Liver pathology and biochemistry in patients with mutations in TRIM37 gene (Mulibrey nanism).

BACKGROUND AND AIMS: Mulibrey nanism (MUL) is a multiorgan disease caused by recessive mutations in the TRIM37 gene. Chronic heart failure and hepatopathy are major determinants of prognosis in MUL patients, which prompted us to study liver biochemistry and pathology in a national cohort of MUL patients. METHODS: Clinical, laboratory and imaging data were collected in a cross-sectional survey and retrospectively from hospital records. Liver histology and immunohistochemistry for 10 biomarkers were assessed. RESULTS: Twenty-one MUL patients (age 1-51 years) with tumour suspicion showed moderate congestion, steatosis and fibrosis in liver biopsies and marginally elevated levels of serum GGT, AST, ALT and AST to platelet ratio index (APRI) in 20%-66%. Similarly, GGT, AST, ALT and APRI levels were moderately elevated in 12%-69% of 17 MUL patients prior to pericardiectomy. In a cross-sectional evaluation of 36 MUL outpatients, GGT, total bilirubin and galactose half-life (Gal½) correlated with age (r = 0.45, p = .017; r = 0.512, p = .007; r = 0.44, p = .03 respectively). The frequency of clearly abnormal serum values of 15 parameters analysed, however, was low even in patients with signs of restrictive cardiomyopathy. Transient elastography (TE) of the liver revealed elevated levels in 50% of patients with signs of heart failure and TE levels correlated with several biochemistry parameters. Biomarkers of fibrosis, sinusoidal capillarization and hepatocyte metaplasia showed increased expression in autopsy liver samples from 15 MUL patients. CONCLUSION: Liver disease in MUL patients was characterized by sinusoidal dilatation, steatosis and fibrosis with individual progression to cirrhosis and moderate association of histology with cardiac function, liver biochemistry and elastography.

Renal findings in patients with Mulibrey nanism.

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.

Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism.

Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for tumors, fatty liver, and type 2 diabetes. MUL is caused by loss-of-function mutations in TRIM37, which encodes an E3 ubiquitin ligase belonging to the tripartite motif (TRIM) protein family and having both peroxisomal and nuclear localization. We describe a congenic Trim37 knock-out mouse (Trim37(-/-)) model for MUL. Trim37(-/-) mice were viable and had normal weight development until approximately 12 months of age, after which they started to manifest increasing problems in wellbeing and weight loss. Assessment of skeletal parameters with computer tomography revealed significantly smaller skull size, but no difference in the lengths of long bones in Trim37(-/-) mice as compared with wild-type. Both male and female Trim37(-/-) mice were infertile, the gonads showing germ cell aplasia, hilus and Leydig cell hyperplasia and accumulation of lipids in and around Leydig cells. Male Trim37(-/-) mice had elevated levels of follicle-stimulating and luteinizing hormones, but maintained normal levels of testosterone. Six-month-old Trim37(-/-) mice had elevated fasting blood glucose and low fasting serum insulin levels. At 1.5 years Trim37(-/-) mice showed non-compaction cardiomyopathy, hepatomegaly, fatty liver and various tumors. The amount and morphology of liver peroxisomes seemed normal in Trim37(-/-) mice. The most consistently seen phenotypes in Trim37(-/-) mice were infertility and the associated hormonal findings, whereas there was more variability in the other phenotypes observed. Trim37(-/-) mice recapitulate several features of the human MUL disease and thus provide a good model to study disease pathogenesis related to TRIM37 deficiency, including infertility, non-alcoholic fatty liver disease, cardiomyopathy and tumorigenesis.

Testicular failure and male infertility in the monogenic Mulibrey nanism disorder.

CONTEXT: Few monogenic mutations causing human male infertility have been identified to date. OBJECTIVE: We studied pubertal development and fecundity in males with Mulibrey nanism (MUL) caused by mutations in the TRIM37 gene. DESIGN, SETTING, AND PATIENTS: Twenty-eight male MUL patients of the Finnish national cohort aged 8.7 to 50.0 yr (median age, 28.8) at the end of observation were followed for 10 yr beginning from 2000-2001. MAIN OUTCOME MEASURES: Clinical characteristics, reproductive hormone levels, semen quality, and testicular histology were assessed. RESULTS: The external genital phenotype was normal. In childhood and prepuberty, serum levels of FSH, LH, testosterone (T), and inhibin B were normal. Puberty started spontaneously at a median age of 12.6 yr (range, 11.1-15.0), and FSH, LH, T, and inhibin B levels increased adequately until midpuberty. Thereafter, testicular growth and virilization proceeded slowly. Concomitantly, FSH, and to a lesser extent LH, showed a progressive increase to hypergonadotropic levels in all patients, whereas inhibin B decreased and T leveled off. Testicular size was small (median volume, 8.7 ml; range, 3.5-18.3 ml in adults). All semen samples showed severe oligoasthenozoospermia or azoospermia. None of the patients had a history of spontaneous fertility, but four men had undergone infertility treatment, which in one case was successful. All histological MUL samples showed varying degrees of degeneration. CONCLUSIONS: All adult MUL males have a unique disorder of testicular function with small testes, elevated FSH and LH, and low inhibin B. In MUL, mutations in TRIM37 lead to disturbance of sexual maturation, and fertility is severely compromised. Thus, TRIM37 is a novel gene causing male infertility.

High frequency of tumours in Mulibrey nanism.

