In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.     

Exclusion of chromosome 15q21.1 in autosomal-recessive Weill-Marchesani syndrome in an inbred Lebanese family

We report an inbred family where 3 siblings had short stature, brachydactyly, limitation of joint movements, microspherophakia, luxated lenses, glaucoma, and heart malformations. Parents of the affected siblings were relatively short, but did not have any of the other features present in their siblings. Those clinical features are consistent with the Weill Marchesani syndrome (MIM 277600). Both autosomal-recessive and autosomal-dominant pedigrees have been reported, with a possible linkage to chromosome 15q21.1 in the latter. Linkage analysis at 15q21.1 in this Lebanese family allowed us to exclude the role of this region in the etiology of the syndrome. Speculations regarding the pathogenesis of the disorder are discussed.     

Spondyloepiphyseal dysplasia.

Skeletal dysplasia with autosomal dominant inheritance was found in four members of one family and in one sporadic case. The syndrome comprises brachydactyly E, platyspondyly, abnormality of the sacroiliac joint, disturbance of metaphyseal modelling, epiphyseal dysplasia, and short stature. This study deals with a particular type of spondyloepiphyseal dysplasia and compares it with similar cases in two previously published papers.     

Short stature, brachydactyly, and Peters'' anomaly (Peters''-plus syndrome): confirmation of autosomal recessive inheritance.

Two sibs with a phenotype characterised by short stature, brachydactyly, and ocular anomalies (Peters' anomaly) are reported (Peters'-plus syndrome). The consanguinity is in agreement with the proposed autosomal recessive inheritance.     

Short trunk stature,brachydactyly, and platyspondyly in three sibs: a new form of brachyolmia or a new skeletal dysplasia?

We present a 27-year-old girl with short trunk stature, generalized rectangular platyspondyly and strike precocious calcification of costal cartilage. She had also brachydactyly, small nails, strabismus and delay of menarche. Her 16-year-old sister had also short trunk stature with severe kyphoscoliosis, hearing loss, brachydactyly, platyspondyly and mild precocious calcification of costal cartilages. Their 12-year-old brother had short trunk stature, kyphoscoliosis, brachydactyly, and platyspondyly but did not show precocious calcification of costal cartilage. The patients shared the following features: short trunk stature, brachydactyly, severe rectangular platyspondyly, broad and short femoral necks and hypoplasia of the ileum. In addition, the older sister had strike precocious calcification of costal cartilage while her sister and brother had severe kyphoscoliosis. Although short trunk stature and severe rectangular platyspondyly without significant epiphyseal or metaphyseal changes were in favor of Hobaek type brachyolmia, this diagnosis was not considered, both because, there were no specific radiological findings of this syndrome, such as elongated vertebral bodies extending beyond the pedicles laterally and all of the patients had brachydactyly which was not present in Hobaek type brachyolmia. The parents were healthy and first cousins signifying autosomal recessive inheritance. We considered that the patients could be affected by a new distinct autosomal recessive type brachyolmia or a new skeletal dysplasia.     

Distinct,autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred

We describe a large inbred kindred from a remote area of Pakistan, comprising eight generations, with a distinct form of spondyloepimetaphyseal dysplasia (SEMD). We evaluated 16 affected individuals: 11 males and 5 females. Analysis of the pedigree strongly suggests autosomal recessive inheritance, and consanguineous loops could account for all the affected individuals being homozygous for the abnormal allele. The clinical findings included short stature evident at birth, short bowed lower limbs, mild brachydactyly, kyphoscoliosis, an abnormal gait, enlarged knee joints, precocious osteoarthropathy, and normal intelligence. Radiographs demonstrated delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse, early osteoarthritic changes, primarily in the spine and hands, and mild brachydactyly. Mild metaphyseal abnormalities were seen predominantly at hips and knees. This distinctive phenotype is distinct from other autosomal recessive forms of SEMD because of the mild degree of metaphyseal involvement, the type of brachydactyly, and the absence of loose joints or other clinical findings. Am. J. Med. Genet. 78:468–473, 1998. © 1998 Wiley-Liss, Inc.     

