TY - JOUR
T1 - Autosomal dominant frontometaphyseal dysplasia
T2 - Delineation of the clinical phenotype
AU - Wade, Emma M.
AU - Jenkins, Zandra A.
AU - Daniel, Philip B.
AU - Morgan, Tim
AU - Addor, Marie C.
AU - Adés, Lesley C.
AU - Bertola, Debora
AU - Bohring, Axel
AU - Carter, Erin
AU - Cho, Tae Joon
AU - de Geus, Christa M.
AU - Duba, Hans Christoph
AU - Fletcher, Elaine
AU - Hadzsiev, Kinga
AU - Hennekam, Raoul C.M.
AU - Kim, Chong A.
AU - Krakow, Deborah
AU - Morava, Eva
AU - Neuhann, Teresa
AU - Sillence, David
AU - Superti-Furga, Andrea
AU - Veenstra-Knol, Hermine E.
AU - Wieczorek, Dagmar
AU - Wilson, Louise C.
AU - Markie, David M.
AU - Robertson, Stephen P.
N1 - Publisher Copyright:
© 2017 Wiley Periodicals, Inc.
PY - 2017/7
Y1 - 2017/7
N2 - Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.
AB - Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.
KW - Frontometaphyseal dysplasia
KW - TAB2
KW - TAK1
KW - keloid
KW - locus heterogeneity
KW - scoliosis
UR - http://www.scopus.com/inward/record.url?scp=85019126356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019126356&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.38267
DO - 10.1002/ajmg.a.38267
M3 - Article
C2 - 28498505
AN - SCOPUS:85019126356
SN - 1552-4825
VL - 173
SP - 1739
EP - 1746
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 7
ER -