Multiple exostoses,mental retardation,hypertrichosis, and brain abnormalities in a boy with a de novo 8q24 submicroscopic interstitial deletion

Multiple exostoses represent a genetically heterogeneous disorder that may occur isolated or as part of a complex contiguous gene syndrome such as Langer-Giedion syndrome on chromosome 8 and the proximal 11p deletion syndrome on chromosome 11. Here we describe a boy with multiple exostoses, hypertrichosis, mental retardation, and epilepsy due to a de novo deletion on chromosome 8q24. Molecular analysis revealed that the deletion interval overlaps with the Langer-Giedion syndrome and involves the EXT1 gene and additional genes located distal to EXT1, but probably not encompassing the TRPS1 gene located proximal to EXT1.     

Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11

Hereditary multiple exostoses (EXT) is an autosomal dominantdisorder of enchondral bone formation characterized by multiplebony outgrowths (exostoses), with progression to osteosarcomain a minority of cases. The exclusive involvement of skeletalabnormalities distinguishes EXT from the clinically more complexLanger – Giedion syndrome (LGS), which is associated withdeletions at chromosome 8q24. Previously, linkage analysis hasrevealed a locus for EXT in the LGS region on chromosome 8q24.However, locus heterogeneity was apparent with 30% of the familiesbeing unlinked to 8q24. We report on two large pedigrees segregatingEXT in which linkage to the LGS region was excluded. To localizethe EXT gene(s) in these families we performed a genome searchincluding 254 microsatellite markers dispersed over all autosomesand the X chromosome. In both families evidence was obtainedfor linkage to markers from the proximal short and long armsof chromosome 11. Two-point analysis gave the highest lod scorefor D11S554 (Z_max = 7.148 at theta = 0.03). Multipoint analysisindicated a map position for the EXT gene between D11S905 andD11S916, with a peak multipoint lod score of 8. 10 at 6 cM fromD11S935. The assignment of a second locus for EXT to the pericentromericregion of chromosome 11 implicates an area that is particularlyrich in genes responsible for developmental abnormalities andneoplasia.     

Interstitial deletion of 11 (P11.2p12): A newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses (EXT2)

Individuals with deletions of the proximal portion of the short arm of chromosome 11 share many manifestations including mental retardation, biparietal foramina, minor facial anomalies, and multiple cartilaginous exostoses. The finding of multiple exostoses in these patients is remarkable as the disorder hereditary multiple exostoses, which is inherited in an autosomal dominant manner, has recently been mapped by linkage to three regions, including proximal 11p. We report the clinical and molecular findings in an additional patient with an 11(p11.2p12) deletion. Cytogenetic and molecular analysis demonstrated a de novo, paternally derived deletion for markers which have been shown to be tightly linked to the 11p locus (EXT2). These data support the location of EXT2 within this region and also provide information regarding the ordering of polymorphic markers on 11p. Deletion 11(p11.2p12) is a rare, yet specific, deletion syndrome involving the EXT2 locus, a gene for parietal foramina, and a mental retardation locus, and therefore can be classified as a contiguous gene deletion syndrome. © 1996 Wiley-Liss, Inc.     

Positional cloning of a gene involved in hereditary multiple exostoses

Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.      

Molecular and clinical examination of an Italian DEFECT11 family.

The DEFECT11 syndrome is a contiguous gene syndrome associated with deletions in the proximal part of chromosome 11p. In this study, we describe in an Italian family the co-existence of multiple exostoses (EXT) and enlarged parietal foramina (FPP), the two major symptoms of this syndrome, with abnormalities of the central nervous system. The latter may be a yet undescribed feature of DEFECT11 syndrome. FISH and molecular analysis allowed us to identify a small deletion on 11p11-p12, further refining the localisation of the FPP gene involved in the DEFECT11 syndrome.     

An interstitial,apparently-balanced chromosomal insertion in the etiology of Langer–Giedion syndrome in an Asian family

Langer–Giedion syndrome (LGS; MIM 150230), also called trichorhinophalangeal syndrome type II (TRPS2), is a contiguous gene syndrome caused by a one-copy deletion in the chromosome 8q23-q24 region, spanning the genes TRPS1 and EXT1. We identified an LGS family with two affected and two unaffected siblings from unaffected parents. To investigate the etiology of recurrence of LGS in this family, array CGH was performed on all family members. We identified a 7.29 Mb interstitial deletion at chromosome region 8q23-q24 in the two affected siblings, but no such deletion in the unaffected family members. However, the mother and one of the two unaffected siblings carried a 1.29 Mb deletion at chromosome region 8q24.1, sharing the distal breakpoint with the larger deleted segment found in the affected siblings. Another unaffected sibling had a 6.0 Mb duplication, sharing the proximal breakpoint of the deletion in the affected siblings. Karyotypic and FISH analyses in the unaffected mother revealed an insertional translocation of 8q23-q24 genomic material into chromosome 13: 46,XX,ins(13;8)(q33;q23q24). This insertional translocation in the mother results in the recurrence of LGS in this family, highlighting the importance of submicroscopic rearrangements in the genetic counseling for LGS.     

Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer--Giedion syndrome

The Langer-Giedion syndrome (tricho-rhino-phalangeal syndrometype II, TRPS II) is characterized by craniofacial dysmorphismand skeletal abnormalities. It combines the clinical featuresof TRPS I and multiple cartilaginous exostoses (EXT). We haveused YAC cloning, Southern blotting, PCR analysis, and fluorescencein situ hybridization to study chromosome 8 deletions, translocatlons,an inversion, and an Insertion in patients with TRPS I, TRPSII or EXT. Our results indicate that the TRPS gene maps morethan 1,000 kb proximal to the EXT1 gene and that both genesare affected in TRPS II. We conclude that TRPS II is not dueto pleiotropic effects of mutations in a single gene, but thatit is a true contiguous gene syndrome.     

Proximal 11p deletion syndrome (P11pDS): additional evaluation of the clinical and molecular aspects

The combination of multiple exostoses (EXT) and enlarged parietal foramina (foramina parietalia permagna, FPP) represent the main features of the proximal 11p deletion syndrome (P11pDS), a contiguous gene syndrome (MIM 601224) caused by an interstitial deletion on the short arm of chromosome 11. Here we present clinical aspects of two new P11pDS patients and the clinical follow-up of one patient reported in the original paper describing this syndrome. Recognised clinical signs include EXT, FPP, mental retardation, facial asymmetry, asymmetric calcification of coronary sutures, defective vision (severe myopia, nystagmus, strabismus), skeletal anomalies (small hands and feet, tapering fingers), heart defect, and anal stenosis. In addition fluorescence in situ hybridisation and molecular analysis were performed to gain further insight in potential candidate genes involved in P11pDS.     

遗传性多发性外生骨疣基因突变研究

目的进一步阐明遗传性多发性外生骨疣（ｈｅｒｅｄｉｔａｒｙｍｕｌｔｉｐｌｅｅｘｏｓｔｏｓｅｓ,ＥＸＴ）的发病机理,并为最终防治本病提供依据。方法采用聚合酶链反应－单链构象多态性分析,在３０个ＥＸＴ家系中进行ＥＸＴ１基因和ＥＸＴ２基因全部外显子突变检测,并对发现的致病突变进行ＤＮＡ测序分析。结果在２个家系中发现了致病突变,并经ＤＮＡ序列分析证实,一个系ＥＸＴ１基因ｅｘｏｎ６区域单个碱基（Ｔ）丢失;另一个系ＥＸＴ２基因ｅｘｏｎ２区域４个碱基（ｔｇｔ）丢失,前者系国内首次报道,后者系尚未见报道的新突变,这两种突变均系移码突变。结论ＥＸＴ１基因或ＥＸＴ２基因突变,可导致ＥＸＴ,本研究结果可直接应用于ＥＸＴ的遗传咨询和产前基因诊断。     

A 137‐kb deletion within the Potocki–Shaffer syndrome interval on chromosome 11p11.2 associated with developmental delay and hypotonia

Potocki–Shaffer syndrome (PSS) is a rare disorder caused by haploinsufficiency of genes located on the proximal short arm of chromosome 11 (11p11.2p12). Classic features include biparietal foramina, multiple exostoses, profound hypotonia, dysmorphic features, and developmental delay/intellectual disability. Fewer than 40 individuals with PSS have been reported, with variable clinical presentations due in part to disparity in deletion sizes. We report on a boy who presented for initial evaluation at age 13 months because of a history of developmental delay, hypotonia, subtle dysmorphic features, and neurobehavioral abnormalities. SNP microarray analysis identified a 137 kb deletion at 11p11.2, which maps within the classically defined PSS interval. This deletion results in haploinsufficiency for all or portions of six OMIM genes: SLC35C1, CRY2, MAPK8IP1, PEX16, GYLTL1B, and PHF21A. Recently, translocations interrupting PHF21A have been associated with intellectual disability and craniofacial anomalies similar to those seen in PSS. The identification of this small deletion in a child with developmental delay and hypotonia provides further evidence for the genetic basis of developmental disability and identifies a critical region sufficient to cause hypotonia in this syndrome. Additionally, this case illustrates the utility of high resolution genomic approaches in correlating clinical phenotypes with specific genes in contiguous gene deletion syndromes. © 2012 Wiley Periodicals, Inc.     

Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion

Aniridia, Wilms tumor, genitourinary abnormalities, growth and mental retardation are the cardinal features of the WAGR 11p13 deletion syndrome. The Potocki-Schaffer syndrome or proximal 11p deletion syndrome (previously DEFECT11 syndrome) is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses and enlarged parietal foramina. Mental handicap, facial dysmorphism and craniosynostosis may also be associated. We report a patient with combined WAGR and Potocki-Shaffer syndromes, and obesity. She presented with aniridia, cataract, nystagmus, corneal ulcers and bilateral congenital ptosis. A left nephroblastoma was detected at 15 months. Other features included moderate developmental delay, growth deficiency, facial dysmorphism, multiple exostoses and cranial lacunae. High-resolution and molecular cytogenetics confirmed a del(11)(p11.2p14.1) deletion with a proximal breakpoint between the cosmid DO8153 and the BAC RP11-104M24 to a distal breakpoint between cosmids CO8160 (D11S151) and F1238 (D11S1446). The deletion therefore includes EXT2, ALX4, WT1 and PAX6. This case appears to be the second patient reported with this combined deletion syndrome and confirms the association of obesity in the WAGR spectrum, a feature previously reported in four cases, and for which the acronym WAGRO has been suggested. Molecular and follow-up data on the original WAGRO case are briefly presented.     

EXT2基因IVS2+1G>A突变致遗传性多发性外生性骨疣

目的　确定一个遗传性外生性骨疣家系的致病基因。方法　应用基因组扫描方法 ,利用 8、11和 19号染色体上的微卫星标记对该家系进行连锁分析 ,确定候选基因 ,然后对候选基因的编码区及外显子与内含子交界处进行测序分析寻找突变 ,并行逆转录 - PCR扩增 m RNA加以证实。结果　该家系致病基因被定位在 11号染色体的 EXT2基因区 ,在 EXT2基因中检测到 1个 IVS2 1G>A(5 36 1G>A)突变 ,该突变与疾病共分离。逆转录 - PCR证实 ,该突变导致编码区的第 316～ 5 36位共 2 2 1个碱基的缺失 ,使 10 6位密码子至 178位密码子及紧随的两个核苷酸的缺失 ,造成移码 ,形成 12 5个氨基酸的截短蛋白。结论　EXT2基因的 IVS2 1G>A突变是导致这个家系发生外生性骨疣的原因。     

Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki-Shaffer syndrome

Potocki-Shaffer syndrome (PSS) is a contiguous gene deletion syndrome that results from haploinsufficiency of at least two genes within the short arm of chromosome 11[del(11)(p11.2p12)]. The clinical features of PSS can include developmental delay, mental retardation, multiple exostoses, parietal foramina, enlarged anterior fontanel, minor craniofacial anomalies, ophthalmologic anomalies, and genital abnormalities in males. We constructed a natural panel of 11p11.2-p13 deletions using cell lines from 10 affected individuals, fluorescence in situ hybridization (FISH), microsatellite analyses, and array-based comparative genomic hybridization (array CGH). We then compared the deletion sizes and clinical features between affected individuals. The full spectrum of PSS manifests when deletions are at least 2.1 Mb in size, spanning from D11S1393 to D11S1385/D11S1319 (44.6-46.7 Mb from the 11p terminus) and encompassing EXT2, responsible for multiple exostoses, and ALX4, causing parietal foramina. Yet one subject with parietal foramina whose deletion does not include ALX4 indicates that ALX4 in this subject may be rendered functionally haploinsufficient by a position effect. Based on comparative deletion mapping of eight individuals with the full PSS syndrome including mental retardation and two PSS families with no mental retardation, at least one gene related to mental retardation is likely located between D11S554 and D11S1385/D11S1319, 45.6-46.7 Mb from the 11p terminus.     

遗传性多发性骨软骨瘤的基因诊断及产前诊断

目的 研究家族遗传性骨软骨瘤病(hereditary multiple exostoses,HME)的致病基因及产前诊断.方法 应用连锁分析方法对一个HME家系EXT1、EXT2和EXT3基因进行分析.致病基因定位后,用PCR-测序法进行了突变分析.结果 在该家系中EXT2基因第6外显子发生1个新的无义突变(c.1006C>T),该突变导致第336位编码谷氨酰胺的密码子CAA变为终止密码子TAA(Gln336X).根据上述结果配合遗传咨询进行了产前诊断,结果显示胎儿正常.结论 在家族遗传性骨软骨瘤家系中发现一新的EXT2基因突变,并应用于产前诊断.     

