Teunissen–Cremers syndrome

Teunissen–Cremers syndrome is a rare autosomal dominant disorder that combines congenital conductive hearing loss from stapes ankylosis with proximal symphalangism, broad thumbs and first toes, short distal phalanges, syndactyly and hyperopia.特尼森-克雷默综合征是一种罕见的常染色体显性遗传病，将镫骨固定所致的先天性传导性听力损失与近端指关节融合、宽拇指与宽拇趾、远端指骨短小、并指及远视结合在一起。

It belongs to the NOG-related spectrum of joint fusion disorders and appears in the molecular literature as stapes ankylosis with broad thumb and toes, because heterozygous loss-of-function variants in NOG explain most reported families.该病属于 NOG 相关关节融合疾病谱，在分子文献中多以镫骨固定伴宽拇指与宽趾出现，因为大多数已报告家系可由 NOG 的杂合功能丧失变异解释。

Terminology and classification

• The eponym honours B. Teunissen and W. R. J. Cremers, who described the founding family in 1990, and the disorder is also called stapes ankylosis with broad thumb and toes, abbreviated SABTT, or symphalangism with congenital conductive deafness.该人名病名纪念 1990 年描述奠基家系的 B. Teunissen 与 W. R. J. Cremers，该病又称镫骨固定伴宽拇指与宽趾，缩写为 SABTT，或称为伴先天性传导性聋的指关节融合。
• In current nosology it is catalogued as OMIM 184460, MONDO:0008484 and ORPHA:140917, while ICD-10 places it in Q87.8, other specified congenital malformation syndromes, and ICD-11 in LD2F.1Y.在当前分类中它被编为 OMIM 184460、MONDO:0008484 与 ORPHA:140917，ICD-10 将其列入 Q87.8 其他特指先天性畸形综合征，ICD-11 则列入 LD2F.1Y。
• It must be separated from other NOG-related entities, namely proximal symphalangism type 1, multiple synostoses syndrome type 1 and facio-audio-symphalangism, which share the gene but differ in the pattern of joint fusion and craniofacial involvement.必须把它与其他 NOG 相关实体区分开，即近端指关节融合 1 型、多发性骨融合综合征 1 型与面-听-指关节融合综合征，它们共享同一基因但关节融合模式与颅面受累不同。
• The label is sometimes shortened to Teunissen–Cremers syndrome or TECS in clinical genetics, and the en dash between the two surnames is part of the standard spelling used by OMIM and Orphanet.在临床遗传学中该名称有时简称为特尼森-克雷默综合征或 TECS，两个姓氏之间的连接号是 OMIM 与 Orphanet 采用的标准拼写的一部分。
• Broad thumbs and first toes are characteristic but not obligatory, so the eponym covers the full spectrum from isolated conductive deafness with subtle symphalangism to the complete skeletal and ocular phenotype.宽拇指与宽拇趾具有特征性但并非必备，因此该人名病名涵盖从伴轻微指关节融合的孤立性传导性聋到完整骨骼与眼部表型的整个谱系。
• Coding terms used in databases include HPO HP:0000381 for stapes ankylosis and HP:0011304 for broad thumb, together with UMLS C1866656, GARD 0012631, MedGen 357104, SCTID 719305006 and Wikidata Q7707070.数据库使用的编码术语包括镫骨固定的 HPO HP:0000381 与宽拇指的 HP:0011304，以及 UMLS C1866656、GARD 0012631、MedGen 357104、SCTID 719305006 与 Wikidata Q7707070。

