Mulibrey nanism

Muscle-liver-brain-eye nanism , Pericardial constriction and growth failure , Perheentupa syndrome

115 patients described all over the world, 85 of which from Finland where it has been estimated an incidence rate of 1\/37000 (Karberg et al.2004). It is an autosomal recessive disorder due to homozygous or compound heterozygous mutations in the TRIM37 gene, (605073) even if sporadic cases have been reported in several ethnic groups (Jagiello et al.2003).

2576 MULIBREY nanism

253250

C538604;D050336

Growth:
Short stature with prenatal onset (birth length and birth weight 1.5 - 2 SD below mean with relatively macrocephaly - occipitofrontal head circumference 0.5 below SD; adult male height 136-161 cm; adult female height 126-151 cm) (Karlberg et al.2006)
Head:
Craniofacial features: triangular face, low nasal bridge, high and broad forehead, and scaphocephaly with occipitofrontal bossing
Eye findings: Mild hypertelorism, telecanthus, yellowish dots in fundi, decreased retinal pigmentation with dispersion, hypoplasia of choroid, astigmatism, strabismus (Karlberg et al.2004)
Mouth: relatively small tongue, dental crowding, hypodontia of second bicuspid (Myllarniemi et al. 1978)
Cardiovascular System:
Constrictive pericarditis, globular shaped heart on x-ray, congestive heart failure, myocardial fibrosis, elevated venous pressure, prominent veins in the neck, congestion in the lungs, abnormal fluid accumulation in the abdomen (ascites), swelling of the arms and\/or legs (peripheral edema) (Perheentupa et al.1973; Cumming et al.1976)
Abdomen: hepatomegaly, sporadic description of urinary tract malformations
Muscle: muscular hypotonia
Central Nervous System: no intellectual disability, dysarthria
Voice: high-pitched voice
Skin: cutaneous nevi flammei
Endocrinology: delayed puberty with irregular menstrual periods, premature ovarian failure, incomplete breast development, infertility, insuline resistance type2 diabetes,possible hypoplasia of different endocrine glands(Haraldsson 1993; Kalberg et al.2004; Karlberg et al.2007).
Radiological findings:
Cerebral: J-shaped sella turcica, absent or small frontal sinus, absent or small sphenoidal sinus
Skeletal: slender long bones with thick cortex and narrow medullary channel, fibrous dysplasia especially in the middle third of tibia.

Mulibrey nanism shares some clinical aspects mainly with two other syndromes (Silver Russel Syndrome and 3-M syndrome spectrum (OMIM 273750)) characterized by growth failure and dysmorphic features (Akawi et al.2011).

Benign tumors especially cystic and benign adenomatous lesions have been identified in different organs (renal cortical cysts, pancreatic cysts, thyroid lesions); the 22% of patients develop fibrous dysplasia of long bones; 6% of reported patients were diagnosed for a Wilms tumor. Female patients with premature ovarian failure are at high risk for ovarian fibrothecomas or other stromal ovarian cells tumors (Hamalainen et al., 2006; Karlberg et al. 2009).

Patients with constrictive pericarditis may be treated with surgery with good results, while treatment with diuretics and digoxin may be prescribed for those affected by progressive heart failure. Hormone replacement therapy may be evaluated in children with growth hormone deficiency, delayed puberty or very irregular menstrual periods, hypothyroidism, hypoadrenocorticism and abnormal gonadal function. All females should be monitored closely for ovarian tumors, especially in presence of premature ovarian failure (Hamalainen et al., 2006; Karlberg et al. 2006; Karlberg et al. 2009).

Growth failure usually progresses during early infancy; after 10 years of age blood fasting glucose levels tend to increase; the diagnosis of Wilmstumour is usually close to 1 year of age, while after puberty all female should undergo to a gynaecological follow-up; GH replacement therapy seems to have better short term effects than on the final adult stature (Kalberg et al.2004; Kalberg et al.2007).

The most life threatening complication is represented by cardiac involvement; life expectancy also depends strictly on precocious diagnosis of respiratory and feeding complications and malignancies (Balg et al.1995; Lapunzina et al.1995; Karlberg et al. 2006).

The 250 Kb critical cytogenetic region for Muliebry nanism encompasses the TRIM37 gene locus on chromosome 17q22 (Avela et al.1997).

A certain number of breast cancer cell lines show amplification of the 17q22-23 chromosome region, resulting in an overexpression of TRIM37 gene which acts as a promotor of cellular transformation by silencing onco-suppressor genes .

Tripartite Motif Containing 37MULTripartite Motif-Containing Protein 37RING-B-Box-Coiled-Coil ProteinMulibrey Nanism ProteinKIAA0898POB1E3 Ubiquitin-Protein Ligase TRIM37Tripartite Motif-Containing 37EC 6.3.2TEF3

Northern blot analysis shows two transcript: the first-one, TRIM37a of about 4.5-kb and the second-one, TRIM37b of approximately 3.9 kb.

This pleiotropic gene contains 4488 nucleotides from 24 exons. The encoded protein is a peroxisomal member of the tripartite motif (TRIM) family including a zinc-binding domains, a RING finger region, a B-box motif and a coiled-coil domain. TRIM37 is related to some Polycomb group (PcG) multiprotein PRC2-like complex and monoubiquitinates histone H2A, mediating an epigenetic transcriptional repression of target genes( Bhatnagar et al 2014).

The results of tissue-specific expression levels of both transcripts TRIM37a and TRIM37b measured in multiple tissue cDNA panels by qPCR also show that TRIM37a is ubiquitously expressed with higher levels in testis and brain, whereas TRIM37b is mainly expressed in testis. In addition tissue level expression is slightly higher in fetal than in adult tissue (Hämäläinen et al. 2006).

To date 23 TRIM37 gene mutations have been reported as pathogenic variants and 18 of those have been associated to mulibrey nanism phenotype. The most common Finnish mutation is a 5 bp deletion resulting in an aberrant splicing site that causes frameshift with induction of a stop codon 10 codons downstream. Compound heterozygosity for two different mutation has also been found (http:\/\/www.ncbi.nlm.nih.gov\/clinvar)

http:\/\/mulibrey.awardspace.com\/ ALA SARKILAHTI. Mulibrey Nanismi ry

http:\/\/www.ncbi.nlm.nih.gov\/clinvar\/?term=Mulibrey (ClinVar)