Pathology Lab II - Developmental Anomalies of the Skeleton

PATHOLOGY LAB II-DEVELOPMENTAL ANOMALIES OF THE SKELETON. Arben Santo. CASE OUTLINE. Skeletal dysplasias Achondroplasia. Case Presentation #1: Sylvia K. Thanatophoric dysplasia. Osteogenesis imperfecta. Case Presentation #2: Henry M. Osteopetrosis. Marfan syndrome. Ehlers-Danlos syndrome. Pseudoxanthoma elasticum. OBJECTIVES. After completing this module the student will be able to: 1. Discuss the concept of bone dysplasias and give examples of diseases. 2. Describe etiology, pathogenesis, clinical manifestations and morphology of

achondroplasia. 3. Describe etiology, pathogenesis, clinical manifestations and morphology of

thanatophoric dysplasia. 4. Describe etiology, pathogenesis, clinical manifestations and morphology of

osteogenesis imperfecta. 5. Describe etiology, pathogenesis, clinical manifestations and morphology of Marfan

syndrome 6. Describe etiology, pathogenesis, clinical manifestations and morphology of Ehlers-

Danlos syndrome. 7. Describe etiology, pathogenesis, clinical manifestations and morphology of

pseudoxanthoma elasticum REFERENCES. 1. Robbins and Cotran Pathologic Basis of Disease, 8

th edition, 2010.

2. Spranger JW, Brill PW et al. Bone dysplasias. 2001

DEFINITION. Synonym: dwarfism

Skeletal dysplasias (skeletal malformations) are generalized disorders of the skeleton.

These disorders are associated abnormal shape and size of the skeleton and disproportion

of the long bones, spine, and head. There are more than 350 well-characterized skeletal

dysplasias. Although each one of them is relatively rare, collectively the birth incidence

of these disorders is 1 in 5000. All skeletal dysplasias are heritable diseases. In general, patients with skeletal dysplasia have disproportionately short stature. Short

stature is defined as a standing height more than 2 standard deviations (SDs) below the

mean (or below the 2.5 percentile) for sex. Short stature is subdivided in proportional and

disproportional short stature. Note that in individuals with proportional short stature, the

body appears normally proportioned, but is abnormally small. Proportional short stature

is due to endocrine disorders (growth hormone deficiency). A disproportionate body habitus may not be immediately apparent on physical

examination. Therefore, anthropometric measurements such as upper to lower segment

ratio, sitting height, and arm span must be measured when evaluating a patient with short

stature. The lower segment is measured from the symphysis pubis to the floor at the

inside of the heel. The upper segment is measured by subtracting the lower segment

measurement from the total height. Sitting height gives a measure of the length of the

head and trunk. It is a measurement of the distance from the highest point on the head to

the base sitting surface. CLASSIFICATION. Skeletal dysplasias are categorized into two anatomic types. The disproportional short

stature results from (1)short limbs but a normal trunk (short limb skeletal dysplasias) or

(1) normal limbs but a short trunk (short-trunk skeletal dysplasia). Short limb skeletal

dysplasias include achondroplasia, thanatophoric dysplasia, and osteogenesis imperfect.

Short-trunk skeletal dysplasias include Morquio syndrome (mucopolysaccharidosis IV)

and Kniest syndrome. The four most common skeletal dysplasias are thanatophoric

dysplasia, achondroplasia, osteogenesis imperfect and achondrogenesis.

CASE PRESENTATION #1: SYLVIA K. A healthy 26-year-old woman with achondroplasia was admitted to the hospital for an

elective cesarean delivery following an uneventful pregnancy. The patient's surgical

history included multiple oral facial surgical procedures for cosmetic reasons and

operations for limb enlongations. Her parents were of normal height, healthy and non-

consanguineous. The patient was 110 cm tall and weighed 62 kg. Physical examination

revealed a large head, small face, short neck, short arms and legs but a normal trunk.

Because of maternal contracted pelvis and breech fetal presentation, the decision was

made for a cesarean delivery, which was performed without complications. A baby girl

was delivered. She showed rhisomelic shortening of all limbs (shortened femurs and

humeruses) but a normal trunk. DEFINITION.

Achondroplasia is the most common form of short-limb skeletal dysplasias and is

compatible with a long life span. Achondroplastic patients have short limbs but trunk

length is normal. The limb involvement is characterized by arms more severely involved

than forearms, and thighs more severely involved than legs. This particular shortening of

the limb bones closest to the trunk (such as humerus and femur) is termed rhisomelic. The average height of an adult male with achondroplasia is 130 cm (51 inches); the

average height of adult female with achondroplasia is 125 cm (49 inches). Note that the

average height of an adult male in the United States is 69.2 inches or 175 cm. GENETICS. Achondroplasia is caused by mutations in the fibroblast growth factor receptor-3

(FGFR3) gene. This gene has been mapped to chromosome 4p16.3. The mutations occur

at the amino acid 380 within the encoded protein and result in a glycine to arginine amino

acid substitution (Gly380Arg). The Gly380Arg mutation activates the FGF receptor. The fibroblast growth factors are involved in cell proliferation and wound healing. They

also play important roles in human limb and craniofacial development. FGFR3 is

believed to be a negative regulator of bone growth. Excessive activation of the gene

results in decreased growth of the long bones. Experiments with FGFR3 knockout mice

showed that bones grow longer in mice which lacked the receptor. Thus, the mutations

observed in achondroplasia are gain-of-function mutations which activate the receptor. Achondroplasia is inherited as a mendelian autosomal dominant trait with complete

penetrance. Achondroplasia may be inherited in a homozygous or heterozygous

manner. The homozygous form, i.e. inheriting two copies of causative mutations from

two parents that are heterozygous, is quite lethal. However, more than 85% of patients

are born from unaffected parents and harbor new mutations. PATHOGENESIS. Mutations of FGFR3 give rise to achondroplasia, and hypochondroplasia and to

thanatophoric dysplasia, a lethal form of dwarfism that resembles homozygous

achondroplasia. FGFR3 mutations affects enchondral bone formation. During enchondral

ossification development, cartilage normally develops into bone. However, the cartilage

cells in cases with achondroplasia develop into bone more slowly than normal.

