Mulibrey nanism

2015-12-01   Maria Piccione  , Emanuela Salzano  

Department of Sciences for Health Promotion and Mother and Child Care G. DAlessandro, University of Palermo, Palermo, Italy. [email protected]; [email protected]

Abstract

Mulibrey (MUscle-LIver-BRain-EYe) nanism is a rare autosomal recessive disorder caused by mutations in TRIM37 gene and characterized by growth failure with prenatal onset, dysmorphic features, muscolar hypotonia, veins congestion secondary to constri

Identity

Name

Mulibrey nanism

Alias

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

Inheritance

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).

Orphanet

2576 MULIBREY nanism

Omim

253250

Mesh

C538604;D050336

Clinics

Phenotype and clinics

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.
Atlas Image
Three major signs with one minor sign or two major signs with three minor signs are required for the clinical diagnosis. SDS = standard deviation scores. Adapted by Karlberg et al. 2004.

Differential diagnosis

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).
Atlas Image
Comparison between Mulibrey Nanism, Silver-Russell and 3-M Syndromes phenotype.

Neoplastic risk

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).

Treatment

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).

Evolution

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).

Prognosis

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).

Cytogenetics

Note

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

Acquired condition

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 .

Genes involved and Proteins

Alias

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

Transcription

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.

Description

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).

Expression

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).

Note

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)

To be noted

Associations

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

Databases

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

Article Bibliography

Pubmed IDLast YearTitleAuthors
12553131976Constrictive pericarditis with dwarfism in two siblings (mulibrey nanism).Cumming GR et al
215481262011Is autosomal recessive Silver-Russel syndrome a separate entity or is it part of the 3-M syndrome spectrum?Akawi NA et al
108888772000Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism.Avela K et al
77355071995Mulibrey nanism.Balg S et al
254700422014TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein.Bhatnagar S et al
163109762006Characterisation of the mulibrey nanism-associated TRIM37 gene: transcription initiation, promoter region and alternative splicing.Hämäläinen RH et al
171009912006Wilms' tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism.Hämäläinen RH et al
83350201993Antibody deficiency and isolated growth hormone deficiency in a girl with Mulibrey nanism.Haraldsson A et al
193340512009High frequency of tumours in Mulibrey nanism.Karlberg N et al
147578542004Mulibrey nanism: clinical features and diagnostic criteria.Karlberg N et al
155909682004Failure of sexual maturation in Mulibrey nanism.Karlberg S et al
77262351995Mulibrey nanism: three additional patients and a review of 39 patients.Lapunzina P et al
2812811978Craniofacial and dental study of mulibrey nanism.Myllärniemi S et al
41245291973Mulibrey nanism, an autosomal recessive syndrome with pericardial constriction.Perheentupa J et al