaucoma screening throughout life including:

• Measurement of intraocular pressure;
• Optic disc examination;
• Visual field assessment, when possible.

Note: Assessment of the optic disc and visual field may be difficult in the presence of media opacities and nystagmus.

Aniridic fibrosis syndrome. Individuals with aniridia with a history of multiple ocular procedures (penetrating keratoplasty, IOLs, and drainage tube insertion) should be monitored for aniridic fibrosis syndrome [Tsai et al 2005].

Wilms tumor. Children with aniridia and a WT1 缺失 require renal ultrasound examinations every three months and follow-up by a pediatric oncologist until they reach age eight years. See Wilms Tumor Overview. (Those without deletion of the WT1 位点 are at very low risk for Wilms tumor and do not require such screening [Grønskov et al 2001, Muto et al 2002].)

Renal function. Because of the increased risk for renal impairment in WAGR syndrome, it has been suggested that renal function be evaluated every few years across the lifetime in those with WAGR syndrome, especially those with bilateral Wilms tumor [Breslow et al 2005].

Hearing. Children with WAGR syndrome and 孤立的 aniridia may have abnormal hearing despite a normal audiogram; thus, detailed audiologic evaluation is recommended [Bamiou et al 2007].

Agents/Circumstances to Avoid

It has been suggested that intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy [Edén et al 2010], and repeated intraocular surgery does predispose to the rare but severe aniridic fibrosis syndrome. Patients should therefore be counseled about these risks before undertaking such surgery.

Evaluation of Relatives at Risk

It is recommended that offspring and sibs of individuals with aniridia have an eye examination in infancy and be offered the option of 遗传咨询 and testing.

See Genetic Counseling for issues related to testing of at-risk relatives for 遗传咨询 purposes.

Therapies Under Investigation

Ongoing research is investigating the role and success of limbal stem cell transplantation and ocular mucous membrane cell transplantation for keratopathies associated with limbal stem cell failure, including aniridia [Polisetti & Joyce 2013, Menzel-Severing et al 2013].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Isolated aniridia and WAGR syndrome are inherited in an 常染色体显性遗传 manner.

Risk to Family Members — Isolated Aniridia

Parents of a 先证者

• Most individuals diagnosed with 孤立的 aniridia have an 受累的 parent.
• A 先证者 with 孤立的 aniridia and no family history may have the disorder as the result of a de novo 致病性变异 or 缺失.
• Because the severity of the 表型 may vary greatly among family members, recommendations for the evaluation of parents of a 先证者 with an apparent de novo 致病性变异 include examination of both parents for evidence of minor degrees of iris hypoplasia or reduced visual acuity caused by foveal hypoplasia and may include genetic testing.

Sibs of a 先证者

• The risk to the sibs of the 先证者 depends on the genetic status of the proband's parents.
• If a parent of the 先证者 has 孤立的 aniridia or has an identifiable PAX6 致病性变异, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a 先证者 appears to be low.
• If a PAX6 致病性变异 cannot be detected in the DNA of either parent of the 先证者, 胚系嵌合 in a parent should be considered. Germline mosaicism for PAX6 intragenic variants has been reported on rare occasions [Grønskov et al 1999].

Offspring of a 先证者. Each child of an individual with 孤立的 aniridia has a 50% chance of inheriting the PAX6 致病性变异 and developing aniridia.

Note: In rare instances of 嵌合 for the PAX6 致病性变异 in the 先证者, the risk to offspring may be lower.

Risk to Family Members — WAGR Syndrome

Parents of a 先证者

• WAGR syndrome caused by a 邻近基因缺失 that includes PAX6 and WT1 that is detected only by FISH testing or deletion/duplication analysis usually occurs de novo; however, rarely an asymptomatic parent may be mosaic for such a deletion; thus, it is appropriate to offer FISH testing or deletion/duplication analysis to both parents.
• In individuals with WAGR syndrome caused by a cytogenetically visible 缺失, it is appropriate to offer 细胞遗传的 testing to both parents to determine if either parent has a balanced 染色体 rearrangement.

Sibs of a 先证者

• If a parent has a balanced 染色体 rearrangement, the risk to the sibs is increased depending on the nature of the chromosome rearrangement.
• If the 先证者 has a de novo 邻近基因缺失 and neither parent has evidence of 嵌合 for the deletion, the risk to sibs is no greater than that in the general population.

Offspring of a 先证者. Individuals with WAGR syndrome caused by a 细胞遗传的 缺失 generally do not reproduce.

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.

Considerations in families with an apparent de novo 致病性变异. When neither parent of a 先证者 with an 常染色体显性遗传 condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including 非生物学父亲 or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer 遗传咨询 (including discussion of potential risks to offspring and reproductive options) to young adults who have 孤立的 aniridia.

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

Prenatal testing using fetal cells obtained by amniocentesis is usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation is possible under the following circumstances:

• For pregnancies at increased risk for 孤立的 aniridia if the PAX6 致病性变异 or regulatory region 缺失 has been identified [Churchill et al 2000]
• For pregnancies at increased risk for WAGR syndrome caused by a 细胞遗传的 缺失 if a balanced 染色体 rearrangement has been identified in a parent
• For pregnancies at increased risk for WAGR syndrome caused by a cryptic 缺失 detectable by FISH or deletion/duplication analysis

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which (1) the PAX6 致病性变异 has been identified or (2) a 染色体 rearrangement detectable by chromosome analysis or FISH has been demonstrated in a parent.

