Heritable Disorders of ConnectiveTissue¶
Chapter 425 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 425
Key Clinical Points¶
- Fibrodysplasia ossificans progressiva (FOP) is caused by an activating mutation in activin receptor A type 1, leading to ectopic bone formation.
- Osteogenesis imperfecta (OI) is characterized by bone fragility, deformity, and blue sclerae; pulmonary disease is the leading cause of death.
- Tumoral calcinosis results from mutations in GALNT3, FGF23, or α-Klotho, causing spontaneous soft tissue calcification.
- Collagen biosynthesis requires a Gly-X-Y repeating sequence; defects in prolyl 4-hydroxylase (P4H1) lead to scurvy.
- Palovarotene is approved for FOP (females >8, males >10) to reduce new heterotopic ossification.
- Surgical removal of ectopic bone in FOP is contraindicated as trauma may trigger further bone formation.
- Type I collagen is the primary protein in dermis, ligaments, tendons, and demineralized bone; Type II is predominant in cartilage.
- Fibrillin mutations (e.g., FBN1) are central to Marfan syndrome and other thoracic aortic diseases.
- Collagen types III, V, VII, IX, XI, XVII, and XXVII are associated with a wide range of specific connective tissue disorders.
- Diagnosis involves matching clinical symptoms to established classifications before determining the necessity of DNA analysis.
DEFINITION & CLASSIFICATION¶
• Definition (Harrison's 22e): Heritable disorders of connective tissue are conditions transmitted genetically in families that produce clinically obvious changes in the bone, cartilage, skin, or relatively acellular tissues such as tendons. • Connective Tissue Composition: ◦ Complex interacting extracellular matrix (ECM) network. ◦ Components: Collagens, proteoglycans, and numerous noncollagenous glycoproteins/proteins. ◦ "The Matrix": Approximately 500 potential building blocks providing tissue-specific function. • Collagen Types & Distribution: ◦ Type I: Most abundant in dermis, ligaments, tendons, and demineralized bone. ◦ Type II: Most abundant protein of cartilage. ◦ Type III: Found in dermis, aorta, uterus, intestine; Type I and III are most abundant in large blood vessels. • Classification Challenges: ◦ Debate exists between classification by clinical presentation vs. causative genes. ◦ 552 genes associated with 771 defined disorders of the skeleton. ◦ Current (2023) nosology uses a "hybrid" dyadic naming system (phenotypic entity + gene). ◦ Factors for grouping: Causal gene, shared radiographic features, or similar clinical course (e.g., lethality).
EPIDEMIOLOGY¶
• Historical Context: ◦ McKusick identified specificity of diseases for select tissues. ◦ Evolution from few known genes to hundreds of different genes in connective tissues. • Clinical Refinement: ◦ Initial classifications (e.g., Ehlers-Danlos syndrome) were refined as more patients were examined. ◦ Recognition of genetic heterogeneity: Different phenotypes can arise from the same gene; same phenotype can result from different mutations.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Tissue Dynamics: ◦ Connective tissues are not inert; they undergo synthesis, degradation, and resynthesis. ◦ Growth phases: Rapid turnover during embryonic development and puberty; slower but steady metabolism in adulthood (except bone). ◦ Degradation factors: Age, malnutrition, physical inactivity, low gravitational stress. • Collagen Biosynthesis Pathway: 1. Synthesis of procollagen (soluble precursor with globular domains at ends) on ribosomes. 2. Entry into rough endoplasmic reticulum (ER) → removal of signal peptides. 3. Post-translational modifications: ◦ Hydroxylation: Proline and lysine in the Gly-X-Y triplet are hydroxylated by prolyl 4-hydroxylase (P4H1) and lysyl hydroxylase (LH1). ◦ Requirement: P4H1 requires ascorbic acid (Vitamin C) as a cofactor; deficiency leads to scurvy. ◦ Glycosylation: Lysine residues glycosylated with galactose or glucose. 4. Assembly: Proα chains form trimer nuclei → fold into triple helix in a zipper-like manner. 5. Transport & Secretion: Folded procollagen moves via COPII vesicles to Golgi → secreted into pericellular space. 6. Processing: Proteases remove N- and C-propeptides → reduces solubility 1000-fold → drives self-assembly into fibrils. 7. Cross-linking: Covalent bonds between α chains provide high tensile strength. • Structural Components: ◦ Minor Collagens: Type V (with Type I) and Type XI (with Type II) modulate fibril assembly/morphology. ◦ SLRPs: Small leucine-rich proteins influence fiber organization. ◦ Elastin & Fibrillin: Fibrillins contain EGF-like domains and cysteine-rich domains; critical for TGF-β signaling. ◦ Proteoglycans: Provide resistance to compression (e.g., in cartilage or aorta).