History

• In 1990 Teunissen and Cremers reported a family in which congenital conductive hearing loss, hyperopia, broad thumbs and first toes, short distal phalanges and syndactyly segregated through several generations.1990 年 Teunissen 与 Cremers 报告了一个家系，其中先天性传导性听力损失、远视、宽拇指与宽拇趾、远端指骨短小及并指在多代中垂直传递。^[1]
• Surgery in the original family disclosed stapes ankylosis with incus fixation, and stapedectomy restored useful hearing in affected members, which established the middle ear defect as the cause of the deafness.原始家系的手术揭示了镫骨固定伴砧骨固定，镫骨切除术使受累成员恢复了可用听力，从而确定中耳缺陷是耳聋的原因。
• A 1999 follow-up refined the clinical description and confirmed autosomal dominant inheritance with variable expression within the same pedigree.1999 年的随访研究细化了临床描述，并确认同一家系内存在表现度变异与常染色体显性遗传。^[2]
• The molecular basis was identified in 2002, when a truncating NOG variant, c.252_253insC leading to p.Gln110Ter in the cysteine-rich C-terminal domain, was found in an affected family.分子基础于 2002 年得到确认，当时在一个受累家系中发现了位于富含半胱氨酸 C 端结构域的截短型 NOG 变异，即导致 p.Gln110Ter 的 c.252_253insC。^[3]
• A 2005 study of three Dutch families with nine affected individuals documented three novel NOG variants and reported that the air-bone gap fell below 10 dB in six of nine operated ears.2005 年对三个荷兰家系共九名受累者的研究记录了三个新的 NOG 变异，并报告九只接受手术的耳中有六只气骨导差降至 10 分贝以下。^[4]
• Later reports added the p.Pro35Ser substitution in 2008 and the p.Cys228Gly substitution in 2015, widening the allelic series while leaving the core phenotype unchanged.后续报道于 2008 年补充了 p.Pro35Ser 替换，2015 年补充了 p.Cys228Gly 替换，扩大了等位基因谱系而核心表型未变。^[5][6]
• In 2012 NOG variants were detected in patients with stapes ankylosis and symphalangism but were absent from 33 patients with otosclerosis, a result that reinforced the distinction between the inherited syndrome and the common acquired fixation of the stapes.2012 年研究在伴指关节融合的镫骨固定患者中检出 NOG 变异，而在 33 例耳硬化症患者中未检出，这一结果强化了遗传性综合征与常见获得性镫骨固定之间的区分。^[7]

Epidemiology

• Orphanet classifies the syndrome as ultra-rare with a prevalence below 1 per 1,000,000 and lists about six families, with onset recognized in infancy or the neonatal period.Orphanet 将该综合征归为超罕见病，患病率低于百万分之一，并列出约六个家系，起病可追溯至婴儿期或新生儿期。
• No population-based incidence is available, because case ascertainment depends on recognizing the combination of congenital conductive deafness and subtle skeletal stigmata.目前没有基于人群的发病率，因为病例发现取决于能否识别先天性传导性聋与轻微骨骼体征的组合。
• Published families originate mainly from Europe, including Dutch and French pedigrees, with additional reports from Asia, so the distribution probably reflects diagnostic awareness rather than true geographic variation.已发表家系主要来自欧洲，包括荷兰与法国家系，另有来自亚洲的报告，因此这种分布更可能反映诊断意识而非真实地理差异。
• Males and females are affected in comparable numbers, consistent with autosomal dominant transmission that is independent of sex.男女受累人数相当，符合不依赖性别的常染色体显性遗传。
• Penetrance is high for the full syndrome but expressivity varies widely, and some carriers show only symphalangism, only broad digits or only mild hearing loss.完整综合征的外显率较高，但表现度差异很大，部分携带者仅表现为指关节融合、仅表现为宽指或仅有轻度听力损失。
• The condition is probably underdiagnosed, because adults with isolated conductive hearing loss are frequently labelled as otosclerosis before hand and foot radiographs are obtained.该病很可能被低估诊断，因为仅有孤立性传导性听力损失的成人常在拍摄手足 X 线片之前被标记为耳硬化症。
• GARD, MedGen and Orphanet list the entity but provide no case counts, and published series remain small, so the true prevalence cannot be estimated from registry data.GARD、MedGen 与 Orphanet 收录该实体但不提供病例数，已发表系列仍然很小，因此无法从登记数据估计真实患病率。
• The burden consists of lifelong hearing surveillance, possible middle ear surgery, hand surgery in selected patients, vision correction for hyperopia and genetic counselling for affected families.疾病负担包括终身听力监测、可能的中耳手术、部分患者的手部手术、远视的视力矫正以及受累家系的遗传咨询。

