Hereditary Disorders of The Skeleton

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Chapter 12

Hereditary Disorders of The Skeleton

Endocrinologists can encounter a great diversity of heritable disorders of the skeleton.1-4 Some are clinical curiosities; some are lethal. Some cause focal bony abnormalities; some feature generalized disturbances of skeletal growth, modeling (shaping), and remodeling (turnover).3 A few are associated with overt derangements in mineral homeostasis. Cumulatively, the number of affected people is substantial.1 Each of these entities is important because all harbor clues concerning specific genes and their products that influence skeletal biology. Furthermore, as individual conditions become understood molecularly, patients are being referred increasingly to endocrinologists.

This chapter describes a number of the more common or instructive of the hereditary disorders of the skeleton.

Sclerosing Bone Disorders

Increased skeletal mass is caused by many rare, often heritable osteochondrodysplasias,1,4 and by a variety of endocrine, metabolic, dietary, hematologic, infectious, and neoplastic diseases (Table 12-1). Osteosclerosis and hyperostosis refer to trabecular versus cortical bone thickening, respectively. A radiographic skeletal survey of the genetic disorders shows where and sometimes how bone mass is increased, and often provides sufficient clues for diagnosis.3,4

Table 12-1

Disorders That Cause High Bone Mass


Modified from reference 6.


Osteopetrosis (OPT; “marble bone disease”) was reported first in 1904 by Albers-Schönberg.5 Traditionally, two principal forms are discussed6: the autosomal recessive, infantile (malignant) type that is typically fatal during the first decade of life if untreated,7 and the autosomal dominant, adult (benign) type with distinctly less severe complications.8 Especially rare “intermediate” forms of OPT present during childhood, when the prognosis is poorly understood.9

Now, the gene defects that cause nearly all cases of OPT are known, greatly improving upon imprecise clinical nosologies.10 Although there are different types of OPT, all true forms result from failure of osteoclasts to resorb skeletal tissue.6 Consequently, the manifestations are largely predictable. Accumulation of primary spongiosa (calcified cartilage deposited during endochondral bone formation) represents the histopathologic hallmark.11 It is understandable, however, that the term osteopetrosis persists generically for radiodense skeletons, but should henceforth be applied with precision based on pathogenesis because therapies for genuine OPTs may be inappropriate or harmful for other sclerosing bone disorders.8

Clinical Features

Infantile OPT manifests in babies.7 There is failure to thrive. Cranial foramina do not widen, often compressing auditory, oculomotor, facial, and optic nerves. Blindness can result from retinal degeneration or raised intracranial pressure.12 Some patients develop hydrocephalus or sleep apnea. Nasal stuffiness due to underdeveloped sinuses occurs early. Dentition is delayed. Recurrent infections and spontaneous bruising and bleeding are common and are due to myelophthisis from excessive bone tissue, osteoclasts, and fibrosis crowding marrow spaces. Extramedullary hematopoiesis with hypersplenism and hemolysis may exacerbate already severe anemia. A large head, frontal bossing, “adenoid” appearance, nystagmus, hepatosplenomegaly, short stature, and genu valgum are noted. Bones are fragile. Untreated patients succumb, usually during the first decade of life, to pneumonia, severe anemia, hemorrhage, or sepsis.6,7

Intermediate OPT causes macrocephaly and short stature, sometimes with cranial nerve palsies, ankylosed teeth leading to osteomyelitis of the jaw, recurrent fractures, and mild or occasionally moderately severe anemia.9

Autosomal dominant “benign” OPT (Albers-Schönberg disease) features brittle long bones and fractures within the axial and the appendicular skeleton, and sometimes compromised vision and hearing, facial nerve palsy, mandibular osteomyelitis,13 psychomotor delay, carpal tunnel syndrome, slipped capital femoral epiphysis, or osteoarthritis.14 Some affected individuals are asymptomatic,8 and rare carriers show no radiographic findings.15

Carbonic anhydrase II (CA II) deficiency features OPT with renal tubular acidosis (RTA) and cerebral calcification.16 Severity varies among affected families.17 In infancy or early childhood, fractures, failure to thrive, developmental delay, or short stature manifest. Mental subnormality is common. Compression of the optic nerves and dental malocclusion are further complications. Metabolic acidosis presents as early as birth. Both proximal and distal RTA have been described,18 although distal (type I) RTA seems better documented and may explain any hypotonia, apathy, and muscle weakness. Periodic hypokalemic paralysis can occur. Life expectancy is uncertain, with the oldest published cases reported in young adults.19

Neuronal storage disease with OPT features severe skeletal manifestations accompanying epilepsy and neurodegenerative disease.20 Transient infantile OPT of unknown cause inexplicably resolves after the first months of life. OPT, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID) is an X-linked recessive condition of boys.21

