- Email: [email protected]
Other Type II Collagen Disorders
57 Other Type II Collagen Disorders
57
285
Other Type II Collagen Disorders DEBORAH KRAKOW
Introduction Achondrogenesis II, hypochondrogenesis, platyspondylic Torrance type, spondyloepiphyseal dysplasia congenita (SEDC) (Chapter 56), Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, Legg-Calve-Perthes disease, spondyloperipheral dysplasia, spondyloepiphyseal dysplasia with metatarsal shortening (Czech type), autosomal dominant spondyloarthropathy, and Stickler syndrome form the type II collagen disorder group. This group is a continuous spectrum of disorders, some of which manifest in the prenatal period, some much later in life.
Disorder
encodes type II collagen. Beyond sharing a common genetic basis of disease, they share some radiographic features and clinical features such as early-onset osteoarthritis in nonlethal disorders. PREVALENCE AND EPIDEMIOLOGY The precise prevalence of this spectrum of disorders is not known but, as a group, type II collagen disorders are not uncommon among the skeletal disorders. For the lethal achondrogenesis II, the disorder is estimated to have a prevalence of 1 : 40,000 to 1 : 60,000.
DEFINITION
ETIOLOGY AND PATHOPHYSIOLOGY
The aforementioned disorders all result from autosomal dominantly inherited disorders in the gene, COL2A1, the gene that
The aforementioned disorders all result from heterozygosity for mutations in the gene that encodes type II collagen, COL2A1.1,2
286
PART 7 Skeletal Dysplasias: An Overview • SECTION TWO Osteochondrodysplasias—Nonlethal
Fig. 57.1 Postnatal radiograph of achondrogenesis II; note lack of ossification of the spine and pubis.
The COL2A1 gene product is the type II collagen molecule. Somatic and germline mosaicism has been reported for type II collagen disorders.3,4 The type II collagen molecule provides structure and strength to connective tissues, particularly cartilage. Cartilage primarily compromises the skeleton during early development and abnormalities in type II collagen can have a profound effect on the patterning and integrity of the skeleton. Type II collagen is also part of the vitreous of the eye, the inner ear, and the nucleus pulposus; thus abnormalities in type II collagen affect the eye, the spine, and hearing. Most of the mutations that produce these disorders result from heterozygosity for missense mutations in COL2A1, and most of these mutations result from substitution of a glycine residue in the triple helix of the gene with a bulkier amino acid.2 Stickler syndrome, which presents with Pierre Robin sequence, mild short stature, and significant myopia and retinal abnormalities, results from heterozygosity for nonsense mutations in COL2A1.5 MANIFESTATIONS OF DISEASE Clinical Presentation The following disorders can present in the prenatal period or immediate newborn period: Achondrogenesis II. Achondrogenesis type II is also referred to as the Langer-Saldino type. This very rare disorder is characterized by extremely shortened arms and legs, a narrow chest with short ribs, hypoplastic lungs, and a lack of normal bone formation (ossification) in the spine and pelvis (Fig. 57.1). Distinctive facial features include a prominent forehead, micrognathia, and cleft palate. The abdomen is relatively enlarged, and often these fetuses
Fig. 57.2 Postnatal radiograph of hypochondrogenesis; note poor ossification of the spine and pubis and similar-shaped bones to achondrogenesis II.
present with hydrops fetalis. Newborns with achondrogenesis type II usually die before or soon after birth. Hypochondrogenesis is very similar to achondrogenesis type II. Affected infants have short arms and legs, a small chest with short ribs, and underdeveloped lungs (Fig. 57.2). Bones in the skull develop normally, but the bones of the vertebrae and pelvis lack proper ossification. Their facies appears flat and oval-shaped, with micrognathia and cleft palate (Pierre Robin sequence) and a high incidence of hydrops fetalis. Most of these infants do not survive to term. For those who do, and survive the newborn period, they are often reclassified as spondyloepiphyseal dysplasia congenita, a relatively similar but milder disorder (see Chapter 56). Stickler syndrome results from heterozygosity for loss of function mutations in COL2A15 and thus is somewhat mechanistically different. These individuals may present in the prenatal period with mild shortening of the rhizomelic segment and significant micrognathia. Long-term, most people with Stickler syndrome have skeletal abnormalities that affect the joints including scoliosis and kyphosis. As children, they may have loose joints, but as they age, their joints become less flexible. Arthritis often appears early in life causing joint pain or stiffness. Of major concern are the eye findings in Stickler syndrome that include glaucoma, cataracts, and retinal detachments, increasing the likelihood of impaired vision and in some cases blindness. Sensorineural hearing loss varies in degree of severity, but is common. Imaging Technique and Findings Ultrasound. Achondrogenesis II and hypochondrogenesis will present in the prenatal period. Achondrogenesis II presents in the first trimester with an increased nuchal fold and frequently a cystic hygroma.6–8 Hypochondrogenesis will present in a similar
Fig. 57.3 Three-dimensional ultrasound of an 18-week fetus with achondrogenesis II; note very flattened facies.
