This case supports an autosomal recessive mechanism of CLDN11‐related disease, which differs from the dominant stop‐loss variants reported previously, and broaden the mutational spectrum and suggest distinct pathogenic mechanisms, with important implications for diagnosis and genetic counselling.
Abstract
CLDN11 has recently been associated with hypomyelinating leukodystrophy caused by de novo stop‐loss variants. Here, we present a new case involving a homozygous variant in order to expand the genetic and clinical spectrum of the disease. We performed a comprehensive clinical, neuroradiological, and genetic evaluation in a child presenting with global developmental delay. Brain MRI and MR spectroscopy were obtained, and next‐generation sequencing with parental segregation analysis was conducted. The patient presented with developmental delay, hypotonia, limb hypertonia, esotropia, and an absence of early developmental milestones in infancy, followed by partial motor improvement and persistent language and cognitive impairment. Brain MRI revealed diffuse supratentorial hypomyelination with stability over time. Genetic analysis identified a novel homozygous CLDN11 start‐loss variant (c.1A>G; p.Met1Val), which is predicted to result in biallelic loss of function. Both parents were found to be heterozygous carriers. This case supports an autosomal recessive mechanism of CLDN11‐related disease, which differs from the dominant stop‐loss variants reported previously. The phenotype partially overlaps with that of earlier cases, but is characterized by milder motor involvement and more pronounced cognitive impairment. These findings broaden the mutational spectrum and suggest distinct pathogenic mechanisms, with important implications for diagnosis and genetic counselling.
Findings support a dose-dependent SLC20A2 disease spectrum and expand the phenotype associated with biallelic loss of function from primary brain calcification toward severe early-onset neurodevelopmental disorder with prominent vascular and leptomeningeal calcification.
Mehmet Burak Mutlu, Abdullah Sezer, Elif Özdemir et al.· Journal of Human Genetics· 0 citations
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This study is the first to report CCDC149 variants in association with Congenital Hypopituitarism, supporting the possibility of impaired ciliary function as an underlying mechanism in this complex disorder.
L. Gregory, Shoshana Rath, Hanna Mandel et al.· European Journal of Endocrin...· 0 citations
The first genetically confirmed Iranian patient, an 18‐month‐old boy presenting with profound developmental delay, axial hypotonia, limb hypertonia, dystonia, oculogyric crises, ptosis, and autonomic dysfunction is reported, expanding the mutational spectrum of SLC18A2‐related disease and highlighting the importance of early genetic diagnosis.
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22q11.2 deletion syndrome (22q11.2 DS) is one of the most common microdeletion syndromes, characterized by congenital anomalies and variable immune dysfunction secondary to thymic hypoplasia. The resulting immune dysregulation frequently predisposes affected individuals to autoimmune manifestations, including immune thrombocytopenia (ITP). Although rituximab is established therapy for refractory ITP, its B cell–depleting mechanism may carry distinct risk in patients whose B cell compartment already depends on impaired T cell–mediated help, potentially resulting in profound and irreversible humoral failure rather than the typically transient hypogammaglobulinemia.
We report the case of a female patient whose initial clinical manifestations included characteristic facial dysmorphism, cleft palate, a hemodynamically significant ventricular septal defect requiring surgical correction at the age of three years, and delayed psychomotor development. Based on these findings, 22q11.2 DS was suspected and subsequently confirmed by fluorescence in situ hybridization (FISH) analysis at the age of nine. At the age of five, she developed severe ITP, refractory to glucocorticoids, intravenous immunoglobulins, and cyclosporine. Immunophenotyping of peripheral blood lymphocytes at this stage already revealed reduced B cell counts (8%, 0.105 × 109/L), while serum IgG levels remained within the normal range. At the age of 12, she received rituximab therapy, achieving a complete normalization of platelet counts. Within the following year, she developed recurrent bilateral pneumonias. Laboratory evaluation revealed severe hypogammaglobulinemia (IgG 0.6 g/L, IgM 0.04 g/L, and IgA 0.06 g/L), with a further reduction in B cell numbers (4%, 0.066 × 109/L). Monthly intravenous immunoglobulin replacement therapy, combined with antibiotic prophylaxis, significantly reduced the frequency of infections. Hypogammaglobulinemia and B cell deficiency persisted without recovery over more than a decade of follow-up. At the age of 24 years, the patient developed severe COVID-19 pneumonia, which ultimately resulted in a fatal outcome.
This case highlights that rituximab, while effective in the treatment of autoimmune cytopenias, may induce severe and persistent hypogammaglobulinemia in patients with underlying primary immunodeficiency and pre-existing B cell abnormalities. Our patient’s humoral failure after rituximab proved persistent, a finding that may be attributable to an underlying thymic-dependent defect in B cell maturation, which could impair normal post-depletion recovery. Comprehensive baseline immunological evaluation and long-term monitoring of immunoglobulin levels and B cell recovery should be considered before B cell–depleting therapies in this population.
Ana Drazic, S. Pasic, Maja Stojanović et al.· Journal of Human Immunity· 0 citations
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