PERINATOLOGY • Vol 20 • No. 2 • Jul–Sep 2019 53 Case Report Osteogenesis Imperfecta Type 2 Sahana Devadas, Rekha Takkalaki Devendrappa*, Sarala Sabhapathy, Manu Malenahalli Ashok *Correspondence Dr Rekha Takkalaki Devendrappa Junior Resident Department of Pediatrics Bangalore Medical College and Research Institute Krishna Rajendra Road Bengaluru 560002, Karnataka India E-mail: [email protected] Abstract Background: Osteogenesis imperfecta (OI), the most common genetic cause of osteoporosis, is a generalized disorder of the connective tissue. OI type 2 may result in stillborns, or the neo- nates may die within the first year of their lives. The disorder includes the following signs: multiple intrauterine fractures of long bones, micromelia, bowing of the extremities to a frog leg position, multiple rib fractures, respiratory insufficiency, soft skull, enlarged anterior and posterior fontanelles, and dark blue– gray sclera. Case Summary: A full-term female neonate, born through vaginal delivery to a primipara mother, had multiple bone frac- tures at birth. The mother gave a history of reduced perception of fetal movements during pregnancy, and it was a second- degree consanguineous marriage. At birth, the neonate had respiratory distress, wide anterior fontanelle fusing with posterior fontanelle, a soft and compressible skull, blue sclera, shortened limbs with frog leg position, and a deformed chest. An infan- togram suggested fracture of the humerus, ulna, forearm, clavicle, rib, and tibia. An X-ray of the skull showed diffuse osteopenia with Wormian bones. Conclusion: Prenatal level 2 ultrasonography screening should be done as early as 16 weeks of gestation as a primary method for assessing early fetal malformations. Key Words: Osteogenesis imperfecta, genetic disease, frac- tures, Wormian bones, micromelia
Osteogenesis Imperfecta Type 2
Dec 10, 2022
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53
*Correspondence
Dr Rekha Takkalaki Devendrappa Junior Resident Department of Pediatrics Bangalore Medical College and Research Institute Krishna Rajendra Road Bengaluru 560002, Karnataka India
E-mail: [email protected]
Abstract Background: Osteogenesis imperfecta (OI), the most common genetic cause of osteoporosis, is a generalized disorder of the connective tissue. OI type 2 may result in stillborns, or the neo- nates may die within the first year of their lives. The disorder includes the following signs: multiple intrauterine fractures of long bones, micromelia, bowing of the extremities to a frog leg position, multiple rib fractures, respiratory insufficiency, soft skull, enlarged anterior and posterior fontanelles, and dark blue– gray sclera.
Case Summary: A full-term female neonate, born through vaginal delivery to a primipara mother, had multiple bone frac- tures at birth. The mother gave a history of reduced perception of fetal movements during pregnancy, and it was a second- degree consanguineous marriage. At birth, the neonate had respiratory distress, wide anterior fontanelle fusing with posterior fontanelle, a soft and compressible skull, blue sclera, shortened limbs with frog leg position, and a deformed chest. An infan- togram suggested fracture of the humerus, ulna, forearm, clavicle, rib, and tibia. An X-ray of the skull showed diffuse osteopenia with Wormian bones.
Conclusion: Prenatal level 2 ultrasonography screening should be done as early as 16 weeks of gestation as a primary method for assessing early fetal malformations.
Key Words: Osteogenesis imperfecta, genetic disease, frac- tures, Wormian bones, micromelia
54 • PERINATOLOGY • Vol 20 • No. 2 • Jul–Sep 2019
Devadas S, et al. Osteogenesis Imperfecta Type 2
Case Report
Introduction Osteogenesis imperfecta (OI), also called brittle bone, osteopsathyrosis, or fragilitas ossium,1-7 is defined as a rare hereditary disorder; it is characterized by increased bone fragility resulting from abnormal collagen for- mation.1,3-10 There are 4 clinical types of OI, the hall- mark of which is bone fragility. Fractures, blue sclera, and dentinogenesis imperfecta are associated findings. It is usually due to qualitative and quantitative defects in the synthesis of collagen type 1.6-8,10 OI occurs in about 1:20,000 to 1:60,000 live births in developed countries.3,8,9 OI could be either recessive (severe) or dominant (mild). The autosomal dominant form occurs equally in all racial and ethnic groups, whereas the autosomal recessive form occurs in ethnic groups with consanguineous marriages.