57 Other Type II Collagen Disorders
287
Fig. 57.5 Two-dimensional ultrasound of a 16-week fetus with Stickler syndrome showing significant micrognathia.
Fig. 57.4 Two-dimensional ultrasound of a 20-week fetus with achondrogenesis II showing very shortened ribs with metaphyseal cupping on sagittal view. Fig. 57.6 Three-dimensional ultrasound of a 20-week fetus with Stickler syndrome showing significant micrognathia.
fashion. The ultrasound findings include a flattened facies (Fig. 57.3), small chest, particularly on sagittal view with short ribs with cupping at the ends (Fig. 57.4), lack of secondary ossification centers, and severe shortening of all the long bones, with relatively normal-looking hands. Ascites, hydrops fetalis, and polyhydramnios are relatively common findings.9 Stickler syndrome can present in the prenatal period, particularly if there is a family history. Findings in the prenatal
period include micrognathia (Figs. 57.5 and 57.6) and mild rhizomelia in some cases.10,11 Magnetic Resonance Imaging. While prenatal magnetic resonance imaging has been useful in some circumstances, its use has not been demonstrated in this set of conditions, nor has prenatal computed tomography. Other Applicable Modality. Postnatal clinical findings and radiographs are diagnostic for this disorder.
CLASSIC SIGNS
POSTNATAL
Achondrogenesis II/Hypochondrogenesis Short trunk with prominent abdomen Striking micromelia Flat midface micrognathia, often cleft palate Hydrops Polyhydramnios Stickler syndrome Midface hypoplasia Cleft palate Micrognathia Mild shortening of the rhizomelic segment
Achondrogenesis II and hypochondrogenesis are lethal. Stickler syndrome is associated with Pierre Robin sequence and should be managed by a surgical team with expertise in the area. Meticulous ongoing evaluation of the eyes should be initiated at an early age. Hearing loss and precious arthrosis are common and should be followed closely to optimize quality of life.
Differential Diagnosis From Imaging Findings 1. Achondrogenesis IA 2. Achondrogenesis IB 3. Spondyloepiphyseal dysplasia congenita 4. Other epiphyseal dysplasias
Synopsis of Treatment Options PRENATAL Achondrogenesis II and hypochondrogenesis are lethal disorders, and interruption of pregnancy should be offered to the patient. If the pregnancy is delivered near term, active resuscitation should not be undertaken and palliative care should be offered. There is no role for cesarean section unless performed for obstetric rather than fetal indications. For Stickler syndrome, a team of individuals should be assembled to prepare for potential airway difficulties in the newborn period, including consideration for the ex utero intrapartum treatment (EXIT) procedure if the micrognathia is severe.
WHAT THE REFERRING PHYSICIAN NEEDS TO KNOW Achondrogenesis II and hypochondrogenesis are lethal. Pregnancy interruption should be offered. Ascites, hydrops fetalis, and polyhydramnios are common complications, and delivery should be offered if indicated. Active intervention for preterm labor should not be undertaken. Mutations are dominantly inherited or sporadic in these conditions because of mutations in COL2A1.
KEY POINTS • Achondrogenesis II and hypochondrogenesis are lethal conditions resulting from missense mutations in COL2A1. • Stickler syndrome results from nonsense mutations in COL2A1. • Severe limb shortening, poor ossification of the spine, and hydrops are common in achondrogenesis II and hypochondrogenesis. • Stickler syndrome presents with mild rhizomelia and micrognathia (Pierre Robin sequence).
SUGGESTED READING Krakow D, Williams J 3rd, Poehl M, et al. Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias. Ultrasound Obstet Gynecol. 2003;21(5):467-472. Robin NH, Moran RT, Ala-Kokko L. Stickler syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA): 1993.
All references are available online at www.expertconsult.com.