Enchondral bone formation is responsible for longitudinal bone growth. Since

lengthening of a bone occurs at the epiphyseal growth plates, long bones in patients with

achondroplasia are abnormally short; however, because periosteal growth is not affected,

the long bones are usually broad (wide). The iliac crest (which is formed by membranous instead of endochondral ossification) is

normal but looks relatively large. The length of the vertebral column is relatively normal. The calvarium is also formed by membranous ossification, and its eventual size is merely

a reflection of brain size. Achondroplastic individuals have brains of normal size, so their

calvaria are likewise of normal size. However, the bones of the face and skull base (maxillae, zygomatic and occipital bones)

are formed by endochondral ossification, and remain relatively small, in comparison to

the skull. The foramina of the skull base and spine and the spinal canal are often small,

which may lead to prominent neurological problems and spinal stenosis. Achondroplasia as a term is inaccurate because implies absent cartilage formation but is

universally accepted.

CLINICAL PRESENTATION. Features of achondroplasia are so distinctive that they can easily be identified both

clinically and radiologically. 1. Intrauterine diagnosis. The diagnosis of achondroplasia may be suspected in the 3

rd trimester by abnormal

ultrasound findings, namely very short limbs associated with normal spine.

2. After birth. After birth, achondroplasia is clinically characterized by short limbs, especially the

proximal segment, with a long trunk and a narrow thorax. Birth height is generally

preserved. The head is large with frontal bossing. Themidface is hypoplastic resulting in

an endochondral growth defect at the base of the skull. Midface hypoplasia describes a

situation in which the upper jaw, zygomatic bones (cheekbones) and orbital cavities (eye

sockets) remain smaller compared to the rest of the face. Patients with midface

hypoplasia have concave-looking face: they show bulging eyes (proptosis), a sunken nose

bridge and a protrusive lower jaw. 3. Infancy. The early motor milestones in infancy and later are delayed because of muscular

hypotonia, but psychomotor development is normal. 4. Childhood and adulthood. In children and adults short stature becomes gradually evident. Final adult height is

approximately 120-130 cm (47-51 inches). Mean adult weights are 45-55 kg (99-120

pounds). The proximal segments of upper and lower extremities (humerus and femur) are

relatively shorter than the middle and distal segments. The trunk is relatively long and is

deformed by excessive lumbar lordosis. The thoracic cage is relatively small and ribs are

short. Pronounced genu varum results from weightbearing. Genu varum (bowleg

deformity) is a deformity in which legs are bowed outward at the knee. COMPLICATIONS. 1. Hydrocephalus. In the newborn with achondroplasia, the jugular foramen is small (due to hypoplastic

occipital bone), leading to frequent dilated ventricles, excessive cerebrospinal

fluid, hydrocephalus and macrocephaly. Up to 10% of achondroplastic individuals have

ventricle shunts.

2. Brain stem compression. Narrowing of the foramen magnum gives rise to chronic brain stem compression at the

cervicomedullary region, causing symptoms of respiratory insufficiency, central apnea,

cyanotic episodes, muscular hypotonia,quadriparesis, or sudden death. These symptoms

are common in the first two years of life. Approximately 5–10% of patients with

achondroplasia have cervical medullary decompression surgery. 3. Spinal stenosis. In adults, leg and lower back pain are reported in half of patients, revealing the first signs

of spinal stenosis.Paresthesia, weakness, altered deep tendon reflexes,

and claudication develop later. Nearly one-third of patients require lumbar laminectomy. 4. Recurrent otitis media. Due to midface underdevelopment, the Eustachian tubes are short, the pharynx is small,

and the tonsils and adenoids are large for the available space. Recurrent otitis media is

common in childhood (90%). 5. Orthodontic problems. Dental crowding, due to maxillary hypoplasia, is found in more than half of cases.

DEFINITION. Thanatophoric dysplasia (TD) is a short-limb skeletal dysplasia that is usually lethal in

the perinatal period. The most salient phenotypic features of thanatophoric dysplasia in

an affected newborn include severe rhizomelic shortening of the limbs, normal trunk

length, macrocephaly, and narrow bell-shaped thorax.

ETIOLOGY AND PATHOGENESIS. Thanatophoric dysplasia is inherited in an autosomal dominant manner. Affected infants

have a de novo mutation in FGFR3 gene. Mutations in FGFR3 gene are responsible for

both achondroplasia and thanatophoric dysplasia. Mutations associated with

thanatophoric dysplasia are more dispersed than those associated with achondroplasia.

These mutations map to amino acids at positions 248, 249, 370, 371, and 373 in the

extracellular domain. CLINICAL PRESENTATION. Most cases of a severe fetal skeletal dysplasia can be diagnosed by prenatal

ultrasonography during the 2nd

or 3rd

trimester of pregnancy. Key ultrasonography

findings include significant shortness of limbs, a very narrow chest and normal trunk

length. Salient phenotypic features in an affected newborn include: (a) severe growth deficiency

with an average length of 40 cm (about 16 in) at term (normal average: 51 cm, 20

inches); (b) marked bilateral shortening of the limbs; (c) macrocephalic head with frontal

bossing; and (d) narrow, bell-shaped thorax with short ribs. NATURAL HISTORY.

Thanatophoric dysplasia is diagnosed prenatally or in the immediate newborn period.

Thanatophoric dysplasia is considered a lethal skeletal dysplasia; most affected infants

die of respiratory insufficiency in the first hours or days of life. Respiratory insufficiency

may be secondary to a small chest cavity and lung hypoplasia, compression of the brain

stem by the small foramen magnum, or a combination of both.

CASE PRESENTATION: HENRY M. A 53 year-old man presented with 10-year history of pain in the left knee. He was

diagnosed with osteogenesis imperfecta during early childhood because of short stature,

blue sclerae and multiple fractures. However, the frequency of fractures gradually

decreased throughout adolescence and he had none over the previous 17 years. At the

time of presentation he was 119.7 cm tall and weighed 39.2 kg. Bone mineral density

(BMD) of the lumbar vertebrae (L2-L4) evaluated by dual-energy X-ray absorptiometry

(DEXA) was extremely low for his age. Bone fragility had never been addressed with

medication. He had severe deformities of the proximal part of his left femur with

subsequent osteoarthritis of his left knee. His left knee had a valgus deformity with a

range of motion from 15° to 120°. The femorotibial angle of the remarkably small knee

was 156°. He underwent cemented total knee arthroplasty on the left knee. One year later,

the patient had relief of pain and he could walk without assistance. DEFINITION. Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by low bone

mass (osteopenia), a propensity to bone fractures with minimal or absent trauma,

dentinogenesis imperfecta (DI), and, in adult years, hearing loss.

