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Frontiers in Immunology 2023Mulibrey nanism (MUL) is a rare disorder caused by gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased... (Review)
Review
INTRODUCTION
Mulibrey nanism (MUL) is a rare disorder caused by gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased risk of Wilms' tumor. Although immune system impairment has been documented in MUL, the underlying mechanisms remain poorly understood.
METHODS
We present a case of MUL with progressive lymphopenia and review similar cases from the literature.
RESULTS
Our patient presented with prenatal onset growth restriction, characteristic dysmorphic features, and Wilms' tumor. She developed progressive lymphopenia starting at 10 years of age, leading to the initiation of intravenous immunoglobulin (IVIG) replacement therapy and infection prophylaxis. Genetic analysis detected a likely pathogenic variant on the maternal allele and copy number loss on the paternal allele in . Subsequently a cardiac magnetic resonance imaging was conducted revealing signs of pericardial constriction raising concerns for intestinal lymphatic losses. The cessation of IVIG therapy did not coincide with any increase in the rate of infections. The patient exhibited a distinct immunological profile, characterized by hypogammaglobulinemia, impaired antibody responses, and skewed T-cell subsets with an altered CD4+/CD8+ ratio, consistent with previous reports. Normal thymocyte development assessed by artificial thymic organoid platform ruled out an early hematopoietic intrinsic defect of T-cell development.
DISCUSSION
The immunological profile of MUL patients reported so far shares similarities with that described in protein-losing enteropathy secondary to CHF in Fontan circulation and primary intestinal lymphangiectasia. These similarities include hypogammaglobulinemia, significant T-cell deficiency with decreased CD4+ and CD8+ counts, altered CD4+/CD8+ ratios, and significantly modified CD4+ and CD8+ T-cell phenotypes toward effector and terminal differentiated T cells, accompanied by a loss of naïve CD45RA+ T lymphocytes. In MUL, CHF is a cardinal feature, occurring in a significant proportion of patients and influencing prognosis. Signs of CHF or constrictive pericarditis have been evident in the case reported here and in all cases of MUL with documented immune dysfunction reported so far. These observations raise intriguing connections between these conditions. However, further investigation is warranted to in-depth define the immunological defect, providing valuable insights into the pathophysiology and treatment strategies for this condition.
Topics: Female; Humans; Agammaglobulinemia; Heart Failure; Immunoglobulins, Intravenous; Kidney Neoplasms; Lymphopenia; Mulibrey Nanism; Mutation; Nuclear Proteins; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Wilms Tumor
PubMed: 38116000
DOI: 10.3389/fimmu.2023.1303251 -
Advances in Experimental Medicine and... 2003
Review
Topics: Animals; DNA-Binding Proteins; Dwarfism; Gene Expression; Humans; Muscle Proteins; Mutation; Peroxisomal Disorders; Phenotype; TEA Domain Transcription Factors; Transcription Factors
PubMed: 14713209
DOI: 10.1007/978-1-4419-9072-3_3 -
Cancer Reports (Hoboken, N.J.) May 2022Mulibrey-Nanism (Muscle-liver-brain-eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors... (Review)
Review
BACKGROUND
Mulibrey-Nanism (Muscle-liver-brain-eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors frequently. In the largest published series of MUL, 8% patients were reported to develop Wilms tumor (WT). The published literature lacks data regarding the best treatment protocol and outcome of this cohort of children with WT and MUL. We report here a 2-year-old boy with WT and MUL and present a review of literature on WT in MUL.
CASE
Our patient had associated cardiac problems of atrial septal defect, atrial flutter and an episode of sudden cardiac arrest. We managed him successfully with chemotherapy, surgery and multi-speciality care. He is alive and in remission at follow-up of 6 months.
CONCLUSION
A total of 14 cases (including present case) of WT have been reported in MUL and treatment details were available for six cases. They were managed primarily with surgery, chemotherapy with/without radiotherapy, and all achieved remission. The outcome data is available only for two cases, one has been followed up till 15 years post treatment for WT and other is our patient.
Topics: Child; Child, Preschool; Humans; Kidney Neoplasms; Male; Mulibrey Nanism; Nuclear Proteins; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Wilms Tumor
PubMed: 34309235
DOI: 10.1002/cnr2.1512 -
Cell Discovery Aug 2023The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure...
The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FIN (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (T) cell development and antibody production. The effects of Trim37 on T cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of T cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.
