(BQ) Part 2 book Elsevier''s integrated review genetics presents the following contents: Musculoskeletal disorders, neurologic diseases, cardiopulmonary disorders, renal, gastrointestinal and hepatic disorders, disorders of sexual differentiation and development, population genetics and medicine, modern molecular medicine.
Musculoskeletal Disorders CONTENTS CONNECTIVE TISSUE AND BONE DISEASES Extracellular Matrix and Connective Tissue Collagen Collagen Genes Disorders of Connective Tissues Differential Considerations MUSCULOSKELETAL DISEASE DUE TO GROWTH FACTOR RECEPTOR DEFECT Achondroplasia MUSCLE CELL DISEASES Muscular Dystrophies Molecular Basis and Genetics of Duchenne and Becker Types of Muscular Dystrophy Mitochondrial Myopathies Myoclonic Epilepsy with Ragged Red Fiber Syndrome Chronic Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome In this chapter, the most common forms of a heterogeneous group of inherited musculoskeletal diseases are highlighted Musculoskeletal disorders have many etiologic origins, including connective tissue/extracellular matrix deficiencies such as osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan syndrome; faulty growth factor biology as seen in achondroplasia; and both structural and metabolic muscle cell abnormalities represented by Becker and Duchenne muscular dystrophies and mitochondrial myopathies, respectively Although individually these may be somewhat rare, collectively the musculoskeletal diseases constitute a significant proportion of human disease ●●● CONNECTIVE TISSUE AND BONE DISEASES Extracellular Matrix and Connective Tissue The extracellular matrix (ECM) is found in the spaces between cells, forming a large proportion of tissue volume It is also found between organs and as such contributes to the body’s 7 shape, plasticity, and partitioning The ECM is composed of three associated macromolecules: (1) fibrous structural proteins such as collagen and elastin, (2) glycoproteins, and (3) proteoglycans and hyaluronic acid Typically, the ECM forms either basement membrane or interstitial matrix and, in doing so, performs several functions, including retaining water, minerals, and nutrients as well as acting as the substrate for cell-cell contact, migration, and adherence Connective tissues have an extensive ECM that serves to bridge, interconnect, and support a variety of cellular and organ structures These structures are typically composed of cells, blood vessels, and a particular type of ECM For example, skin, fibroblasts and blood vessels are interwoven within an extracellular matrix that is an amalgam of structural proteins, proteoglycans, and adhesion molecules Other types of connective tissue include tendon and cartilage Here, the discussion of connective tissues focuses on skin con nective tissue, since much is known about the structure and function of this anatomic element and many wellcharacterized connective tissue diseases are localized to the skin Central to any discussion of skin connective tissue is collagen BIOCHEMISTRY Extracellular Matrix (ECM) The extracellular matrix occupies the intercellular spaces It is most abundant in connective tissues such as the basement membrane, bone, tendon, and cartilage, where definition is given to the ECM by the proportions and organization of various components The elastin of skin and blood cells provides resiliency, collagen provides strength to tendons, and the calcified collagen matrix of bone provides strength and incompressibility Integrins are a family of heterodimeric proteins composed of α and β subunits that are the main cellular receptors for the ECM Integrins have several distinctive features from other adhesion proteins They interact with an arginineglycine–aspartic acid (RGD) motif of ECM proteins Integrins link the intracellular cytoskeleton with the ECM through this RGD motif Without this attachment, cells normally undergo apoptosis Integrins can bind to more than one ligand and many ligands can bind to more than one integrin Examples of integrins include fibronectin receptors and laminin receptors Connective Tissue and Bone Diseases 115 HISTOLOGY HISTOLOGY Types of Connective Tissue Skin Connective tissues are classified by the cells and fibers present in the tissue as well as the characteristics of the ground substance Connective tissue (CT) proper consists of loose connective tissue (areolar tissue) and dense connective tissue, which has more and larger fibers