57 Other Type II Collagen Disorders 288.e1
REFERENCES 1. Deng H, Huang X, Yuan L. Molecular genetics of the COL2A1-related disorders. Mutat Res Rev Mutat Res. 2016;768:1-13. 2. Barat-Houari M, Sarrabay G, Gatinois V, et al. Mutation update for COL2A1 gene variants associated with type II collagenopathies. Hum Mutat. 2016;37(1):7-15. 3. Nagendran S, Richards AJ, McNinch A, et al. Somatic mosaicism and the phenotypic expression of COL2A1 mutations. Am J Med Genet A. 2012;158A(5):1204-1207. 4. Comstock JM, Putnam AR, Sangle N, et al. Recurrence of achondrogenesis type 2 in sibs: additional evidence for germline mosaicism. Am J Med Genet A. 2010;152A(7):1822-1824. 5. Robin NH, Moran RT, Ala-Kokko L. Stickler syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA): 1993. 6. Forzano F, Lituania M, Viassolo A, et al. A familial case of achondrogenesis type II caused by a dominant COL2A1 mutation and “patchy” expression in the mosaic father. Am J Med Genet A. 2007;143A(23):2815-2820.
7. Won HS, Yoo HK, Lee PR, et al. A case of achondrogenesis type II associated with huge cystic hygroma: prenatal diagnosis by ultrasonography. Ultrasound Obstet Gynecol. 1999;14(4):288-290. 8. Soothill PW, Vuthiwong C, Rees H. Achondrogenesis type 2 diagnosed by transvaginal ultrasound at 12 weeks’ gestation. Prenat Diagn. 1993;13(6):523-528. 9. Krakow D, Williams J 3rd, Poehl M, et al. Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias. Ultrasound Obstet Gynecol. 2003;21(5):467-472. 10. Soulier M, Sigaudy S, Chau C, et al. Prenatal diagnosis of Pierre-Robin s e q u e n ce a s p a r t o f S t i ck l e r s y n d ro m e . Pre n a t D i a g n . 2002;22(7):567-568. 11. Lituania M, Tonni G. Bifid uvula and familial Stickler syndrome diagnosed prenatally before the sonographic “equals sign” landmark. Arch Gynecol Obstet. 2013;288(3):483-487.
57
285
Other Type II Collagen Disorders DEBORAH KRAKOW
Introduction Achondrogenesis II, hypochondrogenesis, platyspondylic Torrance type, spondyloepiphyseal dysplasia congenita (SEDC) (Chapter 56), Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, Legg-Calve-Perthes disease, spondyloperipheral dysplasia, spondyloepiphyseal dysplasia with metatarsal shortening (Czech type), autosomal dominant spondyloarthropathy, and Stickler syndrome form the type II collagen disorder group. This group is a continuous spectrum of disorders, some of which manifest in the prenatal period, some much later in life.
Disorder
encodes type II collagen. Beyond sharing a common genetic basis of disease, they share some radiographic features and clinical features such as early-onset osteoarthritis in nonlethal disorders. PREVALENCE AND EPIDEMIOLOGY The precise prevalence of this spectrum of disorders is not known but, as a group, type II collagen disorders are not uncommon among the skeletal disorders. For the lethal achondrogenesis II, the disorder is estimated to have a prevalence of 1 : 40,000 to 1 : 60,000.
DEFINITION
ETIOLOGY AND PATHOPHYSIOLOGY
The aforementioned disorders all result from autosomal dominantly inherited disorders in the gene, COL2A1, the gene that
The aforementioned disorders all result from heterozygosity for mutations in the gene that encodes type II collagen, COL2A1.1,2
286
PART 7 Skeletal Dysplasias: An Overview • SECTION TWO Osteochondrodysplasias—Nonlethal
Fig. 57.1 Postnatal radiograph of achondrogenesis II; note lack of ossification of the spine and pubis.