Brachydactyly, distal symphalangism, scoliosis, tall stature, and club feet: a new syndrome.

Five members of a kindred with brachydactyly and distal symphalangism, normal stature, pes cavus, and scoliosis were ascertained. The pedigree was consistent with autosomal dominant inheritance. The combination of clinical and radiological features is believed to be distinct from those previously reported in patients with brachydactyly/symphalangism.     

LTBP2‐related “Marfan‐like” phenotype in two Roma/Gypsy subjects with the LTBP2 homozygous p.R299X variant

Recessive variants in LTBP2 are associated with eye‐restricted phenotypes including (a) primary congenital glaucoma and (b) microspherophakia/megalocornea and ectopia lentis with/without secondary glaucoma. Nosology of LTBP2 pathology in humans is apparently in contrast with the consolidated evidence of a wide expression of this gene in the developing embryo. Accordingly, in previously published patients with LTBP2‐related eye disease, additional extraocular findings have been occasionally reported and include, among others, high‐arched palate, tall stature, and variable cardiac involvement. Anyway, no emphasis was put on such systemic manifestations. Here, we report two unrelated Roma/Gypsy patients first ascertained for a multisystem disorder mainly characterized by primary congenital glaucoma, complex congenital heart defect, tall stature, long fingers, skin striae and dystrophic scarring, and resembling Marfan syndrome. Heart involvement was severe with polyvalvular heart dysplasia in one, and transposition of great arteries, thoracic arterial tortuosity, polyvalvular heart dysplasia, and neo‐aortic root dilatation in the other. Both patients were homozygous for the recurrent c.895C>T[p.(R299X)] variant, typically found in individuals of Roma/Gypsy descent with an eye‐restricted phenotype. Our findings point out LTBP2 as responsible of a systemic phenotype coherent with the community of syndromes related to anomalies in genes involved in the TGFβ‐pathway. Among these disorders, LTBP2‐related systemic disease emerges as a distinct condition with expanding prognostic implications and autosomal recessive inheritance.     

Glaucoma-lens ectopia-microspherophakia-stiffness-shortness (GEMSS) syndrome: a dominant disease with manifestations of Weill-Marchesani syndromes.

We report on a syndrome of progressive joint stiffness, glaucoma, and lens dislocation observed in three generations and compare it with two previous records of short stature, lens ectopia, and articular limitation. This family confirms the existence of a dominant Weill-Marchesani-like syndrome. We suggest that it could be related to the Moore-Federman syndrome. We coin the acronym GEMSS syndrome (Glaucoma, Ectopia, Microspherophakia, Stiff joints, Short stature) to distinguish this dominant Weill-Marchesani-like syndrome from the classic, recessively inherited syndrome.     

Short stature, brachydactyly, small ears, and a pattern of minor anomalies in brother and sister born to consanguineous parents: a hitherto unreported syndrome?

A 13-year-old boy and his 28-year-old sister had short stature, obesity, and a pattern of minor anomalies including a sloping, narrow forehead; small ears; a narrow nose with prominent bridge and long septum; short upper lip; receding mandible; and short limbs with brachydactyly and clinodactyly of little fingers. The boy also had hypoplastic external genitalia and elevated FSH. Both are of normal intelligence. There is remote consanguinity of the (normal) parents. The 2 sibs probably represent a hitherto un-recognized syndrome of possibly autosomal recessive inheritance.     

Identification and molecular characterisation of a homozygous missense mutation in the ADAMTS10 gene in a patient with Weill–Marchesani syndrome

Weill–Marchesani syndrome is a rare disorder of the connective tissue. Functional variants in ADAMTS10 are associated with Weill–Marchesani syndrome-1. We identified a homozygous missense mutation, c.41T>A, of the ADAMTS10 gene in a 19-year-old female with typical symptoms of WMS1: proportionate short stature, brachydactyly, joint stiffness, and microspherophakia. The ADAMTS10 missense mutation was analysed in silico, with conflicting results as to its effects on protein function, but it was predicted to affect the leader sequence. Molecular characterisation in HEK293 Ebna cells revealed an intracellular mis-targeting of the ADAMTS10 protein with a reduced concentration of the polypeptide in the endoplasmic reticulum. A large reduction in glycosylation of the cytoplasmic fraction of the mutant ADAMTS10 protein versus the wild-type protein and a lack of secretion of the mutant protein are also evident in our results.In conclusion, we identified a novel missense mutation of the ADAMTS10 gene and confirmed the functional consequences suggested by the in silico analysis by conducting molecular studies.     