Case Description A female neonate was born at 40 weeks’ gestation through vaginal delivery. The mother was a 26-year-old primipara; she was in a second degree consanguineous marriage and had regular antenatal care. She denied family history of any skeletal abnormalities; she did not have major illness and was relatively well during pregnancy. The neonate cried immediately after birth; the cry was weak. The Apgar score was 6 and 7 at 1 and 5 minutes, respectively. The neonate’s father was 35 years old.
On examination, the neonate was found to be in a “froglike position,” with abnormal movement of all 4 limbs (Figure 1). She was in respiratory distress with acrocyanosis. She had blue sclera (Figure 2) and micro- gnathia with a high-arched palate. Musculoskeletal system examination revealed pectus excavatum; fixed flexion deformity of the fingers; crepitus of the right humerus, ulnar, and both femurs; and micromelia.
Upon central nervous system examination, it was observed that the neonate had a weak cry and incom- plete Moro reflex. Both anterior and posterior fonta- nelles were wide open and soft, and the sutures were widened.
There were no relevant abnormal findings on examina- tion of the cardiovascular and gastrointestinal systems. A clinical diagnosis of OI type 2 was made. Other
Figure 1. Deformed Limbs in the Neonate
Figure 2. Blue Sclera of the Neonate
investigations done included a skeletal survey; complete blood count; packed cell volume; WBC count and dif- ferential counts; and electrolyte, urea, creatinine, serum calcium, phosphate, and alkaline phosphatase levels. Of these, only serum calcium and phosphate levels were in the normal range, that is, 9.9 mg/dL and 3.2 mg/dL,
PERINATOLOGY • Vol 20 • No. 2 • Jul–Sep 2019 • 55
Devadas S, et al. Osteogenesis Imperfecta Type 2
Case Report
4. Type 4: dominantly inherited OI with normal sclera.
Type 1 is a mild form with recurrent fractures and blue sclera. It has subtypes A and B depending on the absence or presence of dentinogenesis imperfecta. Fractures are less common after puberty. Type 2 is auto- somal recessive and is generally lethal in the neonatal period, with multiple congenital fractures, micromelia, and severe lung disease. Types 3 and 4 represent inter- mediate phenotypes, with type 3 being the most severe, nonlethal form, causing significant bony deformity sec- ondary to multiple fractures, which can be congenital. Type 4 also has subtypes A and B based on the presence of dentinogenesis imperfecta.
Over the past few decades, 5 additional types (ie, types 5–9) have been identified using histologic and molecular findings.
The diagnosis of OI type 2 in our case was based on the clinical features of multiple fractures at birth, blue
Figure 3. Infantogram Showing Genu Varum and Multiple Fractures in the Femur, Tibia, and Fibula
respectively. Infantogram and skull X-ray revealed frac- tures of the right humerus, ulna, and femur (Figure 3); Wormian bones; and osteopenia (Figure 4).
Treatment was mainly supportive with minimal han- dling, intermittent suctioning, and intranasal oxygen administration. The parents were counseled, and the neonate was also reviewed by the orthopedic surgeons and anesthetist for later surgical intervention when she stabilized.
