title: Variable expressivity of the phenotype in two families with brachydactyly type E, craniofacial dysmorphism, short stature and delayed bone age caused by novel heterozygous mutations in the PTHLH gene.
abstract: Brachydactyly refers to shortening of digits due to hypoplasia or aplasia of bones forming the hands and/or feet. Isolated brachydactyly type E (BDE), which is characterized by shortened metacarpals and/or metatarsals, results in a small proportion of patients from HOXD13 or PTHLH mutations, although in the majority of cases molecular lesion remains unknown. BDE, like other brachydactylies, shows clinical heterogeneity with highly variable intrafamilial and interindividual expressivity. In this study, we investigated two Polish cases (one familial and one sporadic) presenting with BDE and additional symptoms due to novel PTHLH mutations. Apart from BDE, the affected family showed short stature, mild craniofacial dysmorphism and delayed bone age. Sanger sequencing of PTHLH revealed a novel heterozygous frameshift mutation c.258delC(p.N87Tfs*18) in two affected individuals and one relative manifesting mild brachydactyly. The sporadic patient, in addition to BDE, presented with craniofacial dysmorphism, normal stature and bone age, and was demonstrated to carry a de novo heterozygous c.166C>T(p.R56*) mutation. Our paper reports on the two novel truncating PTHLH variants, resulting in variable combination of BDE and other symptoms. Data shown here expand the knowledge on the phenotypic presentation of PTHLH mutations, highlighting significant clinical variability and incomplete penetrance of the PTHLH-related symptoms.
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.|NZOZ Center for Medical Genetics GENESIS, Poznan, Poland.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Jamsheer
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Sowińska-Seidler
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Ewelina M
authors.initials: EM
authors.lastname: Olech
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Socha
authors.affiliation: Department of Medical Imaging, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Kozłowski
authors.affiliation: Department of General and Molecular Biology and Genetics, Medical University of Silesia, Katowice, Poland.
authors.forename: Antoni
authors.initials: A
authors.lastname: Pyrkosz
authors.affiliation: Department of Orthopedics and Traumatology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Trzeciak
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.|NZOZ Center for Medical Genetics GENESIS, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Materna-Kiryluk
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.|NZOZ Center for Medical Genetics GENESIS, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Latos-Bieleńska
mesh_terms: D000293:Adolescent; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D059327:Brachydactyly / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004392:Dwarfism / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome
chemical_list: C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein