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A 13-year-old boy was referred to orthopedic surgery for chronic intermittent pain and swelling of the left knee. Initial imaging was consistent with osteochondritis dissecans of the femoral condyle. Follow-up imaging demonstrated unexpected progression, with a mass extending into the notch, replacing the anterior cruciate ligament, and eroding the femoral and tibial condyles. Subsequent surgical biopsy and resection revealed tumoral calcinosis, with an ultimate diagnosis of autosomal recessive familial tumoral calcinosis. This case report highlights the radiographic appearance and progression of a rare disease in this unusual location and the differential diagnosis. KEY POINTS: Tumoral calcinosis (TC) is a rare disease that typically presents in the periarticular soft tissues along extensor surfaces of large joints in adolescents and young adults, with greater frequency in African-descent populations.1,2 TC may cause pain, swelling, and loss of range of motion of the nearby joint.1 On imaging, TC is typically superficial with calcified lobular masses, layering milk of calcium and/or hemorrhage in cysts on magnetic resonance imaging, and only septal enhancement. Atypical features include bone involvement, intra-articular/extrasynovial joint space involvement, and lack of cysts.1,3–5 Hyperphosphatemic TC, normophosphatemic TC, and secondary causes can usually be discerned with history and biochemical analysis (serum calcium, phosphorus, calcitriol, parathyroid hormone, and renal function tests). If the serum calcium and phosphorus are normal, connective tissue disease should be excluded with a negative antinuclear, anti-Smith, anti-centromere, and anti-scleroderma antibody profile.1,6 [ABSTRACT FROM AUTHOR]

Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129∗]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024∗]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.

Author(s): Grace Yu [sup.1] , Faris Hashim [sup.2] , Colleen Macmurdo [sup.3] , Christian Hanna [sup.4] Author Affiliations: (1) grid.412408.b, Department of Pediatrics, Texas A&M Health Science Center, Baylor Scott [...]

Author(s): Grace Yu [sup.1] , Faris Hashim [sup.2] , Colleen Macmurdo [sup.3] , Christian Hanna [sup.4] Author Affiliations: (1) grid.412408.b, Department of Pediatrics, Texas A&M Health Science Center, Baylor Scott [...]

A 13-year-old boy was referred to orthopedic surgery for chronic intermittent pain and swelling of the left knee. Initial imaging was consistent with osteochondritis dissecans of the femoral condyle. Follow-up imaging demonstrated unexpected progression, with a mass extending into the notch, replacing the anterior cruciate ligament, and eroding the femoral and tibial condyles. Subsequent surgical biopsy and resection revealed tumoral calcinosis, with an ultimate diagnosis of autosomal recessive familial tumoral calcinosis. This case report highlights the radiographic appearance and progression of a rare disease in this unusual location and the differential diagnosis., Competing Interests: The planners and faculty for this activity have no relevant financial relationships to disclose. The authors report no funding. The patient and the patient’s father consented to publication of this case report., (Copyright © 2024 Baylor University Medical Center.)

Objective: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism., Methods: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells., Results: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells., Interpretation: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024., (© 2024 American Neurological Association.)

Purpose: De novo variants in CUL3 (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism., Methods: Genetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells., Results: We assembled a cohort of 35 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro . Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells., Conclusion: Our study further refines the clinical and mutational spectrum of CUL3 -associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.