Case report: Extending the spectrum of clinical and molecular findings in FOXC1 haploinsufficiency syndrome

被引:5
作者
Flores, Alexandra Garza [1 ,2 ]
Nordgren, Ida [3 ]
Pettersson, Maria [3 ,4 ]
Dias-Santagata, Dora [5 ,6 ]
Nilsson, Daniel [3 ,4 ]
Hammarsjo, Anna [3 ,4 ]
Lindstrand, Anna [3 ,4 ]
Batkovskyte, Dominyka [3 ]
Wiggs, Janey [7 ]
Walton, David S. [8 ]
Goldenberg, Paula [1 ]
Eisfeldt, Jesper [3 ,4 ]
Lin, Angela E. [1 ]
Lachman, Ralph S. [9 ,10 ,11 ]
Nishimura, Gen [3 ,12 ]
Grigelioniene, Giedre [3 ,4 ,13 ]
机构
[1] Mass Gen Children, Med Genet, Boston, MA USA
[2] Cook Childrens Hosp, Genet Dept, Ft Worth, TX USA
[3] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden
[4] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden
[5] Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA
[6] Harvard Med Sch, Boston, MA USA
[7] Harvard Med Sch, Mass Eye & Ear Infirm, Ocular Genom Inst, Dept Ophthalmol, Boston, MA USA
[8] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA
[9] UCLA Sch Med, Dept Radiol Sci & Pediat, Los Angeles, CA USA
[10] Stanford Univ, Dept Radiol Sci, Stanford, CA USA
[11] UCLA Sch Med, Orthoped Dept, Int Skeletal Dysplasia Registry, Los Angeles, CA USA
[12] Musashino Yowakai Hosp, Dept Radiol, Musashino, Tokyo, Japan
[13] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA USA
基金
瑞典研究理事会;
关键词
FOXC1; Axenfeld-Rieger Syndrome; De Hauwere Syndrome; skeletal anomalies; genome sequencing; case report; AXENFELD-RIEGER-SYNDROME; WHITE-MATTER ABNORMALITIES; 6P DELETION; PHENOTYPE; MUTATIONS; PITX2; DYSPLASIA; ANOMALIES; PATIENT; ADULT;
D O I
10.3389/fgene.2023.1174046
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in FOXC1 are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome (ARS, #602482), an autosomal dominant condition with ophthalmologic anterior segment abnormalities, high risk for glaucoma and extraocular findings including distinctive facial features, as well as dental, skeletal, audiologic, and cardiac anomalies. De Hauwere syndrome is an ultrarare condition previously associated with 6p microdeletions and characterized by anterior segment dysgenesis, joint instability, short stature, hydrocephalus, and skeletal abnormalities. Here, we report clinical findings of two unrelated adult females with FOXC1 haploinsufficiency who have ARS and skeletal abnormalities. Final molecular diagnoses of both patients were achieved using genome sequencing. Patient 1 had a complex rearrangement involving a 4.9 kB deletion including FOXC1 coding region (Hg19; chr6:1,609,721-1,614,709), as well as a 7 MB inversion (Hg19; chr6:1,614,710-8,676,899) and a second deletion of 7.1 kb (Hg19; chr6:8,676,900-8,684,071). Patient 2 had a heterozygous single nucleotide deletion, resulting in a frameshift and a premature stop codon in FOXC1 (NM_001453.3): c.467del, p.(Pro156Argfs*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, pes planovalgus, dental anomalies, hydrocephalus, distinctive facial features, and normal intelligence. Skeletal surveys revealed dolichospondyly, epiphyseal hypoplasia of femoral and humeral heads, dolichocephaly with frontal bossin gand gracile long bones. We conclude that haploinsufficiency of FOXC1 causes ARS and a broad spectrum of symptoms with variable expressivity that at its most severe end also includes a phenotype overlapping with De Hauwere syndrome.
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页数:8
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