EPIDEMIOLOGY. OI is a common disorder; its prevalence is estimated to be 1 per 20,000 live births. The

number of people affected with OI in the United States is estimated to be between 20,000

and 50,000. Both sexes are equally affected The age when symptoms (i.e., fractures) begin widely varies. Patients with severe cases

present with fractures in utero. Patients with mild forms may not have fractures until

adulthood. GENETICS. OI is a heterogeneous genetic disorder of the bone matrix caused by abnormal collagen

microfibril assembly. Up to eight clinical subtypes of OI have been described based on

the clinical, biochemical, and molecular nature of the disorder (Table 1).

In approximately 90% of individuals with osteogenesis imperfecta (i.e., types I to IV, all

inherited in autosomal dominant fashion), mutations in either of the genes encoding the

alpha-1 or alpha-2 chains of type I collagen (COL1A1 or COL1A2) can be identified. Of

those without collagen mutations, a number of them (types VII and VIII) will have

mutations involving the enzyme complex responsible for posttranslational hydroxylation

of the position 3 proline residue of COL1A1. Mutations in two genes encoding proteins

involved in that enzyme complex, CRTAP and LEPRE1, have been shown to cause

autosomal recessive osteogenesis imperfecta. PATHOGENESIS.

The primary pathology in osteogenesis imperfecta (OI) is a disturbance in the synthesis

of type I collagen, which is the predominant protein of the extracellular matrix of most

tissues. In bone, this defect causes osteoporosis, which leads to an increase

in the tendency to fracture. Besides bone, type I collagen is also a major constituent of

dentin, and sclera; therefore, individuals with OI may also have abnormalities of these

structures. 1. Types of collagen. So far, 29 types of collagen have been identified. Type I collagen is the major constituent

of bone, dentin, ligaments, sclera, and skin. Type II collagen is the major constituent of

hyaline cartilage. Type III collagen is the major constituent of the stroma of internal

organs such as liver, kidney, lymph nodes, GI tract, uterus and blood vessels. Type IV

collagen is the major constituent of the basement membranes. 2. Collagen synthesis. The process of collagen formation starts with the synthesis of procollagen (collagen

precursor) in fibroblasts and osteoblasts. Procollagen consists of a long triple helix

protein flanked by two propeptides at its two terminals. Each polypeptide chain in the

structure of the triple helix is named alpha- chain and is composed of a gly-X-Y repeating

sequence (X is proline and Y is lysine most of the times). Each alpha- chain is

synthesized in endoplasmic reticulum. Proline and lysine residues are hydroxylated by

enzymes prolyl-hydroxylase and lysyl-hydroxylass

into hydroxyproline and hydroxylysine. These two unusual amino acids are associated

only with collagen in the body.

Three alpha- chains align in phase to form the triple helix in the Golgi apparatus.

Procollagen is secreted from the cell and then the propeptides are cleaved by proteases to

form the basic unit of the collagen fibrils, tropocollagen. Tropocollagen units line up and

assemble into collagen fibrils and fibers in the extracellular space. Then specific hydroxylysine and hydroxylysine residues are oxidized by the enzyme

lysyl oxidase. This reactionplaces stable crosslinks within (intramolecular crosslinks) and

between the molecules (intermolecular crosslinks), thus stabilizing the array that is

characteristic of collagen. This is the critical step that gives the collagen fibers such

tremendous strength. Vitamin C is required for hydroxylation of lysine and proline. Lack

of vitamin C (scurvy) explains inadequate wound healing. 3. Functional impact of type I genetic collagen mutations. (A) Mutations affecting COL1A1 or COL1A2. A number of genetic defects cause

abnormal type I collagen synthesis. Most OI cases arise from mutations in 1 of 2 genes:

(a) the COL1A1 gene on chromosome 17, and (b) the COL1A2 gene on chromosome 7.

The gene COL1A1 encodes the alpha-1 chain of type I collagen. The gene COL1A2

encodes the alpha-2 chain of type I collagen. Mutations affecting COL1A1 or COL1A2 may produce the OI phenotype via two

mechanisms, chain exclusion and chain non exclusion. Type I collagen is composed of three polypeptide chains (two alpha-1 and one alpha-2)

intertwined into a triple helix, which is maintained by the presence of glycine residues at

regular intervals. In moderately severe forms of OI (Type I), the chain encoded by the

mutated allele is unstable and is consequently destroyed without being incorporated into

the collagen molecule. Therefore, all collagen chains are produced by the normal allele,

and the collagen molecule is qualitatively normal but quantitatively deficient. The second

mechanism involves incorporation of abnormal collagen chains into the collagen

molecule, which is therefore abnormal. The dominant negative effect of the mutated

allele on the normal allele results in the most severe OI phenotypes (types II, III, and IV). (B) Mutations affecting posttranslational hydroxylation of the proline

residues. Posttranslational hydroxylation of the proline residues is dependent on two

proteins that form a protein complex located in the rough endoplasmic reticulum: (a)

cartilage-associated protein (CRTAP), and (b) leucine proline-enriched proteoglycan 1

(LEPRE1). Mutations affecting the genes for these two proteins were recently identified

in patients with recessive forms of OI. These mutations may lead to dysregulation of

posttranslational hydroxylation of the proline residue at position 986 of the alpha-1

chains of type I collagen.

4. Morphological bone abnormalities in osteogenesis imperfecta. Electron microscopic studies of osteogenesis imperfecta demonstrate a decrease in

the diameter of the collagen fibril, relative to the collagen fibril of healthy persons, and

smaller-than-normal apatite crystals. Bones in patients with osteogenesis imperfecta have a smaller external size, reduced

cortical width and reduced cancellous bone volume. Trabeculae in the cancellous bone

are reduced in number and are abnormally thin. CLINICAL MANIFESTATIONS. The clinical features of osteogenesis imperfecta depend on the type, but bone fragility

with multiple fractures and bony deformities are the common hallmark of all types. Other

major presenting signs and symptoms of OI include blue sclerae, hearing loss, and tooth

abnormalities (dentinogenesis imperfecta). 1. Type I osteogenesis imperfecta. This prototypical and most common form of OI is associated with the best prognosis. The

mode of inheritance is autosomal dominant. OI type I is characterized by normal stature

and blue sclera. (A) Bone fragility. The first fractures may occur when the infant begins to walk and,

more importantly, to fall. Fractures generally decrease in frequency after puberty.

Fracture frequency often increases again in the 5th

decade of life and accounts for more

than 25% of lifetime fractures. This is especially noted in postmenopausal women and

men beyond the 5th

decade. There are no bony deformities. Affected individuals may

have anywhere from a few fractures to more than 100, but the fractures usually heal

normally with no resulting deformity.

(B) Dentinogenesis imperfecta. Dentinogenesis imperfecta is rare. Dentinogenesis

imperfecta causes teeth to be discolored (most often a blue-gray or yellow-brown color)

and translucent. Teeth are also weaker than normal, making them prone to rapid wear,

breakage, and loss. These problems can affect both primary teeth and permanent teeth.

(C) Hearing loss. Progressive hearing loss occurs in about 50% of adults with OI type I,

beginning as a conductive hearing loss but becoming a mixed hearing loss in time. (D) Blue sclerae. Blue sclerae are not pathognomonic for OI and can be present in other

diseases. When the sclera is thin and semitransparent, blue color is a reflection of the

dark choroida underneath. (E) Wormian bones. Wormian bones, also known as extra sutural bones, are extra bone

pieces that occur within a suture in the cranium. These are irregular isolated bones which

appear in addition to the usual centers of ossification of the cranium and, although

unusual, are not rare. Their size is greater than 0.6 cm x 0.4 cm. Wormian bones are

arranged in a general mosaic pattern. They are present in normal individuals, but in

individuals with OI they are present in larger numbers that usual.

Wormian bones occur more frequently in more severe forms (type II, III and IV) of

osteogenesis imperfecta. 2. Type II osteogenesis imperfecta. Type II is the most severe form of OI. It is characterized by extreme bone fragility that

almost invariably leads to death in the intrauterine or perinatal period. The cause of death

is most often respiratory failure due to small thorax and rib fractures. Abnormalities

characteristic of OI type II are evident on prenatal ultrasound and at birth. The sclerae are

typically dark blue and radiographs show “crumpled” long bones and fractures in various

stages of healing and severe skeletal deformity. The mode of inheritance is autosomal

dominant.

3. Type III osteogenesis imperfecta. Type III is the next most severe form of OI after type II. It is the most severe form which

is compatible with survival into adulthood. This type has also been referred to as the

„progressive deforming type of OI‟ since deformity progresses even in the absence of

fracture. It is characterized by severe progressive skeletal deformity that may have begun

by birth. Individuals may possess multiple fractures at birth and suffer frequent fractures

thereafter because of the highly fragile nature of their bones. The incidence of fracture

remains high even in adult life. Individuals have severely short stature and because of

their deformity and bone fragility are frequently confined to a wheelchair for life.

Dentinogenesis imperfecta is commonly present. The color of the sclerae progresses from

pale blue in infancy to a normal appearance by adolescence. Hearing loss generally

begins in the teenage years.

4. Type IV osteogenesis imperfecta. Type IV OI is distinguished from type I OI by the slightly increased severity of bone

fragility and by the presence of normal sclerae. Mild to moderate bony deformity of the

long bones and spine is present. Fractures occur throughout life with a relative period of

quiescence between 20 and 30 years of age. Patients have short stature, bowing of long

bones, and vertebral fractures, but minimal shortening of life expentancy.

DEFINITION. Synonyms: Adlers-Schönberg disease, marble bone disease;

Osteopetrosis is a rare inherited disease that affects all bones. Osteopetrosis is

characterized by the failure of osteoclasts to resorb bone and excess accumulation of

bone throughout the body.

As a consequence of osteoclast failure to resorb bone, bone remodeling is impaired. As a

result, continuous accumulation of bone material takes place unassociated with bone

resorption. Individuals have thickened sclerotic bones which have poor mechanic

properties and increased fragility despite increased bone mass. The thickened sclerotic

bones in osteopetrosis may also cause hematopoietic insufficiency, disturbed tooth

eruption, nerve entrapment syndromes, and growth impairment. Osteopetrosis is a

heterogeneous disorder encompassing different molecular lesions and a range of clinical

features. However, all forms share a single pathogenic nexus in the osteoclast.

CLASSIFICATION. Three distinct forms of the disease are based on age and clinical features and account for

most cases. These are infantile, and intermediate and adult onset. 1. Infantile osteopetrosis. (A) Definition. Infantile osteopetrosis (also called malignant osteopetrosis) is the most

severe variant of the disease; it affects infants and is usually fatal before the second

decade of life. (B) Clinical presentation. Its clinical manifestations include: (a) autosomal recessive

inheritance; (b) failure to thrive and growth retardation; (c) excess bone tissue replacing

bone marrow and causing bone marrow failure; patients have pancytopenia (easy

bruising, bleeding, recurrent infections), and extramedullary hematopoiesis

(hepatosplenomegaly); (d) mastoid and nasal sinuses are small and underpneumatized

causing nasal stuffiness; (e) failure of foramina of the skull to widen completely results in

cranial nerve entrapment neuropathies (such as blindness, deafness, facial palsy); (f)

bones are fragile and can fracture easily; (g) children become transfusion-dependent

before the age of 3 months and frequently die in infancy from bone marrow failure and

overwhelming infection (bone marrow transplantation is the only effective therapy).

2. Adult osteopetrosis. Adult osteopetrosis (also called benign osteopetrosis) is diagnosed in late adolescence or

adulthood. Adult osteopetrosis is inherited as an autosomal dominant trait.

Approximately one half of patients are asymptomatic, and the diagnosis is made

incidentally, often in late adolescence because radiologic abnormalities start appearing

only in childhood. Still other patients might present with (a) fractures; (b) osteomyelitis,

(c) bone pains; (c) neuropathies due to cranial nerve entrapment (deafness, facial palsy,

carpal tunnel syndrome) and (d) osteoarthritis.

