Familial Expansile Osteolysis

A number sign (#) is used with this entry because of evidence that familial expansile osteolysis (FEO) is caused by heterozygous mutation in the RANK gene (TNFRSF11A; 603499) on chromosome 18q21.

Heterozygous mutation in the TNFRSF11A gene can also cause early-onset Paget disease of bone-2 (PDB2; 602080), which shows some overlapping features.

Description

Familial expansile osteolysis is an autosomal dominant bone dysplasia characterized by increased bone remodeling with osteolytic lesions mainly affecting the appendicular skeleton. There is medullary and cortical expansion of the bone without sclerosis, leading to painful and disabling deformities and tendency to pathologic fracture. Clinical features include onset of conductive hearing loss in childhood, premature loss of teeth, and variably increased serum alkaline phosphatase (summary by Palenzuela et al., 2002 and Elahi et al., 2007).

Clinical Features

Wallace (1988) and Osterberg et al. (1988) described 40 members of a family with an autosomal dominant bone dysplasia which, while exhibiting some histologic similarity to Paget disease (see 167250), was distinct enough in its features and natural history to be recognized as unique. Focal skeletal changes, with a predominantly peripheral distribution, had their onset in the second decade. Progressive osteoclastic resorption accompanied by medullary expansion led to severe, painful, disabling deformity and a tendency to pathologic fracture. Most affected persons had an associated early-onset deafness and loss of dentition as a result of unique middle ear and jaw abnormalities. Wallace et al. (1989) indicated that 42 members of 5 generations of the northern Ireland family were affected. Levels of serum alkaline phosphatase and urinary hydroxyproline were elevated to a variable degree, whereas other biochemical indices were normal. A therapeutic trial using parenteral dichloro-methylene-diphosphonate produced an initial rapid biochemical response, which was not sustained. Barr et al. (1989) depicted the progressive changes over a 17-year period in a member of the family reported by Osterberg et al. (1988). Many patients in the family had suffered pathologic fractures, severe bone pain, and eventually major limb amputations. Most affected persons had deafness that initially was conductive but later might become mixed conductive and sensorineural in type. The onset of deafness was usually before the age of 10 years. There were also dental abnormalities with bizarre and extensive resorption of the cervical region of the teeth and the root apex.

Dickson et al. (1991) noted that FEO is often associated with early-onset middle ear deafness and premature loss of dentition. Unlike Paget disease, the focal skeletal lesions are characteristically found in the appendicular skeleton. Patients usually present in the second decade with bone pain and deformity. There is an increased risk of fracture. Dickson et al. (1991) demonstrated focal concentrations of multinuclear osteoclasts, which contained viral-like microcylindrical inclusions in their nuclei. Serologic studies did not show any significant difference between viral antibody titers of patients and their age- and sex-matched controls. Dickson et al. (1991) suggested that intranuclear viral-like microcylindrical inclusions of osteoclasts are not a specific feature of Paget disease as had been proposed, but are found in other disorders of osteoclast dysfunction including pycnodysostosis (265800), osteopetrosis (166600), and giant cell tumors.

Palenzuela et al. (2002) reported a large 4-generation kindred of Spanish descent in which 20 individuals had FEO. The patients had bone pain and deformities of the long bones associated with osteoporosis. Additional features included onset of progressive hearing loss in the first decade, loss of dentition in the second decade, and increased serum alkaline phosphatase. The proband was found to have a single osteolytic lesion without sclerotic reaction in the radius. Bone biopsy showed increased bone remodeling, medullary fibrosis, and multinucleated osteoclasts, suggestive of Paget disease. A destructive focal lesion was found in only 1 other family member, and this legion was mainly expansive, but not clearly osteolytic. None of the patients had pathologic fractures. Palenzuela et al. (2002) noted that the disorder was similar to Paget disease, but spared the axial and skull bones, thus distinguishing it from classic Paget disease. In addition, affected individuals in this family had a reduced amount of osteolytic lesions compared to other families with FEO.

Johnson-Pais et al. (2003) reported 2 unrelated patients with FEO, both of whom were initially diagnosed with Paget disease. Both presented with decreased hearing in the first decade, followed by tooth deterioration and loss and the development of osteolytic lesions in the distal lower limb in the second and third decades. One patient also had upper limb involvement. Serum alkaline phosphatase was increased, but sclerotic bone was not present, excluding a diagnosis of Paget disease. Treatment of both patients with a bisphosphonate reduced pain and normalized serum alkaline phosphatase. Family history was negative for bone disease in 1 patient and positive in the other.

Elahi et al. (2007) reported an Iranian family with FEO previously reported by Daneshi et al. (2005). There were 6 affected members spanning 3 generations. The proband was a 31-year-old woman who had hearing loss since childhood, bowing of the tibia, increased thickness of the occipital bone, and diffusion expansion of bones in the hands. There was an increase in uptake and activity at multiple foci of the whole skeleton, and serum alkaline phosphatase and hydroxyproline levels were elevated. The proband and 2 affected family members lacked ossicles in the middle ear.