PubMed: 37528081
DOI: 10.1038/s41421-023-00561-z -
International Journal of Molecular... Dec 2018TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review,... (Review)
Review
TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review, we focus on TRIM37 in the normal cell and in pathological conditions, with an emphasis on the MULIBREY (MUscle-LIver-BRain-EYe) genetic disorder caused by mutations. TRIM37 is characterized by the presence of a RING domain, B-box motifs, and a coiled-coil region, and its C-terminal part includes the MATH domain specific to TRIM37. MULIBREY nanism is a rare autosomal recessive caused by mutations and characterized by severe pre- and postnatal growth failure. Constrictive pericarditis is the most serious anomaly of the disease and is present in about 20% of patients. The patients have a deregulation of glucose and lipid metabolism, including type 2 diabetes, fatty liver, and hypertension. Puzzlingly, MULIBREY patients, deficient for TRIM37, are plagued with numerous tumors. Among non-MULIBREY patients affected by cancer, a wide variety of cancers are associated with an overexpression of TRIM37. This suggests that normal cells need an optimal equilibrium in TRIM37 expression. Finding a way to keep that balance could lead to potential innovative drugs for MULIBREY nanism, including heart condition and carcinogenesis treatment.
Topics: Cardiovascular Diseases; Humans; Immunity, Innate; Inflammation; Mulibrey Nanism; NF-kappa B; Neoplasms; Nuclear Proteins; Polymorphism, Genetic; Tripartite Motif Proteins; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 30586926
DOI: 10.3390/ijms20010067 -
Clinical Dysmorphology Jan 1995Investigation of a 4-year-old boy with 'Russell-Silver-phenotype' led to the relatively rare diagnosis of Mulibrey nanism. Subsequently cardiac investigation confirmed a...
Investigation of a 4-year-old boy with 'Russell-Silver-phenotype' led to the relatively rare diagnosis of Mulibrey nanism. Subsequently cardiac investigation confirmed a constrictive pericarditis which is characteristic of this syndrome, although not included in the acronym (muscle, liver, brain, eye). Identification of this syndrome is important for genetic counselling of the parents (25% recurrence risk, McKusick No. 253250).
Topics: Child, Preschool; Dwarfism; Eye Abnormalities; Face; Humans; Male; Pericarditis, Constrictive; Phenotype; Syndrome
PubMed: 7735507
DOI: No ID Found -
The Annals of Thoracic Surgery Feb 2020Mulibrey nanism syndrome is a rare genetic disorder affecting multiple organ systems. The cardiovascular system is one of the most significantly affected, with...
Mulibrey nanism syndrome is a rare genetic disorder affecting multiple organ systems. The cardiovascular system is one of the most significantly affected, with simultaneous myocardial and pericardial disease. These patients are usually managed by pericardiectomy to resolve the milieu of hemodynamic problems ensuing due to concurrent constrictive and restrictive pathologies. We highlight the use of cardiac transplantation as a definitive management for a hemodynamically decompensated patient with Mulibrey nanism syndrome.
Topics: Echocardiography; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Male; Mulibrey Nanism; Tomography, X-Ray Computed; Young Adult
PubMed: 31260650
DOI: 10.1016/j.athoracsur.2019.05.021 -
Circulation. Genomic and Precision... Jun 2021
Topics: Adult; Female; Humans; Liver Cirrhosis; Mitral Valve Prolapse; Mulibrey Nanism; Rare Diseases
PubMed: 34096331
DOI: 10.1161/CIRCGEN.121.003430 -
American Journal of Medical Genetics.... Oct 2017Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction,...
Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver-Russell syndrome. We report here three patients in two distinct non-Finnish families from North France who were first suspected to have Silver-Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.
Topics: Adolescent; Child; Child, Preschool; Female; France; Gene Rearrangement; Humans; Infant; Male; Mulibrey Nanism; Mutation; Nuclear Proteins; Prognosis; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 28815877
DOI: 10.1002/ajmg.a.38381 -
Pediatric Nephrology (Berlin, Germany) Sep 2017Mulibrey nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth...
BACKGROUND
Mulibrey nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients.
METHODS
Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples.
RESULTS
Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman's space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial-mesenchymal transformation, α-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2-51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration.
CONCLUSIONS
Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Finland; Glomerular Filtration Rate; Humans; Infant; Kidney; Kidney Diseases, Cystic; Kidney Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Mulibrey Nanism; Mutation; Nuclear Proteins; Retrospective Studies; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Young Adult
PubMed: 28432469
DOI: 10.1007/s00467-017-3669-5