CLINICAL FEATURES¶
• Tumoral Calcinosis: ◦ Cause: Mutations in GALNT3, FGF23, or α-Klotho. ◦ Presentation: Spontaneous soft tissue calcification; may occur with hyperphosphatemia (e.g., secondary hyperparathyroidism from hemodialysis, hypoparathyroidism). • Fibrodysplasia Ossificans Progressiva (FOP): ◦ Cause: Activating mutation in activin receptor A type 1. ◦ Presentation: Ectopic bone formation in fascia, tendons, and ligaments. • Osteogenesis Imperfecta (OI): ◦ Cause: Mutations in COL1A1 or COL1A2. ◦ Features: Bone fragility, fractures, deformity, blue sclerae, dentinogenesis imperfecta, hearing loss. ◦ Severity: Range from mildest end (osteoarthritis/osteoporosis) to severe syndromic forms.
DIFFERENTIAL DIAGNOSIS¶
• Clinical Overlap: ◦ Some patients with skin changes similar to Ehlers-Danlos syndrome (EDS) may present with other features like extreme hypotonia or sudden rupture of large blood vessels. ◦ Distinction between benign polymorphisms and pathogenic mutations in noncollagenous genes.
DIAGNOSTIC APPROACH¶
- Clinical Correlation: Match patient signs/symptoms with established clinical classifications.
- Decision Point (DNA Analysis): Determine if genetic testing is indicated based on: ◦ Cost of analysis. ◦ Rigor of the link between clinical phenotype and specific mutation. ◦ Potential for reassurance to patients/families. ◦ Utility for prenatal diagnosis. ◦ Availability of mutation-specific therapies.
MANAGEMENT & TREATMENT¶
- Tumoral Calcinosis Treatment: ◦ Address underlying causes of hyperphosphatemia (e.g., secondary hyperparathyroidism, hypoparathyroidism).
- Fibrodysplasia Ossificans Progressiva (FOP) Management: ◦ Pharmacotherapy: Palovarotene (Approved 2023) for females >8 years and males >10 years to reduce new heterotopic ossification. ◦ Surgical Caution: Do not perform surgical removal of ectopic bone → risk of trauma-induced formation of new heterotopic bone.
- Osteogenesis Imperrence (OI) Management: ◦ Pulmonary focus: Manage complications from repeated pneumonia, restrictive/obstructive disease, scoliosis, and chest wall deformity.
COMPLICATIONS & PROGNOSIS¶
• Osteogenesis Imperfecta (OI): ◦ Primary cause of death: Pulmonary disease. • Fibrodysplasia Ossificans Progressiva (FOP): ◦ Risk of rapid progression of heterotopic bone following physical trauma/surgery.
KEY PEARLS & HIGH-YIELD POINTS¶
• Scurvy Link: P4H1 requires ascorbic acid; deficiency leads to underhydroxylated procollagen and failure of wound healing. • FOP Treatment: Palovarotene is the specific approved agent for reducing new ossification. • Collagen Specificity: ◦ Type I: Bone, skin, tendons (OI, EDS). ◦ Type III: Blood vessels (Vascular EDS, Alport). ◦ Type V: Skin/Cartilage (Classic EDS). • Thoracic Aortic Disease: Linked to mutations in FBN1 (Marfan), COL3A1 (Vascular EDS), and TGF-β signaling pathway genes (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3).
