ABOS Board Review: Skeletal Dysplasias (Part 2)

Question 1

A 7-year-old boy presents with a waddling gait. His mother has similar features. Physical exam reveals an unusually large head, a delayed closure of the anterior fontanelle, and the ability to bring his shoulders together anteriorly.

Which of the following genes is most likely mutated in this condition?

Explanation

The clinical presentation and image demonstrate absent or hypoplastic clavicles typical of cleidocranial dysplasia. This is an autosomal dominant condition caused by a mutation in the RUNX2 (CBFA1) gene, which is essential for osteoblast differentiation.

Question 2

A 4-year-old child presents with severe progressive deformity of the lower extremities, profound short stature, and dentinogenesis imperfecta. Radiographs of the knees show "popcorn" calcifications at the metaphyses.

Which type of osteogenesis imperfecta does this patient most likely have?

Explanation

Type III Osteogenesis Imperfecta is the most severe non-lethal form, characterized by progressive deformity, extreme short stature, and dentinogenesis imperfecta. Popcorn calcifications in the metaphyses are a classic radiographic hallmark seen in these severe cases.

Question 3

A 12-year-old boy presents with a history of recurrent fractures and newly diagnosed facial nerve palsy. Radiographs reveal generalized, extreme osteosclerosis and a classic "bone-in-bone" appearance of the vertebrae. What is the primary cellular defect responsible for this condition?

Explanation

Osteopetrosis is caused by defective osteoclast function, frequently due to mutations (e.g., carbonic anhydrase II or TCIRG1) preventing ruffled border formation and acid secretion. This results in incredibly dense, brittle bones and narrowed neural foramina leading to cranial nerve entrapment.

Question 4

An 8-month-old infant with a known FGFR3 mutation is brought to the clinic. The parents report recent episodes of apnea and generalized hypotonia. Which of the following is the most critical and immediate orthopedic evaluation required for this patient?

Explanation

Achondroplasia (FGFR3 mutation) can cause life-threatening foramen magnum stenosis in infants, leading to central apnea, sudden death, or severe myelopathy. A cervical MRI is mandatory in infants presenting with apneic episodes or unexplained hypotonia.

Question 5

A 68-year-old man with a long-standing history of an enlarged skull and progressive bowing of his tibia presents with a rapidly enlarging, highly painful mass over his proximal tibia. Serum alkaline phosphatase is markedly elevated. What is the most likely diagnosis of this new mass?

Explanation

Secondary osteosarcoma is a rare (approx. 1%) but highly lethal complication of Paget's disease of bone. It must be strongly suspected when a patient with known Paget's disease develops new, severe, localized pain or a rapidly enlarging mass.

Question 6

A 4-year-old boy presents with severe genu varum and short stature. Laboratory evaluation reveals normal serum calcium, low serum phosphate, normal PTH, normal 25-hydroxyvitamin D levels, and highly elevated FGF-23. What is the most appropriate medical management?

Explanation

X-linked hypophosphatemic rickets is caused by a PHEX gene mutation leading to excess FGF-23, which inappropriately wastes phosphate in the kidneys. Standard treatment includes frequent oral phosphate replacement combined with calcitriol to prevent secondary hyperparathyroidism.

Question 7

A 6-year-old boy presents with a short trunk, barrel chest, and coxa vara. He has normal intelligence but exhibits a waddling gait. Radiographs show flattened vertebral bodies (platyspondyly) and delayed epiphyseal ossification. Genetic testing reveals a mutation in COL2A1. Which condition is most likely?

Explanation

Spondyloepiphyseal dysplasia congenita (SEDC) is a type II collagenopathy resulting from a COL2A1 mutation. Because type II collagen is prevalent in articular cartilage and the nucleus pulposus, patients display short-trunk dwarfism, significant spinal involvement, and epiphyseal dysplasia.

Question 8

A newborn is evaluated for severe bilateral, rigid clubfeet. Physical examination reveals disproportionately short limbs, "hitchhiker" thumbs, and cystic swelling of the external ear bilaterally. Which of the following genes is mutated in this condition?

Explanation

The clinical picture of hitchhiker thumbs, cauliflower ears, and severe rigid clubfeet is diagnostic of diastrophic dysplasia. This condition is caused by a mutation in the SLC26A2 gene, which encodes a critical sulfate transporter.

Question 9

A 10-year-old girl presents with knee pain and a waddling gait. Radiographs show small, irregular epiphyses in the hips and knees, but her spine appears radiographically normal. A lateral knee radiograph reveals a distinct double-layered patella. What is the most likely diagnosis?

Explanation

Multiple epiphyseal dysplasia (MED) typically presents with irregular, delayed ossification of the epiphyses with a relatively normal spine. A double-layered patella is a classic, pathognomonic radiographic sign often seen in patients with MED.

Question 10

A 2-year-old presents with bowing of the long bones, premature loss of fully rooted deciduous teeth, and a history of recurrent respiratory infections. Laboratory testing reveals strikingly low serum alkaline phosphatase levels and elevated urinary phosphoethanolamine. What is the primary deficiency in this condition?

Explanation

Hypophosphatasia is a rare metabolic bone disease caused by an ALPL gene mutation, leading to tissue-nonspecific alkaline phosphatase (TNSALP) deficiency. This results in defective bone mineralization, classic premature tooth loss, and characteristically low serum alkaline phosphatase.

Question 11

A 5-year-old child presents with disproportionate short-limb dwarfism that was recognized only after he began walking. His facial features and head circumference are entirely normal. Radiographs show delayed epiphyseal ossification and anterior tongue-like projections of the vertebral bodies. Which gene is most likely mutated?