than loose CT Dense connective tissue can be either irregular, in which the fibers are usually arranged more or less haphazardly, or regular, in which the fibers are arranged in parallel sheets or bundles Specialized CT is distinct in either structure or function from CT proper Examples are adipose tissue, blood, bone, cartilage, hematopoietic tissues, and lymphatic tissues Embryonic CT encompasses mesenchymal and mucoid CT Skin is composed of the epidermis and the dermis The epidermis is composed of two main zones of cells: ■ Stratum corneum: outer layer of cells without nuclei ■ Stratum germinativum: composed of three strata (basal, spinous, granular) The dermis consists of a three-dimensional matrix of loose connective tissue, including fibrous proteins such as collagen and elastin as well as proteins embedded in ground substance (glycosaminoglycans) Skin collagen (type I) is rich in glycine, proline, and hydroxyproline Hydroxyproline is unique to collagens, and synthesis requires vitamin C Collagen A major component of skin connective tissue is the fibrous structural protein collagen The collagens form a family of insoluble, extracellular proteins that are produced by a number of cell types but primarily by fibroblasts Collagen is the most abundant protein found in the human body and is a key structural component of bone, cartilage, tendons, ligaments, and fascia in addition to skin Nineteen types of collagen have been characterized, and each localizes to a specific part of the body The major collagens are type I, of skin, tendons, bone, and ligaments; type II, found in cartilage; type III, found in skin and hollow tubular structures such as arteries, intestines, and uterus; and type IV, represented in all basal laminae (Table 7-1) Types I through III form strong fibers and thus are called fibrillar collagens, while type IV is associated with a multibranched network Fifteen additional types of collagen perform essential functions but are less abundant Collagens have a distinctive primary amino acid sequence featuring a repeated motif of (glycine-X-Y)n, where Y is often proline or hydroxyproline and X can be any amino acid Typically, a fibrillar collagen is synthesized in the endoplasmic reticulum as a precursor molecule—procollagen—that is composed of a short signal peptide, an amino-terminal and carboxy-terminal propeptide, and a central α-chain segment (Fig 7-1) The α-chain segment includes the repeated motif in which glycine represents every third amino acid, and it is this chain that constitutes the biochemical core of collagen Three separate chains coalesce in the Golgi complex to form a triple helix, or tropocollagen, which is characterized by numerous disulfide bonds The formation of a stable triple helix requires the presence of glycine in the restricted space where the three chains come together Collagen triple helices are either heterotrimers or homotrimers, depending on the collagen type The heterotrimeric type I collagen molecule has two identical polypeptide chains called α1(I) and one slightly different chain called α2(I) The homotrimeric type II and type III collagen molecules are composed of three identical α1(II) chains and three identical α1(III) chains, respectively Upon secretion from the originating cell, tropocollagen is processed into individual fibrils that, in turn, assemble into large, linear, insoluble fibers that are strengthened by lysine-mediated covalent cross-links between individual fibrils TABLE 7-1. Characteristics of the Major Collagens COLLAGEN TYPE I II III IV V CHAIN GENE LOCATION DISORDER α1(I) α2(I) α1(II) α1(III) α3(IV) α4(IV) α5(IV) α1(V) α2(V) α3(V) COL1A1 COL1A2 COL2A1 COL3A1 COL4A3 COL4A4 COL4A5 COL5A1 COL5A2 COL5A3 17q21-22 7q21-22 12q13-q14 2q31-q32 2q35-q36 2q36-q37 Xq22.3 9q34.2-34.3 Osteogenesis Ehlers-Danlos syndrome Chondrodysplasias Ehlers-Danlos syndrome Alport syndrome Ehlers-Danlos syndrome 116 Musculoskeletal Disorders Collagen triple helix Tropocollagen Microfibril Subfibril Figure 7-1. Structure of collagen The triple helical structure of collagen— tropocollagen—is the basic unit of microfibrils Many microfibrils bundle together to form a macrofibril (Redrawn with permission from Dr J P Cartailler at Symmation LLC [www.symmation.com].) Fibril Collagen Genes Collagen genes are named starting with the prefix COL, followed by an Arabic numeral indicating the collagen type, the letter “A,” and finally a second Arabic number