Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies

The Marfan syndrome (MFS) is a pleiotropic, autosomal dominant disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a series of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS, and at least 337 mainly unique mutations have been published to date. FBN1 mutations have been found not only in MFS but also in a range of connective tissue disorders collectively termed fibrillinopathies ranging from mild phenotypes, such as isolated ectopia lentis, to severe disorders including neonatal MFS, which generally leads to death within the first two years of life. The present article intends to provide an overview of mutations found in MFS and related disorders and to discuss potential genotype-phenotype correlations in MFS.     

Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies

Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen.     

Fusionsdefizite der Gesichtsmitte und Fehlentwicklungen des Untergesichts

The oculoauriculofrontonasal syndrome (OAFNS) is a rare craniofacial malformation which causes massive disturbance of physiological craniofacial development and can be associated with other malformations; however, cognitive development can be unaffected. It is characterized by vertical median facial clefting in combination with bilateral otomandibular dysplasia. Hypertelorism, orbital dystopia, mandibular and hearing deficiency are key features. The etiology remains uncertain and sporadic occurrence is likely. Interindividual variance in expression must be expected requiring highly individualized age and growth-related treatment concepts in order to achieve a less obtrusive appearance.     

Two novel distinct COL1A2 mutations highlight the complexity of genotype–phenotype correlations in osteogenesis imperfecta and related connective tissue disorders

Osteogenesis imperfecta is a heritable connective tissue disorder characterized by variable symptoms including predisposition to fractures. Despite the identification of numerous mutations, a reliable genotype–phenotype correlation has remained notoriously difficult. We now describe two patients with osteogenesis imperfecta and novel, so far undescribed mutations in the COL1A2 gene, further highlighting this complexity. A 3-year-old patient presented with features reminiscent of a connective tissue disorder, with joint hypermobility, Wormian bones, streaky lucencies in the long bones and relative macrocephaly. The patient carried a heterozygous c.1316G > A (p.Gly439Asp) mutation in the COL1A2 gene located in a triple-helix region, in which glycine substitutions have been assumed to cause perinatal lethal OI (Sillence type II). A second family with type I osteogenesis imperfecta carried a heterozygous nonsense mutation c.4060C > T (p.Gln1354X) within the last exon of COL1A2. Whereas other heterozygous nonsense mutations in COL1A2 do not lead to a phenotype, in this case the mRNA is presumed to escape nonsense-mediated decay. Therefore the predicted COL1A2 propeptide lacks the last 13 C-terminal amino acids, suggesting that the OI phenotype results from decelerated assembly and overmodification of the collagen triple helix. The presented COL1A2 mutations exemplify the complexity of COL1A2 genotype–phenotype correlation in genetic counselling in OI.     

Proximal and distal 15q25.2 microdeletions–genotype–phenotype delineation of two neurodevelopmental susceptibility loci

Distal 15q25.2 microdeletions have recently been reported as a copy number variation (CNV) locus for neurodevelopmental and neuropsychiatric disorders with variable outcome. In addition, more proximal microdeletions of 15q25.2 have been described as a susceptibility locus for cognitive deficits, congenital diaphragmatic hernia (CDH), and Diamond–Blackfan anaemia (DBA). We describe two patients with 15q25.2 deletion, one with the more distal deletion and the other with a deletion overlapping both the distal and proximal 15q25.2 deletions and compare them to the 18 so far reported patients with 15q25.2 deletions. We provide a characterization of the 15q25.2 microdeletions and contribute to the genotype–phenotype delineation for these two novel microdeletion syndromes. © 2012 Wiley Periodicals, Inc.     

Cerebral manifestations,hemihypertrophy and lymphoedema of one leg in a child with epidermal nevus syndrome (Schimmelpenning-Feuerstein-Mims)

The report focuses on a rare variant form of epidermal nevus syndrome (ENS) (Schimmelpenning-Feuerstein-Mims syndrome) describing lesions involving the skin, eyes, skeleton, heart and brain in an 11-year-old boy. Despite his evident brain pathology, the boy lacks neurological symptoms and mental retardation. We describe his unusual MRI appearances and radiographic skeletal findings. To our knowledge this is the first report of ENS with lymphoedema occurring together in the same individual.