Explanation

Pseudoachondroplasia is caused by a mutation in the Cartilage Oligomeric Matrix Protein (COMP) gene. Unlike true achondroplasia, these patients have normal facial features and head size, and their short stature becomes apparent only in early childhood.

Question 12

A 6-year-old boy with Osteogenesis Imperfecta presents with recurrent femoral fractures and severe progressive anterolateral bowing.

What is the surgical treatment of choice to manage the deformity and prevent fractures while allowing for continued longitudinal growth?

Explanation

Telescoping intramedullary rods are the gold standard for long bone deformity correction and fracture prevention in growing children with severe Osteogenesis Imperfecta. They expand with patient growth, reducing the need for frequent surgical rod revisions.

Question 13

A 4-year-old boy presents with a history of recurrent fractures after minimal trauma, blue sclerae, and hearing loss.

Which of the following best describes the underlying genetic defect in the most common form of this condition?

Explanation

Osteogenesis imperfecta (Type I) is primarily caused by autosomal dominant mutations in the COL1A1 or COL1A2 genes. This leads to a quantitative defect (decreased production) of structurally normal type I collagen.

Question 14

A 10-year-old girl is evaluated for short stature and delayed dental eruption. On physical examination, she is able to bring her shoulders together anteriorly in the midline.

What is the genetic mutation responsible for this condition?

Explanation

Cleidocranial dysplasia is an autosomal dominant condition caused by mutations in the RUNX2 (CBFA1) gene. This gene is a critical transcription factor essential for osteoblast differentiation and bone formation.

Question 15

In children with severe osteogenesis imperfecta, cyclical intravenous bisphosphonates are frequently utilized to decrease fracture rates. What is the primary mechanism of action of this medication class at the cellular level?

Explanation

Bisphosphonates, such as pamidronate, accumulate in bone and are ingested by osteoclasts during bone resorption. They inhibit the mevalonate pathway, leading to osteoclast apoptosis and a significant reduction in bone resorption.

Question 16

A 2-year-old boy presents with generalized lower extremity pain, irritability, and bleeding gums. Radiographs show a distinct white line of Frankel and a Pelkan spur at the distal femoral metaphyses. What is the underlying biochemical defect?

Explanation

The clinical picture is classic for scurvy, caused by Vitamin C deficiency. Vitamin C acts as a necessary cofactor for prolyl and lysyl hydroxylase; without it, defective hydroxylation of proline and lysine leads to unstable collagen.

Question 17

A 6-year-old child presents with progressive genu varum, widening of the wrists, and a rachitic rosary. Laboratory studies reveal a normal serum calcium, low phosphorus, and significantly elevated alkaline phosphatase. Which of the following is the most likely initial step in the pathophysiology of this metabolic bone disease?

Explanation

Nutritional rickets typically begins with Vitamin D deficiency, leading to decreased intestinal calcium absorption. The resulting secondary hyperparathyroidism normalizes serum calcium at the expense of phosphorus via renal wasting.

Question 18

A 5-year-old boy presents with progressive bowing of the lower extremities. Laboratory tests show normal calcium, extremely low serum phosphorus, and normal PTH levels. He is diagnosed with X-linked hypophosphatemic rickets. What is the primary mediator of renal phosphate wasting in this disease?

Explanation

X-linked hypophosphatemic rickets is caused by a mutation in the PHEX gene, which leads to elevated circulating levels of FGF-23. FGF-23 potently decreases renal phosphate reabsorption in the proximal tubule, causing profound hypophosphatemia.

Question 19

An infant presents with severe anemia, cranial nerve palsies, and diffuse symmetric osteosclerosis on radiographs. A bone marrow transplant is being considered. What is the primary cellular defect causing this condition?

Explanation

Osteopetrosis is caused by defective osteoclast function. Mutations in carbonic anhydrase II or the TCIRG1 gene prevent the formation of a functional ruffled border and the acidic microenvironment required for bone resorption.

Question 20

An 80-year-old man complains of increasing hat size and dull, aching pain in his right thigh. Radiographs of the femur demonstrate cortical thickening and coarse trabeculae. Which of the following best describes the histologic appearance of his femur during the mixed phase of the disease?

Explanation

Paget's disease in its mixed phase is characterized by a pathognomonic mosaic or jigsaw pattern of lamellar bone. This is due to chaotic osteoclastic resorption followed by rapid, disorganized osteoblastic bone formation leaving prominent cement lines.

Question 21

In addition to hypoplastic or absent clavicles, which of the following is a classic radiographic finding associated with cleidocranial dysplasia?

Explanation

Cleidocranial dysplasia is associated with delayed ossification of midline structures. Classic findings include a widened symphysis pubis, delayed closure of cranial sutures (with wormian bones), and coxa vara.

Question 22

According to the Sillence classification for Osteogenesis Imperfecta, which type is characterized as uniformly lethal in the perinatal period?

Explanation

Sillence Type II Osteogenesis Imperfecta is the most severe form. It is uniformly lethal in the perinatal period, typically due to severe pulmonary hypoplasia and multiple in-utero rib fractures.

Question 23

A 55-year-old woman with end-stage renal disease on hemodialysis presents with severe bone pain. Radiographs of her hands show subperiosteal resorption on the radial aspect of her middle phalanges. What is the primary driver of these osseous changes?

Explanation

Renal osteodystrophy features secondary hyperparathyroidism. Failing kidneys cannot adequately convert 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D, leading to hypocalcemia and a compensatory, destructive rise in PTH.