Discussion OI is a rare, inherited disorder. The most widely accept- able classification was by Sillence et al,11 in 1979, in which they grouped the disorder into 4 types as follows:
1. Type 1: dominantly inherited OI with blue sclera 2. Type 2: perinatally lethally deforming OI with
crumpled femora 3. Type 3: progressively deforming OI with normal
sclera
Figure 4. A Skull X-Ray Showing Wormian Bones and Osteopenia
56 • PERINATOLOGY • Vol 20 • No. 2 • Jul–Sep 2019
sclera, micromelia, and radiologic evidence of osteopenia. Although, there was no positive family history suggestive of OI or other skeletal malformations, it was noted that sporadic cases were most likely in type 2.11
In the case presented here, the findings are in agreement with those of previous authors, who believed that routine biochemical tests are usually normal.3,4,9,12
Literature has reported that fractures result usually from minimal trauma.9 The cause of multiple fractures in utero is speculated to be a result of fetal movements in utero or premature contractions, which the defective bone cannot withstand. The fractures are therefore pathologic7 as they cannot be attributed to birth trauma; they can be consid- ered as intrauterine fractures. Fairney12 says that although blue sclera is a well-documented clinical sign, it is not a reliable clinical feature in small neonates. Glorieux et al4 state that bone fragility and osteopenia, as we found, are the most prominent features of the disease.
Surgery had been the mainstay of management of OI, along with supportive physiotherapy and rehabilitation. However, the persistent brittleness of the bones with repeated fractures made researchers seek alternative treat- ments that will permanently strengthen the bone struc- ture. Bisphosphonates are derived from pyrophosphate, a natural agent that slows or stops the process of bone resorption, thereby resulting in increased bone density and strength; it can be used in medical management.
Conclusion OI is predominantly inherited as an autosomal dominant disorder, and the risk of an affected individual passing the gene to the offspring is 50%. Prenatal level 2 ultrasonog- raphy screening has to be done as early as 16 weeks of gestation as a primary method of assessment of the early fetal malformation. DNA blood testing for detecting gene defects has an accuracy of 60% to 94%. Thus, genetic counseling and prenatal diagnosis with DNA testing has to be done.
References 1. Smith R, Francis MJO, Houghton GR. In: The Brittle Bone
Syndrome: Osteogenesis Imperfecta. 1st ed. Oxford, United Kingdom: Butterworth–Heinemann; 1983:5.
2. Glorieux FH, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res. 2000;15(9):1650–1658.
3. Akiode O, et al. SICOT Online Report 2003 E049: osteogenesis imperfecta congenita in a Nigerian baby. http:// lhcnews.sicot.org/resources/File//IO_reports/12-2003/E049. pdf. Accessed April 2, 2019.
4. Glorieux FH, et al. Osteogenesis imperfecta type V1: a form of brittle bone disease with a mineralization defect. J Bone Miner Res. 2002;17(1):30–38.
5. Mundlos S, et al. Multiexon deletions in the type I collagen COL1A2 gene in osteogenesis imperfecta type IB. Molecules containing the shortened alpha2(I) chains show differential incorporation into the bone and skin extracellular matrix. J Biol Chem. 1996;271(35):21068–21074.
6. Jandl JH. Hereditary disorders of connective tissue: osteogenesis imperfecta. In: Blood Textbook of Haematology. 2nd ed. Massachusetts, MA: Little, Brown and Company; 1996:1285.
7. Lee GR, et al, eds. Hereditary disorders of connective tissue: osteogenesis imperfecta. In: Wintrobe’s Clinical Hematology. Vol 2. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:1637.
8. Engelbert RH, et al. Osteogenesis imperfecta in childhood: treatment strategies. Arch Phys Med Rehabil. 1998;79(12):1590–1594.
9. Behrman RE, Kliegman R, Nelson WE, ed. Inherited osteoporosis: osteogenesis imperfecta. In: Nelson Textbook of Paediatrics. 15th ed. Philadelphia, PA: WB Saunders Ltd; 1996:1978–1980.
10. Sutton D. Textbook of Radiology and Imaging. 7th ed. London, UK: Churchill Livingstone; 2003:72, 74, 411, 423, 476.
11. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16(2):101–116.
12. Fairney A. Metabolic bone disorders: congenital disorders of the bone matrix- osteogenesis imperfecta. In: Harris NH, ed. Postgraduate Textbook of Clinical Orthopedics. Massachusetts, MA: John Wright & Sons Ltd; 1983:311–312.
