SHORT syndrome

SHORT syndrome is a rare autosomal dominant disorder characterized by Short stature, Hyperextensibility of joints, Ocular depression, Rieger anomaly and Teething delay, from which the acronym is derivedSHORT 综合征是一种罕见的常染色体显性遗传病，以身材矮小（Short stature）、关节过度活动（Hyperextensibility of joints）、眼眶凹陷（Ocular depression）、Rieger 异常（Rieger anomaly）和出牙延迟（Teething delay）为特征，缩写由此而来。

The condition was characterized in 1975 and is caused by heterozygous mutations in the PIK3R1 gene, which encodes the regulatory subunit of phosphoinositide 3-kinase该病于1975年被描述，由 PIK3R1 基因的杂合突变引起，该基因编码磷酸肌醇3-激酶的调节亚基。

Fewer than 50 cases have been reported worldwide, and the condition is associated with insulin resistance and a characteristic facial appearance全球报告的病例少于50例，该病与胰岛素抵抗和特征性面部外观相关。

Terminology and classification

• SHORT syndrome is classified as a rare multiple congenital anomaly syndrome with growth and metabolic featuresSHORT 综合征归类为具有生长和代谢特征的罕见多发性先天畸形综合征。^[1]
• The acronym captures the five cardinal features and is used as the diagnostic name of the condition该缩写捕捉了五种主要特征，并作为该病的诊断名称使用。^[1]
• MONDO catalogues the condition as MONDO:0010026 and Orphanet assigns ORPHA:3163, while OMIM does not list a separate entryMONDO 将该病编目为 MONDO:0010026，Orphanet 赋予 ORPHA:3163，而 OMIM 未单独列出条目。
• Alternative names include Aarskog-Ose-Pande syndrome, lipodystrophy-Rieger anomaly-diabetes syndrome and PIK3R1-associated syndromic insulin resistance别名包括 Aarskog-Ose-Pande 综合征、脂肪营养不良-Rieger 异常-糖尿病综合征和 PIK3R1 相关综合征性胰岛素抵抗。^[1]
• The condition is distinguished from other short stature syndromes by the combination of Rieger anomaly, ocular depression and insulin resistance该病通过 Rieger 异常、眼眶凹陷和胰岛素抵抗的组合与其他身材矮小综合征区分。^[1]
• SHORT syndrome is classified as a rare disease with fewer than 50 cases reported worldwideSHORT 综合征归类为罕见病，全球报告病例少于50例。^[1]

History

• SHORT syndrome was first described in 1975 by Gorlin and colleagues, who recognized the characteristic combination of clinical featuresSHORT 综合征由 Gorlin 等于1975年首次描述，他们认识到特征性临床特征的组合。^[1]
• The acronym was introduced to facilitate recognition of the syndrome and to standardize its clinical description该缩写被引入以促进对该综合征的识别并标准化其临床描述。^[1]
• The genetic basis was identified in 2012 when heterozygous PIK3R1 mutations were found in patients with the syndrome遗传基础在2012年被确定，当时在具有该综合征的患者中发现了 PIK3R1 杂合突变。
• The identification of PIK3R1 mutations linked the syndrome to the PI3K-AKT signalling pathway, which is involved in growth and metabolismPIK3R1 突变的鉴定将该综合征与参与生长和代谢的 PI3K-AKT 信号通路联系起来。
• Subsequent studies expanded the clinical spectrum to include insulin resistance, lipodystrophy and diabetes mellitus后续研究扩大了临床谱系，包括胰岛素抵抗、脂肪营养不良和糖尿病。

Epidemiology

• SHORT syndrome is extremely rare, with fewer than 50 cases reported worldwideSHORT 综合征极其罕见，全球报告病例少于50例。^[1]
• The condition is inherited in an autosomal dominant pattern, with both sporadic and familial cases reported该病以常染色体显性模式遗传，报告了散发性和家族性病例。^[1]
• Both sexes are affected equally, with no reported gender predilection两性均等受累，无报告的性别偏好。^[1]
• Symptoms are typically recognized in infancy or early childhood, with growth failure and facial dysmorphism being the presenting features症状通常在婴儿期或幼儿期被识别，生长迟缓和面部畸形是表现特征。^[1]
• Risk factors include a family history of the condition, consistent with its autosomal dominant inheritance危险因素包括该病的家族史，与其常染色体显性遗传一致。^[1]

Pathophysiology

• SHORT syndrome is caused by heterozygous mutations in the PIK3R1 gene, which encodes the p85alpha regulatory subunit of phosphoinositide 3-kinaseSHORT 综合征由 PIK3R1 基因的杂合突变引起，该基因编码磷酸肌醇3-激酶的 p85α 调节亚基。
• PIK3R1 mutations lead to altered PI3K signalling, affecting cell growth, proliferation and glucose metabolismPIK3R1 突变导致 PI3K 信号改变，影响细胞生长、增殖和葡萄糖代谢。
• The dysregulated PI3K-AKT pathway impairs insulin signalling, leading to insulin resistance and a predisposition to diabetes mellitus失调的 PI3K-AKT 通路损害胰岛素信号，导致胰岛素抵抗和糖尿病易感性。
• The skeletal features reflect abnormal bone growth, and the ocular features reflect abnormal development of the anterior segment of the eye骨骼特征反映骨生长异常，眼部特征反映眼前段发育异常。^[1]
• Lipodystrophy, when present, results from abnormal adipose tissue development and distribution当存在脂肪营养不良时，源于脂肪组织发育和分布异常。
• The condition shows variable expressivity, with affected individuals in the same family showing different degrees of severity该病显示可变表达，同一家庭中的受累个体表现出不同程度的严重性。^[1]