Question 24

A neonate is diagnosed with the most common form of short-limb dwarfism. Both parents are of normal height and stature. Which of the following describes the most likely genetic mutation and its mode of inheritance?

Explanation

Achondroplasia is caused by an activating mutation in the FGFR3 gene, inherited in an autosomal dominant pattern. Approximately 80% of cases are spontaneous de novo mutations strongly associated with advanced paternal age.

Question 25

A newborn presents with short stature, severe rigid clubfeet, symphalangism of the PIP joints, and "hitchhiker" thumbs. Cauliflower ears develop within the first few weeks of life. What is the underlying defect in this condition?

Explanation

Diastrophic dysplasia is characterized by a defect in the SLC26A2 gene, which codes for the diastrophic dysplasia sulfate transporter (DTDST). This results in undersulfated proteoglycans in the cartilage extracellular matrix.

Question 26

A 7-year-old boy with Sillence Type III Osteogenesis Imperfecta presents with progressive anterolateral bowing of the femur.

You elect to perform multiple osteotomies and intramedullary fixation. What is the primary biomechanical advantage of using a telescoping rod (e.g., Fassier-Duval) compared to a standard static intramedullary rod?

Explanation

Telescoping rods, such as the Fassier-Duval rod, are anchored in the proximal and distal epiphyses. They elongate as the child grows, thereby protecting the entire length of the bone and preventing the rod from being outgrown or migrating.

Question 27

A 5-year-old child presents with short-trunk dwarfism, significant genu valgum, and normal intelligence. Radiographs reveal platyspondyly and hypoplasia of the odontoid process. Urine testing shows elevated keratan sulfate. Which enzyme is most likely deficient?

Explanation

Morquio syndrome (Mucopolysaccharidosis Type IV) is caused by a deficiency in galactosamine-6-sulfatase (Type IVA) or beta-galactosidase (Type IVB). Odontoid hypoplasia is a critical finding that necessitates early cervical spine evaluation for instability.

Question 28

A 12-year-old girl presents with a limp. Radiographs demonstrate an expansile, ground-glass lesion in the proximal femur with a shepherd's crook deformity. She is also noted to have precocious puberty and irregular café-au-lait spots. What is the underlying molecular defect?

Explanation

McCune-Albright syndrome (polyostotic fibrous dysplasia, endocrine abnormalities, and "Coast of Maine" café-au-lait spots) is caused by a post-zygotic activating mutation in the GNAS1 gene. This leads to constitutive activation of adenylate cyclase and elevated intracellular cAMP.

Question 29

A 25-year-old patient of Ashkenazi Jewish descent presents with severe hip pain. Radiographs demonstrate bilateral avascular necrosis of the femoral heads and an Erlenmeyer flask deformity of the distal femora. Laboratory tests show pancytopenia. What is the most appropriate specific medical therapy for this underlying condition?

Explanation

Gaucher disease is a lysosomal storage disorder caused by a deficiency of glucocerebrosidase. Recombinant enzyme replacement therapy (e.g., imiglucerase) is the standard of care to reduce hepatosplenomegaly, improve cytopenias, and stabilize skeletal disease.

Question 30

A 4-year-old boy presents with a history of recurrent fractures after minimal trauma. Clinical exam reveals blue sclerae and opalescent teeth. Radiographs show generalized osteopenia and anterior bowing of the tibiae.

What is the underlying molecular defect in this patient's condition?

Explanation

Osteogenesis imperfecta is primarily caused by a qualitative or quantitative defect in type I collagen. This typically results from autosomal dominant mutations in the COL1A1 or COL1A2 genes.

Question 31

A 7-year-old girl is evaluated for short stature and dental anomalies, including supernumerary teeth. On physical examination, she is able to bring her shoulders together anteriorly in the midline.

A mutation in which of the following genes is responsible for her presentation?

Explanation

Cleidocranial dysplasia is an autosomal dominant condition caused by a mutation in the RUNX2 (CBFA1) gene. This gene is an essential transcription factor for osteoblast differentiation.

Question 32

A 3-year-old child presents with disproportionate short stature, rhizomelic shortening, and frontal bossing. The parents are of average height. Which of the following best describes the pathogenesis of the child's most likely condition?

Explanation

Achondroplasia is caused by an autosomal dominant, gain-of-function mutation in the FGFR3 gene. This overactive receptor inappropriately inhibits chondrocyte proliferation in the proliferative zone of the physis.

Question 33

A 5-year-old boy presents with severe genu varum. Laboratory studies show normal serum calcium, critically low phosphorus, normal parathyroid hormone, and elevated alkaline phosphatase. Which of the following is the most appropriate definitive medical management?

Explanation

The patient has X-linked hypophosphatemic rickets (PHEX mutation). Standard treatment requires combined oral phosphate and calcitriol (1,25-dihydroxyvitamin D) to correct the deficiency and prevent secondary hyperparathyroidism.

Question 34

A 6-year-old boy presents with a disproportionately short trunk, severe coxa vara, and an abnormal waddling gait. Cervical spine radiographs reveal odontoid hypoplasia. Genetic testing would most likely reveal a mutation affecting which of the following?

Explanation

Spondyloepiphyseal dysplasia congenita (SEDC) is caused by mutations in the COL2A1 gene, which encodes type II collagen. Affected patients frequently suffer from atlantoaxial instability secondary to odontoid hypoplasia.

Question 35

A newborn is noted to have severe micromelia, rigid clubfeet, and "hitchhiker" thumbs. Clinical examination also reveals prominent swelling of the bilateral pinnae. What is the underlying mechanism of this skeletal dysplasia?

