Temple syndrome

Temple syndrome is a rare imprinting disorder caused by loss of the paternal contribution of the 14q32.2 region, most often through maternal uniparental disomy of chromosome 14, and characterized by prenatal growth restriction, hypotonia, feeding difficulty, short stature, small hands and feet and early puberty.坦普尔综合征是一种罕见的印记疾病，由 14q32.2 区域父源贡献缺失所致，最常见的原因是母源 14 号染色体单亲二倍体，特征为产前生长受限、肌张力低下、喂养困难、身材矮小、手足小以及青春期提前。

Diagnosis rests on clinical recognition supported by methylation and copy-number testing of 14q32.2, and management is multidisciplinary, with growth hormone for short stature, gonadotropin-releasing hormone analogues for central precocious puberty and lifelong surveillance for obesity, dyslipidaemia and type 2 diabetes.诊断依靠临床识别并辅以 14q32.2 的甲基化与拷贝数检测，管理需多学科协作，包括用生长激素治疗身材矮小、用促性腺激素释放激素类似物治疗中枢性性早熟，以及终身监测肥胖、血脂异常与 2 型糖尿病。

Terminology and classification

• Temple syndrome, abbreviated TS14, is also called maternal uniparental disomy 14 syndrome or UPD(14)mat, and it is named after I. K. Temple, who described the first patient in 1991.坦普尔综合征缩写为 TS14，又称母源 14 号染色体单亲二倍体综合征，以 1991 年描述首例患者的 I. K. Temple 命名。
• It must not be confused with Temple–Baraitser syndrome, a separate disorder characterized by severe intellectual disability, epilepsy, sparse hair and nail hypoplasia.切不可将其与 Temple–Baraitser 综合征混淆，后者是另一种以严重智力障碍、癫痫、毛发稀疏与指甲发育不良为特征的疾病。
• It is catalogued as OMIM 616222, ORPHA:254516 and MONDO:0014541, while ICD-10 places it in Q87.8, other specified congenital malformation syndromes.它被编为 OMIM 616222、ORPHA:254516 与 MONDO:0014541，ICD-10 将其列入 Q87.8 其他特指先天性畸形综合征。
• ICD-11 has no dedicated code for the entity, and the maternal uniparental disomy subtype is indexed separately as ORPHA:96184, which maps to the broader chromosome anomaly categories.ICD-11 没有针对该实体的专用编码，母源单亲二倍体亚型另编为 ORPHA:96184，映射到更广泛的染色体异常类目。
• Kagami–Ogata syndrome is the paternal uniparental disomy 14 counterpart and presents with a bell-shaped thorax, polyhydramnios, abdominal wall defects and severe developmental delay, so the two disorders must be distinguished by parent of origin.Kagami–Ogata 综合征是父源 14 号染色体单亲二倍体的对应疾病，表现为钟形胸廓、羊水过多、腹壁缺损与严重发育迟缓，因此必须依据亲源加以区分。
• Coding terms include HPO HP:0001511 for intrauterine growth restriction and HP:0000826 for precocious puberty, together with UMLS C4015558, DOID 0111713, NCI C120409, GARD 0026256, MeSH C000726750 and Wikidata Q55784874.编码术语包括宫内生长受限的 HPO HP:0001511 与性早熟的 HP:0000826，以及 UMLS C4015558、DOID 0111713、NCI C120409、GARD 0026256、MeSH C000726750 与 Wikidata Q55784874。

