Pappas John, Rabin Rachel
Associate Professor, Grossman School of Medicine, New York University, New York, New York
Grossman School of Medicine, New York University, New York, New York
neurodevelopmental disorders (-NDDs) represent a clinical spectrum that most commonly includes various degrees of intellectual disability and behavioral findings (most typically an autism spectrum disorder), macrocephaly with or without ventriculomegaly, brain malformations (including Chiari I malformation and syringomyelia), and obesity with generalized overgrowth and advanced bone age. A specific, somewhat different phenotype (denoted -NDD with multiple congenital anomalies [MCA]) has been reported in association with a particular pathogenic variant, c.5218C>T (p.Arg1740Trp), which leads to a higher frequency of multiple congenital anomalies compared to those without this genetic change. Individuals with -NDD with MCA may have microcephaly, congenital heart malformations, urogenital anomalies, eye findings (specifically Coats disease of the retina), severe failure to thrive, hypotonia, hyponatremia, respiratory issues (tracheomalacia, frequent aspiration, hypoventilation), epilepsy, profound intellectual disability with limited-to-no speech, and distinctive craniofacial features.
DIAGNOSIS/TESTING: The diagnosis of a -NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in identified by molecular genetic testing.
Nutritional management of obesity to include diet/exercise; consideration of growth hormone therapy in those with poor growth; standard treatment for developmental delay / autistic features, seizures, hypothyroidism, precocious puberty, hypotonia/hypermobility, scoliosis, refractive error / strabismus, hearing loss, congenital heart defects, and cryptorchidism. Feeding therapy to include consideration of a gastrostomy tube; supplemental oxygen therapy with consideration of tracheostomy in those with tracheomalacia/hypoventilation; sodium supplementation for those with hyponatremia; standard treatment for developmental delay, seizures, joint contractures, sensorineural/conductive hearing loss, Coats disease of the retina, congenital heart defects, cryptorchidism, dysplastic kidneys, and skeletal anomalies. Monitor for psychiatric symptoms, seizures, changes in tone, movement disorders, and developmental progress at each clinic visit; weight checks at home for obesity prevention starting in the second year of life; annual thyroid-stimulating hormone and free T4; clinical evaluation for precocious puberty and scoliosis at each visit during childhood; annual (or as clinically indicated) ophthalmology and audiology evaluations. Monitor for appropriate growth, evidence of aspiration, respiratory sufficiency, seizures, changes in tone, movement disorders, and developmental progress at each clinic visit; electrolyte panel to include sodium level to assess for hyponatremia at each visit during infancy; annual (or as clinically indicated) ophthalmology and audiology evaluations.
-NDDs are inherited in an autosomal dominant manner, although most affected individuals represent simplex cases (i.e., a single occurrence in a family). To date, transmission of a pathogenic variant from a parent to a child has been reported in one family. If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Each child of an individual with a -NDD has a 50% chance of inheriting the pathogenic variant. 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.
神经发育障碍（-NDDs）是一种临床谱系，最常见的包括不同程度的智力残疾和行为表现（最典型的是自闭症谱系障碍）、伴有或不伴有脑室扩大的巨头畸形、脑畸形（包括Chiari I畸形和脊髓空洞症），以及伴有全身过度生长和骨龄提前的肥胖。已报道一种特定的、略有不同的表型（称为伴有多种先天性异常的-NDD [MCA]）与特定的致病变异c.5218C>T（p.Arg1740Trp）相关，与没有这种基因改变的个体相比，该变异导致多种先天性异常的发生率更高。患有-NDD伴MCA的个体可能有小头畸形、先天性心脏畸形、泌尿生殖系统异常、眼部表现（特别是视网膜的Coats病）、严重生长发育迟缓、肌张力减退、低钠血症、呼吸问题（气管软化、频繁误吸、通气不足）、癫痫、严重智力残疾且言语有限或无言语能力，以及独特的颅面特征。
诊断/检测：在先证者具有提示性发现且通过分子遗传学检测鉴定出杂合致病变异时，确立-NDD的诊断。
肥胖的营养管理包括饮食/运动；对生长不良者考虑生长激素治疗；对发育迟缓/自闭症特征、癫痫、甲状腺功能减退、性早熟、肌张力减退/关节活动过度、脊柱侧弯、屈光不正/斜视、听力损失、先天性心脏缺陷和隐睾症进行标准治疗。喂养治疗包括考虑胃造瘘管；对有气管软化/通气不足者考虑气管切开术的补充氧气治疗；对低钠血症患者补充钠；对发育迟缓、癫痫、关节挛缩、感音神经性/传导性听力损失、视网膜Coats病、先天性心脏缺陷、隐睾症、发育异常的肾脏和骨骼异常进行标准治疗。每次门诊就诊时监测精神症状、癫痫发作、肌张力变化、运动障碍和发育进展；从生命第二年开始在家中进行体重检查以预防肥胖；每年检测促甲状腺激素和游离T4；儿童期每次就诊时对性早熟和脊柱侧弯进行临床评估；每年（或根据临床指征）进行眼科和听力评估。每次门诊就诊时监测适当的生长、误吸证据、呼吸功能、癫痫发作、肌张力变化、运动障碍和发育进展；婴儿期每次就诊时检测电解质，包括钠水平以评估低钠血症；每年（或根据临床指征）进行眼科和听力评估。
-NDDs以常染色体显性方式遗传，尽管大多数受影响个体为散发病例（即家族中仅出现一例）。迄今为止，在一个家族中报道了致病变异从父母传递给孩子的情况。如果已知先证者的父母具有在先证者中鉴定出的致病变异，其同胞继承该致病变异的风险为50%。患有-NDD的个体的每个孩子继承致病变异的几率为50%。一旦在受影响的家庭成员中鉴定出致病变异，对于风险增加的妊娠可进行产前检测和植入前基因检测。
