Schaaf Christian P, Marbach Felix
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. Respiratory distress is present in many individuals at birth, with approximately half requiring intubation and mechanical ventilation, and approximately 20% requiring tracheostomy. Skeletal manifestations such as joint contractures, scoliosis, and decreased bone mineral density are frequently observed. All affected individuals show developmental delay, resulting in intellectual disability of variable degree, from low-normal intelligence to severe intellectual disability. Other findings may include short stature, seizures, eye anomalies, and hypogonadism.
DIAGNOSIS/TESTING: The diagnosis of Schaaf-Yang syndrome is established in a proband by identification of a heterozygous pathogenic variant in the paternally derived allele by molecular genetic testing. The 15q11.2 locus that includes is maternally imprinted, meaning that only the paternally derived allele is expressed while the maternally derived allele is inactivated.
: Feeding therapy or supplemental tube feeding may be required for persistent feeding issues; assisted ventilation to include either noninvasive or invasive intervention; CPAP for sleep apnea; growth hormone therapy in those with short stature and/or linear growth concerns; standard therapy for gastroesophageal reflux disease, metabolic syndrome, constipation, skeletal abnormalities, low bone mineral density, developmental delay/cognitive impairment, seizures, eye anomalies, undescended testes, hypogonadism and pubertal abnormalities, and hypothyroidism. : At each visit: measurement of growth parameters and evaluation of nutritional status & safety of oral intake; assessment of developmental progress, educational needs, and self-help skills; monitor for signs and symptoms of constipation, sleep apnea, respiratory insufficiency, scoliosis, progression of contractures, and puberty (from ages 10-17 years). Behavioral assessment annually; DXA scan every two years starting at the age five years, transitioning to every three to five years in adulthood; ophthalmology evaluation as recommended by an ophthalmologist; polysomnography annually for those on long-term GH therapy or as recommended by a sleep specialist.
Schaaf-Yang syndrome is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived allele results in disease; a pathogenic variant on the maternally derived allele does not result in disease because normally the maternally derived allele is silenced). Approximately 50% of individuals diagnosed with SYS inherited a pathogenic variant from a clinically unaffected father and the remainder are . If the father of the proband is heterozygous for the pathogenic variant identified in the proband, the risk to both male and female sibs is 50%. The recurrence risk within the family of the proband's mother is that of the general population. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Schaaf-Yang综合征（SYS）是一种罕见的神经发育障碍，与基因相关的普拉德-威利综合征有多种共同临床特征。通常在出生时表现为全身肌张力减退，大多数受影响个体存在远端关节挛缩。胃肠道/喂养问题在婴儿期和儿童期尤为明显，但成年后可转变为食欲亢进和肥胖。许多个体出生时存在呼吸窘迫，约一半需要插管和机械通气，约20%需要气管造口术。经常观察到关节挛缩、脊柱侧弯和骨密度降低等骨骼表现。所有受影响个体均有发育迟缓，导致不同程度的智力残疾，从低正常智力到严重智力残疾。其他表现可能包括身材矮小、癫痫发作、眼部异常和性腺功能减退。
诊断/检测：通过分子遗传学检测在先证者中鉴定出父源等位基因中的杂合致病变异，从而确立Schaaf-Yang综合征的诊断。包含的15q11.2位点是母系印记的，这意味着只有父源等位基因表达，而母源等位基因失活。
对于持续存在的喂养问题，可能需要喂养治疗或补充管饲；辅助通气，包括无创或有创干预；持续气道正压通气（CPAP）治疗睡眠呼吸暂停；对身材矮小和/或有线性生长问题的患者进行生长激素治疗；对胃食管反流病、代谢综合征、便秘、骨骼异常、骨密度低、发育迟缓/认知障碍、癫痫发作、眼部异常、隐睾、性腺功能减退和青春期异常以及甲状腺功能减退进行标准治疗。每次就诊时：测量生长参数并评估营养状况和经口摄入的安全性；评估发育进展、教育需求和自理技能；监测便秘、睡眠呼吸暂停、呼吸功能不全、脊柱侧弯、挛缩进展和青春期（10至17岁）的体征和症状。每年进行行为评估；从5岁开始每两年进行一次双能X线吸收法（DXA）扫描，成年后改为每三至五年进行一次；按照眼科医生的建议进行眼科评估；对于长期接受生长激素治疗的患者或按照睡眠专家的建议，每年进行多导睡眠图检查。
Schaaf-Yang综合征以常染色体显性、母系印记方式遗传（即父源等位基因上的杂合致病变异导致疾病；母源等位基因上的致病变异不会导致疾病，因为正常情况下母源等位基因是沉默的）。约50%被诊断为SYS的个体从临床未受影响的父亲那里遗传了致病变异，其余为新发突变。如果先证者的父亲对于先证者中鉴定出的致病变异是杂合的，男性和女性同胞的患病风险均为50%。先证者母亲家族中的复发风险与一般人群相同。一旦在受影响的家庭成员中鉴定出致病变异，对于高危妊娠可进行产前检测以及植入前基因检测。
