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Acrofacial Dysostosis
Introduction
Among newborns with birth defects, approximately one-third show craniofacial abnormalities, which cause significant morbidity and mortality. More than 700 distinct craniofacial syndromes have been described to date. Facial dysostoses can be divided into two types: mandibulofacial dysostoses (MFDs) and acrofacial dysostoses (AFDs). MFDs have typically no limb defects, while AFDs are associated with limb abnormalities. At least eight MFDs have been described, with the most common being Treacher Collins syndrome (TCS). AFDs are a genetically heterogeneous group of inherited disorders unified by craniofacial and limb abnormalities. At least 18 distinct types of AFDs have been characterized based on the specific patterns of limb abnormalities. They have been further classified into those with preaxial limb abnormalities, those with postaxial defects, and a subset that cannot be classified into either group. There is significant phenotypic overlap for these disorders.
Disorder
Definition
MFD disorders exhibit a profound effect on facial development and are considered facial dysostoses. AFDs show both facial and limb abnormalities, and are part of the continuum of facial dysostoses.
Prevalence and Epidemiology
The most common MFD is TCS, which occurs with an incidence of about 1 : 50,000 live births. TCS is inherited in an autosomal dominant manner in most cases; however, a rare recessive form has been described. Nager syndrome is the most common AFD and is extremely rare, with fewer than 100 cases reported in the literature.
Etiology, Pathophysiology, and Embryology
TCS results from heterozygous mutations in the gene encoding TCOF1 in the vast majority of cases. Heterozygosity for mutations in POLR1D can also lead to TCS, as can recessively inherited mutations in POLR1C . All three genes, either as binding partners or subunits of a complex, are involved in the RNA polymerase function and ribosomal biogenesis.
Nager syndrome and the allelic but more severe Rodriguez syndrome are autosomal dominant disorders that both result from heterozygosity for mutations in SF3B4 . In about 50% of cases of Nager syndrome, tested mutations have been identified in SF3B4 , suggesting that another gene is responsible for some of the cases. The SF3B4 gene encodes a spliceosomal protein that removes introns and ligates exons during RNA splicing.
Manifestations of Disease
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