Author Affiliations
Dr Sahana Devadas, Professor; Dr Rekha Takkalaki Devendrappa, Junior Resident; Dr Sarala Sabhapathy, Head; Dr Manu Malenahalli Ashok, Junior Resident, Department of Pediatrics, Bangalore Medical College and Research Institute, Bengaluru 560002, Karnataka, India
Devadas S, et al. Osteogenesis Imperfecta Type 2
Case Report
*Correspondence
Dr Rekha Takkalaki Devendrappa Junior Resident Department of Pediatrics Bangalore Medical College and Research Institute Krishna Rajendra Road Bengaluru 560002, Karnataka India
E-mail: [email protected]
Abstract Background: Osteogenesis imperfecta (OI), the most common genetic cause of osteoporosis, is a generalized disorder of the connective tissue. OI type 2 may result in stillborns, or the neo- nates may die within the first year of their lives. The disorder includes the following signs: multiple intrauterine fractures of long bones, micromelia, bowing of the extremities to a frog leg position, multiple rib fractures, respiratory insufficiency, soft skull, enlarged anterior and posterior fontanelles, and dark blue– gray sclera.
Case Summary: A full-term female neonate, born through vaginal delivery to a primipara mother, had multiple bone frac- tures at birth. The mother gave a history of reduced perception of fetal movements during pregnancy, and it was a second- degree consanguineous marriage. At birth, the neonate had respiratory distress, wide anterior fontanelle fusing with posterior fontanelle, a soft and compressible skull, blue sclera, shortened limbs with frog leg position, and a deformed chest. An infan- togram suggested fracture of the humerus, ulna, forearm, clavicle, rib, and tibia. An X-ray of the skull showed diffuse osteopenia with Wormian bones.
Conclusion: Prenatal level 2 ultrasonography screening should be done as early as 16 weeks of gestation as a primary method for assessing early fetal malformations.
Key Words: Osteogenesis imperfecta, genetic disease, frac- tures, Wormian bones, micromelia
54 • PERINATOLOGY • Vol 20 • No. 2 • Jul–Sep 2019
Devadas S, et al. Osteogenesis Imperfecta Type 2
Case Report
Introduction Osteogenesis imperfecta (OI), also called brittle bone, osteopsathyrosis, or fragilitas ossium,1-7 is defined as a rare hereditary disorder; it is characterized by increased bone fragility resulting from abnormal collagen for- mation.1,3-10 There are 4 clinical types of OI, the hall- mark of which is bone fragility. Fractures, blue sclera, and dentinogenesis imperfecta are associated findings. It is usually due to qualitative and quantitative defects in the synthesis of collagen type 1.6-8,10 OI occurs in about 1:20,000 to 1:60,000 live births in developed countries.3,8,9 OI could be either recessive (severe) or dominant (mild). The autosomal dominant form occurs equally in all racial and ethnic groups, whereas the autosomal recessive form occurs in ethnic groups with consanguineous marriages.
Case Description A female neonate was born at 40 weeks’ gestation through vaginal delivery. The mother was a 26-year-old primipara; she was in a second degree consanguineous marriage and had regular antenatal care. She denied family history of any skeletal abnormalities; she did not have major illness and was relatively well during pregnancy. The neonate cried immediately after birth; the cry was weak. The Apgar score was 6 and 7 at 1 and 5 minutes, respectively. The neonate’s father was 35 years old.
On examination, the neonate was found to be in a “froglike position,” with abnormal movement of all 4 limbs (Figure 1). She was in respiratory distress with acrocyanosis. She had blue sclera (Figure 2) and micro- gnathia with a high-arched palate. Musculoskeletal system examination revealed pectus excavatum; fixed flexion deformity of the fingers; crepitus of the right humerus, ulnar, and both femurs; and micromelia.
