Mulibrey nanism and immunological complications: a comprehensive case report and literature review

Abstract

Introduction: Mulibrey nanism (MUL) is a rare disorder caused by TRIM37 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 TRIM37. 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.

Keywords: CD4+ lymphopenia; Mulibrey; case report; hypogammaglobulinemia; pericardial constriction.

Figure 1

Timeline with relevant data from the patient’s history. WT, Wilms’ tumor; CT, chemotherapy; RT, radiotherapy; US, ultrasound; IVIG,intravenous immunoglobuline; MRI, magnetic resonance imaging.

Figure 2

(A) Family pedigree with the inheritance pattern. TRIM37 duplication and deletion are showed. (B) Sanger sequencing of TRIM37 gene revealed the presence of the monoallelic NM_001320987.3 c.2357dupA (p. Asp786GlufsTer7), a duplication leading to a stop codon seven amino acids downstream. (C) Schematic representation of the TRIM37 gene and TRIM37 protein. The positions of mutations and deletions (colored horizontal lines) reported in literature in association with an immunological phenotype are shown in green (Jobic et al) and blue (Bruzzaniti et al) colors. In red is depicted the molecular lesions found in the patient reported in this paper. (D) Flow cytometry plots of peripheral blood mononucleate cells from the patient and two healthy controls. CD4+ and CD8+ cells subsets gated on CD3+ cells and T-cell subsets. (E) Comparison of T-cell differentiation subsets in patient and controls. HC1, healthy control 1; HCs, healthy control 1 and healthy control 2; PT, Mulibrey patient; TEMRA, terminally differentiated effector memory T cells; TEM, T-effector memory; TCM, T-central memory. Black arrow indicates the proband.

Figure 3

(A) CD4+ proliferation assay after 4 days stimulation with phytohemagglutinin 1 mcg/ml or antiCD3 and anti-CD28 1 mcg/ml with or without IL2 10 ng/ml. (B) Exemplary cell trace violet dilution after 4 days stimulation with PHA 1 mcg/ml. (C) CD25-expression level in CD4+ and CD8+ cells after 4 days stimulation with anti-CD3 1 mcg/ml and anti-CD28 1 mcg/ml. (D) Six-week thymocyte development assessed by artificial thymic organoid generated by culturing DLL4-expressing stromal cell line (MS5-hDLL4) with CD34+ cells isolated from peripheral blood cells of the patient compared to healthy control. MFI, mean fluorescence intensity; HC1, healthy control 1; HCs, healthy control 1 and 2; PT, Mulibrey patient; PHA, phytohemagglutinin.