Pathophysiology

• NOG encodes noggin, a secreted antagonist of bone morphogenetic proteins, and heterozygous loss of function reduces this brake on BMP signalling in developing joints and in the middle ear.NOG 编码分泌型骨形态发生蛋白拮抗剂（noggin），杂合功能丧失削弱了发育中的关节与中耳内对 BMP 信号的抑制作用。
• Excess BMP activity promotes fusion of the stapes footplate to the oval window margin and fixation of the incudostapedial assembly, producing a mechanical conductive block of up to 60 dB.BMP 活性过强促进镫骨足板与卵圆窗缘融合以及砧镫复合体固定，形成可达 60 分贝的机械性传导阻滞。
• The same mechanism prevents normal joint cavitation in the proximal interphalangeal joints, leaving bony or fibrous continuity instead of a synovial space.同一机制阻止了近端指间关节的正常关节腔形成，使关节间隙被骨性或纤维性连续取代而缺乏滑膜腔。
• Broad thumbs and first toes with short distal phalanges reflect disturbed phalangeal patterning during limb development rather than secondary remodelling of normally formed bones.宽拇指与宽拇趾伴远端指骨短小反映了肢体发育期指骨模式形成紊乱，而非正常形成骨骼的继发性重塑。
• Genotype-phenotype correlation is weak, and the same variant can produce isolated deafness in one relative and full symphalangism in another, which points to modifier genes and stochastic developmental factors.基因型与表型的相关性较弱，同一变异可在一名亲属中仅引起孤立性耳聋，而在另一名亲属中引起完全性指关节融合，提示存在修饰基因与发育随机因素。
• Hyperopia and cervical vertebral fusion in some families show that noggin-dependent BMP control also contributes to ocular and axial skeletal development.部分家系出现的远视与颈椎融合表明，依赖（noggin）的 BMP 调控也参与眼部与中轴骨骼发育。

Clinical features

• Congenital conductive hearing loss is usually bilateral, non-progressive and moderate to severe, and it is often the presenting problem in infancy or early childhood.先天性传导性听力损失通常为双侧、非进展性且程度中等至重度，常是婴儿期或幼儿期的首发问题。
• Proximal symphalangism fixes the proximal interphalangeal joints, giving stiff fingers, an absent knuckle contour and a positive missing-knuckle sign on inspection.近端指关节融合使近端指间关节固定，导致手指僵硬、指节轮廓消失，检查时呈阳性缺节征。
• Broad thumbs and broad first toes are accompanied by short distal phalanges and variable cutaneous syndactyly, and this combination is the clinical signature of the disorder.宽拇指与宽拇趾伴远端指骨短小及程度不等的皮肤性并指，这一组合是该病的临床标志。
• Hyperopia is reported in the founding family and should be sought, because uncorrected refractive error adds to the developmental burden of a child who already has hearing loss.奠基家系中报告了远视，应主动筛查，因为未矫正的屈光不正会加重已有听力损失儿童的发育负担。
• Cervical vertebral fusion occurred in the original pedigree and may limit neck rotation, so the cervical spine should be examined and imaged when symptoms suggest it.原始家系中出现颈椎融合，可能限制颈部旋转，因此当症状提示时应检查并影像学评估颈椎。
• Speech and language delay, school difficulty and social isolation are secondary consequences of unrecognized or late-treated deafness rather than primary neurological features.言语与语言发育迟缓、学习困难及社交孤立是耳聋未被识别或治疗过晚的继发后果，而非原发性神经系统特征。
• Named complications include progression of conductive loss after failed middle ear surgery, sensorineural loss after stapedectomy, permanent hand stiffness in untreated symphalangism and amblyopia risk in uncorrected hyperopia.具名并发症包括中耳手术失败后传导性听力损失加重、镫骨切除术后感音神经性听力损失、未治疗指关节融合所致永久性手部僵硬以及未矫正远视带来的弱视风险。

Diagnosis

• Pure-tone audiometry typically shows an air-bone gap with preserved bone conduction, and tympanometry is normal, which localizes the loss to the middle ear.纯音测听通常显示气骨导差而骨导保留，鼓室压图为正常，从而把听力损失定位在中耳。
• Temporal bone computed tomography can demonstrate stapes fixation, incus abnormality and narrowing of the oval window, and it helps plan middle ear surgery.颞骨计算机断层扫描可显示镫骨固定、砧骨异常与卵圆窗狭窄，并有助于规划中耳手术。
• Hand and foot radiographs document proximal interphalangeal joint fusion, short distal phalanges and broad terminal tufts, and cervical spine films are added when neck movement is limited.手足 X 线片可记录近端指间关节融合、远端指骨短小与宽大末节指骨簇，颈部活动受限时加拍颈椎片。
• Molecular confirmation relies on NOG sequencing, with deletion and duplication analysis when sequencing is negative, and it allows predictive testing of relatives.分子确诊依赖 NOG 测序，测序阴性时补充缺失与重复分析，并可对亲属开展预测性检测。
• The main differential diagnosis is otosclerosis, which is acquired, appears in adolescence or adulthood and lacks symphalangism, broad digits and hyperopia.主要鉴别诊断是耳硬化症，后者为获得性，见于青少年或成年期，且没有指关节融合、宽指与远视。
• Other NOG-related disorders, Klippel–Feil syndrome, Apert syndrome and isolated syndactyly are separated by the pattern of craniofacial, cervical and limb involvement.其他 NOG 相关疾病、Klippel–Feil 综合征、Apert 综合征与孤立性并指可依据颅面、颈椎与肢体受累模式加以区分。