Clinical features

• The cardinal features are short stature, joint hyperextensibility, ocular depression (deep-set eyes), Rieger anomaly and delayed teething主要特征是身材矮小、关节过度活动、眼眶凹陷（深陷眼）、Rieger 异常和出牙延迟。^[1]
• Rieger anomaly involves abnormal development of the anterior chamber of the eye, with iris hypoplasia and a prominent Schwalbe lineRieger 异常涉及眼前房发育异常，伴有虹膜发育不全和突出的 Schwalbe 线。^[1]
• Additional facial features include a triangular face, prominent forehead, hypoplastic alae nasi and micrognathia额外面部特征包括三角脸、突出的前额、鼻翼发育不全和小颌畸形。^[1]
• Metabolic features include insulin resistance, lipodystrophy and diabetes mellitus, which may develop in adolescence or adulthood代谢特征包括胰岛素抵抗、脂肪营养不良和糖尿病，可能在青春期或成年期发展。
• Complications include visual impairment from glaucoma or Rieger anomaly, diabetes mellitus and its complications并发症包括青光眼或 Rieger 异常引起的视力损害、糖尿病及其并发症。^[1]
• Intelligence is typically normal in SHORT syndrome, distinguishing it from many other short stature syndromesSHORT 综合征的智力通常正常，将其与许多其他身材矮小综合征区分。^[1]

Diagnosis

• Diagnosis is based on the characteristic clinical combination of the five cardinal features, supported by genetic testing诊断基于五种主要特征的特征性临床组合，并由基因检测支持。^[1]
• Genetic testing for PIK3R1 mutations by Sanger sequencing or next-generation sequencing confirms the diagnosis通过 Sanger 测序或下一代测序的 PIK3R1 突变基因检测确认诊断。
• Ophthalmological examination identifies Rieger anomaly and assesses for glaucoma, while metabolic testing identifies insulin resistance and diabetes眼科检查识别 Rieger 异常并评估青光眼，而代谢检测识别胰岛素抵抗和糖尿病。^[1]
• Skeletal radiography may show delayed bone age and other skeletal abnormalities骨骼 X 线可能显示骨龄延迟和其他骨骼异常。^[1]
• The differential diagnosis includes Aarskog syndrome, SHORT syndrome mimics and other causes of short stature with insulin resistance鉴别诊断包括 Aarskog 综合征、SHORT 综合征类似病和其他伴胰岛素抵抗的身材矮小原因。^[1]
• Genetic counselling is important given the autosomal dominant inheritance and the 50 per cent transmission risk to offspring鉴于常染色体显性遗传和50%的后代传播风险，遗传咨询很重要。^[1]

Management

• There is no cure for SHORT syndrome, and management is supportive, targeting the individual manifestationsSHORT 综合征目前无法治愈，管理是支持性的，针对个体表现。^[1]
• Growth hormone therapy may be considered for short stature, although the response is variable可能考虑生长激素治疗身材矮小，尽管反应可变。^[1]
• Management of insulin resistance includes lifestyle modification, metformin and other antidiabetic agents as needed胰岛素抵抗的管理包括生活方式改变、二甲双胍和根据需要使用的其他抗糖尿病药物。
• Ophthalmological surveillance is important for detecting and managing glaucoma and other ocular complications眼科监测对于检测和管理青光眼和其他眼部并发症很重要。^[1]
• Physical therapy may help with joint hyperextensibility and associated musculoskeletal issues物理治疗可能有助于关节过度活动和相关的肌肉骨骼问题。^[1]
• The prognosis is generally good for lifespan, but the metabolic complications require lifelong management寿命预后通常良好，但代谢并发症需要终身管理。

Research and controversies

• The exact mechanism by which PIK3R1 mutations cause the specific combination of features is not fully understoodPIK3R1 突变引起特定特征组合的确切机制尚未完全理解。
• The genotype-phenotype correlation between specific PIK3R1 mutations and the severity of the phenotype is an area of active research特定 PIK3R1 突变与表型严重程度之间的基因型-表型相关性是活跃的研究领域。
• Whether growth hormone therapy is beneficial in SHORT syndrome is debated, with limited evidence from case reports生长激素治疗在 SHORT 综合征中是否有益存在争议，病例报告证据有限。^[1]
• The role of PI3K-AKT pathway dysregulation in the metabolic features is an area of ongoing investigationPI3K-AKT 通路失调在代谢特征中的作用是持续研究的领域。
• The long-term outcomes of patients with SHORT syndrome, particularly regarding diabetes and cardiovascular risk, are not well characterizedSHORT 综合征患者的长期结局，特别是关于糖尿病和心血管风险，尚未充分描述。

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