Robinow syndrome: report of two patients and review of literature

We report two patients with Robinow or fetal face syndrome. We present a thirteen year follow-up on three previously published cases and a review of 32 cases in the literature. The cardinal features of this condition include mesomelic shortening of the forearms, frontal bossing, hypertelorism, wide palpebral fissures, short upturned broad nose with anteverted nares, long philtrum, small chin, brachydactyly, hypoplastic genitalia and a normal karyotype. Development delay and mental retardation was noted in 18% of the reported cases. Early death was identified in about 10% of the cases. Genetic heterogeneity is suggested with autosomal dominant inheritance reported in 8 individuals from 3 families and autosomal recessive inheritance in 8 siblings from 4 families although no clinical differences were identified among those individuals with different inheritance patterns. Male to male transmission was reported in one family. Parental age does not appear to be a factor in the cause of this syndrome.     

Geleophysic dysplasia: 7-year follow-up study of a patient with an intermediate form.

Geleophysic dysplasia (MIM *231050) is a rare autosomal recessive disorder, characterized by short stature with short limbs, brachydactyly, joint contractures, and a good-natured facial appearance. Infiltration of liver and cardiac leaflets has been reported in some patients. Based on the clinical picture and the detection of lysosome-like inclusions in hepatocytes, tracheal mucosa, chondrocytes, and skin fibroblasts, the underlying cause of the conditions is considered to be a generalized lysosomal storage defect. We report on a new case born to consanguineous parents, first observed at age 8 months, and for whom a 7-year follow-up is available.     

Glaucoma-lens ectopia-microspherophakia-stiffness-shortness (GEMSS) syndrome: A dominant disease with manifestations of Weill-Marchesani syndromes

We report on a syndrome of progressive joint stiffness, glaucoma, and lens dislocation observed in three generations and compare it with two previous records of short stature, lens ectopia, and articular limitation. This family confirms the existence of a dominant Weill-Marchesani-like syndrome. We suggest that it could be related to the Moore-Federman syndrome. We coin the acronym GEMSS syndrome (Glaucoma, Ectopia, Microspher-ophakia, Stiff joints, Short stature) to distinguish this dominant Weill-Marchesani-like syndrome from the classic, recessively inherited syndrome. © 1992 Wiley-Liss, Inc.     

Short stature,brachydactyly, nail dysplasia,and mental retardation: Further observation of the Tonoki syndrome

We studied a patient with microcephaly, short stature, type B brachydactyly, nail dysplasia, skeletal anomalies, and mental retardation. The mother of the propositus has brachydactyly of thumbs and a similar physiognomy without mental retardation. This appears to be another observation of the Tonoki syndrome, a distinct autosomal dominant or X-linked clinical entity. Am. J. Med. Genet. 80:403–405, 1998. © 1998 Wiley-Liss, Inc.     

Corneal changes, hyperkeratosis, short stature, brachydactyly, and premature birth: a new autosomal dominant syndrome

We report on an autosomal dominant syndrome consisting of unique corneal epithelial changes, diffuse palmoplantar hyperkeratosis, distal onycholysis, brachydactyly, short stature, premature birth, and dental problems. This condition has been present in seven persons in three generations of one family. Corneal biopsies demonstrate mild dysplastic changes in the epithelium. Skin biopsies show hyperkeratosis and acanthosis. In both eye and skin specimens, results of stains for polysaccharides, amyloid, and tyrosine were unremarkable. Roentgenograms of the hands show short distal phalanges, short 4th metacarpals, and constriction of the heads of some of the metacarpals. In three of four affected relatives, a variable medullary narrowness is seen. In mode of inheritance, clinical appearance, and/or associated defects. This syndrome appears to differ from previously reported conditions that include palmoplantar hyperkeratosis and/or corneal changes.     

