Background: Proteoglycans are large and structurally complex macromolecules which can be found in abundancy in the extracellular matrix and on the surface of all animal cells. Mutations in the genes encoding the enzymes responsible for the formation of the tetrasaccharide linker region between the proteoglycan core protein and the glycosaminoglycan side chains lead to a spectrum of severe and overlapping autosomal recessive connective tissue disorders, collectively coined the 'glycosaminoglycan linkeropathies'.
Results: We report the clinical findings of two novel patients with a complex linkeropathy due to biallelic mutations in B3GAT3, the gene that encodes glucuronosyltransferase I, which catalyzes the addition of the ultimate saccharide to the linker region.
In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.
View Article and Find Full Text PDFSkeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta.
View Article and Find Full Text PDFPurpose: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.
Methods: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.
Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes.
View Article and Find Full Text PDFWe identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome (CNS) diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing, two homozygous truncating mutations, c.1513C>T (p.
View Article and Find Full Text PDFThe semaphorins constitute a large family of secreted and membrane-associated proteins that regulate many developmental processes, including neural circuit assembly, bone formation and angiogenesis. Recently, bi-allelic loss-of-function variants in SEMA3A (semaphorin 3A) were identified in a single patient with a particular pattern of multiple congenital anomalies (MCA). Using homozygosity mapping combined with exome sequencing, we identified a homozygous SEMA3A variant causing a premature stop codon in an 8 year old boy with the same pattern of MCA.
View Article and Find Full Text PDFThe exceptionally large SYNE1 (spectrin repeat-containing nuclear envelope protein 1) gene encodes different nesprin-1 isoforms, which are differentially expressed in striated muscle and in cerebellar and cerebral neurons. Nesprin-1 isoforms can function in cytoskeletal, nuclear, and vesicle anchoring. SYNE1 variants have been associated with a spectrum of neurological and neuromuscular disease.
View Article and Find Full Text PDFAutosomal recessive hypophosphatemic rickets 2 (ARHR2) is a rare form of renal tubular phosphate wasting disorder. Loss of function mutations of the ecto-nucleotide pyrophosphatase/pyrophosphodiesterase 1 gene (ENPP1) causes a wide spectrum of phenotypes, ranging from lethal generalized arterial calcification of infancy to hypophosphatemic rickets with hypertension. Hearing loss was not previously thought to be one of the features of the disease entities and was merely regarded as a complication rather than a part of the disease.
View Article and Find Full Text PDFThe Smith-Lemli-Opitz syndrome (SLOS [MIM 270400]) is an autosomal recessive malformation syndrome that shows a great variability with regard to severity. SLOS is caused by mutations in the Δ7sterol-reductase gene (DHCR7), which disrupt cholesterol biosynthesis. Phenotypic variability of the disease is already known to be associated with maternal apolipoprotein E (ApoE) genotype.
View Article and Find Full Text PDFPurpose: Standard therapy for lupus nephritis is based on non-specific immunosuppression. We aimed to identify specific alterations in T cell and cytokine homeostasis and possible associations with disease activity in children with lupus nephritis (LN).
Methods: The phenotype of circulating T cells from children with LN and healthy controls (HC) was analyzed by flow cytometry.
Background: Endothelial cell injury plays a key role in the pathogenesis of lupus nephritis (LN) and atherosclerosis. The aim of this study was to identify factors involved in the process of endothelial damage in children and adolescents with LN.
Methods: We evaluated the relationship between plasma vascular endothelial growth factor (VEGF), its soluble receptors sVEGFR-1 and sVEGFR-2 and markers of endothelial inflammation and injury (angiopoietin-2 and thrombomodulin, respectively) in 23 children and adolescents with LN (active LN, n = 14; inactive LN, n = 9; mean age 15 years) and 20 healthy controls (HC; mean age 12 years).
Cleidocranial Dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by hypoplastic or absent clavicles, increased head circumference, large fontanels, dental anomalies, and short stature. Hand malformations are also common. Mutations in RUNX2 cause CCD, but are not identified in all CCD patients.