Radiographic Findings

A generalized, symmetrical increase in bone mass is the principal radiographic finding in OPT.22 Cortical and trabecular bone is thickened. In severe disease, all components of skeletal development are disrupted: bone growth, modeling, and remodeling. Furthermore, rachitic changes in growth plates may occur.23 The skull, especially the base, is thickened and dense, and the paranasal and mastoid sinuses are underpneumatized. Vertebrae may show a “bone-in-bone” (endobone) configuration.22

In CA II deficiency, skeletal radiographs typically are abnormal at diagnosis, although findings can be subtle at birth. Remarkably, the osteosclerosis and defective skeletal modeling then diminish over years.16 Cerebral calcification appears on computed tomography (CT) between ages 2 and 5 years and increases during childhood, affecting gray matter of the cortex and basal ganglia.17

In Albers-Schönberg disease, abnormalities appear during childhood. An especially dense skull base, a “rugger-jersey” spine, and enigmatic alternating sclerotic and lucent bands in the metaphyses of major long bones are characteristic (Fig. 12-1). Metaphyses are wide and may have a club shape or “Erlenmeyer flask” appearance.8 Rarely, distal phalanges in the hands are eroded (more common in pycnodysostosis). Pathologic (“chalk-stick”) fractures occur in major long bones.22

Skeletal scintigraphy reveals fractures and osteomyelitis.24 Magnetic resonance imaging (MRI) helps assess patients undergoing bone marrow transplantation, because engraftment restores medullary spaces.25

Histopathologic Findings

Failure of osteoclast action provides a pathognomonic finding in OPT6—primary spongiosa synthesized during endochondral bone formation persists as “islands” of calcified cartilage encased within trabecular bone. Osteoclast numbers are increased, normal, or, rarely, decreased. In infantile OPT, these cells are usually abundant.29 Their nuclei are especially numerous, but the “ruffled borders” and “clear zones” that characterize functioning osteoclasts are absent.30 Fibrosis often crowds marrow spaces. Adult OPT shows increased amounts of osteoid, and osteoclasts can be few and may lack ruffled borders, or they can be especially numerous and large.31

Cause and Pathogenesis

Most patients with OPT have diminished osteoclast-mediated acidification at sites of bone resorption due to defects in CA II, the α3 subunit of the vacuolar proton pump, or chloride channel 7 (CLCN7).32 Heterozygous loss-of-function mutation within CLCN7 causes Albers-Schönberg disease.33 Homozygous or compound heterozygous CLCN7 mutations lead to severe or intermediate OPT.33 Malignant OPT usually is due to deactivating mutations in the gene TCIRG1 (ATP6i), which encodes the α3 subunit of the vacuolar proton pump.34 Defects in the “gray-lethal” and OSTM1 genes cause especially severe OPT.35 OL-EDA-ID represents disruption of an essential modulator of NF-κB.21 Recently, loss-of-function mutations within the genes that encode the receptor activator of nuclear factor-κB (RANK) or its ligand (RANKL) were discovered in especially rare forms of autosomal recessive OPT.36,37

Ultimately, impaired skeletal resorption in OPT causes both myelophthisis and bone fragility resulting from the presence of fewer collagen fibrils interconnecting osteons.11


Because the cause and pathogenesis, pattern of inheritance, and prognosis for the various forms of OPT can differ, a precise diagnosis is crucial before therapy is attempted. For example, infants or young children with CA II deficiency can have radiographic features of malignant OPT, yet sequential studies may show gradual resolution of bony sclerosis.6 Until recently, the patient’s family and investigation into the severity and progression of the disorder were the principal considerations. Now, diagnosis has been advanced greatly by mutation analysis.38

Bone Marrow Transplantation: Bone marrow transplantation from HLA-identical donors has improved remarkably some patients with infantile OPT.32 However, this procedure is not always appropriate6 (e.g., RANKL deficiency)36 because the pathogenetic defect must be corrected by entry of donor cells into the osteoclast lineage.32

Because severely crowded medullary spaces appear less likely to engraft, early intervention is best.39 Use of marrow from HLA-nonidentical donors warrants continued study. Purified progenitor cells in blood from HLA-haploidentical parents have been useful.39a Marked hypercalcemia can occur as osteoclast function begins.40

Dietary and Medical Therapy: Some success has been reported when a calcium-deficient diet is given. Conversely, calcium supplementation may be necessary for symptomatic hypocalcemia or rickets.23 Large oral doses of calcitriol together with dietary calcium restriction (to prevent absorptive hypercalciuria/hypercalcemia) sometimes improves infantile OPT.41 Calcitriol may stimulate defective osteoclasts, but resistance can occur.41 Long-term infusion of PTH helped one infant,42 perhaps by enhancing calcitriol synthesis. Diminished leukocyte production of superoxide serves as the basis for recombinant human interferon-γ-1b treatment for severely affected children.41

