Infantile epileptic spasms syndrome (IESS) is a severe form of infantile epilepsy with a high lifetime morbidity burden. We aimed to assess the long-term epilepsy and neurodevelopmental outcomes based on how children with IESS have been managed over the past few decades. This retrospective multicenter study included children diagnosed with IESS between 1994 and 2021 with a minimum follow-up period of 2 years. Data on demographics, clinical features, medical history, diagnostic evaluations, and treatments used to control spasms were collected. Epilepsy and neurodevelopmental outcomes were assessed at final follow-up. A total of 378 infants with IESS were included. The mean age at onset of spasms was 7.3 (range, 1-24) months and mean follow-up duration was 7.9 (range, 2-28) years. Etiologies were identified in 65.1% of cases, with acquired structural etiologies being the most prevalent (29.9%). Among the genetic and genetic-structural etiologies, tuberous sclerosis complex (n=35), Down syndrome (n=8), Miller-Dieker syndrome (n=3), and 15q duplication syndrome (n=3) were the most common. Vigabatrin was prescribed to 93.9% of the patients, suggesting that it was the mainstay of treatment. At the last follow-up, 77.8% of the children remained on antiseizure medications and 29.1% had drug-resistant epilepsy. Approximately 90% had intellectual disabilities, and half of the eligible individuals had received special education. The IESS imposes a substantial burden on affected children and their families and often leads to chronic epilepsy and impaired cognitive function. Consensus diagnostic and treatment guidelines tailored to the Korean clinical practice are necessary to ensure early diagnosis and timely treatment.

Miller-Dieker Syndrome (MDS) is a rare neurodevelopmental disorder caused by a heterozygous deletion of approximately 26 genes within the MDS locus of human chromosome 17. MDS, which affects 1 in 100,000 babies, can lead to a range of phenotypes, including lissencephaly, severe neurological defects, distinctive facial abnormalities, cognitive impairments, seizures, growth retardation, and congenital heart and liver abnormalities. One hallmark feature of MDS is an unusually smooth brain surface due to abnormal neuronal migration during early brain development. Several genes located within the MDS locus have been implicated in the pathogenesis of MDS, including PAFAH1B1, YWHAE, CRK, and METTL16. These genes play a role in the molecular and cellular pathways that are vital for neuronal migration, the proper development of the cerebral cortex, and protein translation in MDS. Improved model systems, such as MDS patient-derived organoids and multi-omics analyses indicate that WNT/β-catenin signaling, calcium signaling, S-adenosyl methionine (SAM) homeostasis, mammalian target of rapamycin (mTOR) signaling, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and others are dysfunctional in MDS. This review of MDS integrates details at the clinical level alongside newly emerging details at the molecular and cellular levels, which may inform the development of novel therapeutic strategies for MDS.

Polyhydramnios is a non-specific prenatal finding associated with several fetal anomalies, most notably gastrointestinal obstructions, such as esophageal atresia (EA). However, its etiology may extend beyond gastrointestinal causes to include central nervous system (CNS) abnormalities. We report the case of a neonate initially suspected in utero to have EA based on polyhydramnios and a small fetal gastric bubble, but postnatally diagnosed with classical lissencephaly associated with Miller-Dieker syndrome. A 32-year-old primigravida was referred to our center at 28 weeks of gestation on account of suspected fetal EA with polyhydramnios and a small gastric bubble on prenatal ultrasonography (US). No other anomaly was identified, and she was admitted for management at 30 4/7 weeks of gestation. The patient was delivered at 36 3/7 weeks of gestation via emergency cesarean section due to premature rupture of membranes and arrest of vaginal labor. The neonate showed no sign of EA, and that diagnosis was excluded based on successful passage of an orogastric tube and normal abdominal radiography. Mild dysmorphic features, such as micrognathia and hypertelorism, were noted. As the etiology of polyhydramnios remained unclear, neuroimaging was performed. Cranial US findings were unremarkable; however, head magnetic resonance imaging (MRI) on day seven of life revealed a thickened cortex lacking normal sulcation, which is consistent with classical lissencephaly. Chromosomal microarray analysis revealed a deletion on 17p13.3, confirming Miller-Dieker syndrome. The patient was discharged on day 35 after an uneventful neonatal period; however, epileptic spasms and developmental delay were noticed from the age of six months. This case highlights the diagnostic challenge of differentiating between gastrointestinal and neurological causes of polyhydramnios. Although EA is a common differential diagnosis in such cases, the potential for CNS malformations mimicking gastrointestinal pathologies must be considered. Routine fetal ultrasound alone may fail to detect subtle cerebral abnormalities such as lissencephaly, especially in the absence of ventriculomegaly or other signs. Fetal MRI, which has superior soft tissue resolution, should be considered when the etiology of polyhydramnios is uncertain, even if there is no overt CNS anomaly. This case highlights the importance of prompt neuroimaging, including fetal MRI, which may facilitate diagnosis and counseling of families, and optimize postnatal care.

