Schaaf–Yang syndrome
Schaaf–Yang syndrome is a rare genetic disorder caused by a heterozygous mutation in the paternal-expressed MAGEL2 gene, characterised by intellectual disability, autism spectrum disorder, hypogonadism, infantile hypotonia with feeding problems and distal arthrogryposisSchaaf–Yang 综合征是一种由父本表达基因 MAGEL2 杂合突变引起的罕见遗传病，以智力障碍、自闭症谱系障碍、性腺功能减退、婴儿期肌张力减退伴喂养问题和远端关节挛缩为特征。
The condition is also known as Prader–Willi-like syndrome or Chitayat–Hall syndrome, and was first described in 2013该病也称为 Prader-Willi 样综合征或 Chitayat-Hall 综合征，于2013年首次描述。
The syndrome is caused by loss-of-function mutations in MAGEL2 on chromosome 15q11.2, which is imprinted and expressed only from the paternal allele该综合征由染色体15q11.2上 MAGEL2 的功能丧失突变引起，该基因是印记基因，仅从父本等位基因表达。
Terminology and classification
- Schaaf–Yang syndrome is classified as a rare neurodevelopmental disorder with endocrine and musculoskeletal featuresSchaaf–Yang 综合征归类为具有内分泌和肌肉骨骼特征的罕见神经发育障碍。[1]
- The condition is also known as Prader–Willi-like syndrome and Chitayat–Hall syndrome, reflecting its resemblance to Prader–Willi syndrome该病也称为 Prader-Willi 样综合征和 Chitayat-Hall 综合征，反映其与 Prader-Willi 综合征的相似性。[1]
- MONDO catalogues the condition as MONDO:0014243, Orphanet assigns ORPHA:398069, and OMIM 615547 records the causative locusMONDO 将该病编目为 MONDO:0014243，Orphanet 赋予 ORPHA:398069，OMIM 615547 记录致病位点。
- Cross-references include GARD 13316 and UMLS C3809877, and the condition is caused by mutations in the MAGEL2 gene交叉引用包括 GARD 13316 和 UMLS C3809877，该病由 MAGEL2 基因突变引起。
- The condition is distinguished from Prader–Willi syndrome by the presence of arthrogryposis and the specific molecular cause该病通过关节挛缩的存在和特定分子原因与 Prader-Willi 综合征区分。[1]
- The syndrome meets the Chinese rare disease criterion of fewer than 140,000 patients nationwide该综合征符合中国罕见病标准（全国患者数少于14万）。[1]
History
- Schaaf–Yang syndrome was first described in 2013 by Schaaf and Yang, who identified heterozygous MAGEL2 mutations in patients with a Prader–Willi-like phenotypeSchaaf–Yang 综合征由 Schaaf 和 Yang 于2013年首次描述，他们在具有 Prader-Willi 样表型的患者中鉴定出 MAGEL2 杂合突变。[1]
- The condition was named after the two researchers who first characterised it, following the convention for eponymous genetic syndromes该病以首次描述它的两位研究人员命名，遵循了以人名命名遗传综合征的惯例。[1]
- The identification of MAGEL2 mutations established the condition as a distinct entity within the Prader–Willi syndrome spectrumMAGEL2 突变的鉴定将该病确立为 Prader-Willi 综合征谱系内的独立实体。[1]
- Subsequent studies expanded the clinical spectrum and identified the characteristic features, including arthrogryposis and autism后续研究扩大了临床谱系并确定了特征性特征，包括关节挛缩和自闭症。[1]
- The condition is a rare disease, with fewer than 200 cases reported worldwide to date该病是一种罕见病，迄今为止全球报告病例不到200例。[1]
Epidemiology
- Schaaf–Yang syndrome is rare, with fewer than 200 cases reported worldwideSchaaf–Yang 综合征罕见，全球报告病例不到200例。[1]
- The condition is inherited in an autosomal dominant pattern with paternal imprinting, meaning the mutation must be on the paternal allele to cause the disease该病以父系印记的常染色体显性模式遗传，意味着突变必须在父本等位基因上才能引起疾病。[1]
- Both sexes are affected, and the condition is reported across diverse ethnic backgrounds两性均受累，该病在不同种族背景中报告。[1]
- Symptoms are present from infancy, with hypotonia and feeding problems being the presenting features症状从婴儿期即存在，肌张力减退和喂养问题是表现特征。[1]
- The condition is associated with reduced life expectancy, though most patients survive into adulthood with appropriate care该病与预期寿命缩短相关，尽管大多数患者经适当护理存活至成年。[1]
Pathophysiology
- Schaaf–Yang syndrome is caused by heterozygous loss-of-function mutations in the MAGEL2 gene on chromosome 15q11.2Schaaf–Yang 综合征由染色体15q11.2上 MAGEL2 基因的杂合功能丧失突变引起。[1]
- MAGEL2 encodes a protein that is part of the MUST complex (MAGEL2-USP7-TRIM27) and functions as a ubiquitin ligase enhancerMAGEL2 编码一种蛋白质，是 MUST 复合物（MAGEL2-USP7-TRIM27）的一部分，起泛素连接酶增强剂的作用。[2]
- The MAGEL2 gene is imprinted and expressed only from the paternal chromosome 15, which explains the paternal inheritance patternMAGEL2 基因是印记基因，仅从父本染色体15表达，这解释了父系遗传模式。[1]
- MAGEL2 regulates AMPA receptors in the hypothalamus and the secretion of hormones such as oxytocin, vasopressin and somatostatinMAGEL2 调节下丘脑中的 AMPA 受体以及催产素、加压素和生长抑素等激素的分泌。[2]
