Unusually severe expression of craniofacial features in Aarskog‐Scott syndrome due to a novel truncating mutation of the FGD1 gene

Abstract

Aarskog‐Scott syndrome (AAS) is a rare, clinically and genetically heterogeneous condition characterized by facial dysmorphic features, short stature, brachydactyly, and genital anomalies. The X‐linked form is caused by mutations of the FGD1 gene. Although clinical manifestations and diagnostic criteria are well established, diagnosis is not simple, as the spectrum of phenotypical features may be extremely variable. Here, we report on the clinical and genetic characterization of a family in which molecular analyses revealed the inheritance of a novel truncating mutation of the FDG1 gene (c.945insC) in two affected brothers, with one of them displaying unusually severe craniofacial abnormalities. This previously unreported combination of anomalies might be due to the occurrence of two distinct disorders (AAS and hemifacial microsomia) or may represent an extension of the AAS phenotypic spectrum. Our findings highlight the phenotypic heterogeneity of AAS, supporting the opinion that the FGD1 mutations result in a broad spectrum of severity and, in some cases, may express a clinical appearance very different than typically described. © 2006 Wiley‐Liss, Inc.

Exome Sequencing Identifies A Branch Point Variant in Aarskog-Scott Syndrome

“…The protein consists of several important segments such as a proline‐rich SH3‐binding motif, a RhoGEF homology domain (DH), two pleckstrin‐homology domains (PH), and a FYVE‐zinc finger domain (ZF). In ASS, variants have been reported throughout the gene, both missense and protein truncating, but there is no clear correlation between the nature and location of variants and disease severity [Orrico et al., ]. Most variants are private, with the exception of three (c.529dupC, c.1966C>T, and several affecting amino acid Arg443; http://www.LOVD.nl/FGD1) [Orrico et al., , ].…”

Genetics of osteoporosis: accelerating pace in gene identification and validation

“…First, ARHGEF3 speciWcally activates two members of the RhoGTPase family, RHOA implicated in osteoblast diVerentiation (Meyers et al 2005) and RHOB involved in osteoarthritis (Mahr et al 2006). Second, mutations in the FGD1 gene, which encodes another RhoGTPase regulatory protein, cause Aarskog-Scott syndrome which is characterized by multiple skeletal abnormalities (Orrico et al 2007). They Wrst analyzed 17 SNPs in a discovery cohort of 769 female sibs (mean age 54.2 § 12.7 years) recruited from Australia and UK.…”

Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015

“…These approaches will facilitate the distinction of pathogenic variants from polymorphisms, especially in the cases of missense variants 1.8 Estimated frequency of the disease (incidence at birth ('birth prevalence') or population prevalence) Only 35 molecularly proven cases have been published worldwide. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] The majority of patients with a clinical diagnosis where details were published before the advent of molecular testing have not undergone subsequent molecular testing. Experience in Leuven (Prof. JP Fryns: personal communication), a typical-sized clinical genetics unit, suggests that two to three new patients with a proven variant in the FGD1 gene will be identified per year, a similar number as for Angelman and Prader-Willi syndrome.…”

“…It is already acknowledged that some patients with pathogenic variants do not have all the typical clinical features. [13][14][15] The clinical sensitivity depends on variable factors such as age or family history. In reporting cases, a general statement to this effect should be given, even if a quantification can only be made case by case.…”

“…Some features (hypospadias, inguinal or umbilical hernias, cryptorchidism and unusually severe craniofacial features) may need surgical intervention. 15 Radiological assessment of the cervical spine should be carried out, with orthopaedic referral if necessary, as compression of cervical nerve roots may be the consequence of cervical vertebral defects (hypoplasia of the first cervical vertebra, unfused posterior arch, synostosis, anomaly of the odontoid). 18 The effect of growth hormone (GH) treatment on height gain has been reported only in preliminary studies and needs confirmation.…”