Abstract：
OBJECTIVE: Aplasia of lacrimal and salivary glands (ALSG) is a syndromic disorder characterized by aplasia of lacrimal and salivary systems. Reported ophthalmic manifestations of ALSG include aplasia of lacrimal glands, punctal agenesis, lacrimal sac mucocele, and membranous congenital nasolacrimal duct obstruction (CNLDO). Bony CNLDO, a rare clinical entity, has not been associated with any syndromic disorder. This study investigated the relationship between genetic mutations and bony CNLDO in 3 Chinese families with ALSG.
METHODS: Single-center observational case study.
METHODS: Three Chinese families with bony CNLDO, including 7 affected and 9 healthy family members.
METHODS: Slit-lamp ophthalmic examination, comprehensive physical examination, orbital computed tomography (CT) imaging, cervicofacial magnetic resonance imaging, audiometry, and whole exome sequencing on periphery blood were performed. Variants were cross-referenced with 1000 control genomes and various population databases. Pathologic variants were identified using bioinformatic tools.
METHODS: Clinical examination, diagnostic imaging, whole exome sequencing, and bioinformatic analysis findings.
RESULTS: Affected patients showed decreased tear production on the Schimer I test and reduced tear breakup time. Bony CNLDO was observed on CT, showing unilateral or bilateral bony termination at the middle or terminal segment of the nasolacrimal canal. Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid, and submandibular glands. Physical examination revealed normal ears, digits, and facial morphology. Audiometry and dental assessment were conducted on the pediatric patients and yielded normal results. The clinical characteristics of patients aligned with a diagnosis of ALSG. Genomic analysis revealed 3 novel heterozygous missense mutations of the Fgf10 gene: c.316T→C, c.327C→G, and c.332T→G. The inheritance pattern was autosomal dominant with variable penetrance. These variants were not observed in 1000 control genomes and population databases. These variant positions also were shown to be highly conserved across various animal species. Mutated genes and proteins were predicted as deleterious with most computational models, with a few suggesting they may be benign.
CONCLUSIONS: Bony CNLDO was identified as a novel phenotype of ALSG implicated by missense mutations of highly conserved residues in the Fgf10 gene. These cases broadened our knowledge of Fgf10-related phenotypes and prompted clinicians to consider syndromic associations in patients with bony CNLDO.
BACKGROUND: The author(s) have no proprietary or commercial interest in any materials discussed in this article.
METHODS: Single-center observational case study.
METHODS: Three Chinese families with bony CNLDO, including 7 affected and 9 healthy family members.
METHODS: Slit-lamp ophthalmic examination, comprehensive physical examination, orbital computed tomography (CT) imaging, cervicofacial magnetic resonance imaging, audiometry, and whole exome sequencing on periphery blood were performed. Variants were cross-referenced with 1000 control genomes and various population databases. Pathologic variants were identified using bioinformatic tools.
METHODS: Clinical examination, diagnostic imaging, whole exome sequencing, and bioinformatic analysis findings.
RESULTS: Affected patients showed decreased tear production on the Schimer I test and reduced tear breakup time. Bony CNLDO was observed on CT, showing unilateral or bilateral bony termination at the middle or terminal segment of the nasolacrimal canal. Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid, and submandibular glands. Physical examination revealed normal ears, digits, and facial morphology. Audiometry and dental assessment were conducted on the pediatric patients and yielded normal results. The clinical characteristics of patients aligned with a diagnosis of ALSG. Genomic analysis revealed 3 novel heterozygous missense mutations of the Fgf10 gene: c.316T→C, c.327C→G, and c.332T→G. The inheritance pattern was autosomal dominant with variable penetrance. These variants were not observed in 1000 control genomes and population databases. These variant positions also were shown to be highly conserved across various animal species. Mutated genes and proteins were predicted as deleterious with most computational models, with a few suggesting they may be benign.
CONCLUSIONS: Bony CNLDO was identified as a novel phenotype of ALSG implicated by missense mutations of highly conserved residues in the Fgf10 gene. These cases broadened our knowledge of Fgf10-related phenotypes and prompted clinicians to consider syndromic associations in patients with bony CNLDO.
