AUTHOR=Hao Yun , Wang Xiao-Lin , Xiao Jun , Jiao Chun-Lei , Meng Xin-Yao , Guo Jia-Chao , Shao Jing-Fan , Feng Jie-Xiong , He Jin-Peng
TITLE=Diaphyseal and Metaphyseal Modeling Defects—Clinical Findings and Identification of WRAP53 Deficiency in Craniometadiaphyseal Dysplasia
JOURNAL=Frontiers in Genetics
VOLUME=12
YEAR=2021
URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.684905
DOI=10.3389/fgene.2021.684905
ISSN=1664-8021
ABSTRACT=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.