denoting the particular α chain Four distinct genetic loci (COL1A1, COL1A2, COL2A1, and COL3A1) collectively encode the unique chains of the three classic fibrillar collagens—types I, II, and III—and these genes are dispersed throughout the genome COL1A1 is found on chromosome 17, COL1A2 on chromosome 7, COL2A1 on chromosome 12, and COL3A1 on chromosome Type IV collagen is a nonfibrillar, or amorphous, form coded for by the COL4A3 gene on chromosome Overall, there are more than 34 different collagen genes dispersed on at least 15 chromosomes Collagen genes have several interesting features Genes encoding fibrillar collagen are quite similar in structure; the triple helical domain regions consist of greater than 40 exons all of which are multiples of nucleotides Exons are typically 54 nucleotides in length, but multiples of 54 or combinations of 45 and 54 base exons are not uncommon Consistent with the (Gly-X-Y)n primary amino acid sequence motif, each exon begins with a glycine codon The gene COL1A1 that encodes α1(I) will serve as an example The gene is large, spanning 18 kb of genomic DNA and encoding 52 exons that are 45, 54, 99, 108, or 162 base pairs in length Hydroxyproline occupies the Y position in about a third of the exon triplets and is often preceded by proline The model exon in all collagen loci is a 54-bp unit that codes for 18 amino acid residues, or six triplets of Gly-X-Y repeats This model led to the hypothesis that the varied collagen genes, although now widely scattered in the human genome, were derived from a single ancestral gene more than 50 million years ago It is surmised that the numerous genes evolved by successive duplications of a primitive procollagen gene consisting of 54 bp with six Gly-X-Y repeats that underwent subsequent chromosomal rearrangements and sequence divergence These genes have remained highly conserved during evolution BIOCHEMISTRY Glycine Glycine is the smallest amino acid and is a nonessential amino acid Its size is convenient for “small places” in proteins such as the turns of helices These are evolutionarily very stable Substituting the glycine with a larger amino acid can dramatically change the shape of the protein Glycine can also function as an inhibitory neurotransmitter and serve as a co-agonist with glutamate to activate NMDA (N-methyl-d-aspartate) receptors Connective Tissue and Bone Diseases Disorders of Connective Tissues The large number of collagen genes, the widespread distribution of collagen within the body, and the high degree of evolutionarily conserved primary amino acid sequences all strongly suggest that functional collagen is critical for health Accordingly, it follows that defects in collagen synthesis, processing and maturation, and structure would result in tissue dysfunction and human disease This is the case, as more than 1000 mutations have been described in the collagen genes Here, we discuss three such diseases: osteogenesis imperfecta and Ehlers-Danlos syndrome as paradigms of collagen disorders and Marfan syndrome as an important noncollagen disorder Osteogenesis Imperfecta Osteogenesis imperfecta (OI) represents a collection of type I collagen disorders due to mutations in the COL1A1 or COL1A2 genes that are generally characterized by weak bones, dentinogenesis imperfecta, short stature, and adultonset hearing loss Classically, four types of OI have been recognized (Table 7-2) However, with the availability of DNA-based diagnostics, there are now seven subtypes of OI that represent distinct clinical entities Considering all forms of OI, the overall prevalence is roughly per 100,000, and the disease crosses all racial and ethnic boundaries Types I to IV illustrate the more common forms of OI Type I OI is the most common form of OI It is relatively mild and exhibits autosomal dominant inheritance with variable expressivity Clinically, type I individuals exhibit skeletal osteopenia and fractures, dentinogenesis imperfecta (Fig 7-2), joint hypermobility, and blue-colored sclerae Stature is usually within the normal range, but conductive hearing loss 117 that progresses to sensorineural loss occurs in roughly 50% of adult patients Type I OI is most often associated with proteinshortening nonsense, frameshift, or splice site mutations in the COL1A1 gene leading to decreased α1 chains Because type I collagen is a heterotrimer consisting of two α1 chains and one α2 chain, triple helix formation is greatly reduced NEUROSCIENCE Hearing Loss Hearing loss is classified as conductive, sensorineural, central hearing disorder, and presbycusis Lesions involving the external or middle ear characterize conductive hearing loss It is most commonly caused by cerumen impaction, although otitis media is the most common serious cause A lesion of the cochlea or auditory parts of cranial nerve VIII indicates sensorineural hearing loss, which includes hereditary deafness Intrauterine factors causing sensorineural hearing loss include infection, metabolic and endocrine disorders, and anoxia When hearing loss is unilateral, there is usually a cochlear basis, whereas bilateral loss is often due to drug use Aminoglycoside antibiotics are toxic; salicylates, furosemide, and ethacrynic acid can cause transient loss Central hearing disorders occur with lesions of the central auditory pathways The loss is unilateral if there is unilateral pontine cochlear nuclei damage in the brainstem owing to ischemic infarction of the lateral brainstem, multiple sclerosis plaque, neoplasia, or hematoma Bilateral degeneration of nuclei is seen in rare childhood disorders Presbycusis is gradual age-related loss, which may be conductive or central TABLE 7-2. Summary of Osteogenesis Imperfecta (OI) Types OI TYPE CLINICAL FEATURES INHERITANCE I Normal stature, little or no deformity, blue sclerae, hearing loss AD II Lethal in perinatal period, very few survive to year; minimal calvarial mineralization, beaded ribs, compressed femurs, long bone deformity, platyspondyly AD III Progressively deforming bones, moderate deformity at birth, scleral hue varies, dentinogenesis imperfecta, hearing loss, very short stature IV Normal to gray sclerae, mild to moderate deformity, variable short stature, dentinogenesis imperfecta, some hearing loss AD/AR (rare) Structural alteration in type I collagen chains— overmodification AD V Similar to OI type IV plus calcification of interosseous membrane of forearm, anterior radial head dislocation, hyperplastic callus formation, normal sclerae Similar to OI type IV with early-onset vertebral compression fractures, mineralization defect Mild symptoms, short stature, shortened limbs, normal sclerae VI VII BIOCHEMICAL ABNORMALITY 50% reduction in type I collagen synthesis Structural alteration in type I collagen chains— overmodification Increased collagen turnover AD Excessive posttranslational modification to one type I collagen chain None identified Unknown None identified AR A non-collagen type I mutation Data from Sillence DO, Senn A, Danks DM Genetic heterogeneity in osteogenesis imperfecta J Med Genet 1979;16:101–116 AD, autosomal dominant; AR, autosomal recessive 118 Musculoskeletal Disorders ANATOMY Dentinogenesis Imperfecta Dentinogenesis imperfecta results from a failure of odontoblasts to differentiate normally Odontoblasts produce dentin; ameloblasts produce enamel Dentinogenesis imperfecta affects deciduous and permanent teeth, giving them a brown to grayish-blue appearance with an opalescent sheen The enamel wears down quickly, exposing the dentin It occurs because of autosomal recessive inheritance, drug toxicity (tetracycline), and syndromic association Mutations in either COL1A1 or COL1A2 can cause OI types II to IV Each of these forms of OI is transmitted in an autosomal dominant fashion and most often results from missense mutations that alter the important glycine codon in the triple helical domain Interestingly, the phenotypical consequence depends on the nature and position of the glycine amino acid substitution For example, substitutions with large A B Figure 7-2. Dentinogenesis imperfecta is characterized by translucent gray to yellow-brown teeth and involves both deciduous (baby) and permanent teeth The enamel fractures easily This condition occurs in osteogenesis imperfecta, or it can be caused by a separate inherited autosomal dominant trait A, Panoramic radiographic view of permanent dentition with bulb-shaped crowns and large pulpal chambers B, Frontal view showing irregularly formed, opalescent teeth (Courtesy of Rebecca Slayton, DDS, PhD, University of Washington School of Dentistry.) side-chain amino acids or in the C-terminal two thirds of the gene usually predict a severe clinical outcome Some splice site mutations have also been found There is a rare form of OI III that has autosomal recessive transmission This form is associated with consanguinity and is the most common form of OI observed in Africa Types II and III are severe forms of OI Type II is characterized by multiple fractures and perinatal lethality The mean birth weight and length is below the 50th percentile Twenty percent of these infants are stillborn and 90% die within weeks after birth Type III features progressive skeletal abnormalities, including frequent early-onset fractures and progressive kyphoscoliosis Fractures are frequently present at birth Generalized osteopenia leads to poor longitudinal growth that is well below the third percentile in height Blue sclerae are another frequent clinical sign Infants who survive the first months of life generally live reasonably long lives, and approximately one third survive long term In one example, a child was born with 132 fractures at birth and missing bones of the skull This person attained a maximum height of 36 inches and weight of 50 pounds by adulthood This young woman was above average in intelligence, completing college and mastering five languages before her death at age 32 Type IV OI is the most clinically variable of the four paradigm types Presentation may be severe to mild Clinical signs may include somewhat reduced stature, dentinogenesis imperfecta, adult-onset hearing loss, and variable degrees of skeletal osteopenia A particularly interesting skeletal anomaly found in osteogenesis imperfecta is the presence of wormian bones These are irregularly shaped bones within the sutures of the skull; they are found most often within the lambdoid suture and arranged in a mosaic pattern (Fig 7-3) These intrasutural bones have been associated with several congenital disorders but most commonly with OI Other disorders associated with wormian bones include cleidocranial dysplasia, hypophosphatasia, hypothyroidism, and pycnodysostosis They may also occur with no anomaly In this last case, these extra bones tend to be smaller and fewer in number Wormian bones tend to represent a pathologic condition when greater than to 6 mm and when more than 10 are present Interestingly, the name “wormian” has nothing to with the appearance of the bone but honors Olaus Worm, the Danish anatomist who first described them in 1643 It is important to emphasize that those children with undiagnosed osteogenesis imperfecta or another type of bone disease may have the same symptoms as an abused child Bruising, unexplained fractures, and evidence of old fractures in various stages of healing on radiography can lead a physician to consider abuse when a genetic defect has not been eliminated A thorough family history may reveal other minor or variable phenotypes not previously recognized in family members A careful physical examination of the child may reveal additional features associated with OI such as blue sclerae, opalescent and undermineralized teeth, bruising, a triangular face, a barrel-shaped chest, and scoliosis Connective Tissue and Bone Diseases 119 Figure 7-3. Wormian bones are intrasutural cranial bones They are often associated with the lambdoid suture and are generally only considered pathologically significant when greater than × 4 mm in size and 10 or more are arranged in a mosaic pattern Pathologic associations of wormian bones include osteogenesis imperfecta, cleidocranial dysplasia, pycnodysostosis, hypophosphatasia, hypothyroidism, and acro-osteolysis The majority of observations represent normal variants (Courtesy of Owen Lovejoy, PhD, Kent State University, and Melanie McCollum, PhD, University of Virginia School of Medicine.) Figure 7-4. Ehlers-Danlos syndrome, characterized by hyperelastic skin and hypermobile joints, may also be characterized by easy bruising, poor healing, and “cigarette paper” scarring (Courtesy of Joshua Lane, MD, Mercer University School of Medicine.) Ehlers-Danlos Syndrome Ehlers-Danlos syndrome (EDS) is a group of connective tissue disorders featuring joint hypermobility, hyperelasticity of the skin, and abnormal wound healing (Fig 7-4) Historically, EDS was classified into two subtypes, EDS type I and type II, the discriminator being clinical severity However, it is now recognized that EDS represents a continuum of clinical manifestations Today, most of EDS types I and II have been reclassified as classic EDS on the basis of diagnostic criteria Three of four major criteria must be met for diagnosis of EDS: skin hyperextensibility; wide, atrophic scars; joint hypermobility; and a positive family history for EDS