In this case, the child went to the otolaryngology department with the onset of nasal symptoms as the main-complain. After systemic X-ray examination with characteristic imaging changes and genetic test, the patient was diagnosed of osteopetrosis. This is the first case of pediatric osteopetrosis in China with a mutation in TNFRSF11A gene. The molecular analysis of the patient led to the identification of a novel mutations in the TNFRSF11A gene: a nonsense mutations c.1196C > G (p.S399X) in exon 9.Mutations in the human TNFRSF11A gene which leading to osteopetrosis was first reported by Sobacchi [11]. Monogenic mutations of TNFRSF11A has previously been fully documented as the cause of human autosomal recessive osteopetrosis [12,13,14]. It caused amino acid substitutions at moderately conserved position and supporting the diagnosis of autosomal recessive osteopetrosis type 7 [15].
TNFRSF11A(RANK) gene belongs to the tumor necrosis factor (TNF) receptor superfamily and located on chromosome 18 (18q21.33), which encoding a receptor with 616 amino acids [16]. The RANK gene codes for the functional receptor for RANKL. The mutated residues seem to be highly conserved in evolution, so it could be considered that amino acid substitutions at these positions might change the folding of the outer domain thus the interaction with RANKL. RANKL, RANK and TNFRSF11 affect the differentiation of osteoclasts, resulting in a decrease in the number of osteoclasts, while the remaining genes all cause osteoclast dysfunction [17].
RANK-dependent ARO is confirmed to benefit from HSCT, although there is no long-term follow-up data. In the post-HSCT period, patients seem to be particularly prone to hypercalcemia, especially when HSCT surgery is older. These data increase the clinical and molecular heterogeneity of human ARO, further confirming the important role of accurate molecular diagnosis in therapy.
Until now, TNFRSF11A mutations have been observed in patients with the Paget’s disease of bone (PDB), primary ovarian insufficiency, recurrent fevers, familial expansile osteolysis, expansile skeletal hyperphosphatasia and autosomal recessive osteopetrosis [2, 16]. The TNFRSF11A gene encodes RANK, which is fundamental for osteoclast formation. This has been demonstrated before, which impacted osteoclasts maturation and have a severe defect in bone resorption and remodeling.
At present, there is no acceptable best therapy for osteopetrosis, as a result, symptomatic and supportive treatment was given to most patients [18]. HSCT is the only treatment that can offer cure to these patients according to reports, but not all the subtypes can benefit from HSCT (e.g. OSTM1 and some with CLCN7) [13]. Osteopetrosis can be diagnosed by typical x-ray manifestation. Typical bony abnormalities were illustrated, including generalized sclerosis, longitudinal striation of the long bones, extreme metaphyseal flaring or transverse lucent bands, “sandwich” vertebra, flask deformities, “bone-within-bone” appearance. Bone marrow biopsy showed shrinkage of bone marrow cavity, thickening of bone trabecula, reduction of bone marrow hematopoietic cells, and bone marrow fibrosis [9, 19].
The clinical manifestations included rhinitis, alveolar bone osteonecrosis, osteomyelitis of alveolar bone, bone destruction of right maxillary sinus, failure of tooth eruption, roots malformation, caries, optic nerve atrophy, compressive neuropathies, cranial nerve deficit [2]. The child exhibited most of the phenotypic who was diagnosed after two years. She is the first case of osteopetrosis in the family, her parents and old sister are with normal bone density. Her parents are close relatives.
Clinic examination of ear nose and throat (ENT) doctors combining the whole-body radiographic results can lead to early diagnosis of osteopetrosis. Vigorous physical activities should be avoided to prevent severe complications. Thus, routine ENT and dental examination should be applied to prevent sinusitis and osteomyelitis as well. The role of TNFRSF11A mutations in osteopetrosis has been revealed not long ago. Genetic analysis strongly supported the pathogenic role for this mutation. Better understanding of this pathological situation and pathogenesis is so important to plan appropriate immunotherapy to benefit. In summary, we report a novel mutation of TNFRSF11A gene in a Chinese girl with osteopetrosis. Analysis and reporting patients with mutation in this gene can be very helpful to obtain a better picture of the disease phenotype in TNFRSF11A-related osteopetrosis.