High-dose glucocorticoid treatment stabilizes pancytopenia and hepatomegaly. One case report describes inexplicable reversal of malignant OPT after prednisone therapy alone.43 Prednisone and a low-calcium/high-phosphate diet may be effective.44

In CA II deficiency, the RTA has been treated with bicarbonate supplementation, but the long-term impact is unknown. Bone marrow transplantation corrects the OPT and slows cerebral calcification of CA II deficiency, but does not alter the RTA.45


Pycnodysostosis was discovered in 1962.48 Most reports have come from the United States or Europe, but its prevalence seems greatest in Japan.49 Parental consanguinity with autosomal recessive inheritance explains ≈30% of cases. In 1996, loss-of-function mutation of the gene that encodes cathepsin K was identified.50

Clinical Features

Pycnodysostosis is diagnosed during infancy or early childhood because of disproportionate short stature and a relatively large cranium with fronto-occipital prominence, small facies and chin, beaked nose, high-arched palate, obtuse mandibular angle, dental malocclusion with retained deciduous teeth, proptosis, and bluish sclera.51 The anterior fontanel and cranial sutures remain open. Mental retardation affects ≈10% of cases.51 Hands are small and square and fingers are short and clubbed from acro-osteolysis or aplasia of terminal phalanges. Pectus excavatum may occur. Recurrent fractures typically involve the lower limbs and cause genu valgum deformity, although patients usually walk independently. Adult height ranges from 4 ft 3 in to 4 ft 11 in. Recurrent respiratory infections and right heart failure from upper airway obstruction caused by micrognathia trouble some patients.

Radiographic Findings

Pycnodysostosis shares many features with OPT.22 Both cause generalized osteosclerosis and recurrent fractures. The osteosclerosis first appears in childhood, is uniform, and increases with age. The calvarium and the skull base are sclerotic, and orbital ridges are dense. Although long bones have narrow medullary canals, the striking modeling defects of OPT do not occur. Endobones and radiodense striations are absent.22 Other distinguishing findings in pycnodysostosis include delayed closure of cranial sutures and fontanels (prominently the anterior), obtuse mandibular angle, wormian bones, gracile clavicles that are hypoplastic laterally, and hypoplasia or aplasia of the distal phalanges and ribs.52 Hypoplasia of facial bones, sinuses, and terminal phalanges is characteristic. Vertebral bodies are dense with anterior and posterior concavities, but transverse processes are uninvolved. Lumbosacral spondylolisthesis is not uncommon, and lack of segmentation of the atlas and axis may be noted.22

Cause and Pathogenesis

Deactivating mutations in the gene that encodes cathepsin K cause pycnodysostosis.50 Cathepsin K is a lysosomal cysteine protease that is highly expressed in osteoclasts.54 Hence, impaired collagen degradation is a fundamental defect. The rate of bone accretion and the size of the exchangeable calcium pool seem reduced. Bone remodeling and therefore quality are compromised.55 Accordingly, pycnodysostosis can be thought of as a form of OPT.

Additionally, killing activity and interleukin-1 secretion by circulating monocytes is compromised.56 Virus-like inclusions have been reported in osteoclasts.57 Defective growth hormone secretion and low serum insulin-like growth factor 1 levels have been described.58


No medical therapy is recognized. Bone marrow transplantation has not been reported.

The orthopedic challenges have been reviewed briefly.59 Long bone fractures typically are transverse and heal at a satisfactory rate, but delayed union and massive formation of callus can occur. Intramedullary fixation of long bones is formidable because of their hardness.

Extraction of teeth is difficult, and mandibular fracture has occurred.51 Osteomyelitis of the mandible may require antibiotic and surgical treatment.

Progressive Diaphyseal Dysplasia (Camurati-Engelmann Disease)

Progressive diaphyseal dysplasia (PDD) is an autosomal dominant disorder that affects all races. The condition was described by Cockayne in 1920.60 Camurati discovered its heritable nature.61 Engelmann characterized the severe, typical form in 1929.61 In 2001, mutations that are activating defects were identified in the gene that encodes transforming growth factor (TGF)-β1.62

Characteristically in PDD, painful hyperostosis occurs gradually on both periosteal and endosteal surfaces of long bones.22 However, the clinical and radiographic expression is quite variable.63 In severe cases, osteosclerosis is widespread, including the skull and axial skeleton. Some carriers have no radiographic changes, but bone scintigraphy is abnormal.

