“Rare diseases” are defined by the Orphan Drug Act of 1983 as any disease or condition that affects less than 200,000 persons in the United States.¹ Of these, rare genetic skeletal diseases (or skeletal dysplasias) constitute a group of heterogeneous bone disorders arising from a defect in the complex processes of skeletal development, modeling, and remodeling. Due to the emergence of next-generation sequencing, namely whole genome sequencing, whole exome sequencing, and RNAseq, and bioinformatics, the once-undiagnosed diseases have now been characterized and better understood. The undiagnosed disease network (UDN phase 1) reported diagnoses in 35% of previously undiagnosed diseases, of which 10% presented with musculoskeletal phenotype. Seventy-four percent of diagnoses were made by newly found genetic information. Importantly, these new diagnoses led to a change in therapeutic plan in 21% of the all referred cases, and 31 new syndromes were discovered.²

New genetic information and careful phenotyping have together allowed genetic skeletal disorders to be organized into 42 groups based on the 2015 revision of nosology and classification of genetic skeletal disorders.³ The broad categorization of the disease is due to heterogeneity of clinical phenotype, incomplete penetrance, and the limitation in sorting diseases based on metabolic phenotype (metabolomics). To simplify and provide practical clinical guidance, the Skeletal Rare Disease Working Group of International Osteoporosis Foundation made an effort to classify these disorders according to pathogenetic mechanism: altered osteoblast, osteoclast or osteocyte function; altered bone matrix proteins; altered bone microenvironmental regulators: and altered calciotropic hormone activity.⁴

This chapter reviews relatively common and well-studied genetic skeletal disorders that represent different phenotypes, (ie, high vs low bone mass) and pathogeneses (ie, skeletal development, connective tissue defects, enzyme deficiency).

Osteopetrosis is a rare genetic skeletal disorder that is characterized by failure of osteoclastic bone resorption. The clinical spectrum of osteopetrosis is broad from the severe early-onset autosomal recessive “malignant” form to
mild adult-onset autosomal dominant “benign” form. The incidence of the autosomal dominant form is about 1 per 20,000 live births, and the autosomal recessive (infantile) “malignant” form is much rarer (1 per 200,000 to 250,000 live births).⁵

The patients with adult-onset osteopetrosis can be asymptomatic and have a normal life expectancy. Some, however, present with bone pain and frequent fractures accompanied by nerve compression, hearing or visual loss, and carpal tunnel syndrome. The autosomal recessive (infantile) form is lethal, presenting with pathological fractures, impaired hematopoiesis caused by bony expansion into bone marrow cavity resulting in pancytopenia with secondary hematopoiesis, immune deficiency with serious infection such as osteomyelitis, and sepsis.⁵

The defect arises from any step involved in osteoclastic bone resorption including osteoclast differentiation, resorptive pit formation (ruffled border formation), and acidification. Most genetic defects involve the acidification process, and about 70% of the autosomal recessive form is caused by mutations in TCIRG1 (osteoclast vacuolar proton pump) and CLCN7 (H⁺-Cl^– exchange transporter 7) genes.⁶ In a rare autosomal recessive type with a mutation in carbonic anhydrase II gene, patients develop renal tubular acidosis, nephrolithiasis, nephrocalcinosis, basal ganglia calcification, and cognitive dysfunction.⁷

The diagnosis of osteopetrosis is based on clinical and radiographic findings. Notable radiological features include “rugger jersey spine” (normal appearing vertebral body between dense superior and inferior endplates) and “bone-within-bone.” Calvarial and basilar thickening can be seen. Cartilage “bars” or “islands” that represent calcified primary spongiosa are pathognomonic histologic findings.⁸

Treatment depends on the severity and pathogenetic mechanism underlying the osteoclast dysfunction. Calcitriol and PTH analog have been used to stimulate bone remodeling in a milder disease.⁹ Hematopoietic stem cell transplant (HSCT) can repopulate normal osteoclasts and restore bone remodeling but should be used in the specific autosomal recessive form with mutations intrinsic to osteoclasts (osteoclast-poor phenotype).⁸ Clinicians should be aware of potential complications of HSCT such as graft versus host disease. Although not curative, interferon-γ has been used to recover normal hematopoiesis.⁵

Fibrous dysplasia is a rare skeletal disorder with tumor-like fibro-osseous lesions replacing normal skeletal tissue, which can be accompanied by nonskeletal manifestations, such as cutaneous hyperpigmentation (café-au-lait macules) and hyperfunctioning endocrinopathies (McCune-Albright syndrome), which includes gonadotropin-independent precocious puberty, Cushing syndrome, growth hormone excess, FGF23-mediated phosphate wasting, and hyperthyroidism.¹⁰