Explanation

Diastrophic dysplasia is an autosomal recessive disorder caused by a mutation in the SLC26A2 (DTDST) gene, leading to defective sulfate transport. Classic physical findings include cauliflower ears, hitchhiker thumbs, and rigid equinovarus foot deformities.

Question 36

A 14-year-old boy with Osteogenesis Imperfecta Type IV presents with new-onset hyperreflexia, lower extremity weakness, and sleep apnea.

What is the most critical and life-threatening complication responsible for these symptoms?

Explanation

Basilar invagination is a recognized and potentially fatal complication in severe forms of OI due to softening of the skull base. It leads to brainstem and upper cervical cord compression, presenting with myelopathy and sleep apnea.

Question 37

A 7-year-old girl with short stature, corneal clouding, and normal intelligence presents for evaluation. Radiographs show severe platyspondyly and hypoplasia of the odontoid. She is found to be deficient in which of the following enzymes?

Explanation

Morquio syndrome (MPS IV) is caused by a deficiency in galactose-6-sulfatase (Type A). Unlike Hurler or Hunter syndromes, patients with Morquio syndrome typically maintain normal intelligence but suffer from severe skeletal issues like cervical instability.

Question 38

A 9-year-old boy presents with hip pain and a waddling gait. Radiographs show small, fragmented, and irregular epiphyses of the proximal femora, but his spine radiographs are entirely normal. He is found to have a mutation in the MATN3 gene. Which of the following clinical findings is classic for this condition?

Explanation

Multiple Epiphyseal Dysplasia (MED) can be caused by mutations in COMP, MATN3, or Type IX collagen genes. A double-layered (or multipartite) patella is a hallmark radiographic and clinical feature of this dysplasia.

Question 39

A 65-year-old man with increasing hat size and unilateral hearing loss develops sudden, severe right thigh pain. Radiographs of the femur show a new, destructive lytic lesion with cortical breakthrough in an area of pre-existing thickened, coarsened trabeculae. What is the most common malignant transformation in this patient's underlying disease?

Explanation

Paget's disease of bone carries approximately a 1% risk of malignant transformation. The most common secondary malignancy is osteosarcoma, which typically presents with sudden, severe pain and a destructive lesion in pagetic bone.

Question 40

A 4-year-old boy presents with severe anemia, recurrent infections, and hepatosplenomegaly. Skeletal survey reveals generalized, profound osteosclerosis with a "bone-within-a-bone" appearance in the long bones. What is the primary cellular defect responsible for this condition?

Explanation

Osteopetrosis is caused by defective osteoclastic bone resorption, most commonly due to a failure to form the osteoclast ruffled border (often via TCIRG1 or CA2 mutations). Osteoclasts are present in normal or increased numbers but are functionally incompetent.

Question 41

A 12-year-old girl is evaluated for precocious puberty and large café-au-lait spots with irregular, "coast of Maine" borders. Radiographs reveal polyostotic radiolucent bone lesions with a "ground-glass" matrix. What is the underlying genetic mutation?

Explanation

McCune-Albright syndrome consists of polyostotic fibrous dysplasia, café-au-lait spots, and endocrine abnormalities (like precocious puberty). It is caused by a sporadic, post-zygotic activating mutation in the GNAS1 gene.

Question 42

An infant presents with failure to thrive, hypotonia, and severe bowing of all extremities. Radiographs reveal profound global demineralization and widened physes. Laboratory studies demonstrate hypercalcemia and a critically low serum alkaline phosphatase. Which gene is most likely mutated?

Explanation

Hypophosphatasia is a severe metabolic bone disease caused by a mutation in the ALPL gene. This leads to deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity, impairing skeletal mineralization and mimicking rickets radiographically.

Question 43

A 45-year-old patient with end-stage renal disease presents with diffuse bone pain. Radiographs demonstrate osteopenia and alternating sclerotic and lucent bands in the vertebral bodies ("rugger-jersey" spine). Which of the following sets of laboratory values is most typical for this condition?

Explanation

Renal osteodystrophy is driven by secondary hyperparathyroidism. Failing kidneys cannot excrete phosphorus or produce 1,25-dihydroxyvitamin D properly, resulting in hyperphosphatemia, hypocalcemia, and consequently, highly elevated PTH levels.

Question 44

A 2-year-old boy presents with anterolateral bowing of his left tibia. He has six café-au-lait spots with smooth borders on his trunk. Radiographs reveal a narrowed medullary canal and sclerosis at the apex of the bow. Which of the following is true regarding his underlying condition?

Explanation

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by a loss-of-function mutation in the NF1 gene, which encodes neurofibromin. Neurofibromin normally acts as a tumor suppressor by downregulating the Ras signaling pathway.

Question 45

A 4-year-old boy presents with multiple recurrent fractures, blue sclerae, and hearing loss. Radiographs reveal generalized osteopenia and thin cortices.

What is the primary underlying biochemical defect in this condition?

Explanation

Osteogenesis imperfecta is most commonly caused by mutations in the COL1A1 or COL1A2 genes, leading to defective Type I collagen. This results in bone fragility, blue sclerae, and dentinogenesis imperfecta.

Question 46

A 7-year-old girl is evaluated for short stature and an unusual shoulder appearance. Clinical examination reveals hypermobility of the shoulders, allowing them to touch in the midline.

Which of the following genes is mutated in this patient's condition?

Explanation

Cleidocranial dysplasia is an autosomal dominant condition caused by a mutation in the RUNX2 (CBFA1) transcription factor. It is characterized by hypoplastic or absent clavicles and delayed closure of cranial sutures.

