Heterozygous <i>FGF8</i> mutations in patients presenting cryptorchidism and multiple VATER/VACTERL features without limb anomalies

Zeidler, Claudia; Woelfle, Joachim; Draaken, Markus; Mughal, Sadaf S.; Grosse, G.; Hilger, Alina C.; Dworschak, Gabriel C.; Boemers, Thomas M.; Jenetzky, Ekkehart; Zwink, Nadine; Lacher, Martin; Schmidt, Dominik; Schmiedeke, Eberhard; Grasshoff‐Derr, Sabine; Märzheuser, Stefanie; Holland‐Cunz, Stefan; Schäfer, Mattias; Bartels, Enrika; Keppler, Kathleen; Palta, Markus; Leonhardt, Johannes; Kujath, Christina; Rißmann, Anke; Nöthen, Markus M.; Reutter, Heiko; Ludwig, Michael

doi:10.1002/bdra.23278

Cited by 15 publications

(13 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent FGF8 analysis by Zeidler and colleagues [58] in 78 patients with VATER/VACTERL association or VATER/VACTERL-like phenotype revealed two different mutations. While the p.Gly29_Arg34dup mutation in a patient with five CFs (‘ACTERL’) including horseshoe kidney has not been reported yet, the p.Pro26Leu substitution in a patient with two CFs (‘AR’), comprising right-sided renal dysplasia, had earlier been found in a patient with Kallmann syndrome (KS) who did not show any CFs of the VATER/VACTERL association [59].…”

Section: Human Disease Genes In Patients With Vater/vacterl-like Phenmentioning

confidence: 99%

“…However, besides delayed puberty in both and unilateral cryptorchidism in one of the fathers, they were otherwise healthy. This suggests a variable expressivity for mutations in FGF8 in which patients with VATER/VACTERL association may constitute the severe end [58]. According to MGD Fgf8 tm1.3Mrt / Fgf8 tm1.4Mrt mice display abnormal kidney development and absent renal glomerulus [56].…”

Section: Human Disease Genes In Patients With Vater/vacterl-like Phenmentioning

confidence: 99%

See 1 more Smart Citation

Underlying genetic factors of the VATER/VACTERL association with special emphasis on the “Renal” phenotype

et al. 2016

Self Cite

View full text Add to dashboard Cite

The acronym VATER/VACTERL association (OMIM #192350) refers to the rare non-random co-occurrence of the following component features (CFs): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). According to epidemiological studies, the majority of patients with VATER/VACTERL association present with a “Renal” phenotype comprising a large spectrum of congenital renal anomalies. Indeed, all of the identified human disease genes for the VATER/VACTERL association, namely FGF8, FOXF1, HOXD13, LPP, TRAP1, ZIC3 have been associated with renal malformations. This review resumes these genotype-phenotype correlations and suggests that the elucidation of the genetic causes of the VATER/VACTERL association will ultimately provide insights into the genetic causes of the complete spectrum of congenital renal anomalies per se.

show abstract

Section: Human Disease Genes In Patients With Vater/vacterl-like Phenmentioning

confidence: 99%

Section: Human Disease Genes In Patients With Vater/vacterl-like Phenmentioning

confidence: 99%

Underlying genetic factors of the VATER/VACTERL association with special emphasis on the “Renal” phenotype

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Otherwise, it has been shown that some signaling pathways, such as sonic hedgehog, Hox and retinoic acid pathways could also be implicated in the etiology [Solomon, 2011;Brosens et al, 2014]. Individuals with VAC-TERL features were identified with mutations of ZIC3 and FOXF1 [Chung et al, 2011;Hilger et al, 2015], FGF8 [Zeidler et al, 2014], PTEN [Reutter and Ludwig, 2013], and HOXD13 [Garcia-Barcelo et al, 2008]. A study of 69 twins affected by VACTERL association did not show a higher concordance rate in monozygotic twins than in dizygotic twins, and therefore suggested that inherited genetic factors play a limited role in this condition [Bartels et al, 2012b].…”

