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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.
A Dysmorphology Based Systematic Approach Toward Perinatal Genetic Diagnosis in a Fetal Autopsy Series
Published in Fetal and Pediatric Pathology, 2018
Shagun Aggarwal, Ashwani Tandon, Aneek Das Bhowmik, Jamal Mohamed Nurul Jain Safarulla, Ashwin Dalal
Targeted or Whole exome sequencing results were available in four cases (Case 14, 18, 27, 28, Table 1). Case 14 concluded to be a connective tissue disorder, showed double heterozygous putative pathogenic mutations in FBN1 and FBN2 on NGS, which cause Marfan syndrome and Beals syndrome, respectively; supporting autopsy diagnosis. Case 18 was concluded to be a syndromic corpus callosum agenesis with cortical microdysgenesis on basis of gross and histopathological findings, and the history of a previously affected sibling. NGS results showed presence of biallelic EPG5 mutations, indicating a diagnosis of Vici syndrome, which was concordant with clinical features of elder sib. Case 27 was a fetus with early onset unexplained anhydramnios with a similarly affected previous sibling. No definite diagnosis was possible on autopsy, but NGS revealed biallelic ACE mutations confirming autosomal recessive renal tubular dysgenesis as causative. Case 28 had autopsy findings suggestive of a multiple malformation syndrome. NGS results reported a heterozygous ZFPM2 mutation, which was inherited from the father. ZFPM2 variants are reported to be associated with congenital diaphragmatic hernia as seen in this fetus, but this mutation could not explain the additional finding of cystic kidney disease. No other pathogenic variant causative of renal abnormalities could be identified.