遗传性多发性骨软骨瘤的基因诊断及产前诊断

目的 研究家族遗传性骨软骨瘤病(hereditary multiple exostoses,HME)的致病基因及产前诊断.方法 应用连锁分析方法对一个HME家系EXT1、EXT2和EXT3基因进行分析.致病基因定位后,用PCR-测序法进行了突变分析.结果 在该家系中EXT2基因第6外显子发生1个新的无义突变(c.1006C>T),该突变导致第336位编码谷氨酰胺的密码子CAA变为终止密码子TAA(Gln336X).根据上述结果配合遗传咨询进行了产前诊断,结果显示胎儿正常.结论 在家族遗传性骨软骨瘤家系中发现一新的EXT2基因突变,并应用于产前诊断.     

遗传性多发性骨软骨瘤的基因诊断及产前诊断

目的 研究家族遗传性骨软骨瘤病(hereditary multiple exostoses,HME)的致病基因及产前诊断.方法 应用连锁分析方法对一个HME家系EXT1、EXT2和EXT3基因进行分析.致病基因定位后,用PCR-测序法进行了突变分析.结果 在该家系中EXT2基因第6外显子发生1个新的无义突变(c.1006C>T),该突变导致第336位编码谷氨酰胺的密码子CAA变为终止密码子TAA(Gln336X).根据上述结果配合遗传咨询进行了产前诊断,结果显示胎儿正常.结论 在家族遗传性骨软骨瘤家系中发现一新的EXT2基因突变,并应用于产前诊断.     

遗传性多发性骨软骨瘤的基因诊断及产前诊断

目的 研究家族遗传性骨软骨瘤病(hereditary multiple exostoses,HME)的致病基因及产前诊断.方法 应用连锁分析方法对一个HME家系EXT1、EXT2和EXT3基因进行分析.致病基因定位后,用PCR-测序法进行了突变分析.结果 在该家系中EXT2基因第6外显子发生1个新的无义突变(c.1006C>T),该突变导致第336位编码谷氨酰胺的密码子CAA变为终止密码子TAA(Gln336X).根据上述结果配合遗传咨询进行了产前诊断,结果显示胎儿正常.结论 在家族遗传性骨软骨瘤家系中发现一新的EXT2基因突变,并应用于产前诊断.     

遗传性多发性骨软骨瘤的基因诊断及产前诊断

目的 研究家族遗传性骨软骨瘤病(hereditary multiple exostoses,HME)的致病基因及产前诊断.方法 应用连锁分析方法对一个HME家系EXT1、EXT2和EXT3基因进行分析.致病基因定位后,用PCR-测序法进行了突变分析.结果 在该家系中EXT2基因第6外显子发生1个新的无义突变(c.1006C>T),该突变导致第336位编码谷氨酰胺的密码子CAA变为终止密码子TAA(Gln336X).根据上述结果配合遗传咨询进行了产前诊断,结果显示胎儿正常.结论 在家族遗传性骨软骨瘤家系中发现一新的EXT2基因突变,并应用于产前诊断.     

遗传性多发性骨软骨瘤的基因诊断及产前诊断

目的 研究家族遗传性骨软骨瘤病(hereditary multiple exostoses,HME)的致病基因及产前诊断.方法 应用连锁分析方法对一个HME家系EXT1、EXT2和EXT3基因进行分析.致病基因定位后,用PCR-测序法进行了突变分析.结果 在该家系中EXT2基因第6外显子发生1个新的无义突变(c.1006C>T),该突变导致第336位编码谷氨酰胺的密码子CAA变为终止密码子TAA(Gln336X).根据上述结果配合遗传咨询进行了产前诊断,结果显示胎儿正常.结论 在家族遗传性骨软骨瘤家系中发现一新的EXT2基因突变,并应用于产前诊断.     

遗传性多发性骨软骨瘤的基因诊断及产前诊断

目的 研究家族遗传性骨软骨瘤病(hereditary multiple exostoses,HME)的致病基因及产前诊断.方法 应用连锁分析方法对一个HME家系EXT1、EXT2和EXT3基因进行分析.致病基因定位后,用PCR-测序法进行了突变分析.结果 在该家系中EXT2基因第6外显子发生1个新的无义突变(c.1006C>T),该突变导致第336位编码谷氨酰胺的密码子CAA变为终止密码子TAA(Gln336X).根据上述结果配合遗传咨询进行了产前诊断,结果显示胎儿正常.结论 在家族遗传性骨软骨瘤家系中发现一新的EXT2基因突变,并应用于产前诊断.