Mulibrey nanism (MUL) is a monogenic disorder with prenatal-onset growth failure, typical clinical characteristics, cardiopathy and tendency for a metabolic syndrome. It is caused by recessive mutations in the TRIM37 gene encoding for the peroxisomal TRIM37 protein with ubiquitin-ligase activity. In this work, the frequency and pathology of malignant and benign tumours were analysed in a national cohort of 89 Finnish MUL patients aged 0.7-76 years. The subjects had a clinical and radiological evaluation, and histological and immunohistocemical analyses on specimens obtained from biopsy, surgery or autopsy, were performed. The results show that the MUL patients have disturbed architecture with ectopic tissues and a high frequency of both benign and malignant tumours detectable in several internal organs. A total of 210 tumorous lesions were detected in 66/89 patients (74%). Fifteen malignancies occurred in 13 patients (15%), seven of them in the kidney (five Wilms' tumours), three in the thyroid gland, two gynaecological cancers, one gastrointestinal carcinoid tumour, one neuropituitary Langerhans cell histiocytosis and one case of acute lymphoblastic leukaemia (ALL). Tumours detected by radiology in the liver and other organs mainly comprised strongly dilated blood vessels (peliosis), vascularized cysts and nodular lesions. The lesions showed strong expression of the endothelial cell markers CD34 and CD31 as well as the myocyte marker alpha-smooth muscle actin (alpha-SMA). Our findings show that MUL is associated with frequent malignant tumours and benign adenomatous and vascular lesions, as well as disturbed organ development.

Growth and growth hormone therapy in subjects with mulibrey nanism.

OBJECTIVES: Mulibrey nanism is a monogenic disorder with prenatal-onset growth restriction, mild dysmorphic features, and a strong tendency for insulin resistance but no major neurologic handicap. Growth hormone therapy has been shown to promote short-term growth in children born small for gestational age, but the experience with long-term therapy is insufficient. Growth in patients with mulibrey nanism has not been analyzed previously in detail. METHODS: We evaluated the natural growth pattern and long-term impact of growth hormone treatment in the largest cohort of subjects with mulibrey nanism to date. The study included 72 living subjects followed up to 30 years. Thirty (18 female) were treated with recombinant human growth hormone for a median period of 5.7 years. Patients were reviewed at baseline and every 6 to 12 months during the therapy. Evaluation included assessment of height, weight, and pubertal status and laboratory analyses. Glucose metabolism was evaluated by oral glucose-tolerance test. RESULTS: The patients were born small for gestational age with immature craniofacial features. They experienced a continuous deceleration in height (median decrement of 1.1 SDS) and weight for height (median reduction of 17%) in infancy followed by an incomplete catch-up growth lasting up to school age. The final adult height averaged 136 cm in girls and 150 cm in boys. Growth hormone treatment improved the prepubertal growth but had only little impact on adult height (+5 cm). The treated subjects showed earlier bone maturation and growth arrest but not a significant increase in insulin resistance. On the contrary, the subjects who were treated with growth hormone were slimmer and had less metabolic syndrome as young adults. CONCLUSIONS: The patients with mulibrey nanism showed a distinct postnatal growth pattern. The growth hormone treatment was safe and induced a good short-term effect, but the impact on the adult height remained modest.

Tissue expression of the mulibrey nanism-associated Trim37 protein in embryonic and adult mouse tissues.

Mutations in the TRIM37 gene underlie mulibrey nanism (muscle-liver-brain-eye nanism), a rare monogenic developmental disorder characterized by severe growth failure, characteristic dysmorphic features, cardiopathy, failure of sexual maturation, and metabolic syndrome. The TRIM37 protein, a member of the tripartite motif subfamily of RING finger proteins, is highly conserved between human and mouse. High evolutionary conservation is seen also at the gene level. We here show that the mouse Trim37 gene presents several alternative splice variants, including a testis-specific transcript with an additional 3' exon. By Northern blot analysis the highest level of Trim37 mRNA was detected in testis and brain. In embryonic tissues, the Trim37 protein was detected in epithelia, including ducts of the developing pancreas, epithelium of the midgut and nasal epithelium. In adult mouse tissues, Trim37 immunoreactivity was detected in the central and peripheral nervous systems, including enteric ganglia, retina, and the adrenal medulla. Moreover, specific cellular populations in the adenohypophysis, pancreatic islets, intestine and gonads showed intense Trim37 staining. Both nuclear and granular cytoplasmic staining patterns were observed. These findings are in agreement with the clinical manifestations of mulibrey nanism and provide a basis for the future analysis of Trim37 knock-out mice.

Insulin resistance syndrome in subjects with mutated RING finger protein TRIM37.

We evaluated the glucose and lipid metabolism in 65 patients (aged 1.1-55 years) with mulibrey (muscle-liver-brain-eye) nanism (MUL), which is a monogenic disorder with prenatal-onset growth failure and typical clinical characteristics. MUL is caused by mutations in the TRIM37 gene, encoding a peroxisomal protein (TRIM37) with E3 ubiquitin-ligase activity. The subjects underwent clinical evaluation, abdominal ultrasonography, and laboratory measurements, including a 3-h oral glucose tolerance test. The results showed a dramatic change in glucose and lipid metabolism with age in MUL subjects. While the children had low fasting glucose and insulin levels, 90% of the adults had high fasting and postload insulin values (up to 1,450 mU/l). A 10-fold decrease in the fasting glucose-to-insulin ratio and a 4-fold decrease in whole-body insulin sensitivity index were observed. Insulin resistance, fatty liver, high serum leptin, hypertension, and acantosis nigricans were already evident in many slim prepubertal children. Half of the adults had type 2 diabetes, and an additional 42% showed impaired glucose tolerance. Seventy percent fulfilled the National Cholesterol Education Program criteria for metabolic syndrome. The peroxisomal targeting and the functional link of TRIM37 to the ubiquitin-proteosome pathway may provide novel clues to the development of metabolic syndrome.