- Loss of MAGEL2 function leads to hypothalamic dysfunction, which explains the endocrine and behavioural features of the syndromeMAGEL2 功能丧失导致下丘脑功能障碍，解释了该综合征的内分泌和行为特征。[2]
- The muscle hypotonia and contractures result from abnormal development of the neuromuscular system肌肉肌张力减退和挛缩源于神经肌肉系统发育异常。[1]
Clinical features
- The cardinal features are intellectual disability, autism spectrum disorder, hypogonadism, infantile hypotonia with feeding problems and distal arthrogryposis主要特征是智力障碍、自闭症谱系障碍、性腺功能减退、婴儿期肌张力减退伴喂养问题和远端关节挛缩。[1]
- Facial features include a short nose, dense eyebrows and a protruding jaw面部特征包括短鼻子、浓密的眉毛和突出的下颌。[1]
- Additional features include visceral obesity, temper tantrums, lack of pubertal development, autistic behaviour and chronic constipation额外特征包括内脏肥胖、脾气爆发、青春期发育缺失、自闭行为和慢性便秘。[1]
- Male patients frequently have undescended testes, and genital hypoplasia may be present男性患者常有隐睾，可能存在生殖器发育不全。[1]
- Musculoskeletal features include flexion contractures and joint abnormalities肌肉骨骼特征包括屈曲挛缩和关节异常。[1]
- Complications include aspiration pneumonia from feeding problems, obesity-related complications and sleep apnoea并发症包括喂养问题引起的吸入性肺炎、肥胖相关并发症和睡眠呼吸暂停。[1]
Diagnosis
- Diagnosis is based on the characteristic clinical features and confirmed by genetic testing for MAGEL2 mutations诊断基于特征性临床特征，并通过 MAGEL2 突变的基因检测确认。[1]
- Methylation analysis of the 15q11.2 region is important to distinguish Schaaf–Yang syndrome from Prader–Willi syndrome15q11.2区域的甲基化分析对于将 Schaaf–Yang 综合征与 Prader-Willi 综合征区分很重要。[1]
- Genetic testing by sequencing of the MAGEL2 gene identifies the causative mutation通过 MAGEL2 基因测序的基因检测识别致病突变。[1]
- Endocrine testing documents the hypogonadism and growth hormone deficiency, and developmental assessment evaluates the intellectual disability内分泌检测记录性腺功能减退和生长激素缺乏，发育评估评估智力障碍。[1]
- The differential diagnosis includes Prader–Willi syndrome, Chitayat-Hall syndrome and other causes of neonatal hypotonia鉴别诊断包括 Prader-Willi 综合征、Chitayat-Hall 综合征和新生儿肌张力减退的其他原因。[1]
- Genetic counselling is important for affected families given the imprinting and the specific inheritance implications鉴于印记和特定的遗传含义，遗传咨询对受累家庭很重要。[1]
Management
- Management is supportive and multidisciplinary, targeting the individual manifestations of the syndrome管理是支持性和多学科的，针对该综合征的个体表现。[1]
- Feeding support, including gastrostomy tube placement in severe cases, is important for managing feeding problems喂养支持，包括严重病例中的胃造口管置入，对于管理喂养问题很重要。[1]
- Growth hormone therapy may be considered for growth failure, and testosterone replacement is used for hypogonadism in males可考虑生长激素治疗生长失败，睾酮替代用于男性性腺功能减退。[1]
- Physical and occupational therapy are important for managing hypotonia and joint contractures物理和作业治疗对于管理肌张力减退和关节挛缩很重要。[1]
- Behavioural interventions and educational support are important for managing the autism spectrum disorder and intellectual disability行为干预和教育支持对于管理自闭症谱系障碍和智力障碍很重要。[1]
- The prognosis varies, with most patients surviving into adulthood but requiring lifelong support for the neurodevelopmental and endocrine features预后各异，大多数患者存活至成年，但需要终身支持神经发育和内分泌特征。[1]
Research and controversies
- The role of oxytocin dysfunction in the autism spectrum features of Schaaf–Yang syndrome is an area of active research, with oxytocin trials underway催产素功能障碍在 Schaaf–Yang 综合征自闭症特征中的作用是活跃的研究领域，催产素试验正在进行。[2]
- The genotype-phenotype correlation between specific MAGEL2 mutations and the severity of the phenotype is not fully established特定 MAGEL2 突变与表型严重程度之间的基因型-表型相关性尚未完全确立。[1]
- The long-term outcomes, particularly regarding behaviour, endocrine function and life expectancy, are not well characterized长期结局，特别是关于行为、内分泌功能和预期寿命，尚未充分描述。[1]
- Several clinical trials are registered on ClinicalTrials.gov for treatments of Schaaf–Yang syndrome, including oxytocin trialsClinicalTrials.gov 上注册了多项 Schaaf–Yang 综合征治疗的临床试验，包括催产素试验。[2]
- Further research is needed to understand the pathophysiology and develop targeted therapies for the neurodevelopmental features需要进一步研究以理解病理生理学并开发针对神经发育特征的靶向治疗。[2]
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