Fibrous dysplasia is a mosaic disease caused by a postzygotic activating mutation in GNAS, the gene encoding the alpha subunit of the stimulatory G protein (Gsα).¹¹ Missense mutations (R201H, R201C, R201G) have been reported.^12,13 The mutations occur in skeletal pluripotent cells in an initial developmental stage, and the mutated cells are randomly distributed to any location in the skeleton from craniofacial bones to the axial and appendicular skeleton. As a result, bone marrow stromal cells proliferate and differentiate into skeletal progenitors at the expense of adipogenesis or hematopoiesis; tumor-like fibro-osseous lesions proliferate and replace normal skeletal tissue. The histologic patterns are diverse from thin, irregular, and disconnected bony trabecular type (so-called “Chinese writing”) to sclerotic pagetoid and sclerotic hypercellular patterns. Abnormal collagen in Sharpey fibers, at sites of insertion of tendons and ligaments, and retracted/stellate shaped osteoblasts are hallmarks of the diagnosis. In some cases, osteomalacic changes are noted likely due to excessive FGF23 production, which causes a lag in mineralization.¹⁴

The clinical spectrum ranges from none or mild symptoms to disabling deformities with chronic pain, swelling, and pathological fractures depending on the location and extent of skeletal involvement: isolated (monostotic), multiple bones (polyostotic), or the entire skeleton (panostotic). The disease affects any skeletal site, most commonly the proximal metaphysis of the femur and skull base.¹⁵ Appendicular skeletal involvement causes limb pain and pathologic fractures (Figure 1). Craniofacial skeletal involvement may lead to facial deformities and cranial nerve impingement with hearing or
vision impairment. Vertebral bone involvement can cause scoliosis. With aging, active proliferative lesions become sclerotic as mutant stem cells fail to self-renew and their progeny are consumed by apoptosis.¹⁶ As a result, skeletal lesions are usually stable in adulthood, although the pain persists along with impaired mobility. The risk of malignancy is minimal; a study reported 28 cases of sarcoma among 1,122 cases of fibrous dysplasia.¹⁷

The diagnosis is based on the finding of two or more typical clinical features. The expansion of lesions from the medullary space with cortical thinning can be seen on radiographs. Bone scintigraphy can delineate the extent of the disease. Molecular testing is helpful in distinguishing other fibro-osseous lesions with similar clinical pictures (ie, osteofibrous dysplasia and ossifying fibromas of the mandible or maxilla).^10,14

The goal of management is to relieve pain and prevent skeletal deformity and fracture. An open-label phase III study using diphosphonate demonstrated a decrease in the severity of bone pain.¹⁸ An IL-6 receptor antagonist and receptor activator of nuclear factor-κ B (NFκB) ligand (RANKL) antagonist are also possible therapeutic options. Patients might need surgery to manage refractory pain at weight-bearing sites or to correct deformity. Fracture or impending fracture of the proximal femur can be stabilized with insertion of intramedullary nails.¹⁹

Osteogenesis imperfecta (OI), or brittle bone disease, is relatively common with a prevalence of around 1 in every 20,000 births.²⁰ It is a collagen disorder resulting from a mutation in genes involved in collagen synthesis (COL1A1 or COL1A2). About 85% to 90% of patients who have clinical OI have abnormalities of type I collagen, the most abundant structural protein of bone, skin, and extracellular matrix.²¹ Different mutations result in varying degrees of disruption in type 1 collagen synthesis, which accounts for the heterogenous phenotype in OI, ranging from perinatal death to late-onset mild osteopenia.²¹ Most patients present with osteopenia/osteoporosis with fragility fractures, hearing defects, blue sclera, and dentinogenesis imperfecta (Figure 2).

The Sillence classification described four types of OI (I-IV) based on the clinical phenotype.²² Type I is the mildest form of the disease. Patients usually have osteopenia with classic features of postnatal fractures, blue sclera, hearing loss, and dental imperfections. In many cases, the disease is not detected until late adulthood. Patients rarely suffer from long bone deformities and are of average height. Type II (lethal perinatal type) has high mortality in utero or in early infancy due to multiple pathological fractures, pulmonary hypoplasia, and CNS malformations. Families with this severe form benefit from genetic counseling and early prenatal screening. Type III is described as a progressively deforming type, the most severe survivable form. The patients often sustain multiple fractures in childhood, complicated with growth retardation, long bone deformities, and kyphoscoliosis, which can compromise cardiorespiratory function. Type IV is a moderate form of the disease. The classification of OI has evolved as new genes have been discovered. The 2015 revision of nosology and classification of genetic skeletal disorders added type V, which presents with calcification of the interosseous membranes and/or hypertrophic callus and distinct radiographic findings from types I-IV.³