The COL2A1 gene product is the type II collagen molecule. Somatic and germline mosaicism has been reported for type II collagen disorders.3,4 The type II collagen molecule provides structure and strength to connective tissues, particularly cartilage. Cartilage primarily compromises the skeleton during early development and abnormalities in type II collagen can have a profound effect on the patterning and integrity of the skeleton. Type II collagen is also part of the vitreous of the eye, the inner ear, and the nucleus pulposus; thus abnormalities in type II collagen affect the eye, the spine, and hearing. Most of the mutations that produce these disorders result from heterozygosity for missense mutations in COL2A1, and most of these mutations result from substitution of a glycine residue in the triple helix of the gene with a bulkier amino acid.2 Stickler syndrome, which presents with Pierre Robin sequence, mild short stature, and significant myopia and retinal abnormalities, results from heterozygosity for nonsense mutations in COL2A1.5 MANIFESTATIONS OF DISEASE Clinical Presentation The following disorders can present in the prenatal period or immediate newborn period: Achondrogenesis II. Achondrogenesis type II is also referred to as the Langer-Saldino type. This very rare disorder is characterized by extremely shortened arms and legs, a narrow chest with short ribs, hypoplastic lungs, and a lack of normal bone formation (ossification) in the spine and pelvis (Fig. 57.1). Distinctive facial features include a prominent forehead, micrognathia, and cleft palate. The abdomen is relatively enlarged, and often these fetuses
Fig. 57.2 Postnatal radiograph of hypochondrogenesis; note poor ossification of the spine and pubis and similar-shaped bones to achondrogenesis II.
present with hydrops fetalis. Newborns with achondrogenesis type II usually die before or soon after birth. Hypochondrogenesis is very similar to achondrogenesis type II. Affected infants have short arms and legs, a small chest with short ribs, and underdeveloped lungs (Fig. 57.2). Bones in the skull develop normally, but the bones of the vertebrae and pelvis lack proper ossification. Their facies appears flat and oval-shaped, with micrognathia and cleft palate (Pierre Robin sequence) and a high incidence of hydrops fetalis. Most of these infants do not survive to term. For those who do, and survive the newborn period, they are often reclassified as spondyloepiphyseal dysplasia congenita, a relatively similar but milder disorder (see Chapter 56). Stickler syndrome results from heterozygosity for loss of function mutations in COL2A15 and thus is somewhat mechanistically different. These individuals may present in the prenatal period with mild shortening of the rhizomelic segment and significant micrognathia. Long-term, most people with Stickler syndrome have skeletal abnormalities that affect the joints including scoliosis and kyphosis. As children, they may have loose joints, but as they age, their joints become less flexible. Arthritis often appears early in life causing joint pain or stiffness. Of major concern are the eye findings in Stickler syndrome that include glaucoma, cataracts, and retinal detachments, increasing the likelihood of impaired vision and in some cases blindness. Sensorineural hearing loss varies in degree of severity, but is common. Imaging Technique and Findings Ultrasound. Achondrogenesis II and hypochondrogenesis will present in the prenatal period. Achondrogenesis II presents in the first trimester with an increased nuchal fold and frequently a cystic hygroma.6–8 Hypochondrogenesis will present in a similar
Fig. 57.3 Three-dimensional ultrasound of an 18-week fetus with achondrogenesis II; note very flattened facies.
57 Other Type II Collagen Disorders
287
Fig. 57.5 Two-dimensional ultrasound of a 16-week fetus with Stickler syndrome showing significant micrognathia.
Fig. 57.4 Two-dimensional ultrasound of a 20-week fetus with achondrogenesis II showing very shortened ribs with metaphyseal cupping on sagittal view. Fig. 57.6 Three-dimensional ultrasound of a 20-week fetus with Stickler syndrome showing significant micrognathia.
fashion. The ultrasound findings include a flattened facies (Fig. 57.3), small chest, particularly on sagittal view with short ribs with cupping at the ends (Fig. 57.4), lack of secondary ossification centers, and severe shortening of all the long bones, with relatively normal-looking hands. Ascites, hydrops fetalis, and polyhydramnios are relatively common findings.9 Stickler syndrome can present in the prenatal period, particularly if there is a family history. Findings in the prenatal
period include micrognathia (Figs. 57.5 and 57.6) and mild rhizomelia in some cases.10,11 Magnetic Resonance Imaging. While prenatal magnetic resonance imaging has been useful in some circumstances, its use has not been demonstrated in this set of conditions, nor has prenatal computed tomography. Other Applicable Modality. Postnatal clinical findings and radiographs are diagnostic for this disorder.
CLASSIC SIGNS
POSTNATAL
Achondrogenesis II/Hypochondrogenesis Short trunk with prominent abdomen Striking micromelia Flat midface micrognathia, often cleft palate Hydrops Polyhydramnios Stickler syndrome Midface hypoplasia Cleft palate Micrognathia Mild shortening of the rhizomelic segment
Achondrogenesis II and hypochondrogenesis are lethal. Stickler syndrome is associated with Pierre Robin sequence and should be managed by a surgical team with expertise in the area. Meticulous ongoing evaluation of the eyes should be initiated at an early age. Hearing loss and precious arthrosis are common and should be followed closely to optimize quality of life.