Clinical Variability

Whyte et al. (2000) reported a mother and teenaged daughter with a metabolic bone disease characterized by expansile hyperostosis, early-onset deafness, premature tooth loss, and increased serum alkaline phosphatase. Both patients had bone pain and swelling of the fingers, mainly affecting the proximal interphalangeal joint. The mother was more severely affected and had been diagnosed with juvenile Paget disease. She had absence of the middle ear ossicles, intermittent hypercalcemia, and bowing and widening of the long bones. Radiographs of the daughter showed cortical thickening of the appendicular skeleton, with coarse trabecular pattern, areas of sclerosis, and expansion of the medullary cavities in the metacarpals. Radiographs of the mother showed thickening of the skull with some areas of sclerosis, deformed humeral heads, and undertubulation and irregular cortical thickening of the long bones. Bone biopsy showed increased numbers of osteoclasts and osteoblasts, but not the characteristic findings of Paget disease. The findings were consistent with increased bone remodeling and turnover. Whyte et al. (2000) noted the phenotypic similarity to FEO, but commented that the painful involvement of the fingers, changes in the mother's skull, and lack of osteolytic expansion in the long bones differentiated the disorder from FEO. Whyte et al. (2000) termed the disorder 'expansile skeletal hyperphosphatasia (ESH).' In this mother and daughter, Whyte and Hughes (2002) identified a heterozygous 15-bp duplication in exon 1 of the TNFRSF11A gene (g.84dup15), affecting the signal peptide. The mutation was similar to mutations observed in patients with FEO, indicating that the 2 disorders are allelic.

Schafer et al. (2014) reported a 32-year-old Mexican man with severe panostotic expansile bone disease associated with a heterozygous 12-bp in-frame duplication in the TNFRSF11A gene, resulting in the insertion of 4 amino acids in the signal peptide. The patient had deafness at birth and early tooth loss in childhood without replacement by permanent teeth. At age 4 years, his long bones showed progressive bowing deformities, and he had multiple fractures. The disorder was progressive: by his early twenties, his limbs were severely deformed, resulting in an inability to walk or to use his hands. He also had diffuse skeletal pain, and had developed a large mandibular mass, initially deemed inoperable, that interfered with eating. Laboratory studies showed increased alkaline phosphatase, and radiographs showed medullary expansion, increased lucency from fat, thick and disorganized trabeculae, and cortical thinning. The middle ear cavity on the right contained a small rudimentary fused ossicle. The mutation was similar to mutations observed in FEO, and was predicted to result in increased TNFRSF11A signaling, thus expanding the phenotype associated with such mutations.

Inheritance

The transmission pattern of FEO in the family reported by Palenzuela et al. (2002) was consistent with autosomal dominant inheritance.

Mapping

Hughes et al. (1994) mapped the FEO locus to chromosome 18q21.1-q22 by linkage to DNA markers. A YAC contig of the region was also available and the locus was considered to lie between the microsatellite markers D18S64 and D18S51. The distance between these markers is 7-15 cM and a maximum lod score of 11.5 was obtained at a recombination value of 0 for D18S64. A homologous condition in the mouse is also caused by a mutation on mouse chromosome 18 in an area homologous to human 18q.

Molecular Genetics

Hughes et al. (2000) noted that the critical region to which FEO was mapped contains the TNFRSF11A gene encoding receptor activator of nuclear factor-kappa-B (RANK), which is essential in osteoclast formation. They identified 2 different heterozygous insertion mutations in exon 1 of the TNFRSF11A gene: an 18-bp duplication (84dup18; 603499.0001) in affected members of 3 families with FEO, and a 27-bp duplication (75dup27; 603499.0002) in an affected member of 1 family with Paget disease of bone (PDB2; 602080). Both mutations affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappa-B (NF-kappa-B; 164011) signaling in vitro, consistent with the presence of an activating mutation.

In affected members of a large family of Spanish origin with FEO, Palenzuela et al. (2002) identified a heterozygous 84dup18 mutation in the TNFRSF11A gene.

In 2 unrelated patients with FEO, Johnson-Pais et al. (2003) identified a heterozygous 18-bp duplication (g.83_100dup; 603499.0008) in exon 1 of the TNFRSF11A gene, resulting in an in-frame insertion of 6 amino acids in the signal peptide. The mutation resulted in the same changes at the protein level as the g.84_101dup mutation (603499.0001) identified in other families with FEO. Although functional studies were not performed, the mutation was predicted to increase the length of the signal peptide, decreasing proper cleavage and resulting in a gain of function with increased RANK signaling and increased osteoclastic activity. The duplication events were predicted to result from the formation of a stable hairpin structure facilitated by a repetitive unit in this nucleotide sequence. One patient had a family history of bone disease.

Elahi et al. (2007) identified a heterozygous g.84dup18 mutation in the TNFRSF11A gene in affected members of an Iranian family with FEO. Haplotype analysis suggested that the mutation arose independently in most of the reported families with this mutation.