Molecular Genetic Pathogenesis

PAX6 belongs to the PAX (paired box) family of genes that code for highly conserved DNA-binding proteins believed to be important in controlling organogenesis by altering expression of other genes [van Heyningen & Williamson 2002]. PAX6 is expressed in ocular, neural, nasal, and pancreatic tissue during development. Heterozygous pathogenic variants of PAX6 appear to disturb ocular morphogenesis, resulting in aniridia and related ocular phenotypes, and also may produce mild central nervous system defects [Sisodiya et al 2001, Free et al 2003, Ellison-Wright et al 2004, Valenzuela & Cline 2004]. Homozygous or 复合杂合 loss of PAX6 function leads to anophthalmia and central nervous system defects and are often fatal [Hodgson & Saunders 1980, Glaser et al 1994, Schmidt-Sidor et al 2009].

Gene structure.PAX6 occupies 22 kb on 染色体 11p13. Alternatively spliced transcript variants encoding multiple 异型体 have been observed for this 基因. The longest transcript encoding the longest isoform is NM_000280.4. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 300 PAX6 pathogenic variants have been identified, more than 90% of which are predicted to disrupt transcription or translation and are likely to be pathogenic variants causing 先天的 eye disorders [Prosser & van Heyningen 1998, Tzoulaki et al 2005]:

• Approximately 60% are intragenic 功能丧失性 variants that introduce a premature termination codon into the PAX6 开放阅读框架 and (occasionally) variants of up- or downstream regulatory sequences [Prosser & van Heyningen 1998, Crolla & van Heyningen 2002, Tzoulaki et al 2005, Hingorani et al 2009].
• Approximately 25% are 错义 variants that have been detected in less severe forms of aniridia, and which may code for near-to-功能丧失性 protein, or are associated with other ocular phenotypes such as 孤立的 foveal hypoplasia [Azuma et al 1998, Vincent et al 2003, Chauhan et al 2004, Tzoulaki et al 2005, Hingorani et al 2009].
• The rest comprise C-terminal extension pathogenic variants (e.g., frameshifts, stop codon variants) which can be associated with moderately severe aniridia sometimes with retinal changes, and other variants which are not easily classifiable [Hingorani et al 2009].

Four CpG dinucleotides in exons 8, 9, 10, and 11 are the most common mutation sites, accounting for 21% of all reported pathogenic variants [Tzoulaki et al 2005]. Large deletions that may involve other genes (e.g., WT1) also produce aniridia.

Many pathogenic variants have been reported in PAX6, both in aniridia and in related ocular phenotypes including Peters anomaly, foveal hypoplasia, and optic nerve anomalies:

• Of the PAX6 pathogenic variants known to cause aniridia, most lead to loss of protein function and comprise nonsense variants (39%), splice variants (13%), frameshifting deletions and insertions (25%), 非移码 insertions and deletions (6%), 错义 variants (12%), and run-on variants (5%) [Prosser & van Heyningen 1998, Tzoulaki et al 2005].
• Of the approximately 30 known pathogenic variants for non-aniridia eye disorders, 69% are 错义 variants [Tzoulaki et al 2005].

Normal 基因产物.PAX6 encodes the PAX6 protein, a 422-amino acid protein [NP_000271.1] that acts as a 转录因子. PAX6 contains a paired 结构域 and a paired-type homeodomain, both with DNA-binding capability, separated by a lysine-rich linker region. A C-terminal proline, serine, and threonine-rich (PST) domain acts as a transcriptional activator. PAX6 protein is thought to act as the major controller of ocular development during embryogenesis by effects on cellular proliferation, differentiation, migration, and adhesion; several target genes have been identified [van Heyningen & Williamson 2002]. PAX6 protein expression continues in the adult retina, lens, and cornea and may help maintain good ocular health [Koroma et al 1997, van Heyningen & Williamson 2002].

Various 异型体 of PAX6 protein are derived through alternative 剪接 (PAX6-ex12, PAX6-5a,6', PAX6-5a). The ratios of these isoforms may be critical to normal ocular development [Singh et al 2002].

Abnormal 基因产物. The molecular consequence of most PAX6 pathogenic variants is loss of protein function. This was previously believed to occur primarily through premature protein truncation but is now hypothesized to arise from nonsense-mediated decay [Prosser & van Heyningen 1998, Tzoulaki et al 2005]. Pathogenic 错义 variants are believed to produce proteins with reduced function, and protein modeling predicts that 88% of missense PAX6 variants can be linked to changes in intrinsic stability (77%) and/or to the ability to bind DNA (30%) [Alibés et al 2010]. This results in the variant ocular phenotypes or (if protein function is greatly reduced) in aniridia. Reduction of expression of alternatively spliced PAX6 protein 异型体 can also cause an altered or less severe 表型 [Azuma et al 1999, Vincent et al 2003, Chauhan et al 2004].

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Suggested Reading

• Haber DA. Wilms tumor. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 38. Available online.
• Hingorani M, Hanson I, van Heyningen V. Aniridia. Eur J Hum Genet. 2012;20:1011鈥�7. [PMC free article: PMC3449076] [PubMed: 22692063]
• Sheffield VC, Alward WLM, Stone EM. The glaucomas. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 242. Available online.

Revision History

• 14 November 2013 (me) Comprehensive update posted live
• 12 July 2008 (me) Comprehensive update posted to live Web site
• 15 July 2005 (me) Comprehensive update posted to live Web site
• 20 May 2003 (me) Review posted to live Web site
• 2 September 2002 (am) Original submission