There are six major types of EDS (Table 7-3) Newer terminology has replaced the use of Roman numerals to designate types Classic EDS is an autosomal dominant disease caused by mutations in genes encoding the α chains of type V collagen Specifically, approximately 50% of patients presenting with classic EDS have mutations in either COL5A1 or COL5A2 The genetic defects responsible for the remaining half of the patients have not been identified Of patients with COL5A mutations, one half have inherited the mutation from a parent and the other half harbor a new mutation that occurred in a parental gamete or during their own early embryonic development Both protein-truncating mutations and glycine substitution mutations have been found in COL5A-associated EDS Marfan Syndrome Marfan syndrome is a systemic connective tissue disorder that typically manifests as skeletal, ocular, and cardiovascular defects Individuals are typically tall with arachnodactyly (Fig 7-5) Ectopia lentis, mitral valve prolapse, and dilation of the ascending aorta are also common Unlike osteogenesis imperfecta and Ehlers-Danlos syndrome, Marfan syndrome is caused by mutations in the FBN1 gene that encodes fibrillin, a glycoprotein that is the major structural component of extracellular microfibrils Microfibrils are part of the ECM and form a network for elastin deposition in the formation of elastic fibers Microfibrils are 120 Musculoskeletal Disorders ANATOMY ANATOMY Ciliary Body of the Eye Craniosynostosis The ciliary body lies behind the iris and is attached to the lens by ciliary zonules It produces aqueous humor and controls accommodation—the changing of lens shape Craniosynostosis is the premature closure of sutures in the skull that leads to a change in the shape of the skull Major sutures include coronal, sagittal, metopic, and lambdoid There are several types of craniosynostosis: ■ Brachycephaly: premature closure of coronal sutures ■ Scaphocephaly, also called dolichocephaly: premature closure of the sagittal suture ■ Trigonocephaly: premature fusion of the metopic suture ■ Plagiocephaly: premature fusion of one of the coronal or lambdoid sutures ■ Acrocephaly, oxycephaly, and turricephaly: premature closure of the coronal and lambdoid sutures; creates pyramidal shape widely distributed in the body, but they are most abundant in ligaments, the aorta, and the ciliary zonules of the lens—all tissues prominently affected in Marfan syndrome Several skeletal phenotypes are associated with Marfan syndrome These individuals are noted for tall stature, where the mean height is greater than the 97th percentile, along with a decrease in the upper body segment to lower body segment ratio, designated as US:LS Normally, US:LS is 0.93, but in individuals with Marfan syndrome it is 0.85 or at least standard deviations below the mean for age, sex, and race Often the arm span exceeds height, an advantageous characteristic for some sports such as basketball It is not unusual for normal males and females to also meet this criterion; however, arm span exceeds height by more than 8 cm in only 5% to 6% of normal individuals The greater the arm span exceeds height, the less likely that normal individuals will be identified Other skeletal features frequently found in Coronal Metopic Sagittal Lambdoid TABLE 7-3. Summary of Ehlers-Danlos Syndrome Types TYPE FORMER TYPE Classic I and II Hypermobility III Vascular IV Kyphoscoliosis VI Arthrochalasis VIIA VIIB Dermatosparaxis VIIC CLINICAL FEATURES Skin hyperextensibility, velvety skin Fragile skin—bruises and tears easily Poor wound healing leading to widened, atrophic scarring Molluscoid pseudotumors on elbows and knees; spheroid bodies on shins and forearms Hypermobile joints Mitral valve prolapse Hypermobile, unstable joints Chronic joint pain Mitral valve prolapse Fragile blood vessels and organs—at risk for rupture, aneurysm, dissection Thin, fragile skin—bruises easily Veins visible beneath skin Characteristic facies—protruding eyes, thin nose and lips, malar flattening, hypoplastic mandible Progressive scoliosis Fragile eyes Progressive muscle weakness Hypermobile joints prone to dislocations, especially hips Skin hyperextensibility—prone to bruising Early-onset arthritis Increased risk of bone loss and fracture Extremely fragile, sagging skin Hypermobile joints—may delay development of motor skills PREVALENCE in 20,000–40,000 Most common form: in 10,000–15,000 One of the most