Clinical Presentation

PDD typically presents during childhood with limping or a broad-based and waddling gait, leg pain, muscle wasting, and diminished subcutaneous fat in the extremities mimicking muscular dystrophy.64 However, severely affected patients also have a characteristic body habitus that includes an enlarged head with prominent forehead, proptosis, and thin limbs with thickened bones. Cranial nerve palsies can develop when the skull is affected. Puberty sometimes is delayed. Raised intracranial pressure may occur. Palpable bony thickening, skeletal tenderness, and sometimes hepatosplenomegaly are present, as well as Raynaud’s phenomenon and other findings suggestive of vasculitis.65 Radiologic studies typically show progressive disease, but the course is variable and symptom remission sometimes occurs during adult life.

Radiologic Features

Hyperostosis of major long bone diaphyses, the principal finding, represents proliferation of new bone on both periosteal and endosteal surfaces.22 Shafts of long bones gradually widen and develop irregular surfaces. Sclerosis is fairly symmetrical and spreads to involve metaphyses, but the epiphyses are characteristically spared (Fig. 12-2). Tibias and femurs most often are involved, less frequently the radii, ulnae, humeri, and, occasionally, the short tubular bones. Clavicles, scapulae, and the pelvis also may become thickened. Age of onset, rate of progression, and degree of bony involvement are highly variable. With mild disease, scintigraphic abnormalities may be confined to the lower limbs. Maturation of the new bone increases the hyperostosis. However, in severely affected children, some skeletal areas may appear osteopenic.

Clinical, radiographic, and scintigraphic findings are generally concordant.66 Occasionally, however, bone scans are unremarkable despite marked radiographic changes. This seems to reflect advanced but quiescent disease. Increased radioisotope accumulation with few radiographic alterations can represent early skeletal involvement.

Cause and Pathogenesis

The clinical and laboratory features of severe PDD and its responsiveness to glucocorticoid treatment indicate an inflammatory connective tissue disease.65 Now, the disorder is known to involve mutations in a specific region of the gene that encodes TGF-β1. Consequently, a “latency-associated peptide” encoded by this gene remains bound to TGF-β1, keeping this enhancer of bone formation active.62 Aberrant differentiation of precursor cells to osteoblasts has been discussed as a pathogenetic mechanism.68

Endosteal Hyperostosis

In 1955, van Buchem et al.71 described hyperostosis corticalis generalisata. Subsequently, additional forms of endosteal hyperostosis were characterized.72 The hallmark of these disorders is thickening of cortical bone primarily on endosteal surfaces.22

Van Buchem disease is an autosomal recessive condition71 that is considerably rarer than the number of case reports might suggest.73 The principal clinical feature is progressive asymmetrical enlargement of the jaw during puberty. The mandible becomes markedly thickened with a wide angle, but no prognathism is noted. Dental malocclusion is uncommon. Affected individuals may be symptom free, but cranial sclerosis also occurs and recurrent facial nerve palsy, deafness, and optic atrophy from narrowing of cranial foramina are common and can develop during infancy. Long bones may hurt with applied pressure but are not fragile.71 Endosteal cortical thickening leads to homogenously dense diaphyses with narrowed medullary canals. However, long bones are shaped properly. Osteosclerosis also affects the skull base, facial bones, vertebrae, pelvis, and ribs.22 Serum alkaline phosphatase from bone may be increased, but calcium and inorganic phosphate levels are unremarkable.

Sclerosteosis, like van Buchem disease, is an autosomal recessive disorder that occurs primarily in people of Dutch ancestry.72 However, sclerosteosis differs from van Buchem disease in that patients are excessively tall and have syndactyly.72 At birth, only fused fingers may be noted.73a Syndactyly reflects cutaneous or bony fusion of the middle and index fingers. During early childhood, skeletal overgrowth involves especially the skull and causes facial disfigurement. Progressive bone thickening widens the jaw, resulting in prognathism.74 Patients become tall and heavy. Deafness and facial palsy are prominent problems. A small skull vault may increase intracranial pressure, causing headaches and compressing the brain stem.75 Intelligence is normal. Life expectancy can be shortened.76 Long bones become widened as cortices thicken. Vertebral pedicles, ribs, and the pelvis may become dense. Fusion of ossicles and narrowing of the internal auditory canals and cochlear aqueducts may occur.72 Enhanced osteoblast activity with failure of osteoclasts to compensate explains the dense bone of sclerosteosis.75 No abnormality of calcium homeostasis or of pituitary function has been documented.77 No specific medical treatment is available. Surgical correction of syndactyly is difficult if there is bony fusion. Management of the neurologic dysfunction has been reviewed.75

Deactivating mutations in the gene that encodes sclerostin (SOST) cause sclerosteosis,78,79 whereas van Buchem disease results from a 52-kb deletion that diminishes a downstream enhancer of SOST.80

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