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. © 2002 Wiley‐Liss, 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.     

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.     

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.     

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.     

WAGR syndrome and multiple exostoses in a patient with del(11)(p11.2p14.2)

The WAGR syndrome (Wilms' tumour, aniridia, genital anomalies, and mental retardation) is well documented to be associated with a deletion of 11p13. We present a patient with a del(11)(p11.2p14.2) who as well as all the features of WAGR syndrome has multiple exostoses. We suggest that this could be a possible locus for hereditary multiple exostoses.     

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.     

The First Korean Patient with Potocki-Shaffer Syndrome: A Rare Cause of Multiple Exostoses

Potocki-Shaffer syndrome (PSS, OMIM #601224) is a rare contiguous gene deletion syndrome caused by haploinsufficiency of genes located on the 11p11.2p12. Affected individuals have a number of characteristic features including multiple exostoses, biparietal foramina, abnormalities of genitourinary system, hypotonia, developmental delay, and intellectual disability. We report here on the first Korean case of an 8-yr-old boy with PSS diagnosed by high resolution microarray. Initial evaluation was done at age 6 months because of a history of developmental delay, hypotonia, and dysmorphic face. Coronal craniosynostosis and enlarged parietal foramina were found on skull radiographs. At age 6 yr, he had severe global developmental delay. Multiple exostoses of long bones were detected during a radiological check-up. Based on the clinical and radiological features, PSS was highly suspected. Subsequently, chromosomal microarray analysis identified an 8.6 Mb deletion at 11p11.2 [arr 11p12p11.2 (Chr11:39,204,770-47,791,278)×1]. The patient continued rehabilitation therapy for profound developmental delay. The progression of multiple exostosis has being monitored. This case confirms and extends data on the genetic basis of PSS. In clinical and radiologic aspect, a patient with multiple exostoses accompanying with syndromic features, including craniofacial abnormalities and mental retardation, the diagnosis of PSS should be considered.     

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.     

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.     

Intronic deletion and duplication proximal of the EXT1 gene: A novel causative mechanism for multiple osteochondromas

Multiple osteochondromas (MO) is a syndrome in which benign cartilage‐capped neoplasms develop at the surface of the long bones. Most cases are caused by exonic changes in EXT1 or EXT2, but 15% are negative for these changes. Here we report for the first time a family of MO patients with germline genomic alterations at the EXT1 locus without detectable mutations or copy number alterations of EXT exonic sequences. Array‐CGH showed an 80.7 kb deletion of Intron 1 of EXT1 and a 68.9 kb duplication proximal of EXT1. We identified a breakpoint between the distal end of the duplicated region and a sequence distal of the deleted region in the first intron. This breakpoint was absent in non‐affected family members. The configuration of the breakpoint indicates a direct insertion of the duplicated region into the deletion. However, no other breakpoint was found, which suggests a more complex genomic rearrangement has occurred within the duplicated region. Our results reveal intronic deletion and duplication as a new causative mechanism for MO not detected by conventional diagnostic methods. © 2013 Wiley Periodicals, 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.      

Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype

Biallelic exostosin-2 (EXT2) pathogenic variants have been described as the cause of the Seizures-Scoliosis-Macrocephaly syndrome (OMIM 616682) characterized by intellectual disability, facial dysmorphisms and seizures. More recently, it has been proposed to rename this disorder with the acronym AREXT2 (autosomal recessive EXT2-related syndrome). Here, we report the third family affected by AREXT2 syndrome, harboring compound missense variants in EXT2, p.Asp227Asn, and p.Tyr608Cys. In addition, our patients developed multiple exostoses, which were not observed in the previously described families. AREXT2 syndrome can be considered as a multiorgan Congenital Disorder of Glycosylation caused by a significant, but non-lethal, decrease in EXT2 expression, thereby affecting the synthesis of the heparan sulfate proteoglycans, which is relevant in many physiological processes. Our finding expands the clinical and molecular spectrum of the AREXT2 syndrome and suggests a possible genotype/phenotype correlation in the development of the exostoses.     

