Identification of novel mutation in RANKL by whole-exome sequencing in a Thai family with osteopetrosis; a case report and review of RANKL osteopetrosis

Pongtawat Lertwilaiwittaya, Bhoom Suktitipat, Phongphak Khongthon, Warut Pongsapich, Chanin Limwongse, Manop Pithukpakorn, Pongtawat Lertwilaiwittaya, Bhoom Suktitipat, Phongphak Khongthon, Warut Pongsapich, Chanin Limwongse, Manop Pithukpakorn

Abstract

Background: Osteopetrosis is a rare form of skeletal dysplasia characterized by increased bone density that leads to bone marrow failure, compressive neuropathy, and skeletal dysmorphism. Molecular diagnosis is essential as it guides treatment and prognosis. We report Thai siblings with an ultra-rare form of osteopetrosis.

Methods: The older brother and the younger sister presented with chronic mandibular osteomyelitis in their 20s. Since childhood, they had visual impairment, pathological fracture, and skeletal dysmorphism. Quadruplet whole-exome sequencing was performed and confirmed with Sanger sequencing. Novel mutation in TNFSF11 (RANKL) c.842T>G, p.Phe281Cys was identified in a homozygous state in both siblings.

Results: Surgical debridement, antibiotic, and hyperbaric oxygen therapy were used and discontinued over a 6-month period with normalization of C-reactive protein. Hematopoietic stem cell transplantation candidacy was excluded by molecular diagnosis.

Conclusion: We report a novel mutation in an ultra-rare form of osteopetrosis. Our siblings manifested with a milder phenotype in comparison with nine cases previously published.

Trial registration: ClinicalTrials.gov NCT02666768.

Keywords: TNFSF11; bone; genome; osteopetrosis; skeletal dysplasia.

Conflict of interest statement

The authors have declared that they have no conflict of interests exist.

© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

Figures

FIGURE 1
FIGURE 1
Skeletal survey of the older brother. (a) X‐ray AP view of skull (arrow: thickening bony calvarium). (b) X‐ray Lateral view of skull (arrows: hypoplasia of paranasal air sinuses). (c) X‐ray Panoramic view of mandible (arrows: cortical disruption of mandible and missing teeth from osteomyelitis). (d) X‐ray of chest. (e) X‐ray AP view of TL spine (arrows: sandwich vertebrae). (f) X‐ray of upper extremities (arrow: Erlenmeyer flask deformity; metaphyseal flaring of right Humerus). (g) X‐ray of lower extremities (arrow: healed pathological fracture of right Tibia)
FIGURE 2
FIGURE 2
Skeletal survey of the younger sister. (a) X‐ray AP view of skull. (b) X‐ray Lateral view of skull. (c) X‐ray Panoramic view of mandible (arrow: cortical disruption of mandible and missing teeth from osteomyelitis). (d) X‐ray of chest. (e) X‐ray AP view of TL spine. (f) X‐ray of upper extremities. (g) X‐ray of lower extremities (Both Tibia) (arrow: metaphyseal flaring of right Tibia)
FIGURE 3
FIGURE 3
Pedigree demonstrating height and the results of Sanger sequencing of TNFSF11 (NM_003701.4)
FIGURE 4
FIGURE 4
Pathological examination of the elder brother's surgical specimen (H&E stain, 100×). (a) Necrotic bone in the background of chronic non‐specific inflammation; consistent with chronic osteomyelitis. (b) Viable bone with fibrovascular tissue. No osteoclasts observed; consistent with osteoclast‐poor nature of the disease

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