Geleophysic dysplasia: 7-year follow-up study of a patient with an intermediate form

Geleophysic dysplasia (MIM *231050) is a rare autosomal recessive disorder, characterized by short stature with short limbs, brachydactyly, joint contractures, and a good-natured facial appearance. Infiltration of liver and cardiac leaflets has been reported in some patients. Based on the clinical picture and the detection of lysosome-like inclusions in hepatocytes, tracheal mucosa, chondrocytes, and skin fibroblasts, the underlying cause of the conditions is considered to be a generalized lysosomal storage defect. We report on a new case born to consanguineous parents, first observed at age 8 months, and for whom a 7-year follow-up is available. Am. J. Med. Genet. 86:82–85, 1999. © 1999 Wiley-Liss, Inc.     

A distinctive autosomal recessive syndrome of severe disproportionate short stature with short long bones, brachydactyly, and hypotrichosis in two consanguineous Arab families

Disproportionate short stature is a heterogeneous group of hereditary disorders, which are classified according to their mode of inheritance, their clinical skeletal and non-skeletal manifestations, and their radiological characteristics. Herein, we inform on eight individuals with severe disproportionate short stature from two unrelated consanguineous families of Arab-Muslim ancestry. The adult height of the affected individuals is between 112 cm and 127 cm, and is due to pre- and post-natal growth retardation, which probably manifests as early as the second trimester of pregnancy. At a young age, the phenotype is characterized by a short stature, a relatively large head, and a long triangular face, and this phenotype later evolves to one with in which the head is relatively small, the mandible is large and pointy. The affected individuals have normal cognitive abilities and lack any neurological deficits. Other typical features include a prominent nose, a voice with an unusual high-pitched sound, relatively small ears, clinodactyly, brachydactyly, small hands, hypoplastic fingernails, a waddling gait, and sparse hair post-pubertally. Typical skeletal changes include short long bones, especially the femurs and humeri, with mild metaphyseal changes and very short femoral necks. After due consideration of the other hereditary causes of disproportionate short stature and close examination of the pedigrees of the two families, we concluded that these eight individuals have the same hitherto unreported form of severe disproportionate short stature that is inherited in the autosomal recessive mode.     

高度近视人群METTL4基因的单核苷酸多态分析

目的:分析位于18p11.31的METTL4基因的单核苷酸多态(SNPs),探讨它们与高度近视发病的关系。方法:收集正常对照人群71例及高度近视患者177例,其中常染色体显性遗传家系先证者(AD组)59例、常染色体隐性遗传家系先证者(AR组)46例、无明显家系的散发患者(SF组)52例。制备外周血基因组DNA,PCR扩增METTL4基因的外显子序列,应用异源双链-单链构象多态性(HA-SSCP)方法分析PCR产物,对存在差异条带的PCR产物进行测序分析。结果:在METTL4基因的编码区发现2个SNPs位点:SNP7438A→C位于第2外显子,Glu 230 Asp,在GenBank未见报道;SNP131C→A位于第4外显子,Gln310Lys。正常人与高度近视各组SNP7438A→C的基因型分布无明显差异;AR高度近视组、SF高度近视组的SNP131C→A基因型分布与对照人群无显著差异,而AD高度近视与对照组差异显著(P<0.05)。结论: SNP7438A→C与高度近视的发病无关。SNP131C→A与AD高度近视发病的关系需要进一步研究。     

Silver-Russell 综合征研究进展

Silver-Russell综合征是一组遗传异质性的疾病,主要临床表现为胎儿严重的宫内生长发育迟缓及出生后生长发育迟缓和矮身材。1953年Silver等首先报道报告了2例先天性的躯体不对称、低体重、矮身材、尿中促性腺激素增高的病例。以后陆续有零散病例报告。目前研究发现此病有三种遗传方式:即母源第7号染色体单亲双体、常染色体显性遗传及常染色体隐性遗传。本文综述了Silver-Russell综合征的临床诊断标准及研究进展。