Medical Case Studies

A case study of a child with a novel heterozygous missense variant in MAGEL2 (c.1651G>A; p.Val551Ile), inherited from the paternal line. This variant has not been reported in the literature. MAGEL2 is maternally imprinted and paternally expressed, meaning pathogenicity depends on which parental allele transmits the mutation. The case highlights broad neurodevelopmental and psychiatric features, variability in expression across three generations, and the emergence of both challenges and extraordinary cognitive strengths. MAGEL2 encodes a 1,249-amino-acid protein belonging to the MAGE family, expressed most prominently in the hypothalamus, where it plays vital roles in neurodevelopment and neuroendocrine regulation — including ubiquitin-proteasome system regulation, endosomal trafficking, neuropeptide processing, and RNA metabolism.

Proteus syndrome and imprinting disorders such as MAGEL2- and UBE3A-related conditions are rare and typically studied separately. Their coexistence in a single patient provides a unique opportunity to understand multi-hit genetic contributions to neurodevelopment and growth. Clinical assessment, developmental history, imaging review (2018–2025), and genetic testing including tissue-based sequencing and exome analysis were performed. Variants in AKT1, MAGEL2, and UBE3A were identified and correlated with phenotype. The patient exhibited hallmark features of Proteus syndrome due to mosaic AKT1 p.E17K, Angelman-like features linked to UBE3A c.454A>G (p.K152E), and ADHD/behavioral traits consistent with MAGEL2 c.1651G>A (p.Val551Ile). Symptoms included asymmetric cranial overgrowth, speech apraxia, hypotonia, hypersalivation, pigmentation changes, ADHD onset at age 7, hyperactivity, impulsivity, obsessive tendencies, and specific phobias. Imaging showed progressive calvarial thickening. Family history confirmed variable expression of MAGEL2 traits across three generations. This case underscores how mosaic and imprinted variants converge to produce complex blended phenotypes: AKT1 drives structural growth abnormalities, MAGEL2 contributes to behavioral traits, and UBE3A underlies Angelman-like symptoms — illustrating a multi-hit model of neurodevelopmental disease with clear imprinting contrasts.

This case study documents the clinical decline of a 78–79-year-old male with pre-existing cirrhosis, chronic kidney disease (CKD), and multiple comorbidities, whose hospital course was complicated by recurrent cholecystitis, sepsis, urinary obstruction, and progressive multi-organ dysfunction. Despite repeated admissions and clear radiologic evidence of acute cholecystitis, surgical removal of the gallbladder (cholecystectomy) was never performed. Instead, a sequence of medical management decisions, delayed interventions, and systemic oversights culminated in worsening hepatic decompensation, recurrent sepsis, and eventual transition to supportive care. This case highlights the dangers of polypharmacy, catheter dependence, and surgical deferral in a high-risk cirrhotic patient.