Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.

Pachydysostosis of the fibula in a case of familial adenomatous polyposis.

BACKGROUND: Familial Adenomatous Polyposis (FAP) is a colorectal cancer (CRC) predisposition syndrome caused by germline APC mutations and characterised by an increased risk of CRC and colonic polyps and, in certain forms, of specific prominent extraintestinal manifestations, namely osteomas, soft tissue tumours and dental anomalies. Pachydysostosis of the fibula is a rare clinical entity defined by unilateral bowing of the distal portion of the fibula and elongation of the entire bone, without affectation of the tibia. CLINICAL REPORT: We report a 17-year-old male, who presented with a non-progressive bowing of the right leg detected at 18 months of age caused by a fibula malformation (later characterized as pachydysostosis) and a large exophytic osteoma of the left radius, noticed at the age of 15 years, without gastrointestinal symptoms. There was no relevant family history. Detailed characterisation revealed multiple osteomas, skin lesions and dental abnormalities, raising the hypothesis of FAP. This diagnosis was confirmed by genetic testing [c.4406_4409dup p.(Ala1471Serfs*17) de novo mutation in the APC gene] and endoscopic investigation (multiple adenomas throughout the colon, ileum and stomach). DISCUSSION: This case report draws attention to the phenotypic spectrum of skeletal manifestations of FAP: this patient has a congenital fibula malformation, not previously associated with this syndrome, but which is likely to have been its first manifestation in this patient. This clinical case also illustrates the challenges in the early diagnosis of FAP, especially without family history, and highlights the importance of a multidisciplinary approach and the adequate study of rare skeletal abnormalities.