Bones are fragile and might fracture easily. Approximately 40% of patients have

recurrent fractures. Osteomyelitis of the mandible occurs in 10% of patients. Bone

marrow function is not compromised. 3. Intermediate osteopetrosis. Intermediate type osteopetrosis, may affect children or adults and may present with either

the clinical features of the infantile manifestation or be asymptomatic. It consists of an

autosomal recessive mode of inheritance and is shown on radiological survey as diffuse

osteosclerosis. EPIDEMIOLOGY. Osteopetrosis is a rare disease. Overall incidence is estimated to be 1 case in 100,000-

500,000 population. However, the actual incidence is unknown because epidemiologic

studies have not been conducted ETIOLOGY AND PATHOGENESIS. The primary underlying defect in all types of osteopetrosis is failure of the osteoclasts to

reabsorb bone. A number of heterogeneous molecular or genetic defects can result in

impaired osteoclastic function. The exact molecular defects or sites of these mutations

largely are unknown. The defect might lie in the osteoclast lineage itself or in the

mesenchymal cells that form and maintain the microenvironment required for proper

osteoclast function. The only genetic defect known to cause a subtype of infantile

osteopetrosis is carbonic anhydrase II deficiency (CA II). The carbonic anhydrases have

important physiologic functions in the body to accelerate the association of CO2 and H2O

to form H2CO3, which dissociates to H+ and HCO3¯. Carbonic anhydrase II is the most

catalytically active of the group. Osteoclasts are particularly rich in carbonic anhydrase

II. Deficiency of CA II impairs the production of H+ by the osteoclast and, thus, bone

resorption is blocked, leading to the development of osteopetrosis. The carbonic

anhydrase II gene has been defined and located on chromosome 8.

IMAGING STUDIES. The diagnosis of disease is based on radiologic findings. Patients usually have

generalized osteosclerosis. Bones may be uniformly sclerotic and clublike. The entire

skull is thickened and dense, especially at the base. Sinuses are small and

underpneumatized. Vertebrae are extremely radiodense. They may show alternating

bands, known as the rugger-jersey sign. Radiographs may show evidence of fractures or

osteomyelitis.

DEFINITION. Marfan syndrome is an inherited connective-tissue disorder transmitted as an autosomal

dominant trait. Cardinal features of the disorder include (a) tall stature, (b) ectopia lentis,

(c) aortic root dilatation, (d) aortic dissection and (e) mitral valve prolapse. About three

quarters of patients have an affected parent; new mutations account for the remainder. The disease is named after Bernard Marfan, a pediatrician and professor of Paris

University. In 1896, Marfan presented the case of a 5-year-old girl named Gabrielle

pointing out her disproportionate limbs. ETIOLOGY.

Marfan syndrome results from mutations in the fibrillin-1 (FBN1) gene on chromosome

15, which encodes for the glycoprotein fibrillin. Fibrillin is a major building block

of microfibrils. Microfibrils are an abundant component of the extracellular matrix and

can be found alone as microfibril bundles or associated with elastin in elastic fibers.

Inelastic fibers of large blood vessels such as aorta, microfibrils serve as a substrate for

elastin. Tropoelastin is then deposited on the microfibrillar matrix and the elastic fiber if

formed. Within the bone, fibrillin microfibrils are unassociated with elastic elements and can be

found in the periosteum, compact bone and cancellous bone. Zonular fibers of suspensory

ligaments of crystalline lens are well known as independent microfibrils. Fibrillin-1 mutation or deficiency prevents microfibril formation and has the following

consequences: (a) deficient elastin formation which weakens aortic wall; the progressive

aortic dilatation and eventual aortic dissection occur because of tension caused by left

ventricular ejection impulses; (b) deficient fibrillin deposition leads to reduced structural

integrity of the lens zonular fibers, and ligaments; (c) fibrillin-1 mutation leads to rib and

long bone overgrowth and kyphosis. CLINICAL MANIFESTATIONS. Marfan syndrome is currently diagnosed using criteria based on an evaluation of the

family history, molecular data, and 6 organ systems. The diagnosis cannot be based on

molecular analysis alone because molecular diagnosis is not generally available, mutation

detection is imperfect, and not all FBN1 mutations are associated with Marfan

syndrome. At this time, the diagnosis of Marfan syndrome remains mainly clinical.

1. Skeletal manifestations. (A) Dolichostenomelia. Patients with Marfan syndrome are excessively tall. Body

proportions show dolichostenomelia, which refers to disproportionately long limbs

compared with the trunk. In practice three measurements are made with the patient

standing: height, upper segment (top of the head to top of the symphysis pubis), and

lower segment (top of the symphysis pubis to floor). Normal individuals have a mean US/LS ratio of 0.92. Patients with Marfan syndrome mean US/LS ratio of 0.85 which indicates

dolichostenomelia. Arm span-to-height ratio in patients with Marfan syndrome is greater than 1.05.

(B) Arachnodactyly. Arachnodactyly is very common sign in patients with Marfan

syndrome. Arachnodactyly ("spider fingers") is a condition in which the fingers are

abnormally long and slender in comparison to the palm of the hand. Arachnodacyly is

demonstrated by two signs: positive wrist sign (Walker sign) and positive thumb sign

(Steinberg sign). These are two simple maneuvers that help demonstrate arachnodactyly.

First, the thumb sign is positive if the thumb, when completely opposed within the

clenched hand, projects beyond the ulnar border. Second, the wrist sign is positive if the

distal phalanges of the first and fifth digits of one hand overlap when wrapped around the

opposite wrist.

(C) Pectus excavatus and pectus carinatum. Ribs undergo excessive longitudinal growth.

The result is pectus excavatus (depression of sternum) and pectus carinatum (protrusion

of sternum).

(D) Scoliosis. More than 60% of patients have scoliosis. The most important problem

related to scoliosis is the progression of the deformity and the resulting collateral effects.

Progression is most likely with curvature of more than 20° in growing patients.

(E) Dolichocephaly and high arched palate. Dolichocephaly refers to the condition where

the head is disproportionately long (in diameter from front to back) and narrow compared

to the normal head.

The opposite condition to dolichocephaly is brachycephaly. Brachycephaly refers to the

condition where the head is disproportionately short in diameter from front to back. High

arched palate is a condition where the roof of the mouth is higher in the mouth than

normal.

2. Ocular findings. About 50% of patients have ectopia lentis, which is a displacement or subluxation of the

crystalline lens of the eye. The underlying mechanism of ectopia lentis is the disruption

or dysfunction of the zonular fibers of the lens. This may present at birth or develop

during childhood or adolescence.

3. Cardiovascular involvement. Cardiovascular involvement is the most serious problem associated with Marfan

syndrome and is associated with decreased life expectancy. Echocardiographic evidence

of cardiovascular involvement exists in >95% of adults with Marfan syndrome. The

cardiovascular abnormalities in Marfan syndrome include the following: (A) Progressive aortic root dilatation involving the sinuses of Valsalva. The ascending

aorta bears the main stress of the left ventricular ejection leading to progressive dilatation

in the sinuses of Valsalva. Aortic regurgitation is the result. It manifests at an early age.

