Tetra-amelia syndrome

Tetra-amelia syndrome is an ultra-rare congenital disorder in which all four limbs fail to form, usually accompanied by severe craniofacial, pulmonary, genital and pelvic malformations that make it lethal in utero or in the newborn period.四肢缺失综合征是一种超罕见先天性疾病，四个肢体均未形成，通常伴有严重的颅面、肺、生殖器与骨盆畸形，导致其在宫内或新生儿期致死。

It is genetically heterogeneous, with biallelic loss-of-function variants in WNT3 or RSPO2 explaining the described families and a small number of other limb-reduction loci producing overlapping phenotypes.该病具有遗传异质性，已描述家系可由 WNT3 或 RSPO2 的双等位基因功能丧失变异解释，另有少数其他肢体缩减相关基因座产生重叠表型。

Terminology and classification

• The term combines the Greek tetra, meaning four, with amelia, the complete absence of a limb, and it appears as tetra-amelia or tetraamelia in the literature.该术语由表示四的希腊词（tetra）与表示肢体完全缺如的（amelia）组合而成，在文献中写作（tetra-amelia）或（tetraamelia）。
• It is distinct from meromelia, in which only part of a limb is missing, and from phocomelia, in which the hand or foot is attached close to the trunk because an intercalary segment failed to form.它与仅部分肢体缺如的残肢畸形不同，也与因中间节段未形成而使手或足附着于躯干附近的海豹肢畸形不同。
• The main entry is OMIM 273395 for WNT3-related tetra-amelia, with ORPHA:294971, MONDO:0017439, ICD-10 Q73.0, ICD-11 LB9B, MeSH C536498 and UMLS C2931216.主要条目为 WNT3 相关四肢缺失的 OMIM 273395，另有 ORPHA:294971、MONDO:0017439、ICD-10 Q73.0、ICD-11 LB9B、MeSH C536498 与 UMLS C2931216。
• RSPO2-related tetra-amelia with lung aplasia is a distinct molecular subset, and the family reported in 2008 was negative for WNT3 and for heparan sulfate genes, which established locus heterogeneity.伴肺不发育的 RSPO2 相关四肢缺失是独立的分子亚型，2008 年报告的家系对 WNT3 及硫酸肝素相关基因均为阴性，从而确立了基因座异质性。
• Historical labels include autosomal recessive tetra-amelia and complete limb aplasia, and a form associated with ectodermal dysplasia was catalogued separately as MIM 273390.历史名称包括常染色体隐性四肢缺失与完全性肢体不发育，而伴外胚层发育不良的类型被单独编为 MIM 273390。
• Coding uses HPO HP:0003057 for tetraamelia and GARD 0005148, together with Wikidata Q2406697, while the ICD-10 category Q73.0 covers congenital absence of unspecified limb.编码采用四肢缺失的 HPO HP:0003057 与 GARD 0005148，以及 Wikidata Q2406697，ICD-10 的 Q73.0 类目则涵盖未特指肢体的先天性缺如。

