Diaphyseal and Metaphyseal Modeling Defects—Clinical Findings and Identification of WRAP53 Deficiency in Craniometadiaphyseal Dysplasia

Background: Diaphyseal and metaphyseal modeling defects lead to severe changes in bone mass and shape, which are common features in osteoporosis that linked to non-vertebral fractures. Original mechanism of diaphyseal and metaphyseal modeling defects has proved elusive. Studying rare syndromes can elucidate mechanisms of common disorders and identify potential therapeutic targets.Methods: We evaluated a family pedigree with craniometadiaphyseal dysplasia (CRMDD, OMIM 269300), a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and absent of normal metaphyseal flaring and diaphyseal constriction. Systemic radiographic examination and serum hormone test were made for this rare disease. One patient and her two normal parents were examined by means of whole-exome sequencing (WES) to identify the candidate pathogenic gene and rule out mucopolysaccharidosis and Prader–Willi Syndrome by means of Sanger sequencing.Results: There are several conspicuous radiographic characteristics: (1) bullet-shaped phalanges, (2) long and narrow pelvic inlet, absent of supra-acetabular constriction, (3) round rod-shaped long tubular bones, (4) prominent aiploic mastoid, (5) bending-shaped limb, genua varus and genu varum, and (6) congenital dislocation of elbow. Here, we did not find any wormian bones, and there are several typical clinical characteristics: (1) macrocephaly and wide jaw, (2) Avatar elf-shaped ears, pointed and protruding ears, (3) hypertrophy of limbs, (4) flat feet and giant hand phenomenon, (5) nail dystrophy, (6) limb deformity, (7) high-arched palate, (8) superficial hemangiomas, (9) tall stature, and intellectual disability. In this patient, we found biallelic frameshift deletion mutations in WRAP53, and those two mutations were transmitted from her parents respectively.Conclusions: We describe her clinical and radiological findings and presented a new subtype without wormian bones and with a tall stature. Our study showed that craniometadiaphyseal dysplasia was caused by a deficiency of WRAP53 with autosomal recessive inheritance.

The presence of Wormian bones increases the fracture resistance of equine cranial bone

Wormian (intrasutural) bones are small, irregular bones, that are found in the cranial sutures of the skull. The occurrence of Wormian bones in human skulls has been well documented but few studies have detected the presence of such bones in domestic animals. Although some research has linked the presence of Wormian bones to bone pathology, its anatomical significance in healthy individuals is not known. To the best of our knowledge, no previous study has examined the biomechanical features of Wormian bone. This study uses microCT imaging of the parietal bone region to determine the frequency of occurrence of Wormian bones in horse skulls and, through 3-point bending tests, to calculate the mechanical differences that result from the presence of such bones. In addition, bone properties such as bone mineral density (BMD) and stiffness were measured and analysed to determine the influence of Wormian bone. Our findings on 54 specimens taken from 10 horses (ages ranging from 4 to 29 years) showed that Wormian bone was present in 70% of subjects and that its occurrence was unrelated to age or sex. 3-point bend tests revealed that the stiffness normalised by cross section area (P = 0.038) was lower in samples where Wormian bone was present. An idealised Finite Element simulation confirmed that the presence of Wormian bone reduced the maximum stress and strain, as well as their distribution throughout the sample. We consequently conclude that the presence of Wormian bones, which are confined to the calvaria, increase the compliance of the bone and reduce the likelihood of skull fracture. As all skull samples were collected from a local abattoir, ethical approval was not required for this work.

Wormian bones: shape, location and relation to each other

The material of the study was the skull of an 8-year-old girl. In the cranioscopy, the following were identified: on the right side, the bone of the sphenoid fontanel or epipteric bone; bones of lambdoid suture - on the right side in the amount of 5, on the left side -1 bone; preinterparietal bone, ospreinterparietale.By the craniometric method, the height and width of the bones were determined. The bone of the sphenoid fontanelle or epipteric bone is located between the frontal, parietal bones, the greater wing of the sphenoid bone, and the squama of the temporal bone. The width of the epipteric bone is 16.5 mm, height 9.5 mm. The bones of the lambdoid suture in the amount of 5 on the right and the 1st on the left were located in an elongated state.The largest bone was located in the middle of the right lambdoid suture; apparently, it was formed by the union of at least two Wormian bones. Preinterparietal bone has a triangular shape, the base of the triangle facing the sagittal suture, the tip, slightly rounded - in the direction of the occipital bone. The lateral angles of the preinterparietal bone are serrated, which, in principle, clearly distinguishes it from the parietal bones. The bone was single, no sutures or grooves dividing the preinterparietal bone into parts were observed. The width of the bone is 18.5 mm, height 13.8 mm.