A diastolic murmur over the aortic valve may be present.

(B) Aortic dissection involving ascending aorta. Aortic dissection is a tear in the wall of

the aorta that causes blood to flow between the layers of the wall of the aorta and force

the layers apart. Aortic dissection is a medical emergency and can quickly lead to death,

even with optimal treatment. (C) Mitral valve prolapse. Mitral valve prolapse is a less significant cardiac anomaly in

patients with Marfan syndrome. Mitral valve prolapse is the displacement of abnormally

thickened, redundant mitral leaflet(s) into the left atrium during systole. Mitral valve

prolapsed has been found in 60-70% of cases, leads to severe mitral regurgitation in 10%

of cases. Aortic regurgitation and aortic dissection are the main causes of death.

PROGNOSIS. If untreated, Marfan syndrome is highly lethal; the average age at death is 30-40 years.

About 90% of patients died from aortic dissection or from congestive heart failure due to

chronic aortic regurgitation. With pharmacological and surgical treatment patients life

expectancy is now about 70 years.

DEFINITION. Ehlers-Danlos syndrome (EDS) is the name given to a group of more than 10 different

inherited disorders; all involve a genetic defect in collagen and connective-tissue

synthesis and structure. The underlying collagen abnormality is different for each type.

The collagen defect has been identified only for a couple of types. Frequency of Ehlers-

Danlos syndrome (all types combined) has been reported as 1 per 5000 to 1 per 10,000

population. The inheritance mode of Ehlers-Danlos syndrome can be autosomal

dominant, autosomal recessive or sex-linked. The skeleton is not affected. CLINICAL MANIFESTATIONS COMMON TO ALL TYPES. 1. Skin hyperextensibility. The skin is usually white and soft, and translucent. The underlying vessels are sometimes

visible. The skin is easy to pull, once released it immediately returns to its original state

2. Skin fragility. Fragility of dermal skin is common, with frequent bruises and lacerations. Poor wound

healing is not rare. The use of sutures is usually a problem in patients, in whom easy

dehiscence and cigarette-paper–like scars may be observed. Frequently, these scars are

found on the knees. 3. Joint hyperextensibility. The joints are hyperextensible, sometimes dramatically, but

the degree of involvement is variable. The digit joints are most commonly affected, but

all the joints can show alterations. Dislocations can occur, but patients are usually able to

quickly reduce them with no pain. Historically some patients with EDS achieved fame in

circuses as contorsionists (“The India Rubber Man”, “The Elastic Lady”, “The Human

Pretzel”).

CLINICAL PRESENTATION OF SPECIFIC TYPES. 1. Type I EDS (the gravis form). Type I EDS is the most frequent form: it accounts for 43% of patients. Inheritance is

autosomal dominant. All four clinical manifestations are severely expressed. Patients

have marked skin extensibility with frequent lacerations and subsequent scarring in

different body locations. Surgical sutures heal poorly, with easy dehiscence. Joint

hypermobility is severe and affects all parts of the body. Spontaneous dislocations can

occur, but immediate reduction is easy. Patients display kyphoscoliosis, hallus valgus,

pes planus (i.e. flat feet), and genu recurvatum. Bruises are less common in this type than

in other forms. The primary defect is found in the genes that encode the alpha-1 and alpha-2 procollagen

chains of the type V collagen (COL5A1 and COL5A2). Type V collagen is a heterotrimer

with three different alpha- chains. Its distribution is similar to that of types I and III

collagen but in much smaller quantities

2. Type II EDS (the mitis form). This phenotype is similar to type I EDS, but the clinical features are milder. Type II EDS affects 35% of patients and is inherited in an autosomal dominant pattern. 3. Type III EDS. Type III EDS affects 10% of patients and is inherited in an autosomal dominant pattern.

Patients with this variant have minimal or no skin changes, but they do have a striking

hyperextensibility in many joints. This hyperextensibility usually causes orthopedic

consequences (severe osteoarthritis) in the long term. The collagen defect has not been

identified. 4. Type IV EDS. Type IV EDS affects 6% of patients and is inherited in an autosomal recessive pattern.

The skin is also fragile but not extensible. Patients have prominent venous markings,

which are readily visible through the skin. Joint hyperextensibility is absent. Type IV is

characterized by severe arterial and visceral lesions. Patients are subject to spontaneous

rupture of the medium-sized arteries, bowel, or both. The prognosis is poor and patients

have short lifespan. Median life expectancy in these patients is 45-50 years. Deficient

type III collagen (mutations in the gene COL3A1) Type IV is characterized by mutations

in the gene COL3A1 and decreased amount of type III collagen.

DEFINITION. Pseudoxanthoma elasticum (PXE) is a rare, genetic disorder characterized by progressive

calcification and fragmentation of elastic fibers in the skin, the retina, and the

cardiovascular system. The skeleton is not affected. Although autosomal dominant and

autosomal recessive inheritance patterns have been reported, no molecular evidence for

autosomal dominant inheritance has been established to date. Current research supports a

common (probably exclusive) autosomal recessive inheritance of PXE. CLINICAL MANIFESTATIONS. 1. Skin manifestations. PXE commonly involves the elastic fibers present in the mid and deep reticular dermis of

skin, the Bruch membrane of the eye, and the blood vessels.

The cutaneous manifestations of PXE are of cosmetic concern. Patients typically have a

normal life span. The mortality and morbidity of PXE vary based on the extent of

extracutaneous involvement. The cutaneous manifestations of PXE are highly characteristic. The lesions usually

develop in early childhood and are noted in adolescence. Patients present to

dermatologist when they are 10-15 years of age. Small yellow papules 1-5 mm in diameter are seen on examination. These changes are

noted on the middle or lateral part of the neck, antecubital fossae, the axillae, the

popliteal spaces, the inguinal and periumbilical area. As the disease progresses papules

coalesce to form plaques and the skin takes a cobblestone appearance. Lesions are

symmetric. With the progression of the disease the skin of the neck, the axillae, and the

groin may become soft, lax, and wrinkled, hanging in folds.

2. Cardiovascular manifestations. Calcification of the elastica media and intima of the blood vessels with vascular lumen

stenosis of occlusion leads to a variety of physical findings. In adults, peripheral pulses

are often severely diminished. Renal artery involvement leads to hypertension, and

coronary artery disease causes angina pectoris and subsequent myocardial infarction.