Differential Diagnosis From Imaging Findings 1. Achondrogenesis IA 2. Achondrogenesis IB 3. Spondyloepiphyseal dysplasia congenita 4. Other epiphyseal dysplasias
Synopsis of Treatment Options PRENATAL Achondrogenesis II and hypochondrogenesis are lethal disorders, and interruption of pregnancy should be offered to the patient. If the pregnancy is delivered near term, active resuscitation should not be undertaken and palliative care should be offered. There is no role for cesarean section unless performed for obstetric rather than fetal indications. For Stickler syndrome, a team of individuals should be assembled to prepare for potential airway difficulties in the newborn period, including consideration for the ex utero intrapartum treatment (EXIT) procedure if the micrognathia is severe.
WHAT THE REFERRING PHYSICIAN NEEDS TO KNOW Achondrogenesis II and hypochondrogenesis are lethal. Pregnancy interruption should be offered. Ascites, hydrops fetalis, and polyhydramnios are common complications, and delivery should be offered if indicated. Active intervention for preterm labor should not be undertaken. Mutations are dominantly inherited or sporadic in these conditions because of mutations in COL2A1.
KEY POINTS • Achondrogenesis II and hypochondrogenesis are lethal conditions resulting from missense mutations in COL2A1. • Stickler syndrome results from nonsense mutations in COL2A1. • Severe limb shortening, poor ossification of the spine, and hydrops are common in achondrogenesis II and hypochondrogenesis. • Stickler syndrome presents with mild rhizomelia and micrognathia (Pierre Robin sequence).
SUGGESTED READING Krakow D, Williams J 3rd, Poehl M, et al. Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias. Ultrasound Obstet Gynecol. 2003;21(5):467-472. Robin NH, Moran RT, Ala-Kokko L. Stickler syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA): 1993.
All references are available online at www.expertconsult.com.
57 Other Type II Collagen Disorders 288.e1
REFERENCES 1. Deng H, Huang X, Yuan L. Molecular genetics of the COL2A1-related disorders. Mutat Res Rev Mutat Res. 2016;768:1-13. 2. Barat-Houari M, Sarrabay G, Gatinois V, et al. Mutation update for COL2A1 gene variants associated with type II collagenopathies. Hum Mutat. 2016;37(1):7-15. 3. Nagendran S, Richards AJ, McNinch A, et al. Somatic mosaicism and the phenotypic expression of COL2A1 mutations. Am J Med Genet A. 2012;158A(5):1204-1207. 4. Comstock JM, Putnam AR, Sangle N, et al. Recurrence of achondrogenesis type 2 in sibs: additional evidence for germline mosaicism. Am J Med Genet A. 2010;152A(7):1822-1824. 5. Robin NH, Moran RT, Ala-Kokko L. Stickler syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA): 1993. 6. Forzano F, Lituania M, Viassolo A, et al. A familial case of achondrogenesis type II caused by a dominant COL2A1 mutation and “patchy” expression in the mosaic father. Am J Med Genet A. 2007;143A(23):2815-2820.
7. Won HS, Yoo HK, Lee PR, et al. A case of achondrogenesis type II associated with huge cystic hygroma: prenatal diagnosis by ultrasonography. Ultrasound Obstet Gynecol. 1999;14(4):288-290. 8. Soothill PW, Vuthiwong C, Rees H. Achondrogenesis type 2 diagnosed by transvaginal ultrasound at 12 weeks’ gestation. Prenat Diagn. 1993;13(6):523-528. 9. Krakow D, Williams J 3rd, Poehl M, et al. Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias. Ultrasound Obstet Gynecol. 2003;21(5):467-472. 10. Soulier M, Sigaudy S, Chau C, et al. Prenatal diagnosis of Pierre-Robin s e q u e n ce a s p a r t o f S t i ck l e r s y n d ro m e . Pre n a t D i a g n . 2002;22(7):567-568. 11. Lituania M, Tonni G. Bifid uvula and familial Stickler syndrome diagnosed prenatally before the sonographic “equals sign” landmark. Arch Gynecol Obstet. 2013;288(3):483-487.