Question 47

A 65-year-old man presents with progressive bowing of his right tibia, increasing thigh pain, and increasing hat size. Radiographs reveal cortical thickening and coarsened trabeculae of the tibia. Which of the following best describes the initial pathogenesis of this disease?

Explanation

Paget's disease begins with an initial osteolytic phase driven by intense focal osteoclastic resorption. This is followed by a mixed osteoblastic-osteoclastic phase, and finally a sclerotic phase.

Question 48

A 5-year-old child presents with disproportionate short stature, rhizomelic shortening, and a prominent forehead. The genetic mutation responsible for this condition primarily affects which zone of the physis?

Explanation

Achondroplasia is caused by a gain-of-function mutation in FGFR3, which inhibits chondrocyte proliferation. This defect primarily impairs the proliferative zone of the physis.

Question 49

A newborn presents with micromelia, bilateral clubfeet, hitchhiker thumbs, and swelling of the auricles (cauliflower ears). A defect in which of the following mechanisms is responsible for this condition?

Explanation

Diastrophic dysplasia is caused by a mutation in the SLC26A2 (DTDST) gene, leading to defective sulfate transport. This impairs proteoglycan sulfation in cartilage matrix.

Question 50

A 3-year-old boy presents with progressive bowing of the legs and short stature. Laboratory evaluation shows low serum phosphate, normal calcium, normal PTH, and elevated alkaline phosphatase. Genetic testing reveals a mutation in the PHEX gene. Which of the following is the primary pathophysiologic mechanism?

Explanation

In X-linked hypophosphatemic rickets, a PHEX mutation leads to overproduction of FGF23. FGF23 decreases renal phosphate reabsorption, causing hypophosphatemia and rickets.

Question 51

A 45-year-old patient with end-stage renal disease complains of generalized bone pain. Laboratory results reveal elevated serum phosphorus, decreased serum calcium, and markedly elevated parathyroid hormone. Which of the following radiographic findings is most characteristic of this condition in the spine?

Explanation

Renal osteodystrophy typically produces a 'rugger jersey' spine due to sclerotic bands at the superior and inferior endplates of the vertebral bodies. This is a manifestation of secondary hyperparathyroidism.

Question 52

An infant is evaluated for failure to thrive, hepatosplenomegaly, and cranial nerve palsies. Radiographs show diffusely dense, bone-within-a-bone appearance in the spine. A mutation in which of the following enzymes is most commonly associated with the malignant autosomal recessive form of this disease?

Explanation

Malignant infantile osteopetrosis is commonly caused by a mutation in Carbonic Anhydrase II. This results in a defective osteoclast ruffled border and an inability to create the acidic environment necessary for bone resorption.

Question 53

A 10-month-old infant presents with irritability, bleeding gums, and painful swollen lower extremities. Radiographs of the knees show a dense zone of provisional calcification, a radiolucent band beneath it, and a marginal spur (Pelkan spur). Which of the following steps in collagen synthesis is primarily impaired?

Explanation

The clinical presentation describes scurvy (Vitamin C deficiency). Vitamin C is an essential cofactor for prolyl and lysyl hydroxylase, and its absence prevents proper hydroxylation of proline and lysine.

Question 54

A 9-year-old boy presents with bilateral knee and hip pain, and a waddling gait. Radiographs demonstrate delayed, irregular, and fragmented ossification centers of the femoral heads and knees, while the spine is completely normal. Mutations in which of the following genes are most commonly associated with this condition?

Explanation

Multiple Epiphyseal Dysplasia (MED) spares the spine and typically presents with fragmented epiphyses. It is most commonly associated with a mutation in the Cartilage Oligomeric Matrix Protein (COMP) gene.

Question 55

A 4-year-old boy presents with short trunk dwarfism, a barrel chest, and coxa vara. Radiographs reveal flattening of the vertebral bodies and delayed ossification of the femoral head and neck epiphyses. An abnormality in which of the following proteins is the underlying cause?

Explanation

Spondyloepiphyseal dysplasia (SED) affects both the spine and epiphyses. It is caused by a mutation in the COL2A1 gene, resulting in defective Type II collagen.

Question 56

A 6-year-old child presents with a painful, firm mass on his back following minor trauma, and a short, malformed great toe. Over several weeks, the mass gradually turns into bone. Which of the following is the most appropriate management regarding the back mass?

Explanation

Fibrodysplasia ossificans progressiva (FOP) is caused by an ACVR1 gene mutation. Biopsy or surgical excision of the heterotopic ossification triggers explosive new bone formation and must be strictly avoided.

Question 57

A 6-year-old girl with osteogenesis imperfecta is treated with intravenous pamidronate.

What is the primary mechanism of action of this medication in this patient?

Explanation

Bisphosphonates like pamidronate are internalized by osteoclasts and induce apoptosis by inhibiting the mevalonate pathway. This reduces bone resorption and increases bone mass in patients with OI.

Question 58

A 15-year-old boy presents for evaluation of delayed dental eruption. Examination reveals open skull sutures and absent clavicles.

Which of the following associated orthopedic conditions should also be screened for in this patient?

Explanation

Patients with cleidocranial dysplasia frequently develop coxa vara and scoliosis. Screening for these orthopedic manifestations is standard in managing the condition.

Question 59

An 18-month-old child presents with enlarged wrists, bowing of the legs, and frontal bossing. Laboratory studies demonstrate low serum 25-hydroxyvitamin D, low-normal calcium, low phosphorus, and significantly elevated parathyroid hormone. Which of the following is the most likely diagnosis?

Explanation

Nutritional rickets is characterized by vitamin D deficiency leading to decreased calcium and phosphate absorption. This causes secondary hyperparathyroidism, which normalizes calcium at the expense of severe hypophosphatemia and bone demineralization.

Question 60

A 55-year-old woman presents with a pathologic fracture of her proximal humerus. Radiographs show a well-defined lytic lesion. Laboratory values reveal hypercalcemia, hypophosphatemia, and markedly elevated alkaline phosphatase. Which of the following describes the histological appearance of this bone lesion?

Explanation

The clinical scenario is classic for primary hyperparathyroidism leading to a brown tumor (osteitis fibrosa cystica). Histologically, brown tumors consist of numerous multinucleated giant cells and osteoclasts in a highly vascular, hemorrhagic stroma.

Question 61

A neonate is born with severe extremity deformities, blue sclerae, and a soft skull. Radiographs show crumpled long bones, beaded ribs, and multiple fractures. The infant dies shortly after birth due to respiratory failure.

Which Sillence classification type of osteogenesis imperfecta does this patient have?

Explanation

Sillence Type II is the perinatal lethal form of osteogenesis imperfecta. It is characterized by severe in utero fractures, 'crumpled' bones, and death usually due to pulmonary hypoplasia.

Question 62

An 8-year-old boy presents with the ability to bring his shoulders together in the midline. Radiographs reveal hypoplastic clavicles as shown.

Which of the following genes is mutated in this condition?

Explanation

Cleidocranial dysplasia is caused by a mutation in the RUNX2 (CBFA1) gene, which is essential for osteoblast differentiation. It is characterized by delayed fontanelle closure, hypoplastic clavicles, and supernumerary teeth.

Question 63

A 10-year-old girl with delayed fontanelle closure, open skull sutures, and supernumerary teeth is evaluated for a waddling gait. What is the most common orthopedic abnormality requiring surgical intervention in this syndrome?

Explanation

The patient has cleidocranial dysplasia. Coxa vara is a common finding and represents the most frequent orthopedic manifestation requiring surgical intervention, such as a valgus producing subtrochanteric osteotomy.

Question 64

A 4-year-old child sustains a femur fracture after a minor fall. He has blue sclerae, normal dentition, and no significant hearing loss. Radiographs show generalized osteopenia.

What is the most likely Sillence classification for this patient?

Explanation

Osteogenesis Imperfecta (OI) Type I is the mildest and most common form, characterized by blue sclerae, normal dentition, and a quantitative defect in Type I collagen. Type IV patients typically have white sclerae.

Question 65

A 12-year-old boy with a history of multiple fractures presents with progressive loss of forearm rotation. Radiographs demonstrate calcification of the interosseous membrane and a dislocated radial head. Which of the following is characteristic of his specific condition?

Explanation

This presentation is classic for Osteogenesis Imperfecta Type V, caused by an IFITM5 mutation (not COL1A1/COL1A2). It is uniquely associated with hyperplastic callus formation and calcification of the forearm interosseous membrane.

Question 66

A pediatric patient with osteogenesis imperfecta is started on intravenous pamidronate. Which of the following best describes the cellular mechanism of action of this medication?

Explanation

Nitrogen-containing bisphosphonates like pamidronate inhibit farnesyl pyrophosphate synthase in the mevalonate pathway. This leads to osteoclast apoptosis, thereby reducing bone resorption and increasing bone density.

Question 67

A 6-year-old girl with osteogenesis imperfecta type III presents with severe anterolateral bowing of the tibia.

What is the most appropriate surgical management for her tibial deformity?

Explanation

The standard of care for severe long bone bowing in growing children with OI is multiple-level osteotomies combined with telescopic intramedullary rodding (e.g., Fassier-Duval rods) to maintain alignment as the child grows.

Question 68

A 2-year-old boy with frontal bossing and rhizomelic shortening of the limbs is diagnosed with a condition caused by a gain-of-function mutation in the FGFR3 gene. In which zone of the physis does this mutation exert its primary effect?

Explanation

Achondroplasia is caused by a gain-of-function mutation in FGFR3, which abnormally inhibits chondrocyte proliferation. This effect primarily occurs in the proliferative zone of the physis.

Question 69

An 8-month-old infant with achondroplasia presents with witnessed episodes of apnea, cyanosis, and hyperreflexia. What is the most appropriate next step in evaluation?

Explanation

Infants with achondroplasia are at high risk for foramen magnum stenosis, which can cause cervicomedullary compression leading to central apnea, hyperreflexia, and sudden death. MRI of the cervicomedullary junction is diagnostic.

Question 70

A 5-year-old child presents with disproportionate short stature, normal facial features, and a waddling gait. Radiographs show delayed epiphyseal ossification and platyspondyly. A mutation in the COMP gene is identified. Which of the following cellular locations accumulates the abnormal protein?

Explanation

Pseudoachondroplasia is caused by mutations in the COMP gene. The mutant cartilage oligomeric matrix protein misfolds and accumulates in the rough endoplasmic reticulum of chondrocytes, causing premature cell death.

Question 71

A 7-year-old boy presents with bilateral hip pain and a waddling gait. Radiographs demonstrate small, fragmented proximal femoral epiphyses bilaterally and double-layered patellae. Spine radiographs are completely normal. What is the most likely diagnosis?

Explanation

Multiple epiphyseal dysplasia (MED) presents with delayed/fragmented epiphyses (often mimicking bilateral Perthes) and characteristic double-layered patellae. The spine is typically normal, distinguishing it from spondyloepiphyseal dysplasias.

