Mulibrey nanism

Keyword

Mulibrey nanism; TRIM37; dwarfism; Wilms'tumor.

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Identity

Other names	Muscle-liver-brain-eye nanism
	Pericardial constriction and growth failure
	Perheentupa syndrome
Atlas_Id	10125
Genes implicated in	TRIM37
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).

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.
	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).
	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 Wilms'tumour 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).
Cytogenetics of cancer	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

Gene Name	TRIM37 (tripartite motif-containing 37)
Alias	Tripartite Motif Containing 37 MUL Tripartite Motif-Containing Protein 37 RING-B-Box-Coiled-Coil Protein Mulibrey Nanism Protein KIAA0898 POB1 E3 Ubiquitin-Protein Ligase TRIM37 Tripartite Motif-Containing 37 EC 6.3.2 TEF3
Location	17q22

DNA/RNA
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.

Protein
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).

Mutations

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)

Bibliography

Constrictive pericarditis with dwarfism in two siblings (mulibrey nanism)

Cumming, G. R., Kerr, D., Ferguson, C. C

J. Pediat. 1976 ; 88: 569-572.

PMID 1255313

Is autosomal recessive Silver-Russel syndrome a separate entity or is it part of the 3-M syndrome spectrum?

Akawi NA, Ali BR, Hamamy H, Al-Hadidy A, Al-Gazali L.

Am J Med Genet A. 2011 Jun;155A(6):1236-45

PMID 21548126

Gene encoding a new RING-B-box-coiled-coil protein is mutated in mulibrey nanism

Avela, K., Lipsanen-Nyman, M., Idanheimo, N., Seemanova, E., Rosengren, S., Makela, T. P., Perheentupa, J., de la Chapelle, A., Lehesjoki, A.-E.

Nature Genet. 2000 ;25: 298-301.

PMID 10888877

Mulibrey nanism

Balg, S., Stengel-Rutkowski, S., Dohlemann, C., Boergen, K.

Clin. Dysmorph. 1995 ; 4: 63-69.

PMID 7735507

TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein

Bhatnagar, S., Gazin, C., Chamberlain, L., Ou, J., Zhu, X., Tushir, J. S., Virbasius, C.-M., Lin, L., Zhu, L. J., Wajapeyee, N., Green, M. R.

Nature 2014; 516: 116-120

PMID 25470042

Characterisation of the mulibrey nanism-associated TRIM37 gene: transcription initiation, promoter region and alternative splicing

H&aulm;mäläinen RH, Joensuu T, Kallijärvi J, Lehesjoki AE

Gene 2006 Jan 17;366(1):180-8.

PMID 16310976

Wilms'tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism.

Hamalainen, R. H., Mowat, D., Gabbett, M. T., O'Brien, T. A., Kallijarvi, J., Lehesjoki, A.-E.

Clin. Genet. 2006 ; 70: 473-479.

PMID 17100991

Antibody deficiency and isolated growth hormone deficiency in a girl with mulibrey nanism

Haraldsson, A., van der Burgt, C. J. A. M., Weemaes, C. M. R., Otten, B., Bakkeren, J. A. J. M., Stoelinga, G. B. A

Europ. J. Pediat. 1993 ;152: 509-512.

PMID 8335020

A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity

Jagiello, P., Hammans, C., Wieczorek, S., Arning, L., Stefanski, A., Strehl, H., Epplen, J. T., Gencik, M

Hum. Mutat. 2003 ; 21: 630-635.

PMID Hum.

High frequency of tumours in Mulibrey nanism

Karlberg N, Karlberg S, Karikoski R, Mikkola S, Lipsanen-Nyman M, Jalanko H.

J Pathol. 2009 Jun;218(2):163-71.

PMID 19334051

Mulibrey nanism: clinical features and diagnostic criteria

Karlberg, N., Jalanko, H., Perheentupa, J., Lipsanen-Nyman, M

J. Med. Genet. 2004 ; 41: 92-98.

PMID 14757854

Failure of sexual maturation in mulibrey nanism. (Letter)

Karlberg, S., Tiitinen, A., Lipsanen-Nyman, M

Eng. J. Med. 2004 ; 351: 2559-2560.

PMID 15590968

Mulibrey nanism: three additional patients and a review of 39 patients

Lapunzina, P., Rodriguez, J. I., de Matteo, E., Gracia, R., Moreno, F.

Am. J. Med. Genet. 1995 ; 55: 349-355.

PMID 7726235

Craniofacial and dental study of mulibrey nanism

Myllarniemi, S., Koski, K., Perheentupa, J

Cleft Palate J. 1978 ;15: 369-377.

PMID 281281

Mulibrey nanism, an autosomal recessive syndrome with pericardial constriction

Perheentupa, J., Autio, S., Leisti, S., Raitta, C., Tuuteri, L.

Lancet 1973 ; 302: 351-355.

PMID 4124529

Citation

This paper should be referenced as such :

Piccione M, Salzano E

Mulibrey nanism;

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Tumors/MulibreyID10125.html

External links

OMIM	253250
Orphanet	MULIBREY nanism
MeSH	C538604  D050336
MedGen	C538604  D050336
ICD-10	Q87.1
Other database	(ClinVar)
Association	ALA SARKILAHTI. Mulibrey Nanismi ry

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

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