A 3-year-old male with chronic abdominal distention, constipation, and severe malnutrition is diagnosed with pediatric intestinal pseudo-obstruction (PIPO) after extensive evaluation that excluded mechanical, malabsorptive, metabolic, inflammatory, and infectious causes. Aside from speech delay, he has a normal neurologic exam. Whole exome sequencing reveals a pathogenic methyl-CpG binding protein 2 (MECP2) variant, suggesting atypical Rett syndrome. Management includes promotility agents and a gastrostomy tube with cyclic feedings of peptide-based formula, leading to resolution of symptoms. This case highlights the diagnostic complexity of PIPO and the need to consider genetic etiologies, including MECP2-related disorders, even in patients with mild neurologic findings. Early genetic testing and multidisciplinary care are essential for diagnosis and management in this atypical presentation of Rett syndrome with manifestation of PIPO.

The purpose of this study was to explore the genotypic and phenotypic presentation of males with MECP2 -related neurodevelopmental disorders. When variants in the MECP2 gene are discovered in patients, Rett syndrome becomes a possible diagnosis. Rett syndrome, however, does not encapsulate all phenotypic variations in MECP2 gene mutations, and specific diagnosis can become tricky especially in the male population as mutations in the gene were historically thought to affect females only. The authors present a rare case of a male with a previously unpublished genetic variant resulting in a distinct clinical presentation not meeting the criteria for typical or atypical Rett syndrome. This patient's institutional electronic medical record was accessed, and information was reviewed. It was discovered that this patient had a maternally inherited variant in his MECP2 gene, resulting in a unique and previously undescribed form of MECP2 -related neurodevelopmental disorder, presenting with language regression followed by speech apraxia and motor discoordination. Literature reports on various phenotypes associated with MECP2 gene mutations and elaborates on previously identified forms of typical and atypical Rett syndrome. Through this case report, the authors uncovered a pathogenic variant in MECP2 resulting in a rare phenotype of MECP2 -related neurodevelopmental disorder that has not previously been described. This should encourage clinicians to think more broadly when approaching diagnosis of children with developmental differences. This also reinforces that Rett syndrome or MECP2 mutations can often present on a spectrum, and it may be beneficial to modify diagnostic criteria to reflect this.

NEUROD2, encoding the neurogenic differentiation factor 2, is essential for neurodevelopment. To date, heterozygous missense variants in this gene have been identified in eight patients (from six unrelated families) with epileptic encephalopathy and developmental delay. We describe a child with initial clinical suspicion of Rett/Rett-like syndrome, in whom exome sequencing detected a novel de novo variant (c.388G > A, p.Glu130Lys) in NEUROD2. Interestingly, a missense change affecting the same codon, c.388G > C (p.Glu130Gln), was previously identified in other two patients. Our results suggest that Glu130 might represent a potential mutational hotspot of NEUROD2. Furthermore, the clinical findings (especially the absence of clinically overt seizures) strengthen the NEUROD2-phenotypic spectrum, implying that developmental delay may also manifest isolatedly. We suggest inclusion of NEUROD2-associated developmental and epileptic encephalopathies (DEEs) in the differential diagnosis of atypical Rett syndrome as well as gene panels related to autism spectrum disorder.

Introduction  IQSEC2-related encephalopathy is an X-linked childhood neurodevelopmental disorder with intellectual disability, epilepsy, and autism. This disorder is caused by a mutation in the IQSEC2 gene, the product of which plays an important role in the development of the central nervous system. Case Report  We describe the symptomatology, clinical course, and management of a 17-month-old male child with a novel IQSEC2 mutation. He presented with an atypical Rett syndrome phenotype with developmental delay, autistic features, midline stereotypies, microcephaly, hypotonia and epilepsy with multiple seizure types including late-onset infantile spasms. Spasms were followed by worsening of behavior and cognition, and regression of acquired milestones. Treatment with steroids led to control of spasms and improved attention, behavior and recovery of lost motor milestone. In the past 10 months following steroid therapy, child lags in development, remains autistic with no further seizure recurrence. Conclusion  IQSEC2-related encephalopathy may present with Rett atypical phenotypes and childhood spasms. In resource-limited settings, steroids may be considered for spasm remission in IQSEC2-related epileptic encephalopathy.