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。     

Familial 14-Mb deletion at 21q11.2–q21.3 and variable phenotypic expression

We report a familial case with a proximal interstitial deletion of chromosome 21q [del(21q)]. Although the mother in the family was phenotypically normal, her first child was affected with both sensorineural hearing loss and moderate mental retardation, and the second affected child had mild mental retardation but not sensorineural hearing loss. We determined breakpoints of the del(21q) in the mother and her two affected children by fluorescence in situ hybridization analysis using 45 DNA clones and the molecular analysis using 21 DNA markers. The proximal breakpoint of the del(21q) was located at a region between 0.33 Mb and 0.46 Mb distal to the centromere, and the distal breakpoint was at a region between 14.6 Mb and 14.9 Mb. The finding indicates that the three individuals had an approximate 14-Mb deletion within 21q11.2–q21.3. Molecular analysis showed that both affected children shared the same maternal haplotype of their del(21q), but a crossover was detected in the paternally inherited normal chromosome 21. These data suggest that unmasking of deleterious genes on the paternally derived chromosome 21 of the two children as a result of the deletion may affect the extent of their mental retardation and/or sensorineural hearing loss. Usher syndrome 1E may be a candidate disease locus related to the sensorineural hearing loss of the first child. Received: March 1, 2002 / Accepted: June 14, 2002     

Hypertension in Potocki-Shaffer syndrome: A case report

Potocki-Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome caused by heterozygous deletion of 11p11.2p12. Typical features described in patients with PSS include developmental delay, intellectual disability, multiple cartilaginous exostoses, biparietal foramina, craniofacial abnormalities, and genitourinary anomalies. While hypertension has been noted in three patients with PSS, it has not been described in most patients with this syndrome. This report details the evaluation and treatment of a teenager with PSS who presented on several occasions during childhood with elevated blood pressure measurements. The renin level was elevated, likely indicating a secondary cause for the HTN. The patient's BP responded to monotherapy with Angiotensin Converting Enzyme Inhibitor (ACEI).     

Detection and delineation of an unusual 17p11.2 deletion by array-CGH and refinement of the Smith–Magenis syndrome minimum deletion to 650 kb

Smith–Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome and it is characterized by an interstitial deletion of chromosome 17p11.2. SMS patients have a distinct phenotype which is believed to be caused by haploinsufficiency of one or more genes in the associated deleted region. Five non-deletion patients with classical phenotypic features of SMS have been reported with mutations in the retinoic acid induced 1 (RAI1) gene, located within the SMS critical interval. Happloinsufficiency of the RAI1 gene is likely to be the responsible gene for the majority of the SMS features, but other deleted genes in the SMS region may modify the overall phenotype in the patients with 17p11.2 deletions. SMS is usually diagnosed in the clinical genetic setting by FISH analysis using commercially available probes. We detected a submicroscopic deletion in 17p11.2 using array-CGH with a resolution of approximately 1 Mb in a patient with the SMS phenotype, who was not deleted for the commercially available SMS microdeletion FISH probe. Delineation of the deletion was performed using a 32K tiling BAC-array, containing 32,500 BAC clones. The deletion in this patient was size mapped to 2.7 Mb and covered the RAI1 gene. This case enabled the refinement of the SMS minimum deletion to 650 kb containing eight putative genes and one predicted gene. In addition, it demonstrates the importance to investigate deletion of RAI1 in SMS patients.     

Smith-Magenis syndrome and Moyamoya disease in a patient with del(17)(p11.2p13.1)

Chromosomal rearrangements causing microdeletions and microduplications are a major cause of congenital malformation and mental retardation. Because they are not visible by routine chromosome analysis, high resolution whole-genome technologies are required for the detection and diagnosis of small chromosomal abnormalities. Recently, array-comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) have been useful tools for the identification and mapping of deletions and duplications at higher resolution and throughput. Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome caused by deletion or mutation of the retinoic acid induced 1 (RAI1) gene and is often associated with a chromosome 17p11.2 deletion. We report here on the clinical and molecular analysis of a 10-year-old girl with SMS and moyamoya disease (occlusion of the circle of Willis). We have employed a combination of aCGH, FISH, and MLPA to characterize an approximately 6.3 Mb deletion spanning chromosome region 17p11.2-p13.1 in this patient, with the proximal breakpoint within the RAI1 gene. Further, investigation of the genomic architecture at the breakpoint intervals of this large deletion documented the presence of palindromic repeat elements that could potentially form recombination substrates leading to unequal crossover.     

A 4 Mb cryptic deletion associated with inv(8)(q13.1q24.11) in a patient with trichorhinophalangeal syndrome type I.

We report on an 11 year old girl with trichorhinophalangeal syndrome type I (TRPS1), postaxial polydactyly of the fingers, and a de novo paracentric inversion on the long arm of chromosome 8 involving bands q13.1 and q24.11. Molecular analysis using FISH and polymorphic DNA markers detected an approximately 4 Mb, cytogenetically unidentified deletion occurring between two STSs markers, AFMB331YA9 and D8S1200, around the region of the distal inversion breakpoint. Although the deletion is large, mental retardation was not present in the patient. This is the first report of a cryptic deletion in a TRPS1 patient, both ends of which were analysed at the molecular level. The data obtained are useful for defining the location of the putative mental retardation gene(s) in TRPS1 and Langer-Giedion syndrome (TRPS2), as well as a locus for postaxial polydactyly.