serious forms: in 100,000–200,000 Rare Rare Rare In 2002, Steinmann et al questioned the existence of EDS V as a distinct entity The phenotype, described in 1975, was poorly defined and may have represented another disorder Connective Tissue and Bone Diseases A B C D 121 E Figure 7-5. Individuals with Marfan syndrome have characteristic arachnodactyly with joint hypermobility A, Long fingers B, Positive wrist sign (Walker sign) C, Positive thumb sign (Steinberg sign) D and E, Hypermobile joints individuals with Marfan syndrome are dolichocephaly (Fig 7-6), prominent brow, hypognathic or retrognathic mandible, and high-arched and narrow palate Vertebral and pectus deformities are present in 30% to 60% of individuals Although the skeletal features may be the most readily recognized phenotype of Marfan syndrome, the earliest manifestation may be mitral valve disease Eighty percent of individuals will show evidence of prolapse; in more than 25% of these individuals, prolapse will progress to regurgitation by adulthood Aortic regurgitation is also common and progressive in 70% of individuals Because of the altered fibrillin within the aorta, dilatation of the aortic root, where maximum stress occurs, is a serious concern (Fig 7-7) Dilatation is seen in approximately 25% of children and 70% to 80% of adults These individuals carry a significant risk of aortic dissection that may begin as a gradual dilatation at the aortic root that progresses into the ascending aorta Marfan syndrome does not preclude childbirth by females, but these women must be monitored regularly by echocardiography Marfan syndrome is an autosomal dominant disease; approximately 75% of the cases are inherited and 25% 122 Musculoskeletal Disorders represent de novo mutations Over 500 independent FBN1 gene mutations are associated with Marfan syndrome, nearly 70% of which are missense mutations This suggests that the production of normal microfibrils is altered by the presence of mutant fibrillin In the heterozygous state, this defines autosomal dominant disorders—the interaction between mutant and normal fibrillin is sufficient for disease expression Allelic heterogeneity at the FNB1 locus accounts for the overall symptom variability observed in individuals with Marfan syndrome and between different affected families Some clinical variability can also be seen within a family sharing the same mutation, suggesting that other genetic or epigenetic factors play a role in disease expression Differential Considerations Osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan syndrome all share variably expressed phenotypic features This is also true for other conditions discussed Cephalic index (CI) ≤75.9 CI = Head width¥100 Head length Figure 7-6. Dolichocephaly The head is long and narrow The cephalic index can be calculated to determine whether a shape is dolichocephalic or within normal limits Normal aorta throughout this text as well as conditions not discussed in this text Careful consideration of all physical and clinical findings is important in establishing a presumptive diagnosis A definitive diagnosis is easily attainable with molecular analysis for each of these disorders with a specific known family mutation or in situations in which limited mutations are associated with a disorder, such as for achondroplasia (see next section) An equally definitive diagnosis is also possible with other tests such as muscle biopsy used for muscular dystrophies Less secure diagnoses are described in Table 7-4 ●●● MUSCULOSKELETAL DISEASE DUE TO GROWTH FACTOR RECEPTOR DEFECT Achondroplasia Achondroplasia, also known as short-limb dwarfism, is the most common form of dwarfism and occurs in roughly in 20,000 live births In short-limbed dwarfism, affected individuals have short stature and particularly short arms and legs; the average height of adult men is 132 cm and that of adult women is 125 cm Although all bones formed from cartilage are involved in achondroplasia, the proliferation of cartilage is greatly retarded in the metaphyses of long bones In essence, the maturation of the chondrocytes in the growth plate of the cartilage is affected Other skeletal abnormalities include macrocephaly with frontal bossing, midface hypoplasia, and genu varum (Fig 7-8) The spine and ribs are also affected, as is the cartilaginous base of the skull Life span and intelligence are typically normal, although 5% to 7% of infants with achondroplasia die