History

• In 1991 Temple and colleagues described a girl with maternal uniparental disomy of chromosome 14, hypotonia, developmental delay, short stature and precocious puberty, which established the eponym.1991 年 Temple 及其同事描述了一名母源 14 号染色体单亲二倍体女孩，表现为肌张力低下、发育迟缓、身材矮小与性早熟，从而确立了该人名病名。^[1]
• Through the 1990s further patients with UPD(14)mat were reported, and the imprinted region was localized to 14q32.2 with its cluster of paternally and maternally expressed genes.整个 1990 年代又报告了更多母源单亲二倍体患者，印记区域被定位到 14q32.2，并识别出其中父源与母源表达的基因簇。^[2]
• Mouse work on the orthologous region of chromosome 12, including the chr12aF1 domain, showed that imprinted gene dosage controls prenatal growth, muscle mass and pubertal timing.针对小鼠 12 号染色体同源区域（包括 chr12aF1 结构域）的研究表明，印记基因剂量调控产前生长、肌肉量与青春期启动时间。
• A 2014 study of 51 patients defined the core phenotype, with birth weight around 1.9 standard deviations below the mean, adult height about 2 standard deviations below the mean, hypotonia in 93 percent and early puberty in 86 percent.2014 年一项 51 例患者的研究界定了核心表型，出生体重约低于均值 1.9 个标准差，成年身高约低于均值 2 个标准差，肌张力低下占 93%，青春期提前占 86%。^[3]
• In 2017 deletions of DLK1 were linked to central precocious puberty in five affected females, identifying the gene most closely associated with the reproductive phenotype.2017 年发现 DLK1 缺失与五名受累女性的中枢性性早熟相关，从而确定了与生殖表型关系最密切的基因。^[4]
• A 2020 study dissected the domain into a DLK1, RTL1 and DIO3 cluster and a MEG3, GTL2, RTL1as and MEG8 cluster, clarifying which transcripts are lost or gained in each molecular subtype.2020 年的一项研究将该结构域划分为 DLK1、RTL1 与 DIO3 基因簇以及 MEG3、GTL2、RTL1as 与 MEG8 基因簇，阐明了各分子亚型中哪些转录本缺失或增多。^[5]
• International cohorts published between 2022 and 2026, including 15 patients, 60 Japanese patients, 71 patients and 7 Chinese children, refined the frequency of each feature and the response to growth hormone.2022 年至 2026 年间发表的国际队列，包括 15 例、60 例日本患者、71 例患者与 7 例中国儿童，细化了各特征的频率以及对生长激素的反应。^[6][7][8][9]

Epidemiology

• Orphanet classifies the syndrome as ultra-rare with a prevalence below 1 per 1,000,000, and its older case count of about 53 patients has been overtaken by published cohorts exceeding 150 individuals.Orphanet 将该综合征归为超罕见病，患病率低于百万分之一，其早期约 53 例的病例数已被超过 150 人的已发表队列超越。
• No population-based incidence exists, because ascertainment depends on recognizing growth restriction with hypotonia and on access to methylation testing.目前没有基于人群的发病率，因为病例发现依赖对生长受限伴肌张力低下的识别以及甲基化检测的可及性。
• Among 71 molecularly characterized patients, maternal uniparental disomy accounted for 52 percent, hypomethylation for 41 percent and deletion for 6 percent, shifting earlier estimates that gave disomy 60 to 75 percent.在 71 例经分子确诊的患者中，母源单亲二倍体占 52%，低甲基化占 41%，缺失占 6%，修正了早期认为二倍体占 60% 至 75% 的估计。^[8]
• Males and females are affected in equal proportions, as expected for an imprinting disorder that is not located on a sex chromosome.男女受累比例相同，这符合不位于性染色体上的印记疾病的预期。
• Most cases are sporadic, and recurrence risk is low unless a parent carries a deletion or an imprinting defect that can be transmitted.大多数病例为散发，除非父母携带可传递的缺失或印记缺陷，否则再发风险较低。
• Diagnoses are increasing because methylation testing is now offered to children with unexplained small-for-gestational-age birth and early puberty.由于目前对不明原因小于胎龄出生与青春期提前的儿童提供甲基化检测，诊断数量正在增加。
• The disorder is probably underdiagnosed, because its growth restriction and hypotonia overlap with Silver–Russell syndrome and its obesity and hypotonia overlap with Prader–Willi syndrome.该病很可能被低估诊断，因为其生长受限与肌张力低下与 Silver–Russell 综合征重叠，而肥胖与肌张力低下又与 Prader–Willi 综合征重叠。
• The burden includes growth hormone injections, puberty suppression, metabolic surveillance, educational support and counselling about adult height and fertility.疾病负担包括生长激素注射、青春期抑制、代谢监测、教育支持以及关于成年身高与生育的咨询。

Pathophysiology

• The 14q32.2 imprinted domain contains paternally expressed DLK1, RTL1 and DIO3 and maternally expressed MEG3, MEG8 and RTL1as, and the phenotype follows from an imbalance between these two sets.14q32.2 印记结构域包含父源表达的 DLK1、RTL1 与 DIO3 以及母源表达的 MEG3、MEG8 与 RTL1as，表型源于这两组基因之间的失衡。
• Loss of the paternal contribution lowers DLK1, RTL1 and DIO3 dosage, whereas maternally expressed transcripts are present in excess, and this combination drives the full phenotype.父源贡献缺失降低 DLK1、RTL1 与 DIO3 的剂量，而母源表达的转录本相对过剩，这种组合驱动了完整表型。
• DLK1 encodes a Notch ligand involved in adipogenesis and in the timing of pubertal activation, and its deficiency is the most direct explanation for central precocious puberty in these patients.DLK1 编码参与脂肪生成与青春期启动时序的 Notch 配体，其缺失是这些患者出现中枢性性早熟最直接的解释。^[4]
• RTL1 supports placental development and skeletal muscle growth, so its reduced dosage contributes to intrauterine growth restriction, hypotonia and the characteristic body composition.RTL1 支持胎盘发育与骨骼肌生长，因此其剂量降低会导致宫内生长受限、肌张力低下与特征性体成分改变。
• DIO3 inactivates thyroid hormone in fetal tissues, and altered local thyroid hormone exposure may contribute to growth and neurodevelopmental differences.DIO3 在胎儿组织中灭活甲状腺激素，局部甲状腺激素暴露的改变可能促成生长与神经发育差异。^[10]
• Methylation defects at the IG-DMR and MEG3-DMR silence the paternal allele without changing the DNA sequence, which is why epimutations reproduce the disomy phenotype.IG-DMR 与 MEG3-DMR 的甲基化缺陷在不改变 DNA 序列的情况下沉默父源等位基因，这就是表观突变能重现二倍体表型的原因。^[5]