Section: Vacterl Associationmentioning

confidence: 99%

Genetic Testing in a Cohort of Complex Esophageal Atresia

et al. 2017

View full text Add to dashboard Cite

The objective of the present study is to describe a cohort of complex esophageal atresia and the yield of genetic tests performed for such patients. We selected 45 patients with complex esophageal atresia (EA), namely those having at least one associated anomaly. We reviewed their medical records to assess clinical features, other diagnoses, and genetic investigations. Most of the patients had a diagnosis of VACTERL association (56%) with no genetic variant identified. Interestingly, 5 patients in the cohort (11%) had a right pulmonary hypoplasia or agenesis. A majority of our cohort (73%) had genetic testing; 60% were karyotyped (abnormal in 4 of the 27 patients tested), 31% had aCGH (abnormal in 1 of the 14 patients tested), and 31% had diepoxybutane (DEB) testing for Fanconi anemia (abnormal in 2 of the 14 patients tested). One patient had exome sequencing studies, but no candidate gene was identified. Various anomalies were associated with EA, and overall a genetic variant could be identified in 7 of the 33 patients tested. Chromosomal studies such as aCGH and chromosomal breakage studies should be considered, and their yield varied between 7 and 14%. Other genetic investigations such as exome sequencing could possibly have even higher yields but will need to be assessed in a large cohort. Improved genetic diagnoses in EA may improve the management of these patients by directing specific surveillance and management schemes.

show abstract

“…Furthermore, in 66% of naturally cryptorchid mice, treatment with LH-releasing hormone reportedly induces epididymo-testicular descent, while increasing testosterone secretion and normalizing morphology of the underdeveloped cryptorchid epididymis [Hadziselimovic, 1981]. Notably, FGF8 mutation contributes to formation of the VATER/VACTERL association and is involved in cryptorchidism development [Zeidler et al, 2014].…”

Section: Role Of Gonadotropin-releasing Hormone and Fgfsmentioning

confidence: 99%

Involvement of Fibroblast Growth Factors and Their Receptors in Epididymo-Testicular Descent and Maldescent

Hadžiselimović¹

2015

Mol Syndromol

View full text Add to dashboard Cite

Maldescent of the epididymo-testicular unit can occur as an isolated event or as a component of various syndromes. When part of a syndrome, crypto-epididymis is usually accompanied by other genital and/or extragenital features. Epididymis development is primarily regulated by androgens, and successful epididymo-testicular unit development and descent requires an intact hypothalamic-pituitary-gonadal axis. The developing gonadotropin-releasing hormone system is essential for epididymo-testicular descent and is highly sensitive to reduced fibroblast growth factor (FGF) signaling. Our understanding of the impact of FGFR1 in the process of epididymo-testicular descent has recently improved. At later stages of embryonic development, the undifferentiated epididymal mesenchyme is a specific domain for FGFR1 expression. The majority of individuals with syndromic crypto-epididymis, as well as individuals with isolated maldescent of the epididymo-testicular unit, exhibit some disturbance of FGF, FGFR1 and/or genes involved in hypothalamic-pituitary-gonadal axis regulation. However, the mechanisms underlying FGF dysregulation may differ between various syndromes.

show abstract

Heterozygous FGF8 mutations in patients presenting cryptorchidism and multiple VATER/VACTERL features without limb anomalies

Abstract: Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.

Cited by 15 publications

References 54 publications

Underlying genetic factors of the VATER/VACTERL association with special emphasis on the “Renal” phenotype

Underlying genetic factors of the VATER/VACTERL association with special emphasis on the “Renal” phenotype

Genetic Testing in a Cohort of Complex Esophageal Atresia

Involvement of Fibroblast Growth Factors and Their Receptors in Epididymo-Testicular Descent and Maldescent

Contact Info

Product

Resources

About