Katherine Ford

Background: Congenital analbuminemia (CAA) is an ultrarare autosomal recessive disorder caused by biallelic pathogenic variants in the ALB gene, leading to absent or severely reduced serum albumin. Although historically considered a benign biochemical condition, emerging evidence suggests that pediatric CAA may be associated with clinically relevant multisystem manifestations. Methods: We conducted a longitudinal integrative study involving five children from two kindreds, all with genetically confirmed CAA. Their clinical features were thoroughly documented, along with extended coagulation tests and immunological profiling. Results: All patients presented with persistent hypoalbuminemia, early-onset edema, gastrointestinal morbidity (frequently leading to misdiagnosis as protein-losing enteropathy), antenatal complications, recurrent respiratory infections, and dyslipidemia. Genetic testing revealed an ALB splice-site mutation (c.1428 + 2T > C) in one kindred and a novel homozygous frameshift insertion (p.Glu69Ter) in the second. Coagulation profiling identified a reproducible prothrombotic signature, including elevated fibrinogen, D-dimer, and strikingly increased FXI activity, with one patient suffering life-threatening cerebral thrombosis. Immunological evaluation demonstrated preserved leukocyte and lymphocyte counts, preserved or elevated IgG levels, variable antigen-specific vaccine responses, reduced kappa-deleting recombination excision circle values in the tested patients, and skewing of CD4⁺ T cells toward effector memory subsets, consistent with immune dysregulation rather than frank immunodeficiency. Conclusions: This study provides detailed multisystem phenotyping of pediatric CAA and supports the view that CAA may present with clinically relevant gastrointestinal, metabolic, infectious, and hemostatic manifestations beyond isolated hypoalbuminemia. Early molecular diagnosis may reduce unnecessary invasive investigations and facilitate individualized monitoring for infectious and thrombotic complications. Larger multicenter studies with longitudinal follow-up and functional validation are required to confirm these findings.

Pontocerebellar hypoplasia (PCH) encompasses a group of autosomal recessive neurodegenerative disorders marked by cerebellar and pontine atrophy. Multiple subtypes of PCH have been identified, among which the rare subtype PCH type 16 is caused by MINPP1 genetic variants. MINPPI encodes an enzyme essential for inositol polyphosphate dephosphorylation, regulating calcium and iron homeostasis. We conducted genome sequencing on a proband from the consanguineous family, who presented with a severe neurodegenerative disorder, to identify the underlying cause of disease. A comprehensive clinical assessment in addition to neuroradiological findings are described. We performed the functional validation of the identified variant and conducted untargeted metabolomic analyses. The clinical and radiological assessment of the patient showed a congenital brain anomaly and neurodegenerative symptoms. Further genetic analysis identified a homozygous loss-of-function variant (c.1401del, p.Ser468Valfs10*) in MINPP1, providing molecular confirmation of a clinical PCH diagnosis. While real-time quantitative PCR (RT-qPCR) showed that MINPP1 gene expression was unaffected in the proband, Western blot analysis demonstrated reduced protein abundance, supporting a pathogenic role of the variant. Metabolomic profiling revealed elevated lipid levels and disrupted inositol metabolism, providing further insights into the disease mechanism. These findings establish the pathogenicity of the p.Ser468Valfs10* variant in MINPP1 and highlight inositol metabolism as a potential pathway involved in PCH16, advancing the understanding of the pathophysiology of the disease.