Chromosome 17p13.3 is a region of genomic instability associated with different neurodevelopmental diseases. The malformation spectrum of 17p13.3 microdeletions ranges from an isolated lissencephaly sequence to Miller-Dieker syndrome, while 17p13.3 microduplications result in autism, learning disabilities, microcephaly and other brain malformations. This study aims to provide a more comprehensive delineation of the clinical and genetic characteristics associated with 17p13.3 alterations. We retrospectively analyzed the next-generation sequencing (NGS) data of more than 40 thousand patients from January 2016 to December 2021 and identified 38 pediatric patients with copy-number variations (CNVs) or single-nucleotide variations (SNVs) in 17p13.3 region. Published patients with CNVs in the 17p13.3 region were also collected and we performed a Chi-square test to compare the phenotype spectrum of microdeletions and microduplications. Among the 27 CNV patients, 20 patients with microdeletions and 7 patients with microduplications were found. PAFAH1B1 was the most frequently deleted gene and CRK was the most frequently duplicated gene. Affected genes in 11 SNV patients included PAFAH1B1 and PRPF8. Developmental delay was the most common abnormality detected in the 38 patients (29/38, 76.3%). Of note, Case 10 presented omphalocele and Case 23 presented scoliosis, webbed neck and bone cyst, all of which were unusual variant phenotypes in this region. The Chi-square test revealed that epilepsy, lissencephaly and short stature were statistically significant with microdeletions, while behavioral abnormalities and hand and foot abnormalities were significant with microduplications (p < 0.01). While PAFAH1B1, YWHAE and CRK are associated with major phenotypes of 17p13.3, RTN4RL1 may be involved in white matter changes and HIC1 might contribute to the occurrence of omphalocele. This study provided a comprehensive understanding of genetic information and phenotype spectrum of the 17p13.3 region.

Ring chromosome 17 and 17p13.3 deletion syndrome are phenotypically heterogeneous diseases with similar clinical features. The ring chromosome 17 phenotypic features range from the Miller-Dieker syndrome characterized by deletion of the PAFAH1B1 gene, lissencephaly, hypotonia, dysphagia, café au lait spots, and severe intellectual disability, to a milder phenotype characterized by microcephaly, seizures, delayed development, minor facial dysmorphic features, clinodactyly, short stature, café au lait spots, retinal flecking, and deletion of the YWHAE and CRK genes. Similarly, the phenotypic features of the 17p13.3 deletion syndrome range from the Miller-Dieker syndrome caused by loss of function of the PAFAH1B1 gene and characterized by lissencephaly, microcephaly, seizures, hypotonia, and severe intellectual disability to a milder phenotype characterized by nonspecific white matter changes, microcephaly, seizures, delayed development, short stature, and deletion of the YWHAE and CRK genes. Café au lait spots and retinal or axillary freckling have been noted in the ring chromosome 17 syndrome but not in 17p13.3 deletion syndrome. We report a 5-year-old girl with a history of intrauterine growth retardation, short stature, intractable epilepsy, expressive language disorder, clinodactyly, multiple café au lait spots, and retinal freckling who was initially diagnosed with 17p13.3 deletion syndrome involving YWHAE and CRK but not PAFAH1B1 on CGH array. However, cytogenetic analysis of G-banded chromosomes revealed mosaic ring chromosome 17. Optical genome mapping simultaneously identified the 17p13.3 deletion and the mosaic ring chromosome 17. This case report highlights the limitations of the arrays and sequencing methods for identifying structural variants, the need to investigate further deletions and duplications identified by arrays, mainly considering atypical phenotypic features, and suggests that OGM could be used as a first-tier test with exome sequencing for the diagnosis of patients with dysmorphic features, intellectual disability, and seizure disorder.