within the first year of life from central or obstructive apnea due to brainstem compression or midface hypoplasia Enlarged aorta (aneurysm) Figure 7-7. Aortic aneurysm The aortic root is the site of greatest pressure Mutations in fibrillin weaken the connective tissue of the aorta, causing bulging, tearing, and dissection Musculoskeletal Disease Due to Growth Factor Receptor Defect 123 TABLE 7-4. Security of Diagnosis SECURITY LEVEL OF SECURITY Definite 100% Probable 80–99% Possible 50–79% Rule out 1–49% Unknown 0% EXPLANATION The diagnosis is absolutely not in question Full genetic counseling is appropriate relative to prognosis, treatment, and recurrence risk Absolute diagnosis is not able to be made A remote possibility of other diagnoses exists Reevaluation of diagnosis should occur with each follow-up visit Full genetic counseling is given just as for “definite diagnosis.” Diagnosis is considered likely, but the presence or absence of some historical, clinical, or laboratory findings leaves some question about the diagnosis No specific genetic counseling can be offered, but the family should be informed of the diagnostic possibilities and of any opportunities for helping arrive at a diagnosis The diagnosis being considered is among a list of possibilities, none being particularly likely Specific genetic counseling cannot be given Follow-up is very important to monitor growth and development and to check for new findings that may make the diagnosis more likely There is no real clue to the diagnosis Continued follow-up is essential, and new diagnostic tests should be pursued No specific genetic counseling can be offered except that a 4–6% empirical risk of recurrence can be given ANATOMY & EMBRYOLOGY Appendicular Skeleton The appendicular skeleton consists of the pectoral and pelvic girdles with the limbs Ossification of long bones begins by the eighth week of development, although all primary centers and most secondary centers of ossification are present at birth For the diaphysis of long bones, bone is ossified from a primary center, whereas for the epiphysis, ossification occurs from a secondary center The epiphyseal plate consists of cartilage formed between diaphysis and epiphysis, and it is eventually replaced by bone when bone growth ceases Flat and irregular bones have no diaphysis or epiphysis Achondroplasia results from mutations in the fibroblast growth factor receptor (FGFR3) gene Four FGFR genes have been identified that interact with at least 23 different fibroblast growth factors; the receptors are all transmembrane tyrosine kinases involved in binding fibroblast growth factor and subsequent cell signaling The FGFRs share a common protein structure, characterized by three extracellular immunoglobulinlike domains, an acidic box, a lipophilic transmembrane domain, and intracellular tyrosine kinase domains (Fig 7-9) FGFR3 is expressed at high levels in the prebone cartilage rudiments of all bones and in the central nervous system Defective FGFR proteins lead to altered interaction with fibroblast growth factor, which affects signal transduction The most common mutations, G1138A and G1138C (discussed below), introduce a charged amino acid into the hydrophobic domain of the receptor and activate dimerization This region of the receptor regulates the kinase activity.The mutations, therefore, cause constitutive activation in a ligand-independent manner Since FGFRs are widely expressed in bone, consequences of mutations are more profound in bone development Figure 7-8. Achondroplasia Note the short limbs relative to the length of the trunk Also note the prominent forehead, low nasal root, and redundant skinfolds in the arms and legs (From Jorde LB, Carey JC, Bamshad MJ, White RL Medical Genetics, 3rd ed Philadelphia, Elsevier, 2006, p 67.) ... chromosomes 6p 22- p24, 6q21-q25, 1q 42, 1q21-q 22, 13q 32- q34, 8p21-p 22, 22 q11-q 12, 5q21-q33, and 10p11-p15 Two of these are supported in multiple studies: chromosomes 8p and 22 q Chromosome 8p21 -22 has been... α1(I) ? ?2( I) α1(II) α1(III) α3(IV) α4(IV) α5(IV) α1(V) ? ?2( V) α3(V) COL1A1 COL1A2 COL2A1 COL3A1 COL4A3 COL4A4 COL4A5 COL5A1 COL5A2 COL5A3 17q21 -22 7q21 -22 12q13-q14 2q31-q 32 2q35-q36 2q36-q37 Xq 22. 3... NEUROFIBROMATOSIS NF1 17q11 .2 Neurofibromin-1 in 4500 AD with variable expression, complete penetrance Before age years NF2 22 q 12. 2 Merlin (neurofibromin -2) in 40,000–50,000 Between ages 15 and 25 years Major