Omodysplasia type II (autosomal dominant) is a very rare skeletal dysplasia with facial dysmorphism and urogenital abnormalities. Causal are alterations in the FZD2 gene. We describe a prenatally detected case with shortened upper extremities, cleft lip and palate and suspected genital hypoplasia. The de novo mutation in the FZD2 gene in the affected fetus, which has not been described yet, was found in the literature and is most likely the cause of the symptoms. To our knowledge, it is the first publication of the de novo mutation in the FZD2 gene. Die Omodysplasie Typ II (autosomal-dominant) ist eine sehr seltene Erkrankung, welche mit einer Skelettanomalie, fazialen Dysmorphie und urogenitalen Auffälligkeiten einhergeht. Kausal finden sich Alterationen im FZD2-Gen. Wir beschreiben einen pränatal detektierten Fall mit verkürzten oberen Extremitäten, Lippen-Kiefer-Gaumenspalte und Verdacht auf Genitalhypoplasie. Beim betroffenen Fetus wurde in der Literatur die noch nicht beschriebene de novo Mutation im Gen FZD2 nachgewiesen, die höchstwahrscheinlich ursächlich für die Symptomatik ist. Nach unserem Wissen, ist es die Erstpublikation der de novo Mutation im Gen FZD2.

Genetic and metabolic disorders present unique challenges in understanding the pathophysiology and outcomes of specific symptoms and presentations due to their broad spectrum of manifestations and etiologies. In this case report, we have studied a 26-year-old who was diagnosed with omodysplasia, a rare form of skeletal dysplasia. She exhibits atypical symptoms of psychosis and was diagnosed with schizophreniform disorder at an early age. Various antipsychotic medications were administered; however, minimal to no improvement was noted in the symptoms. On the contrary, she reported adverse effects to some antipsychotics. She continued to exhibit delusions and hallucinations and showed clinical improvement after treatment with olanzapine. Her clinical course was further complicated by the presence of borderline personality traits, which went unnoticed earlier. Here, we would like to highlight the course of her symptoms, the different treatments administered, and the possible link between omodysplasia and treatment-resistant schizophrenia.

Skeletal dysplasias broadly include disorders of cartilage or bone. Omodysplasia-1 is a type of skeletal dysplasia caused by biallelic loss of function variants in the GPC6 gene. GPC6 codes for the protein glypican 6 (GPC6) (OMIM *604404), which stimulates bone growth. We report a family in which five out of nine children were presented with a skeletal dysplasia characterized phenotypically by mild short stature and rhizomelia. All affected individuals were found to have homozygous missense variants in GPC6: c.511 C>T (p.Arg171Trp). Radiograph findings included rhizomelic foreshortening of all four extremities, coxa breva, and ulna minus deformity. Using a Hedgehog (Hh) reporter assay, we demonstrate that the variant found in this family results in significantly reduced stimulation of Hh activity when compared to the wild-type GPC6 protein, however protein function is still present. Thus, the milder phenotype seen in the family presented is hypothesized due to decreased GPC6 protein activity versus complete loss of function as seen in omodysplasia-1. Given the unique phenotype and molecular mechanism, we propose that this family's findings widen the phenotypic spectrum of GPC6-related skeletal dysplasias.

Deciphering non-canonical WNT signaling has proven to be both fascinating and challenging. Discovered almost 30 years ago, non-canonical WNT ligands signal independently of the transcriptional co-activator β-catenin to regulate a wide range of morphogenetic processes during development. The molecular and cellular mechanisms that underlie non-canonical WNT function, however, remain nebulous. Recent results from various model systems have converged to define a core non-canonical WNT pathway consisting of the prototypic non-canonical WNT ligand, WNT5A, the receptor tyrosine kinase ROR, the seven transmembrane receptor Frizzled and the cytoplasmic scaffold protein Dishevelled. Importantly, mutations in each of these signaling components cause Robinow syndrome, a congenital disorder characterized by profound tissue morphogenetic abnormalities. Moreover, dysregulation of the pathway has also been linked to cancer metastasis. As new knowledge concerning the WNT5A-ROR pathway continues to grow, modeling these mutations will likely provide crucial insights into both the physiological regulation of the pathway and the etiology of WNT5A-ROR-driven diseases.

Human Robinow syndrome (RS) and dominant omodysplasia type 2 (OMOD2), characterized by skeletal limb and craniofacial defects, are associated with heterozygous mutations in the Wnt receptor FZD2. However, as FZD2 can activate both canonical and non-canonical Wnt pathways, its precise functions and mechanisms of action in limb development are unclear. To address these questions, we generated mice harboring a single-nucleotide insertion in Fzd2 (Fzd2em1Smill), causing a frameshift mutation in the final Dishevelled-interacting domain. Fzd2em1Smill mutant mice had shortened limbs, resembling those of RS and OMOD2 patients, indicating that FZD2 mutations are causative. Fzd2em1Smill mutant embryos displayed decreased canonical Wnt signaling in developing limb mesenchyme and disruption of digit chondrocyte elongation and orientation, which is controlled by the β-catenin-independent WNT5A/planar cell polarity (PCP) pathway. In line with these observations, we found that disruption of FZD function in limb mesenchyme caused formation of shortened bone elements and defects in Wnt/β-catenin and WNT5A/PCP signaling. These findings indicate that FZD2 controls limb development by mediating both canonical and non-canonical Wnt pathways and reveal causality of pathogenic FZD2 mutations in RS and OMOD2 patients.