Peripheral artery disease leads to muscle pain in the limbs during exercise, which is

relieved by a short period of rest (intermittent claudication). Gastrointestinal hemorrhage, usually gastric in origin, is the most significant vascular

complication of PXE, because of the fragility of calcified submucosal vessels.

Hemorrhaging may occur in the 2nd

-4th

decade, without warning. Depending on its

severity, hospitalization, blood transfusion, and surgery may be necessary. Ten percent of

patients with PXE experience a gastrointestinal hemorrhage at some point in their lives.

Less commonly, hemorrhaging may occur in the urinary tract or cerebrovascular system 3. Ocular manifestations. The characteristic ocular manifestations of PXE are angioid streaks of the retina, which

are slate gray to reddish brown curvilinear bands radiating from the optic disc. Angioid

streaks result from calcification of the elastic fibers in the Bruch membrane of the retina,

with cracking and fissuring. This ocular change is symmetric bilaterally and is noted

several years after the onset of cutaneous lesions, in patients aged 20-40 years. Angioid

streaks are present in 85% of patients with PXE. Although these lesions are highly

characteristic of PXE, they are not pathognomonic. Angioid streaks are found in a variety

of other conditions.

Loss of central vision is progressive with each hemorrhage, but peripheral vision is

always spared.

ETIOLOGY. PXE is caused by mutations in the ATP-binding cassette transporter C6 (ABCC6), also

known as multidrug resistance–associated protein 6 (MRP6) gene, which has been

mapped to chromosome 16. To date, genetic studies have identified 90 different disease-

causing mutations, mainly missense and nonsense mutations. The ABCC6 gene encodes

for the cellular transport protein ABCC6/MRP6. The normal function of ABCC6/MRP6,

including its physiological substrate remains unknown but it may participate directly in

the active transport of drugs into subcellular organelles. The multidrug resistance-

associated protein 6 is a transmembrane transporter that is expressed in kidney and liver.

Looks like PXE is a generalized metabolic disorder of cellular transport and not just a

purely structural disorder of connective tissue. PROGNOSIS. The prognosis of PXE largely depends on the extent of extracutaneous organ

involvement. Patients typically have a normal life span, but acute gastrointestinal

hemorrhage, myocardial infarction, or cerebral hemorrhage may be fatal.

1. Anna was a 20-year-old female intercollegiate basketball player. In the preparticipation physical examination, the university physician detected a grade 1/6 systolic ejection murmur during auscultation and recommended that the athlete be evaluated by the team cardiologist. The physical examination revealed significant skeletal involvement. She was usually tall, slender, and loose jointed, with disproportionately long arms, legs, fingers, and toes compared with the trunk. Indeed, she had long arm span and high lower body to upper body ratio. Her arm span was greater than her height, and her floor-to-pubis measurement exceeded her pubis-to-vertex measurement. Closer observation revealed that her fingers were long and thin, and she had pectus carinatum. She had a high, arched palate. There was no evidence of scoliosis, thoracic lordosis, or kyphoscoliosis, but she did present with excessive ligamentous laxity. For example, she was able to position her fingers in a way that her thumbs protruded from her clenched fists. Which of the following conditions is most likely to produce these findings?

Marfan syndrome

Osteopetrosis

Osteogenesis imperfecta

Pseudoxanthoma elasticum

Paget disease of bone

2. A 29-year-old woman was diagnosed with a hereditary generalized disease of the skeleton at the age of 6. She had had multiple fractures throughout her childhood. Family history revealed that 3 of 13 relatives examined had a similar disorder. Physical examination revealed a young woman of short stature, 130 cm (4’3”) tall. Body weight was 40 kg. She had multiple skeletal deformities and frontal bossing. Laboratory findings revealed a hemoglobin of 10 g/dL (reference range: 12-16), red blood cell count of 3.3 million/mm3 (reference range: 4.2-5.4), and white blood cell count of 5,500/mm3 (reference range: 4,000-10,000). Radiographic examination revealed densely sclerotic bones with poor differentiation between cortical and cancellous bone, and numerous old fractures with abundant callus. The most likely diagnosis is:

Osteopetrosis

Achondroplasia

Osteogenesis imperfecta

Thanatophoric dysplasia

Marfan syndrome

3.

Anna was a 20-year-old woman intercollegiate basketball player. In the preparticipation physical examination, the university physician detected a grade 1/6 systolic ejection murmur during auscultation and recommended that the athlete be evaluated by the team cardiologist. The physical examination revealed significant skeletal involvement. She was usually tall, slender, and loose jointed, with disproportionately long arms, legs, fingers, and toes compared with the trunk. Indeed, she had long arm span and high lower body to upper body ratio. Her arm span was greater than her height, and her floor-to-pubis measurement exceeded her pubis-to-vertex measurement. Closer observation revealed that her fingers were long and thin, and she had pectus carinatum. She had a high, arched palate. There was no evidence of scoliosis, thoracic lordosis, or kyphoscoliosis, but she did present with excessive ligamentous laxity. For example, she was able to position her fingers in a way that her thumbs protruded from her clenched fists. Which of the following additional clinical findings is most likely to be revealed by a closer examination of this patient?

Yellow plaques in the anterior neck

Congenital hip dislocation

Ectopia lentis

Skin bruises and purpura

Poor wound healing

4. A 29-year-old woman was diagnosed with a hereditary generalized disorder of the skeleton at the age of 6. She had had multiple fractures throughout her childhood. Family history revealed that 3 of 13 relatives examined had a similar disorder. Physical examination revealed a young woman of short stature, 130 cm (4’3”) tall. Body weight was 40 kg. She had multiple skeletal deformities and frontal bossing. Laboratory findings revealed a hemoglobin of 10 g/dL (reference range: 12-16), red blood cell count of 3.3 million/mm3 (reference range: 4.2-5.4), and white blood cell count of 5,500/mm3 (reference range: 4,000-10,000). Radiographic examination revealed densely sclerotic bones with poor differentiation between cortical and cancellous bone, and numerous old fractures with abundant callus. The generalized hereditary skeletal disorder in this patient is most likely caused by mutations in genes that regulate which of the following cell types?

