Piepkorn type of osteochondrodysplasia: Defining the severe end of FLNB‐related skeletal disorders in three fetuses and a 106‐year‐old exhibit

Abstract

The Piepkorn type of lethal osteochondrodysplasia (POCD) is a rare and lethal dwarfing condition. Four cases have been reported to date. The characteristic features are distinctly shortened "flipper-like" limbs, polysyndactyly, excessive underossification, especially of the limb bones and vertebrae, and large (giant) chondrocytes in the cartilaginous bone primordia. These characteristics allowed the diagnosis of Piepkorn type of osteochondrodysplasia in four new cases, three fetuses of 15 to 22 weeks and one 106-year-old museum exhibit. Piepkorn type of osteochondrodysplasia has been assigned to the giant cell chondrodysplasias such as atelosteogenesis type 1 (AO1) and boomerang dysplasia (BD). Analysis of the Filamin B gene in 3p14.3, which is associated with these disorders, allowed the identification of the first FLNB mutations in Piepkorn type of osteochondrodysplasia. The heterozygous missense mutations, found in the three fetuses, were located in exons 28 and 29, encoding the immunoglobulin-like repeat region R15, one of three mutational hot spots in dominant FLNB-related skeletal disorders. Direct preparations and alcian blue staining revealed single upper and lower arm and leg bone primordia, preaxial oligodactyly, and polysyndactyly with complete fusion and doubling of the middle and end phalanges II-V to produce eight distal finger rays. Considering the unique clinical features and the extent of underossification, Piepkorn type of osteochondrodysplasia can be regarded as a distinct entity within the AO1-BD-POCD continuum.

History and highlights of the teratological collection in theNarrenturm, Vienna (Austria)

“…Due to the oftentimes limited access to museum specimens efforts are increasingly directed to increase their visibility, for example through online distributions that even include extended reality modalities (Mikami et al, 2022). What makes teratological collections worth examining, researched with both radiographs and magnetic resonance imaging (Beighton et al, 1993(Beighton et al, , 2005Pumberger et al, 2003;Rehder et al, 2018), indicating the open attitude to perform additional diagnostics on museal specimens, a premise which is not always obvious or possible. Although the clinical characteristics sometimes permit diagnostic speculation in (neonatal) bone dysplasias, the recognition of distinctive radiographic changes remains the prime method to the establishment of a firm diagnosis, as was done within this report.…”

“…Besides a wealth of common and rare congenital anomalies, a substantial number of skeletal dysplasias are present within the extant collections. Interestingly, in the past, multiple specimens in the Narrenturm collection were already researched with both radiographs and magnetic resonance imaging (Beighton et al, 1993, 2005; Pumberger et al, 2003; Rehder et al, 2018), indicating the open attitude to perform additional diagnostics on museal specimens, a premise which is not always obvious or possible. Although the clinical characteristics sometimes permit diagnostic speculation in (neonatal) bone dysplasias, the recognition of distinctive radiographic changes remains the prime method to the establishment of a firm diagnosis, as was done within this report.…”

Severe skeletal dysplasia caused by a novel FLNB gene mutation

“…In addition, there is delayed or absent ossification of the vertebrae 13. Individuals suspected of having POCD have perinatal-lethal micromelic dwarfism with flipper-like limbs and pronounced craniofacial dysmorphism 13 14. Features include absent ossification of all long bones, vertebrae and pelvis.…”

“…Features include absent ossification of all long bones, vertebrae and pelvis. In addition, some ossification of the pubic bones, ribs, scapulae, skull and clavicles can be observed 13 14. Individuals with AOIII have a milder condition than AOI with survival beyond the neonatal period possible.…”

Craniofacial disorders and dysplasias: Molecular, clinical, and management perspectives

“…Inheritance is autosomal dominant and marked by macrobrachycephaly, craniosynostosis, prominent forehead, hypertelorism, exophthalmos and occasional cleft palate. Other features are polysyndactyly with total syndactyly of all fingers and toes, flipper-like limbs, hypoplastic or absent thumbs and octodactyly ( Rehder et al, 2018 ; Robertson, 2008 ). The treatment of craniofacial involvement in filamin B disorders include multidisciplinary evaluation for possible surgical intervention for the cleft palate, and conservative management of dental conditions.…”