Question 72

A 6-year-old child with a barrel-shaped chest, short trunk, and severe coxa vara is diagnosed with spondyloepiphyseal dysplasia congenita (SEDC). Which of the following routine screenings is critical for this patient?

Explanation

SEDC is caused by a type II collagen mutation (COL2A1). Because type II collagen is also highly expressed in the vitreous humor, these patients are at high risk for severe myopia and retinal detachment.

Question 73

A newborn presents with micromelic short stature, bilateral clubfeet, "hitchhiker" thumbs, and cystic swelling of the pinnae. A defect in which of the following cellular processes is responsible for this condition?

Explanation

Diastrophic dysplasia is characterized by hitchhiker thumbs, cauliflower ears, and severe clubfeet. It is caused by a mutation in the SLC26A2 gene, resulting in a defect in the diastrophic dysplasia sulfate transporter (DTDST).

Question 74

A 6-year-old girl with normal intelligence presents with short stature, corneal clouding, and knock knees. Urine analysis reveals excessive excretion of keratan sulfate. She is at highest risk for which of the following orthopedic emergencies?

Explanation

This patient has Morquio syndrome (MPS type IV), marked by keratan sulfate in the urine and normal intelligence. Odontoid hypoplasia is a hallmark, putting patients at extreme risk for atlantoaxial subluxation and myelopathy.

Question 75

A 4-year-old boy presents with progressive bowing of the legs and short stature. Laboratory tests show normal serum calcium, low serum phosphate, normal PTH, and elevated alkaline phosphatase. Genetic testing reveals a PHEX mutation. Which of the following is the primary pathophysiologic mechanism?

Explanation

X-linked hypophosphatemic rickets is caused by a PHEX mutation, resulting in elevated levels of FGF23. Excessive FGF23 inhibits renal reabsorption of phosphate, leading to profound phosphaturia and rickets.

Question 76

A 7-year-old child with X-linked hypophosphatemic rickets has been treated with oral phosphate and calcitriol but continues to have severe limb deformities and progressive nephrocalcinosis. What novel targeted therapy can be initiated to directly address the underlying pathophysiology?

Explanation

Burosumab is a monoclonal antibody that binds and inhibits FGF23. It directly addresses the underlying cause of X-linked hypophosphatemia, improving phosphate homeostasis and reducing the need for oral supplements that cause nephrocalcinosis.

Question 77

An infant presents with failure to thrive, hepatosplenomegaly, and cranial nerve palsies. Radiographs show generalized osteosclerosis with a "bone-in-bone" appearance. The most severe form of this disease is characterized by a defect in which of the following?

Explanation

Infantile malignant osteopetrosis is commonly caused by a mutation in the TCIRG1 gene, which encodes a subunit of the osteoclast vacuolar proton pump. This results in the failure of the ruffled border to acidify the resorption pit.

Question 78

A 65-year-old man presents with increasing head size, unilateral hearing loss, and progressive anterior bowing of the tibia. A biopsy of the affected bone would most likely demonstrate which of the following histologic findings?

Explanation

Paget disease of bone is characterized by chaotic bone remodeling. The classic histologic finding is a "mosaic" or "jigsaw puzzle" pattern of lamellar bone demarcated by irregular, prominent cement lines.

Question 79

A 72-year-old man with a long-standing history of polyostotic Paget disease suddenly develops severe, unrelenting pain and swelling in his right thigh. Radiographs show cortical destruction and a soft tissue mass. What is the most likely diagnosis?

Explanation

Malignant transformation occurs in about 1% of patients with Paget disease. The most common secondary malignancy is osteosarcoma, which typically presents with new-onset, severe localized pain and an expansile lytic lesion.

Question 80

A 55-year-old patient with end-stage renal disease presents with diffuse bone pain. Labs reveal elevated PTH, low calcium, and high phosphate. Radiographs show subperiosteal resorption of the radial aspect of the middle phalanges. What is the primary sequence of events causing this patient's elevated PTH?

Explanation

Renal osteodystrophy is driven by secondary hyperparathyroidism. Failing kidneys cannot excrete phosphate or synthesize active Vitamin D (calcitriol), leading to hyperphosphatemia and hypocalcemia, which persistently stimulate the parathyroid glands.

Question 81

A 6-month-old infant presents with craniosynostosis, failure to thrive, and severe rickets-like skeletal deformities. Laboratory findings are notable for significantly decreased serum alkaline phosphatase and elevated urinary phosphoethanolamine. What is the definitive treatment for this condition?

Explanation

The patient has hypophosphatasia, an inborn error of metabolism caused by a mutation in the ALPL gene (tissue-nonspecific alkaline phosphatase). The definitive medical therapy is enzyme replacement with asfotase alfa.

Question 82

A 4-month-old infant with achondroplasia is brought to the clinic by her parents due to observed episodes of breath-holding and central apnea during sleep. On examination, the infant exhibits hyperreflexia in both lower extremities. What is the most appropriate next step in management?

Explanation

Infants with achondroplasia are at high risk for foramen magnum stenosis, which can cause severe cervicomedullary compression. Symptoms such as central apnea, hyperreflexia, or quadriparesis warrant an urgent cervical spine MRI to evaluate the need for surgical decompression.

Question 83

A 6-year-old child presents for an orthopaedic evaluation. He has short-trunk dwarfism, a cleft palate, and severe myopia. Radiographs reveal coxa vara and flattened vertebral bodies. Prior to the patient undergoing general anesthesia for an unrelated procedure, which of the following imaging studies is mandatory?