View Article and Find Full Text PDFThe 3M syndrome is a rare autosomal recessive disorder recently ascribed to mutations in the CUL7 gene and characterized by severe pre- and postnatal growth retardation. Studying a series of 33 novel cases of 3M syndrome, we have identified deleterious CUL7 mutations in 23/33 patients, including 19 novel mutations and one paternal isodisomy of chromosome 6 encompassing a CUL7 mutation. Lack of mutations in 10/33 cases and exclusion of the CUL7 locus on chromosome 6p21.
View Article and Find Full Text PDFNievergelt syndrome (NS) is an autosomal dominant mesomelic dysplasia characterized by specific deformities of the radius, ulna, fibula and a rhomboid shape of the tibia. Phenotypically overlapping conditions such as mesomelic dysplasia, Savarirayan-type (MIM 605274), have been described, but their pathogenesis also remains unknown. We report on a girl with fibular agenesis, severely abnormal, triangular tibiae, urogenital tract malformations, failure to thrive, convulsions and recurrent apnoeas leading to respiratory arrest at the age of 4 months.
View Article and Find Full Text PDFTransient, symptomatic zinc deficiency in breast-fed, low-birthweight infants is a rare, but probably underrecognized disorder hallmarked by periorificial and acral dermatitis. Unlike in acrodermatitis enteropathica, symptoms disappear when nursing ends. We report a breast-fed, preterm infant with demarcated, erythematous, and exudative patches with overlying crusts on the perioral, perianal, and acral areas.
View Article and Find Full Text PDFIn humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG).
View Article and Find Full Text PDFCerebral cavernous malformation (CCM) is a Mendelian model of stroke, characterized by focal abnormalities in small intracranial blood vessels leading to hemorrhage and consequent strokes and/or seizures. A significant fraction of cases is inherited as an autosomal dominant trait with incomplete penetrance. Among Hispanic Americans, virtually all CCM is attributable to a founder mutation localized to 7q ( CCM1 ).
View Article and Find Full Text PDFWe had the opportunity to investigate the early abnormalities of the eyes in a family with osteoporosis-pseudoglioma syndrome. This syndrome combines severe premature osteoporosis with a bilateral eye disorder, leading to early onset blindness. Using colour doppler imaging in the 4-month-old girl from this affected family we demonstrated persistent hyperplastic primary vitreous in both eyes.
View Article and Find Full Text PDFAn X;17 translocation breakpoint was characterised in a 5-year-old female with hypomelanosis of Ito (HI) who exhibits characteristic hypopigmented lesions, psychomotor retardation, and choroid plexus papilloma. A YAC clone containing the locus DXS1 from Xq12 was found by fluorescence in situ hybridisation to cross the translocation breakpoint. Cosmid clones positive for DXS1 were used to identify and clone the translocation junction fragment from the patient's DNA.
View Article and Find Full Text PDFMedulloblastoma is the most frequent paediatric brain tumour. Because of the uniform histology, a common genetic mechanism has been postulated. Loss of heterozygosity (LOH) studies support evidence that a candidate gene, which functions as a tumour-suppressor gene, is located in 17p13.
View Article and Find Full Text PDFIn a study of nine families with "site-specific" ovarian cancer (criterion: three or more cases of epithelial ovarian cancer and no cases of breast cancer diagnosed at age < 50 years) we have obtained evidence of linkage to the breast-ovarian cancer susceptibility gene, BRCA1 on 17q12-21. If the risk of cancer in these families is assumed to be restricted to the ovary, the best estimate of the proportion of families linked to BRCA1 is .78 (95% confidence interval .
View Article and Find Full Text PDFWe present a female patient with laryngeal anomalies, tracheostenosis and pre- and postaxial polydactyly. Bilateral duplication of the hallux, polydactyly of hands, growth retardation and conductive hearing defect are consistent with oral-facial-digital (OFD) type II syndrome. Three similar cases of OFD syndrome with hypoplasia of the larynx, epiglottis and/or trachea without tibial dysplasia have been previously reported by Silengo and Temtamy and McKusick.
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