TABLES¶
• Table 425-1: Constituents of Connective Tissues and Associated Heritable Conditions ◦ Collagen I: Bone, cornea, dermis, tendon → OI (fractures, blue sclerae), EDS, Caffey disease. ◦ Collagen III: Dermis, aorta, uterus, intestine → Vascular EDS; Basement membranes → Alport syndrome (COL4A3/A4/A5), Brain small-vessel disease (COL4A1/A2). ◦ Collagen V: Placental tissue, bone, dermis, cornea → Classic EDS; Uterus, dermis, cornea, cartilage → Bethlem myopathy and Ullrich congenital muscular dystrophy. ◦ Collagen VII: Skin, amniotic membrane, mucosal epithelium → Dystrophic epidermolysis bullosa; Descemet’s membrane, endothelial cells → Corneal dystrophy. ◦ Collagen IX: Cartilage, vitreous → Stickler syndrome (Spondyloepiphyseal dysplasia, high myopia); Calcifying cartilage → Multiple epiphyseal dysplasia. ◦ Collagen XI: Cartilage, intervertebral disk → Various chondrodysplasias; Dermis, tendon, cartilage → Myopathic EDS. ◦ Collagen XVII: Corneal epithelial cells → Junctional epidermolysis bullosa; Pia, blood vessels of developing human cerebral cortex → Knobloch syndrome. ◦ Collagen XXVII: Chondrocytes, epithelial cell layers → Steel syndrome (Osteochondrodysplasia); Cartilage, tendon, ligament, bone → Pseudoachondroplasia, Multiple epiphyseal dysplasia. ◦ Elastin: Dermis, arterial wall, lung → Cutis laxa, Marfan syndrome, Weill-Marchesani-syndrome, Stiff skin syndrome, Geleophysic dysplasia. ◦ Fibrillin 2: Bruch membrane → Congenital contractural arachnodactyly (CCA/Beals-Hecht); Dermis, tendons, ligaments → Glomerulopathy with fibronectin deposits. • Table 425-4: Heritable Thoracic Aortic Disease and Associated Genes ◦ COL3A1 → Vascular EDS. ◦ FBN1 → Marfan syndrome. ◦ MFAP5 → Familial thoracic aortic aneurysm 9. ◦ LOX → Familial thoracic aortic aneurysm 10. ◦ TGFBR1/2, SMAD3, TGFB2/3 → Loeys-Dietz syndrome (1-5). ◦ SMAD2 → Arterial aneurysms and dissections. ◦ ACTA2 → Familial thoracic aortic aneurysm 6. ◦ MYH11 → Familial thoracic aortic aneurysm 4. ◦ MYLK → Familial thoracic aortic aneurysm 7. ◦ PRKG1 → Familial thoracic aortic aneurysm 8.
Reference Tables¶
TABLE 425-1 Constituents of Connective Tissues and Their Associated Heritable Conditions PROTEIN Collagen I¶
Harrison's 22e, p.3321
| PROTEIN | TISSUE DISTRIBUTION | DISEASE | KEY MANIFESTATIONS |
|---|---|---|---|
| Collagen I | Bone, cornea, dermis, tendon | Osteogenesis imperfecta | Bone fragility with fractures and deformity; blue sclerae; dentinogenesis imperfecta; hearing loss |
| EDS (various rare types) | Joint hypermobility; skin hyperextensibility; skin fragility; soft connective tissue fragility |
||
| Caffey disease | Subperiosteal new bone formation; soft tissue swelling; fever and irritability |
||
| Cartilage, vitreous | Various chondrodysplasias | ||
| Collagen III | Dermis, aorta, uterus, intestine | Vascular EDS | Arterial, intestinal, and uterine fragility; thin translucent skin; easy bruising |
| Basement membranes | Alport syndrome (COL4A3/A4/A5) | ||
| Brain small-vessel disease (COL4A1/A2) | |||
| Collagen V | Placental tissue, bone, dermis, cornea |
Classic EDS | Joint hypermobility; skin hyperextensibility; atrophic scarring |
| Uterus, dermis, cornea, cartilage | Bethlem myopathy and Ullrich congenital muscular dystrophy |
||
| Collagen VII | Skin, amniotic membrane, mucosal epithelium |
Dystrophic epidermolysis bullosa | Skin blistering; oral and esophageal blistering; corneal erosions |
| Descemet’s membrane, endothelial cells |
Corneal dystrophy | ||
