Myhre syndrome: new reports, review, and differential diagnosis

Abstract

C olorectal cancer (CRC) is the third most common cancer diagnosed in both men and women, and the second most common cause of cancer deaths in the United States. There were approximately 150 000 new cases resulting in 57 000 deaths in 2002.1 CRC is one of the most studied cancer types and its underlying aetiology best elucidated. Colorectal tumorigenesis involves a multistep process including genetic and epigenetic alterations of numerous CRC related genes that may act as either oncogenes or tumour suppressor genes. [2][3][4][5] The majority of sporadic CRCs are characterised by deletions of large chromosomal segments, which are thought to represent the loss of wild type tumour suppressor genes.6 7 About 15% of sporadic CRCs, on the other hand, show microsatellite instability (MSI), characterised by the insertion and/or deletion of simple repeat sequences and indicative of the involvement of defective mismatch repair. Birt-Hogg-Dubé syndrome (BHD, OMIM 135150) is an inherited autosomal dominant syndrome characterised by a triad of cutaneous lesions consisting of fibrofolliculomas, trichodiscomas, and acrochordons. 10 A wide spectrum of neoplastic and non-neoplastic features has been described in BHD patients, 11 including diverse types of kidney tumours 12-17 and spontaneous pneumothorax.12-16 18 BHD has also been reported to be associated with colonic polyposis and colorectal neoplasia, 13 19-22 although a large study of 223 patients from 33 BHD families could not establish such a relation. 23 We recently reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. 13 The BHD gene has been mapped to chromosome subband 17p11.2 12 14 and recently identified to encode a novel protein named follicullin. 15 Based on the presence of inactivating BHD mutations in BHD patients, and the detection of LOH in a significant proportion of BHD related tumours, the BHD gene was considered to be a tumour suppressor gene. A 44% frequency of frameshift mutations within a mononucleotide (C) 8 tract (nt 1733-1740) has been detected in BHD patients, 15 and this repeat tract represents a BHD mutational hot spot.13 15 Other studies have reported the presence of frameshift mutations within intragenic mononucleotide tracts of the TGFBR2 and BAX genes in CRC cell lines and tumours with high level MSI.24 25 The poly C tract of the BHD gene may therefore be a potential site of mutation in CRC characterised by MSI.We have evaluated the role of the BHD gene in 47 unselected colorectal tumours (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analysing 46 of the tumours for LOH in the chromosome region surrounding the BHD locus. Furthermore, alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues where a sufficient quantity of DNA was available. We report the detection of two novel somatic missense mutations of ...

Myhre and LAPS syndromes: clinical and molecular review of 32 patients

“…Other features noted included hearing loss, hypermetropia, congenital heart defect, cryptorchidism and pilonidal dimple. A total of 19 cases have subsequently been reported (6 females and 13 males) [2][3][4][5][6][7][8][9][10][11][12] highlighting variability in (i) the severity of the growth deficiency ranging from À6 to À2 SD and (ii) the degree of intellectual disability in which intelligence ranges from low to normal.…”

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

“…Only 16 patients have been reported with this syndrome to date. [18][19][20][21][22][23][24][25][26][27][28] As patients with larger overlapping deletions do not have clear characteristics of Myhre syndrome and recessive inheritance for Myhre syndrome cannot be excluded, sequencing analysis of the coding genes residing in the SRO was performed on patient 3, who had the most resemblance with Myhre syndrome, as well as on two other unrelated patients with suspicion of Myhre syndrome. No mutations were however identified.…”

Myhre syndrome in a female with previously undescribed symptoms: Further delineation of the phenotype

“…Developmental delay is common, autism and difficult social relationships have been described [Titomanlio et al, 2001;Burglen et al, 2003]. A thick skin was observed in a number of patients [Titomanlio et al, 2001;Burglen et al, 2003]. Titomanlio et al [2001] saw a thickening of the dermis with anomalous subcutaneous tissue at skin histology.…”

“…The syndrome seems to be characterized mainly by short stature with a ''muscular'' build, generalized nonprogressive stiffness of joints, and a distinctive face with prognathism. Developmental delay is common, autism and difficult social relationships have been described [Titomanlio et al, 2001;Burglen et al, 2003]. A thick skin was observed in a number of patients [Titomanlio et al, 2001;Burglen et al, 2003].…”

“…One case was reported with thickening of the dermis with anomalous subcutaneous tissue [Titomanlio et al, 2001]. There is considerable phenotypic overlap with acromicric dysplasia, Moore-Federman syndrome, Weill-Marchesani syndrome, and geleophysic dysplasia and there has been some discussion concerning the distinctness of these disorders [Winter et al, 1989;Figuera, 1996;Hennekam et al, 1996;Burglen et al, 2003]. Nevertheless, Myhre syndrome is generally accepted as a distinct clinical entity since features present in acromicric dysplasia, Weill-Marchesani syndrome, and geleophysic dysplasia, notably structural eye abnormalities and cardiac valve thickening, are lacking.…”