Raine Syndrome (OMIM #259775), Caused By FAM20C Mutation, Is Congenital Sclerosing Osteomalacia With Cerebral Calcification (OMIM 259660).

Abstract

In 1985, we briefly reported infant sisters with a unique, lethal, autosomal recessive disorder designated congenital sclerosing osteomalacia with cerebral calcification. In 1986, this condition was entered into Mendelian Inheritance In Man (MIM) as osteomalacia, sclerosing, with cerebral calcification (MIM 259660). However, no attestations followed. Instead, in 1989 Raine and colleagues published an affected neonate considering unprecedented the striking clinical and radiographic features. In 1992, "Raine syndrome" entered MIM formally as osteosclerotic bone dysplasia, lethal (MIM #259775). In 2007, the etiology emerged as loss-of-function mutation of FAM20C that encodes family with sequence similarity 20, member C. FAM20C is highly expressed in embryonic calcified tissues and encodes a kinase (dentin matrix protein 4) for most of the secreted phosphoproteome including FGF23, osteopontin, and other regulators of skeletal mineralization. Herein, we detail the clinical, radiological, biochemical, histopathological, and FAM20C findings of our patients. Following premortem tetracycline labeling, the proposita's non-decalcified skeletal histopathology after autopsy indicated no rickets but documented severe osteomalacia. Archival DNA revealed the sisters were compound heterozygotes for a unique missense mutation and a novel deletion in FAM20C. Individuals heterozygous for the missense mutation seemed to prematurely fuse their metopic suture and develop a metopic ridge sometimes including trigonocephaly. Our findings clarify FAM20C's role in hard tissue formation and mineralization, and show that Raine syndrome is congenital sclerosing osteomalacia with cerebral calcification. © 2016 American Society for Bone and Mineral Research.

• Authors: Michael P Whyte, William H McAlister, Michael D Fallon, Mary Ella Pierpont, Vinieth N Bijanki, Shenghui Duan, Ghada A Otaify, William S Sly, Steven Mumm
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 32 Issue 4 Pg. 757-769 (04 2017) ISSN: 1523-4681 [Electronic] United States
• PMID: 27862258 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2016 American Society for Bone and Mineral Research.

Chemical References

• Extracellular Matrix Proteins
• FGF23 protein, human
• Fibroblast Growth Factor-23
• Casein Kinase I
• FAM20C protein, human

Topics

• Abnormalities, Multiple (diagnostic imaging, genetics, metabolism)
• Adult
• Calcinosis (diagnostic imaging, genetics, metabolism)
• Casein Kinase I (genetics, metabolism)
• Cerebrum (diagnostic imaging, metabolism, pathology)
• Cleft Palate (diagnostic imaging, genetics, metabolism)
• Exophthalmos (diagnostic imaging, genetics, metabolism)
• Extracellular Matrix Proteins (genetics, metabolism)
• Female
• Fibroblast Growth Factor-23
• Humans
• Infant, Newborn
• Male
• Microcephaly (diagnostic imaging, genetics, metabolism)
• Osteomalacia (diagnostic imaging, genetics, metabolism)
• Osteosclerosis (diagnostic imaging, genetics, metabolism)