History

• Tetra-amelia appears in twentieth-century case reports, and by the 1980s series had described the full lethal phenotype with craniofacial and visceral anomalies.四肢缺失在二十世纪的病例报告中已有记载，到 1980 年代系列研究已描述了伴颅面与内脏异常的完整致死性表型。^[1]
• In 1985 a report of six male fetuses documented the consistent combination of absent limbs, facial clefts and pulmonary hypoplasia.1985 年一份涉及六名男胎的报告记录了肢体缺如、面部裂隙与肺发育不良的一致组合。^[2]
• In 1987 the association with ectodermal dysplasia was separated as a distinct form, catalogued as MIM 273390.1987 年与无汗性外胚层发育不良的关联被区分为独立类型，编为 MIM 273390。^[3]
• Further reports in 1991, 1993 and 1994 refined the radiological and autopsy findings and emphasized that most affected pregnancies end in stillbirth.1991 年、1993 年与 1994 年的进一步报告细化了影像学与尸检所见，并强调大多数受累妊娠以死产告终。^[4]
• In 2004 a homozygous WNT3 nonsense variant, p.Gln83Ter, was found in four fetuses from a large consanguineous family, mapping the first locus to 17q21 within an 8.9 Mb region.2004 年在一个大型近亲婚配家系的四名胎儿中发现了纯合 WNT3 无义变异 p.Gln83Ter，将首个基因座定位到 17q21 内一段 8.9 兆碱基的区域。^[5]
• A 2008 report of a sixth family with tetra-amelia and lung hypo- or aplasia found no WNT3, HS6ST1 or HS6ST3 variants, proving that at least one further locus existed.2008 年报告的第六个家系表现为四肢缺失伴肺发育不良或不发育，未发现 WNT3、HS6ST1 或 HS6ST3 变异，证明至少还存在另一个基因座。^[6]
• In 2018 biallelic RSPO2 loss-of-function variants were identified, and the mechanism was traced to stabilization of RNF43 and ZNRF3 with suppression of WNT signalling independent of LGR4, LGR5 and LGR6.2018 年鉴定出双等位基因 RSPO2 功能丧失变异，机制可追溯至 RNF43 与 ZNRF3 的稳定化，并以不依赖 LGR4、LGR5 与 LGR6 的方式抑制 WNT 信号。^[7]

Epidemiology

• Orphanet classifies tetra-amelia as ultra-rare with a prevalence below 1 per 1,000,000 and an antenatal onset.Orphanet 将四肢缺失归为超罕见病，患病率低于百万分之一，起病时间为产前期。
• A 2021 estimate placed the incidence at about 2.4 per 10,000,000 births, one of the lowest figures among limb reduction defects.2021 年的一项估计将发病率定为约每千万例出生 2.4 例，属于肢体缩减缺陷中最低的数字之一。^[8]
• Amelia of any limb occurs in roughly 1 per 71,000 pregnancies, and tetra-amelia represents a very small fraction of that total.任一肢体的缺失大约每 71,000 例妊娠出现 1 例，而四肢缺失只占其中极小的一部分。^[9]
• Consanguinity is the strongest risk factor, because the WNT3 and RSPO2 forms are autosomal recessive and most reported families are consanguineous.近亲婚配是最强的危险因素，因为 WNT3 与 RSPO2 相关类型均为常染色体隐性，而已报告家系大多为近亲婚配。
• Males and females are affected equally, and an early series consisting only of male fetuses reflects sampling rather than a sex effect.男女受累情况相同，早期仅由男胎组成的系列反映的是抽样而非性别效应。
• Cases have been reported from the Middle East, Europe, Asia and the Americas, and this distribution probably reflects access to prenatal diagnosis and publication rather than true variation.病例报告来自中东、欧洲、亚洲与美洲，这种分布更可能反映产前诊断的可及性与发表机会而非真实差异。
• Most affected pregnancies are terminated or end in stillbirth, so live-birth prevalence is close to zero and registry figures underestimate the incidence at conception.大多数受累妊娠被终止或以死产结束，因此活产患病率接近于零，登记数字低估了受孕时的发生率。
• The burden falls on prenatal counselling, palliative delivery planning, bereavement support and, for the rare survivors, lifelong prosthetic and personal assistance.疾病负担落在产前咨询、姑息性分娩计划、丧亲支持，以及针对极少数存活者的终身假肢与生活协助上。