Clinical features

• Prenatal growth restriction is the rule, with small-for-gestational-age birth in 68 to 100 percent of cohorts, often accompanied by oligohydramnios and a small placenta.产前生长受限几乎普遍存在，各队列中 68% 至 100% 为小于胎龄出生，常伴羊水过少与胎盘偏小。^[6]
• Neonatal hypotonia affects 93 to 100 percent, and feeding difficulty requiring tube feeding affects 53 to 87 percent, which together delay early motor milestones.新生儿期肌张力低下占 93% 至 100%，需管饲的喂养困难占 53% 至 87%，二者共同延迟早期运动里程碑。^[6][8]
• Short stature affects about 73 percent between 1 and 3 years of age, and small hands and feet are present in 87 and 96 percent respectively.1 至 3 岁之间身材矮小约占 73%，小手与小足分别见于 87% 与 96% 的患者。^[3][8]
• Central precocious puberty occurs in 62 to 89 percent, with menarche around 10 years 2 months in the 2014 series, and it is the endocrine hallmark of the disorder.中枢性性早熟占 62% 至 89%，2014 年系列中月经初潮约在 10 岁 2 个月，是该病的内分泌标志。^[3][7]
• Obesity develops in 20 to 49 percent, hyperphagia in about 20 percent, fat mass is increased and lean mass is reduced, which together create a metabolic risk profile from childhood.肥胖见于 20% 至 49%，贪食约见 20%，脂肪量增加而瘦体重减少，共同构成从儿童期开始的代谢风险谱。^[6][8]
• Facial and orthopedic features include trigonocephaly, a flat nasal bridge, a broad nose, micrognathia, a high-arched palate, joint laxity, clinodactyly and kyphoscoliosis.面部与骨科特征包括三角头畸形、鼻梁低平、宽鼻、小下颌、高腭弓、关节松弛、弯指畸形与脊柱后侧凸。
• Neurodevelopment is usually mildly affected, with a median intelligence quotient around 91, special education in 54 percent, type 2 diabetes in 12.8 percent and hypercholesterolaemia in 26.5 percent of the Japanese cohort.神经发育通常轻度受累，中位智商约 91，日本队列中特殊教育占 54%，2 型糖尿病占 12.8%，高胆固醇血症占 26.5%。^[7]

Diagnosis

• Clinical suspicion arises with small-for-gestational-age birth, hypotonia, feeding difficulty and early puberty, but the Netchine–Harbison score for Silver–Russell syndrome is met by only 56.5 percent of molecularly confirmed patients.临床上遇到小于胎龄出生、肌张力低下、喂养困难与青春期提前应提高怀疑，但经分子确诊的患者中仅 56.5% 达到 Silver–Russell 综合征的 Netchine–Harbison 评分标准。^[8]
• Methylation analysis of 14q32.2 by methylation-specific multiplex ligation-dependent probe amplification or a methylation array detects disomy, epimutation and deletion in a single assay.采用甲基化特异性多重连接依赖探针扩增或甲基化芯片分析 14q32.2 的甲基化状态，可在一次检测中识别二倍体、表观突变与缺失。
• Chromosomal microarray and single nucleotide polymorphism array define the size of a deletion and can suggest uniparental disomy from loss-of-heterozygosity patterns.染色体微阵列与单核苷酸多态性芯片可确定缺失范围，并可通过杂合性缺失模式提示单亲二倍体。
• Subtype determination matters for counselling, because a de novo epimutation carries a low recurrence risk whereas an inherited deletion may segregate in the family.确定亚型对咨询至关重要，因为新发表观突变的再发风险低，而遗传性缺失可能在家族中传递。^[11]
• The differential diagnosis includes Silver–Russell syndrome, Prader–Willi syndrome, Kagami–Ogata syndrome, Temple–Baraitser syndrome and idiopathic short stature with early puberty.鉴别诊断包括 Silver–Russell 综合征、Prader–Willi 综合征、Kagami–Ogata 综合征、Temple–Baraitser 综合征以及伴青春期提前的特发性矮小。
• Endocrine assessment includes bone age, a gonadotropin-releasing hormone stimulation test, insulin-like growth factor 1, thyroid function, fasting glucose and a lipid profile.内分泌评估包括骨龄、促性腺激素释放激素兴奋试验、胰岛素样生长因子 1、甲状腺功能、空腹血糖与血脂谱。

