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An Approach to Inherited Pulmonary Disease
Published in Stephen D. Litwin, Genetic Determinants of Pulmonary Disease, 2020
Individuals with a pleiotropic gene for a complex phenotype may not manifest all of the features of the phenotype that are identifiable in other family members. In the case of the Marfan syndrome, an individual may have dislocated lenses and aortic regurgitation but no arachnodactyly. One parent and one child of that person may show all the features of the syndrome. From the pattern of phenotypes in that pedigree the simplest inference of genotype would be that the individual with part of the syndrome does indeed have the gene, yet the arachnodactyly is not expressed. This qualitative difference in gene expression is called variable expressivity. Pedigrees of a similar type may include people who presumably have the gene for an abnormal phenotype yet show no features of that phenotype at all. The term used for absence of expression of a gene when expression is expected is nonpenetrance. Thus a dominant phenotype could be nonpenetrant in a heterozygote or homozygote, and an X-linked recessive phenotype could be nonpenetrant in a hemizygote.
Homocystinuria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Skeletal abnormalities are prominent, especially genu valgum (Figure 18.6). Valgus may also be present in the ankles, often along with pes cavus. The feet may be everted (Figure 18.7). Some patients may be tall and thin and have a marfanoid appearance (Figures 18.8 and 18.9), but true arachnodactyly is rare, and some patients have a failure to thrive or shortness of stature. Pectus excavatum or carinatum may be present (Figure 18.9). There is a generalized osteoporosis. This is the most common musculoskeletal change, and 50 percent of patients have osteoporosis by the end of the second decade. Roentgenograms (Figures 18.10–18.12) characteristically reveal platyspondyly. There may be posterior biconcave or fish-mouth appearance, and there may be impressive compression fractures or kyphoscoliosis [12, 13].
Disorders of bone and connective tissue
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Other disorders to be distinguished include homocystinuria (autosomal recessive), patients with isolated lens dislocation due to spherophakia, who by chance are tall and thin, and neuromuscular disorders giving a ‘marfanoid’ habitus. A separate dominant syndrome of arachnodactyly with contractures but no internal complications (Beals syndrome) has also been described and is due to deficiency of fibrillin 2 (FBN2). The Loeys-Dietz syndrome, in which aneurysms are prominent, results from defects in the allied TGFR-β genes. The pathophysiology as well as the phenotype of the Marfan syndrome and of the Loeys-Dietz syndrome are closely related through activation of the TGF pathway, which is open to therapeutic intervention.
Familial exudative vitreoretinopathy with TGFBR2 mutation without signs of Loeys-Dietz syndrome
Published in Ophthalmic Genetics, 2021
Toshiaki Asano, Kazuma Oku, Hiroyuki Kondo
Loeys-Dietz Syndrome (LDS) is an autosomal dominant systemic connective tissue disorder first reported by Loeys et al. in 2005 (2). It is characterized by the presence of an aortic aneurysm, aortic dissection, arachnodactyly, and scoliosis. These findings are similar to those of Marfan syndrome, however LDS usually does not have a subluxation of the crystalline lens. Patients with LDS have a characteristic facial appearance of hypertelorism and craniosynostosis associated with bifid uvula and cleft palate (2,3). Genes of the transforming growth factor (TGF) signaling systems, TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3, are known to be causative for LDS (4,5). Based on the clinical variations, LDS, including type 1 LDS, is subcategorized by the presence of craniofacial involvement consisting of cleft palate, craniosynostosis, or hypertelorism. These findings are not present in type 2 LDS, and some patients have a bifid uvula (6). Type 2 LDS is caused by mutations in the TGFBR2 gene (2,6).
The clinical and molecular spectrum of autosomal dominant limb-girdle muscular dystrophies focusing on transportinopathy
Published in Expert Opinion on Orphan Drugs, 2019
Corrado Angelini, Valentina Pegoraro, Giovanna Cenacchi
At onset the most involved muscles were the proximal lower limb muscles and then weakness spread to upper girdle muscles, involving especially the triceps. Abnormal long fingers (arachnodactyly) was a characteristic feature as well as neck, axial and limb muscle weakness (flexor more than extensor muscles). The main clinical sign in patients was that they were able to raise their arm horizontally laying in bed, but not in the standing position because of scapular winging. The early onset patients became wheelchair-bound around 30 years of age, while in later onset milder cases walking ability was preserved up to age 65 years. Other main characteristic features observed in the early onset phenotype were bulbar signs (i.e. dysphagia, dysarthria), distal and axial weakness occurred variably in the family members (Table 2). The severity of the phenotype did not increase in successive generations, differently from what reported [25,30]. Gamez et al. proposed a genetic anticipation phenomenon that is usually found in triplet expansion disorders, such as myotonic dystrophy type 1. It was only apparent in this LGMD kindred because most affected children were from less affected mothers, but other epigenetic factors might play a role.
Spontaneous radial artery pseudoaneurysm in an infant due to idiopathic medial hypoplasia – a case report
Published in Case Reports in Plastic Surgery and Hand Surgery, 2019
William W. Kesler, Joseph J. Maleszewski, Alexander H. Payatakes
Ehlers-Danlos syndrome is a group of inherited connective tissue disorders presenting with problems related to collagen synthesis and processing. Classically, patients have hyperelastic skin, joint hypermobility, multiple ecchymoses, and subcutaneous pseudotumors [13]. Six types are currently recognised, with rare subtypes found in individual families. Type IV (Sack-Barabas) is the predominantly vascular form, with autosomal dominant and recessive variants. The genetic defect in COL3A1 results in decreased or absent production of type III collagen, which is vital for vessel wall integrity and platelet plug formation. Patients bruise easily, and pseudoaneurysms of the subclavian, axillary, radial arteries may occur after minor trauma or angiography. Spontaneous ruptures of the aorta, major visceral arteries, and peripheral arteries in this population have also been reported [13]. Surgery is reserved for patients with life-threatening conditions [13]. Marfan syndrome, the most common inherited connective tissue disorder, occurs due to an autosomal dominant mutation in the FBFN1 (fibrillin 1) gene. Classically, patients have long bones and often arachnodactyly, dural ectasia, aortic root disease, or mitral prolapse. Spontaneous radial artery aneurysms have been reported in patients with this disorder [14]. Loeys-Dietz syndrome is an autosomal dominant disorder involving a mutation in the transforming growth factor-beta (TGF-β) pathway. Five types have been identified; patients often have hypertelorism and V-shaped uvulae. Aortic root dissection is present in 98% of patients, with generalised arterial tortuosity and peripheral aneurysms (brachial, carotid) present in 92% [15].