BACKGROUND: The author(s) have no proprietary or commercial interest in any materials discussed in this article.
摘要：
目的：泪腺和唾液腺发育不全（ALSG）是一种以泪腺和唾液系统发育不全为特征的综合征。报告的ALSG的眼科表现包括泪腺发育不全，泪点发育不全,泪囊黏液囊肿和膜性先天性鼻泪管阻塞（CNLDO）。BonyCNLDO,一种罕见的先天性泪露的病因,没有与任何综合征有关。本研究调查了三个中国ALSG家族的基因突变与骨CNLDO之间的关系。
方法：单中心观察性个案研究。
方法：3个中国骨性CNLDO家庭，包括7个受影响的家庭成员和9个健康家庭成员。
方法：裂隙灯眼科检查，全面体检,眼眶计算机断层扫描(CT),颈面部磁共振成像（MRI），对外周血进行了听力测量和全外显子组测序.变体与1000个对照基因组和各种群体数据库交叉引用。使用生物信息学工具鉴定病理变异。
方法：临床检查，诊断成像,全外显子组测序和生物信息学分析结果。
结果：受影响的患者在SchimerI试验中泪液产生减少，泪液破裂时间缩短。在计算机断层扫描上观察到BonyCNLDO，在鼻泪管的中段或末端显示单侧或双侧骨性终止。颈面部MRI显示泪腺发育不全或缺失，腮腺和颌下腺。体格检查显示耳朵正常,数字和面部形态。对儿科患者进行了听力测定和牙科评估，结果正常。与ALSG诊断相符的患者的临床特征。基因组分析揭示了Fgf10基因的三个新的杂合错义突变：c.316T>C，c.327C>G，c.332T>G.遗传方式为常染色体显性遗传，外显率可变。在1000个对照染色体和群体数据库中未观察到这些变体。这些变体位置也显示在各种动物物种中高度转化。在大多数计算模型中，突变的基因和蛋白质被预测为“有害的”，其中一些表明它们可能是“良性的”。
结论：BonyCNLDO被鉴定为ALSG的一种新表型，与Fgf10基因中高度保守残基的错义突变有关。这些病例扩大了我们对Fgf10相关表型的认识，并促使临床医生考虑骨性CNLDO患者的综合征关联。
方法：单中心观察性个案研究。
方法：3个中国骨性CNLDO家庭，包括7个受影响的家庭成员和9个健康家庭成员。
方法：裂隙灯眼科检查，全面体检,眼眶计算机断层扫描(CT),颈面部磁共振成像（MRI），对外周血进行了听力测量和全外显子组测序.变体与1000个对照基因组和各种群体数据库交叉引用。使用生物信息学工具鉴定病理变异。
方法：临床检查，诊断成像,全外显子组测序和生物信息学分析结果。
结果：受影响的患者在SchimerI试验中泪液产生减少，泪液破裂时间缩短。在计算机断层扫描上观察到BonyCNLDO，在鼻泪管的中段或末端显示单侧或双侧骨性终止。颈面部MRI显示泪腺发育不全或缺失，腮腺和颌下腺。体格检查显示耳朵正常,数字和面部形态。对儿科患者进行了听力测定和牙科评估，结果正常。与ALSG诊断相符的患者的临床特征。基因组分析揭示了Fgf10基因的三个新的杂合错义突变：c.316T>C，c.327C>G，c.332T>G.遗传方式为常染色体显性遗传，外显率可变。在1000个对照染色体和群体数据库中未观察到这些变体。这些变体位置也显示在各种动物物种中高度转化。在大多数计算模型中，突变的基因和蛋白质被预测为“有害的”，其中一些表明它们可能是“良性的”。
结论：BonyCNLDO被鉴定为ALSG的一种新表型，与Fgf10基因中高度保守残基的错义突变有关。这些病例扩大了我们对Fgf10相关表型的认识，并促使临床医生考虑骨性CNLDO患者的综合征关联。
