Broad phenotypic spectrum of SYNGAP1-related disorder: a case with epilepsy, severe developmental delay, and atypical sensory features

We report a 2.5-year-old male of Eastern European ancestry who exhibited normal development until 6 months of age, followed by global developmental delay and progressive neurological symptoms. Clinical evaluation revealed hypotonia with peripheral hypertonia, postural instability, pes valgus, impaired fine motor skills, and absence of speech. Behavioral and sensory abnormalities included autism spectrum disorder, stereotypic upper limb movements, sensory integration disorder, hypersensitivity to light, wind, and sound during infancy, and poor pain perception. Additional findings comprised sleep disturbances, attention deficits, and excessive salivation. Ophthalmologic assessment revealed spasmus nutans at 8 months, esotropia, hypermetropia, astigmatism, amblyopia, and nystagmus. Dysmorphic features included microcephaly, low-set and slightly protruding ears, downslanting palpebral fissures, long eyelashes, and an open mouth. Gastrointestinal symptoms included chronic constipation, and MRI demonstrated an arachnoid cyst under observation. EEG showed generalized epileptiform discharges, and generalized-onset seizures were suspected.
Whole-exome sequencing identified a heterozygous pathogenic de novo variant in SYNGAP1 [NM_006772.3:c.3718C>T p.Arg1240*], consistent with SYNGAP1-related intellectual developmental disorder (MRD5) [MIM:612621]. The phenotype aligns with the classical spectrum of SYNGAP1-related disorders, including intellectual disability, epilepsy, and behavioral abnormalities. Notably, features such as pronounced sensory hypersensitivity, spasmus nutans, and a distinctive urinary odor broaden the clinical spectrum associated with SYNGAP1 pathogenic variants.
This case demonstrates the wide range of manifestations that can occur in SYNGAP1-related disorders and underscores the importance of thorough clinical phenotyping combined with genomic analysis for accurate diagnosis and optimized patient care.

本研究报告1例2.5岁东欧血统男性个体，其在6月龄前发育均正常，随后出现全面发育迟缓及进行性神经症状。临床评估显示其存在肌张力低下伴外周肌张力增高、姿势不稳、足外翻、精细运动功能受损及言语能力缺失。行为及感觉异常包括孤独症谱系障碍、刻板性上肢运动、感觉统合失调、婴儿期对光、风及声音超敏，以及痛觉减退。其他临床表现还包括睡眠障碍、注意缺陷及流涎过多。眼科评估显示，该患儿8个月时出现点头痉挛，另有内斜视、远视、散光、弱视及眼球震颤。畸形特征包括小头畸形、低位且略突出的双耳、睑裂下斜、长睫毛及张口状态。胃肠道症状为慢性便秘，头颅MRI提示存在蛛网膜囊肿并予以随访观察。脑电图检测到全面性癫痫样放电，怀疑存在全面性发作性癫痫。
全外显子组测序检测到SYNGAP1基因[NM_006772.3:c.3718C>T p.Arg1240*]存在杂合致病性新发变异，符合SYNGAP1相关智力发育障碍（MRD5）[MIM:612621]的诊断标准。该患者的表型与SYNGAP1相关障碍的经典表型谱一致，涵盖智力障碍、癫痫及行为异常。值得注意的是，显著的感觉超敏、点头痉挛及特征性尿气味等表现，进一步拓宽了与SYNGAP1致病性变异相关的临床表型谱。
本病例展示了SYNGAP1相关障碍可出现的多样化临床表现，同时强调了全面的临床表型分析结合基因组检测，对于实现精准诊断及优化患者诊疗照护的重要性。