Management

• Care is shared among otology, audiology, clinical genetics, hand surgery, ophthalmology and speech therapy, and the family should be involved in every decision.诊疗由耳科、听力学、临床遗传学、手外科、眼科与言语治疗共同承担，家庭应参与每一项决策。
• Hearing aids are the first option for young children and for patients who decline or are unsuitable for surgery, and they should be fitted early to protect speech development.助听器是幼儿以及拒绝手术或不适合手术患者的首选，应尽早验配以保护言语发育。
• Stapedectomy or stapedotomy with prosthesis placement can close the air-bone gap, and reported series show closure below 10 dB in a substantial proportion of operated ears.镫骨切除或镫骨切开加假体置入可关闭气骨导差，已报告系列显示相当比例的手术耳可关闭至 10 分贝以下。
• Middle ear surgery carries risks of sensorineural hearing loss, vertigo, prosthesis displacement and refixation, so the indication must weigh the expected gain against these hazards.中耳手术存在感音神经性听力损失、眩晕、假体移位与再固定等风险，因此手术指征必须权衡预期获益与这些危险。
• Long-term audiometric follow-up is required after surgery, because refixation and progressive conductive loss can occur years later.术后需要长期听力学随访，因为再固定与进行性传导性听力损失可能在数年之后出现。
• Hand surgery for symphalangism is offered only when stiffness impairs grasp or daily activities, and realistic goals should be discussed because joint reconstruction gives modest functional gains.仅在僵硬影响抓握或日常活动时才考虑针对指关节融合的手部手术，应讨论现实目标，因为关节重建带来的功能改善有限。
• Hyperopia is corrected with glasses, and children need vision screening for amblyopia, while speech therapy and educational support address the consequences of early deafness.远视用眼镜矫正，儿童需接受弱视筛查，而言语治疗与教育支持可处理早期耳聋带来的后果。
• Genetic counselling explains autosomal dominant inheritance with a 50 percent recurrence risk, variable expressivity, and the options of prenatal or preimplantation testing when the family variant is known.遗传咨询应说明常染色体显性遗传的 50% 再发风险、表现度变异，以及在家系变异已知时可选择产前或胚胎植入前检测。

Research and controversies

• The durability of stapes surgery in this syndrome is poorly documented, and prospective cohorts with audiometric follow-up beyond five years are needed.该综合征中镫骨手术的持久性记录不足，需要听力学随访超过五年的前瞻性队列。
• Genotype-phenotype correlation remains weak, and studies of modifier genes within the BMP pathway may explain why identical variants produce different degrees of joint fusion.基因型与表型的相关性仍然较弱，对 BMP 通路内修饰基因的研究可能解释相同变异为何导致不同程度的关节融合。
• Mouse models of Nog loss reproduce joint fusion, but the middle ear phenotype has been studied less thoroughly, and animal work could clarify the developmental timing of stapes fixation.Nog 缺失的小鼠模型可重现关节融合，但中耳表型研究较少，动物实验可阐明镫骨固定的发育时间窗。
• The boundary between inherited stapes ankylosis and otosclerosis is clinically important, and shared BMP and TGF-beta signalling suggests that some molecular lessons may transfer between the two conditions.遗传性镫骨固定与耳硬化症之间的界限具有临床意义，共享的 BMP 与 TGF-beta 信号提示部分分子认识可能在两种疾病之间迁移。
• BMP pathway inhibitors are hypothetical candidates for nonsurgical treatment, but no trial exists and any intervention would have to preserve normal skeletal development.BMP 通路抑制剂是非手术治疗的假设性候选，但目前没有试验，任何干预都必须保全正常骨骼发育。
• International registries and consensus diagnostic criteria are lacking, and the small number of published families, mostly from Europe, limits generalization to other populations.目前缺乏国际登记系统与共识诊断标准，而已发表家系数量少且多来自欧洲，限制了对其他人群的外推。