Osteoclasts

Myofibroblasts

Fibroblasts

Osteoblasts

Myeloblasts

5. A 12-month-old boy presented with fever, failure to thrive, and hepatosplenomegaly. Radiograph of chest was done to rule out chest infection. On the chest radiograph a generalized increase in bone density was noted and then a skeletal survey was done. Laboratory studies revealed severe anemia. Long bones showed uniformly dense shaft and metaphyses were uniformly sclerotic with widening of both distal ends of the bone. The entire skull was thickened and dense. Sinuses were small and underpneumatized. Vertebrae were extremely dense. The small bones such as metacarpals, metatarsals and phalanges were clublike. The articular cartilage was not affected and joint space was normal. Which of the following is the most likely diagnosis?

Osteopetrosis

Osteogenesis imperfecta

Marfan syndrome

Pseudoxanthoma elasticum

Paget disease of bone

6. Anna was a 20-year-old woman intercollegiate basketball player. In the preparticipation physical examination, the university physician detected a grade 1/6 systolic ejection murmur during auscultation and recommended that the athlete be evaluated by the team cardiologist. The physical examination revealed significant skeletal involvement. She was usually tall, slender, and loose jointed, with disproportionately long arms, legs, fingers, and toes compared with the trunk. Indeed, she had long arm span and high lower body to upper body ratio. Her arm span was greater than her height, and her floor-to-pubis measurement exceeded her pubis-to-vertex measurement. Closer observation revealed that her fingers were long and thin, and she had pectus carinatum. She had a high, arched palate. There was no evidence of scoliosis, thoracic lordosis, or kyphoscoliosis, but she did present with excessive ligamentous laxity. For example, she was able to position her fingers in a way that her thumbs protruded from her clenched fists. Molecular diagnostic studies will most likely demonstrate that this patient has a mutation in the gene encoding which of the following proteins?

Fibroblast growth factor receptor

Multidrug resistance-associated protein 6

Collagen type 1

Dystrophin

Fibrillin

7.

Anna was a 20-year-old woman intercollegiate basketball player. In the preparticipation physical examination, the university physician detected a grade 1/6 systolic ejection murmur during auscultation and recommended that the athlete be evaluated by the team cardiologist. The physical examination revealed significant skeletal involvement. She was usually tall, slender, and loose jointed, with disproportionately long arms, legs, fingers, and toes compared with the trunk. Indeed, she had long arm span and high lower body to upper body ratio. Her arm span was greater than her height, and her floor-to-pubis measurement exceeded her pubis-to-vertex measurement. Closer observation revealed that her fingers were long and thin, and she had pectus carinatum. She had a high, arched palate. There was no evidence of scoliosis, thoracic lordosis, or kyphoscoliosis, but she did present with excessive ligamentous laxity. For example, she was able to position her fingers in a way that her thumbs protruded from her clenched fists. The cardiologists explained to the patient that her hereditary skeletal developmental disorders is condition is a potentially fatal disease. He explained that the life expectancy for patients with this disorder has increased more than 25% since 1972 and the median cumulative probability of survival has risen from 49 to 74 years. Which of the following is the most likely cause of death in patients with this disorder?

Malignant transformation

Subarachnoidal hemorrhage

Aortic dissection

Chronic renal failure

Intestinal perforation

8. A 24-year-old woman presented with low back pain. Her medical history included a distal radius fracture at age 9 and several digital fractures in childhood. She denied smoking or consuming alcohol, she had adequate calcium intake, and her menstrual history was non-contributory. Her father, who had been diagnosed with osteoporosis, had had more than a dozen fractures, including a hip fracture at age 54. Her sister, age 35, also had osteoporosis. On examination, the patient was 167 cm tall and weighed 52 kg. She had blue-gray sclera and normal dentition. Musculoskeletal examination demonstrated scoliosis and paralumbar tenderness. Other systems were intact. Lumbar radiographs confirmed an L1 compression fracture, and CT scan demonstrated fracture stability without cord impingement. Osteoporosis was suspected, and dual-energy x-ray absorptiometry assessment of bone mineral density confirmed severe disease in the lumbar spine and femoral neck. Secondary causes of osteoporosis were ruled out. A diagnosis of osteogenesis imperfecta was established. Which of the following types of the disease is this patient most likely to have?

a. Type I

b. Type II

c. Type III

d. Type IV

9. Anna was a 20-year-old woman intercollegiate basketball player. In the preparticipation physical examination, the university physician detected a grade 1/6 systolic ejection murmur during auscultation and recommended that the athlete be evaluated by the team cardiologist. The physical examination revealed significant skeletal involvement. She was usually tall, slender, and loose jointed, with disproportionately long arms, legs, fingers, and toes compared with the trunk. Indeed, she had long arm span and high lower body to upper body ratio. Her arm span was greater than her height, and her floor-to-pubis measurement exceeded her pubis-to-vertex measurement. Closer observation revealed that her fingers were long and thin, and she had pectus carinatum. She had a high, arched palate. There was no evidence of scoliosis, thoracic lordosis, or kyphoscoliosis, but she did present with excessive ligamentous laxity. For example, she was able to position her fingers in a way that her thumbs protruded from her clenched fists. The disease encountered in this patient follows which of the following patterns of inheritance?

Mitochondrial

Autosomal recessive

X-linked dominant

Autosomal dominant

Multifactorial

10. A 24-year-old woman presented with low back pain. Her medical history included a distal radius fracture at age 9 and several digital fractures in childhood. She denied smoking or consuming alcohol, she had adequate calcium intake, and her menstrual history was non-contributory. Her father, who had been diagnosed with osteoporosis, had had more than a dozen fractures, including a hip fracture at age 54. Her sister, age 35, also had osteoporosis. On examination, the patient was 167 cm tall and weighed 52 kg. She had blue-gray sclera and normal dentition. Musculoskeletal examination demonstrated scoliosis and paralumbar tenderness. Other systems were intact. Lumbar radiographs confirmed an L1 compression fracture, and CT scan demonstrated fracture stability without cord impingement. Osteoporosis was suspected, and dual-energy x-ray absorptiometry assessment of bone mineral density confirmed severe disease in the lumbar spine and femoral neck. Secondary causes of osteoporosis were ruled out. A diagnosis of osteogenesis imperfecta was established. The

molecular genetic studies in this patient will most likely demonstrate a mutation in the gene encoding which of the following proteins?

Fibrillin

Multidrug resistance-associated protein 6

Collagen type 1

Dystrophin

Fibroblast growth factor receptor