Year: 2012
Type: dissertation
Study design: Observational Study
Abstract: Mulibrey nanism (MUL; OMIM 253250) is an autosomal recessive disorder belonging to the Finnish disease heritage and currently classified as a peroxisomal disorder. MUL is characterized by intrauterine-onset growth restriction, typical dysmorphic features, restrictive perimyocardial heart disease, and severe insulin resistance. The causative gene, TRIM37, is located on chromosome 17q22-q23 and encodes for a peroxisomal protein (TRIM37) with ubiquitin E3-ligase activity, suggesting its role in proteasomal protein degradation. All 19 mutations identified to date, including 4 in Finnish patients, are likely to produce a non-functioning protein. For many decades, the clinical care and follow-up of Finnish MUL patients were based at the Children s Hospital in Helsinki, generating a unique clinical experience and data set for this patient group. In follow-up, it became evident that a substantial proportion of these patients developed hypogonadism, were infertile, and had an increased risk of developing tumors. Thus, the principal focus of this study was to characterize the hypogonadism and infertility associated with this disorder, and furthermore to define the tumors and tumor predisposition in MUL, both clinically and immunohistochemically. A total of 92 Finnish patients (0.7-77 years) were included in the study; 22 post pubertal females participated in the female hypogonadism study, and 28 male patients participated in the male hypogonadism study. All hospital records were evaluated, and physical, laboratory, and radiological examinations were performed according to clinical protocols. Biopsies (taken on clinical grounds) and autopsy samples were used for histological and immunohistochemical studies. In addition, 15 freshly frozen samples from sporadic ovarian fibrothecomas were analyzed for the role of TRIM37 in the development of these tumors. All MUL patients developed hypogonadism due to a primary gonadal defect and were either infertile or severely subfertile. Women demonstrated spontaneous puberty, incomplete breast development, and early irregularity of menstrual periods with subsequent ovarian failure. Their ovaries were hypoplastic and their uteri were small. The men also experienced spontaneous puberty with somewhat small testes characterized by varying degrees of degeneration and few mature germ cells. Semen samples showed either severe oligoasthenozoospermia or azoospermia. No spontaneous pregnancies had been conceived among the MUL patients. Four men had undergone infertility treatment, which in one case was successful, resulting in the delivery of a healthy child. The MUL patients displayed a high frequency of both benign and malignant tumors especially of endocrine origin. A total of 232 tumorous lesions in several different organs were discovered in the patient cohort. Histologically, the architecture of several organs was disturbed, indicating aberrant organogenesis. One of the most frequent tumors was ovarian fibrothecomas, which are fairly uncommon in the general population, found in 55% of the female patients. The study of inherited monogenic disorders has contributed substantially to our understanding of gene function and human disease. In MUL, mutations in TRIM37 lead to failure of sexual maturation in both females and males, and fertility is seriously compromised. In addition, the patients are at a very high risk for developing benign and malignant tumors in several different organs. This study suggests a role for TRIM37 protein in the cellular functions governing gametogenesis, gonadal function, and proliferation.
Source: Työväentutkimus Vuosikirja
Author: Susann Karlberg
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1491379792