Intrafamilial phenotypic variability in a Polish family with Sensenbrenner syndrome and biallelic WDR35 mutations.
Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy. Cranioectodermal dysplasia is characterized by craniofacial, skeletal, and ectodermal abnormalities. About 50 patients have been described to date. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disorder. Mutations in five genes: IFT122, WDR35, IFT43, WDR19, and IFT52 have been associated with CED. All known genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Here, we report a family with two children affected by Sensenbrenner syndrome, a 9-year-old girl and her older sister who died in infancy due to respiratory, liver, and renal insufficiency. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, preaxial polydactyly of left hand, narrow chest, craniosynostosis, dolichocephaly, high anterior hairline, epicanthal folds and telecanthus, depressed nasal bridge, low-set ears, and additional ectodermal abnormalities. The patient presented with chronic tubulointerstitial renal disease. She had abnormal echogenicity on renal ultrasound, reduced glomerular filtration, albuminuria and tubular proteinuria, hypocalciuria and hypocitraturia, accompanied by pre-hypertensive state. This pattern of renal abnormality was regarded as nephronophthisis. Psychomotor development was apparently normal. Molecular analysis in one of the affected individuals identified compound heterozygosity for a nonsense (c.1922T>G, p.(Leu641*)) and missense (c.2522A>T, p.(Asp841Val)) variants in WDR35. We present a detailed clinical descriptions of two female siblings showing an intrafamilial phenotypic variability of the disease, and illustrating the potential lethality of CED.
Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
Joanna
http://orcid.org/0000-0002-4662-9336
J
Walczak-Sztulpa
Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
Anna
A
Wawrocka
Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
Agata
A
Sobierajewicz
Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
Lukasz
L
Kuszel
Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.
Jan
J
Zawadzki
Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.
Ryszard
R
Grenda
Department of Anthropology, The Children's Memorial Health Institute, Warsaw, Poland.
Anna
A
Swiader-Lesniak
Department of Ophthalmology, The Children's Memorial Health Institute, Warsaw, Poland.
Beata
B
Kocyla-Karczmarewicz
Department of Diagnostic Imaging, The Children's Memorial Health Institute, Warsaw, Poland.
Anna
A
Wnuk
Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
Anna
A
Latos-Bielenska
Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
Krystyna H
KH
Chrzanowska
D000483:Alleles; D001842:Bone and Bones / Q000002:abnormalities* / Q000503:physiopathology; D002648:Child; D002923:Cilia / Q000235:genetics / Q000473:pathology; D018389:Codon, Nonsense; D003398:Craniosynostoses / Q000235:genetics* / Q000503:physiopathology; D003598:Cytoskeletal Proteins; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D053823:Hedgehog Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000503:physiopathology; D020125:Mutation, Missense; D011044:Poland; D011506:Proteins / Q000235:genetics*; D035781:Siblings
D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C558596:WDR35 protein, human
Sensenbrenner syndrome; WDR35; anthropometric measurements; chondrodysplasia; ciliopathy; progressive renal disease