Explanation

The patient's clinical presentation is classic for Spondyloepiphyseal Dysplasia (SED) congenita (COL2A1 mutation). These patients frequently have odontoid hypoplasia and atlantoaxial instability, making flexion-extension cervical spine radiographs mandatory prior to general anesthesia to prevent catastrophic neurological injury during intubation.

Question 84

A newborn is evaluated in the NICU. The infant has severely shortened limbs, bilateral rigid clubfeet, "hitchhiker" thumbs, and prominent cystic swelling of the external ears. The genetic mutation responsible for this condition primarily disrupts which of the following physiological processes?

Explanation

The clinical picture describes diastrophic dysplasia, an autosomal recessive condition caused by mutations in the SLC26A2 gene. This gene encodes a sulfate transporter, and its defect impairs the sulfation of proteoglycans in cartilage matrix.

Question 85

A 4-year-old boy presents with progressive bowing of his lower extremities. Laboratory testing reveals normal serum calcium, low serum phosphorus, normal PTH, normal 25-OH vitamin D, and normal 1,25-OH vitamin D levels. Alkaline phosphatase is elevated. What is the primary pathophysiological mechanism underlying his condition?

Explanation

This presentation is characteristic of X-linked hypophosphatemic rickets, caused by a PHEX gene mutation that leads to excessive levels of FGF23. Elevated FGF23 inhibits renal phosphate reabsorption and 1-alpha hydroxylase activity, resulting in renal phosphate wasting with normal calcium levels.

Question 86

An 8-year-old child is evaluated for disproportionate short stature and a waddling gait. He has significant joint laxity but completely normal facial features and normal intelligence. Radiographs demonstrate delayed epiphyseal ossification and irregular metaphyses. Which of the following genes is most likely mutated?

Explanation

The patient has pseudoachondroplasia, which is an autosomal dominant condition caused by mutations in the Cartilage Oligomeric Matrix Protein (COMP) gene. Unlike true achondroplasia (FGFR3 mutation), these patients present with normal facies and typically normal intelligence.

Question 87

A 5-year-old boy presents with short stature, severe kyphoscoliosis, and corneal clouding. He also has hepatosplenomegaly. Urine analysis is highly positive for keratan sulfate. A deficiency in which of the following enzymes is responsible for this skeletal dysplasia?

Explanation

The patient has Morquio syndrome (Mucopolysaccharidosis Type IV), which is uniquely characterized by the accumulation of keratan sulfate. It is most commonly caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase (Type IVA).

Question 88

A 12-year-old girl sustains a low-energy proximal femur fracture. Radiographs show a distinct "ground-glass" lytic lesion in the proximal femur with a shepherd's crook deformity. She has several large, irregular hyperpigmented macules on her back and a history of precocious puberty. The underlying mutation for this syndrome results in abnormal function of which of the following?

Explanation

This is McCune-Albright syndrome, featuring polyostotic fibrous dysplasia, café-au-lait spots, and endocrinopathies. It is caused by an activating post-zygotic mutation in the GNAS1 gene, which encodes the Gs-alpha protein subunit, leading to excessive intracellular cAMP.

Question 89

A 10-year-old boy of Ashkenazi Jewish descent presents with severe acute right hip pain. Radiographs demonstrate avascular necrosis of the right femoral head and a classic "Erlenmeyer flask" deformity of the distal femurs bilaterally. He also has significant splenomegaly. A defect in which of the following enzymes is the primary etiology?

Explanation

The patient has Gaucher disease, an autosomal recessive lysosomal storage disorder caused by a deficiency in beta-glucocerebrosidase. The accumulation of glucocerebroside in macrophages expands the marrow cavity, causing bone pain crises, osteonecrosis, and Erlenmeyer flask deformities.

Question 90

A 14-year-old patient presents with bilateral knee pain and a waddling gait. Radiographs show flattened, irregular epiphyses at the knees and hips, and a characteristic "double-layer" appearance of the patella on the lateral view. Which of the following gene mutations is most commonly associated with this specific radiographic finding?

Explanation

Multiple Epiphyseal Dysplasia (MED) can be caused by various mutations, but the classic "double-layer" patella is highly characteristic of the severe, autosomal dominant form caused by mutations in the COMP gene.

Question 91

A 15-year-old girl presents for evaluation of hypermobility of the shoulders.

A radiograph of her chest and shoulders is provided. Which of the following orthopaedic conditions is most frequently associated with the underlying syndrome shown?

Explanation

The image demonstrates absent or severely hypoplastic clavicles, pathognomonic for cleidocranial dysplasia (RUNX2 mutation). A very common orthopaedic manifestation in these patients is coxa vara, which may require a valgus-producing subtrochanteric osteotomy.

Question 92

A 2-year-old girl with recurrent fragility fractures, osteopenia, and blue sclerae

is diagnosed with Osteogenesis Imperfecta and is initiated on cyclic intravenous pamidronate. What is the primary mechanism of action of this pharmacological therapy?

Explanation

Pamidronate is a nitrogen-containing bisphosphonate used to increase bone mineral density in children with Osteogenesis Imperfecta. It acts by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway, leading to osteoclast apoptosis and decreased bone resorption.

Skeletal Dysplasias of the Spine - Arab Board MCQ Prep

Master ABOS Board Review: Skeletal Dysplasias & Metabolic Bone Diseases | Part 2

Key Takeaway

Master ABOS Board Review: Skeletal Dysplasias & Metabolic Bone Diseases | Part 2

Chapter Index