Pathophysiology

• Limb development begins with WNT-dependent induction of the limb bud, and WNT3 is required for the earliest outgrowth of both the forelimb and the hindlimb.肢体发育始于依赖 WNT 的肢芽诱导，而 WNT3 是前肢与后肢最早向外生长所必需的。
• Biallelic WNT3 loss abolishes limb bud initiation rather than truncating a formed limb, which explains why the defect is complete amelia instead of distal deficiency.双等位基因 WNT3 缺失使肢芽起始失败，而不是截断已形成的肢体，这解释了为何缺陷表现为完全性四肢缺失而非远端短缺。^[5]
• RSPO2 potentiates WNT signalling by blocking the transmembrane E3 ligases RNF43 and ZNRF3, so its loss accelerates WNT receptor turnover and silences the pathway.RSPO2 通过阻断跨膜 E3 泛素连接酶 RNF43 与 ZNRF3 来增强 WNT 信号，因此其缺失会加速 WNT 受体周转并使该通路沉默。^[7]
• The same RSPO2 pathway governs lung branching morphogenesis, which is why RSPO2-related cases show lung aplasia while WNT3-related cases more often show lung hypoplasia.同一 RSPO2 通路调控肺分支形态发生，这就是 RSPO2 相关病例出现肺不发育而 WNT3 相关病例更多表现为肺发育不良的原因。
• Craniofacial, genital, anal and pelvic anomalies arise because these structures depend on early WNT signalling and on developmental interactions with the forming limbs.颅面、生殖器、肛门与骨盆异常的出现，是因为这些结构依赖早期 WNT 信号以及与外形成中肢体之间的发育性相互作用。
• Phenotypic differences among families with the same gene suggest modifier loci and pathway redundancy, and no clear genotype-phenotype correlation has been established.同一基因不同家系之间的表型差异提示存在修饰基因座与通路冗余，目前尚未建立明确的基因型与表型相关性。

Clinical features

• All four limbs are absent, and the shoulder and pelvic girdles are hypoplastic or absent, leaving a trunk-only body habitus.四个肢体均缺如，肩带与骨盆带发育不良或缺如，形成仅有躯干的体型。
• Craniofacial anomalies include cleft lip and palate, micrognathia, low-set ears and defects of skull ossification.颅面异常包括唇裂与腭裂、小下颌、低位耳以及颅骨骨化缺陷。
• Pulmonary hypoplasia or aplasia causes immediate respiratory failure, and it is the usual cause of death in liveborn infants.肺发育不良或不发育导致出生后立即出现呼吸衰竭，是活产婴儿常见的死亡原因。^[6]
• Genital anomalies range from ambiguous to absent external genitalia, and cryptorchidism is common.生殖器异常从外生殖器模糊到完全缺如不等，隐睾较为常见。
• Anal atresia, pelvic hypoplasia and vertebral anomalies are frequent and require assessment at autopsy or at birth.肛门闭锁、骨盆发育不良与椎体异常较为常见，需要在尸检或出生时进行评估。
• Cardiac and renal malformations occur in a minority and should be sought by echocardiography and ultrasonography.心脏与肾脏畸形见于少数患者，应通过超声心动图与超声检查主动寻找。
• Survival beyond infancy is exceptional, and survivors have profound motor disability that requires adapted seating, powered mobility and continuous personal assistance.存活超过婴儿期极为罕见，存活者存在严重的运动障碍，需要适配座椅、电动代步工具与持续的生活协助。

Diagnosis

• Prenatal ultrasound shows absent limbs, often with polyhydramnios, lung hypoplasia and facial clefting, and the limb buds may be absent as early as the first trimester.产前超声显示肢体缺如，常伴羊水过多、肺发育不良与面部裂隙，肢芽在早至妊娠早期即可缺如。
• Fetal magnetic resonance imaging refines lung volume and delineates associated craniofacial and visceral anomalies.胎儿磁共振成像可更准确地评估肺容积，并描绘相关的颅面与内脏异常。
• Postnatal examination and skeletal radiographs document the extent of limb absence and the pelvic and vertebral defects.出生后查体与骨骼 X 线片可记录肢体缺如的范围以及骨盆与椎体缺陷。
• Molecular confirmation uses WNT3 and RSPO2 sequencing with deletion and duplication analysis, and consanguinity raises the prior probability of a recessive form.分子确诊采用 WNT3 与 RSPO2 测序并辅以缺失与重复分析，近亲婚配会提高隐性类型的先验概率。
• Differential diagnosis includes Roberts syndrome, TAR syndrome, thalidomide embryopathy, amniotic band sequence, WNT7A-related phocomelia and Holt-Oram syndrome.鉴别诊断包括 Roberts 综合征、TAR 综合征、沙利度胺胚胎病、羊膜带序列征、WNT7A 相关海豹肢畸形与 Holt-Oram 综合征。^[10]
• Autopsy with photographic and radiological documentation supports counselling, and the 25 percent recurrence risk of autosomal recessive forms should be explained.尸检并留存照片与影像资料有助于咨询，同时应说明常染色体隐性类型的 25% 再发风险。