| Collagen IX | Cartilage, vitreous | Stickler syndrome | Spondyloepiphyseal dysplasia; early-onset osteoarthritis; high myopia; vitreoretinal abnormalities; hearing loss; cleft palate; midfacial hypoplasia |
| Calcifying cartilage | Multiple epiphyseal dysplasia | ||
| Collagen XI | Cartilage, intervertebral disk | Various chondrodysplasias | Skeletal dysplasia; ocular manifestations; hearing loss; orofacial findings |
| Dermis, tendon, cartilage | Myopathic EDS | ||
| Collagen XVII | Corneal epithelial cells | Junctional epidermolysis bullosa | Blistering of the skin and mucosae (mild to severe) |
| Pia, blood vessels of the developing human cerebral cortex |
Knobloch syndrome | ||
| Collagen XXVII | Chondrocytes, epithelial cell layers in developing tissues, including stomach, lung, gonad, skin, cochlea, and tooth |
Steel syndrome | Osteochondrodysplasia with hip dislocations; dislocations of radial heads; carpal coalition; short stature; facial dysmorphism; scoliosis |
| Cartilage, tendon, ligament, bone | Pseudoachondroplasia | ||
| Multiple epiphyseal dysplasia | |||
| Elastin | Dermis, arterial wall, lung | Cutis laxa | Wrinkled, redundant, sagging inelastic skin |
| Williams syndrome | Cardiovascular disease (especially supravalvular aortic stenosis); orofacial features; intellectual deficit; connective tissue abnormalities; endocrine abnormalities |
||
| Dermis, arterial wall, lung | Marfan syndrome | ||
| Weill-Marchesani-syndrome | |||
| Stiff skin syndrome | |||
| Geleophysic dysplasia | |||
| Fibrillin 2 | Bruch membrane | Congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome |
Tall stature; arachnodactyly; (kypho)scoliosis; pectus deformities; contractures; muscle hypoplasia; mild cardiovascular involvement; long, narrow face, highly arched palate, micrognathia, crumpled external ears |
| Acromelic dysplasia | Relative short stature; brachydactyly; toe walking; early onset carpal tunnel syndrome; short palpebral fissures |
||
| Dermis, tendons, ligaments | Glomerulopathy with fibronectin deposits | ||
| Spondylometaphyseal dysplasia, corner fracture type |
TABLE 425-4 Heritable Thoracic Aortic Disease and Associated Genes and Proteins Extracellular matrix proteins¶
Harrison's 22e, p.3332
| GENE | PROTEIN | CONDITION | OMIM | LOCUS | |
|---|---|---|---|---|---|
| Extracellular matrix proteins |
COL3A1 | α1(III) collagen chain | Vascular EDS | 130050 | 2q32 |
| FBN1 | Fibrillin 1 | Marfan syndrome | 154700 | 15q21.1 | |
| MFAP5 | Microfibrillar associated protein 5 | Familial thoracic aortic aneurysm 9 | 616166 | 12p13.31 | |
| LOX | Lysyl oxidase | Familial thoracic aortic aneurysm 10 | 617168 | 5q23.1 | |
| TGFBR1 | Transforming growth factor receptor 1 | Loeys-Dietz syndrome 1 | 609192 | ||
| TGFBR2 | Transforming growth factor receptor 2 | Loeys-Dietz syndrome 2 | 610168 | ||
| SMAD3 | Mothers against decapentaplegic drosophila homolog 3 | Loeys-Dietz syndrome 3 | 613795 | ||
| TGFB2 | Transforming growth factor β2 | Loeys-Dietz syndrome 4 | 614816 | ||
| TGFB3 | Transforming growth factor β3 | Loeys-Dietz syndrome 5 | 615582 | ||
| SMAD2 | Mothers against decapentaplegic drosophila homolog 2 | Arterial aneurysms and dissections | / | ||
| ACTA2 | Smooth muscle actin α2 | Familial thoracic aortic aneurysm 6 | 611788 | ||
| Smooth muscle contraction |
MYH11 | Smooth muscle myosin heavy chain 11 | Familial thoracic aortic aneurysm 4 | 132900 | 16p13.11 |
| MYLK | Myosin light chain kinase | Familial thoracic aortic aneurysm 7 | 613780 | 3q21.1 | |
| PRKG1 | Protein kinase cGMP-dependent type 1 | Familial thoracic aortic aneurysm 8 | 615436 | 10q11.2-q21.1 |