Management

• Care is coordinated by pediatric endocrinology, clinical genetics, nutrition, developmental pediatrics and orthopedics, with the family involved in goal setting.诊疗由儿童内分泌科、临床遗传学、营养科、发育儿科与骨科协调，家庭参与目标设定。
• Growth hormone therapy improves height, with one cohort moving from a height standard deviation score of minus 1.78 to 0.11 after five years and adult heights approaching the target range.生长激素治疗可改善身高，一个队列治疗五年后身高标准差评分从负 1.78 升至 0.11，成年身高接近目标范围。^[12]
• Gonadotropin-releasing hormone analogues are used for central precocious puberty to slow bone maturation and preserve adult height, and they also address the psychosocial burden of early puberty.促性腺激素释放激素类似物用于中枢性性早熟，以延缓骨成熟并保全成年身高，同时缓解青春期提前带来的心理社会负担。
• Feeding support is the priority in infancy, and after weaning the focus shifts to obesity prevention through portion guidance, diet quality and regular physical activity.婴儿期以喂养支持为优先，断奶后重点转向通过份量指导、饮食质量与规律体育活动预防肥胖。
• Metabolic surveillance includes fasting glucose, glycated haemoglobin, lipids and blood pressure, because type 2 diabetes and dyslipidaemia are common in adolescence and adulthood.代谢监测包括空腹血糖、糖化血红蛋白、血脂与血压，因为 2 型糖尿病与血脂异常在青春期与成年期较为常见。
• Developmental and educational support includes speech therapy, occupational therapy and individualized school planning for the roughly half of patients who need special education.发育与教育支持包括言语治疗、作业治疗以及为约半数需要特殊教育的患者制定个体化学校计划。
• Orthopedic management addresses kyphoscoliosis and joint laxity, with bracing for progressive curves and physiotherapy for stability and gross motor function.骨科管理针对脊柱后侧凸与关节松弛，对进展性弯曲使用支具，并以物理治疗改善稳定性与粗大运动功能。
• Genetic counselling explains the low recurrence risk of sporadic epimutations, the higher risk with inherited deletions and the availability of prenatal testing when the molecular defect is known.遗传咨询应说明散发性表观突变的低再发风险、遗传性缺失的较高风险，以及分子缺陷已知时可采用产前检测。

Research and controversies

• Genotype-phenotype relationships by molecular mechanism remain incompletely defined, and larger cohorts are needed to determine whether disomy, epimutation and deletion differ in growth or metabolic outcome.不同分子机制对应的基因型与表型关系仍未完全明确，需要更大规模队列判断二倍体、表观突变与缺失在生长或代谢结局上是否存在差异。
• The link between DLK1 and pubertal timing is the clearest molecular lead, and research is exploring how Notch signalling interacts with kisspeptin neurons and hypothalamic maturation.DLK1 与青春期时序的关联是最明确的分子线索，研究正在探索 Notch 信号如何与（kisspeptin）神经元及下丘脑成熟相互作用。^[4]
• Long-term adult height data after growth hormone therapy are still limited, and the optimal age to start treatment and the value of combining it with puberty suppression are debated.生长激素治疗后的长期成年身高数据仍然有限，最佳起始年龄以及与青春期抑制联用的价值仍存争议。^[12]
• The metabolic natural history is poorly characterized, and prospective studies are needed to separate the effects of the imprinting defect from those of obesity and early puberty.代谢自然史研究不足，需要前瞻性研究把印记缺陷本身的效应与肥胖和青春期提前的效应区分开。
• Standardized diagnostic criteria are lacking, and the performance of Silver–Russell scoring systems in Temple syndrome suggests that syndrome-specific tools are needed.目前缺乏标准化诊断标准，Silver–Russell 评分系统在坦普尔综合征中的表现提示需要针对该综合征的专用工具。^[8]
• Adult outcomes including fertility, body composition, psychiatric health and employment are only beginning to be described, and the 2025 Japanese cohort reported college entry or employment in 98.2 percent of school-age patients.包括生育、体成分、精神健康与就业在内的成年结局刚刚开始被描述，2025 年日本队列报告 98.2% 的学龄期患者升入大学或就业。^[7]