Management

• Fetal medicine and clinical genetics should coordinate counselling as soon as the diagnosis is suspected, because the prognosis for the RSPO2 and most WNT3 forms is lethal.一旦怀疑诊断，胎儿医学与临床遗传学应即刻协调咨询，因为 RSPO2 相关类型与多数 WNT3 相关类型的预后为致死性。
• Delivery should be planned at a tertiary center with neonatal and palliative care teams available.分娩应计划在有新生儿与姑息治疗团队的三级中心进行。
• If an infant is born alive, respiratory support is offered according to the family goals, but lung aplasia is incompatible with sustained survival.若婴儿活产，可按家庭意愿提供呼吸支持，但肺不发育无法维持长期存活。
• Feeding, temperature control and comfort care form the core of neonatal palliative management when curative treatment is not possible.当无法进行治愈性治疗时，喂养、体温维持与舒适照护构成新生儿姑息管理的核心。
• For the exceptional survivor, multidisciplinary rehabilitation includes adapted seating, powered wheelchairs, prostheses and occupational therapy.对极少数存活者，多学科康复包括适配座椅、电动轮椅、假肢与作业治疗。
• Reconstructive limb surgery is not feasible when no limb bud exists, so surgical effort is confined to correctable craniofacial, anal or cardiac anomalies.当不存在肢芽时无法进行肢体再造手术，因此外科工作仅限于可矫正的颅面、肛门或心脏异常。
• Bereavement counselling and psychosocial support should be offered to families after termination, stillbirth or neonatal death.在终止妊娠、死产或新生儿死亡之后，应向家庭提供丧亲咨询与心理社会支持。
• Genetic counselling explains the 25 percent recurrence risk, offers prenatal diagnosis in later pregnancies and addresses consanguinity.遗传咨询应说明 25% 的再发风险，在后续妊娠中提供产前诊断，并讨论近亲婚配问题。

Research and controversies

• WNT pathway redundancy and the reasons why WNT3 loss sometimes spares the lungs remain unresolved, and conditional animal models could separate limb from lung requirements.WNT 通路的冗余以及 WNT3 缺失有时不累及肺的原因仍未解决，条件性动物模型可将肢体与肺的需求分开研究。
• The RSPO2-RNF43-ZNRF3 axis is a candidate drug target for tissue regeneration, although any WNT-modulating therapy would carry oncogenic risk.RSPO2-RNF43-ZNRF3 轴是组织再生的候选药物靶点，但任何调节 WNT 的治疗都伴随致癌风险。
• Lung-limb developmental coupling is poorly understood, and studying shared enhancers may explain the RSPO2 lung phenotype.肺与肢体的发育耦联尚不清楚，研究共享增强子可能解释 RSPO2 相关肺表型。
• International registries are needed to define the natural history of survivors and the true conception incidence of tetra-amelia.需要国际登记系统来界定存活者的自然史以及四肢缺失的真实受孕发生率。^[8]
• Prenatal diagnostic accuracy for limb absence and lung hypoplasia varies with gestational age and operator experience, and first-trimester detection needs prospective evaluation.产前诊断肢体缺如与肺发育不良的准确性随孕周与操作者经验而变化，早孕期检出率需要前瞻性评估。
• Germline editing and prenatal therapy remain hypothetical, and the ethical framework for lethal developmental disorders must be debated before any clinical translation.生殖系编辑与产前治疗仍属假设，致死性发育疾病的伦理框架必须在任何临床转化之前得到讨论。