Upon central nervous system examination, it was observed that the neonate had a weak cry and incom- plete Moro reflex. Both anterior and posterior fonta- nelles were wide open and soft, and the sutures were widened.
There were no relevant abnormal findings on examina- tion of the cardiovascular and gastrointestinal systems. A clinical diagnosis of OI type 2 was made. Other
Figure 1. Deformed Limbs in the Neonate
Figure 2. Blue Sclera of the Neonate
investigations done included a skeletal survey; complete blood count; packed cell volume; WBC count and dif- ferential counts; and electrolyte, urea, creatinine, serum calcium, phosphate, and alkaline phosphatase levels. Of these, only serum calcium and phosphate levels were in the normal range, that is, 9.9 mg/dL and 3.2 mg/dL,
PERINATOLOGY • Vol 20 • No. 2 • Jul–Sep 2019 • 55
Devadas S, et al. Osteogenesis Imperfecta Type 2
Case Report
4. Type 4: dominantly inherited OI with normal sclera.
Type 1 is a mild form with recurrent fractures and blue sclera. It has subtypes A and B depending on the absence or presence of dentinogenesis imperfecta. Fractures are less common after puberty. Type 2 is auto- somal recessive and is generally lethal in the neonatal period, with multiple congenital fractures, micromelia, and severe lung disease. Types 3 and 4 represent inter- mediate phenotypes, with type 3 being the most severe, nonlethal form, causing significant bony deformity sec- ondary to multiple fractures, which can be congenital. Type 4 also has subtypes A and B based on the presence of dentinogenesis imperfecta.
Over the past few decades, 5 additional types (ie, types 5–9) have been identified using histologic and molecular findings.
The diagnosis of OI type 2 in our case was based on the clinical features of multiple fractures at birth, blue
Figure 3. Infantogram Showing Genu Varum and Multiple Fractures in the Femur, Tibia, and Fibula
respectively. Infantogram and skull X-ray revealed frac- tures of the right humerus, ulna, and femur (Figure 3); Wormian bones; and osteopenia (Figure 4).
Treatment was mainly supportive with minimal han- dling, intermittent suctioning, and intranasal oxygen administration. The parents were counseled, and the neonate was also reviewed by the orthopedic surgeons and anesthetist for later surgical intervention when she stabilized.
Discussion OI is a rare, inherited disorder. The most widely accept- able classification was by Sillence et al,11 in 1979, in which they grouped the disorder into 4 types as follows:
1. Type 1: dominantly inherited OI with blue sclera 2. Type 2: perinatally lethally deforming OI with
crumpled femora 3. Type 3: progressively deforming OI with normal
sclera
Figure 4. A Skull X-Ray Showing Wormian Bones and Osteopenia
56 • PERINATOLOGY • Vol 20 • No. 2 • Jul–Sep 2019
sclera, micromelia, and radiologic evidence of osteopenia. Although, there was no positive family history suggestive of OI or other skeletal malformations, it was noted that sporadic cases were most likely in type 2.11
In the case presented here, the findings are in agreement with those of previous authors, who believed that routine biochemical tests are usually normal.3,4,9,12
Literature has reported that fractures result usually from minimal trauma.9 The cause of multiple fractures in utero is speculated to be a result of fetal movements in utero or premature contractions, which the defective bone cannot withstand. The fractures are therefore pathologic7 as they cannot be attributed to birth trauma; they can be consid- ered as intrauterine fractures. Fairney12 says that although blue sclera is a well-documented clinical sign, it is not a reliable clinical feature in small neonates. Glorieux et al4 state that bone fragility and osteopenia, as we found, are the most prominent features of the disease.
Surgery had been the mainstay of management of OI, along with supportive physiotherapy and rehabilitation. However, the persistent brittleness of the bones with repeated fractures made researchers seek alternative treat- ments that will permanently strengthen the bone struc- ture. Bisphosphonates are derived from pyrophosphate, a natural agent that slows or stops the process of bone resorption, thereby resulting in increased bone density and strength; it can be used in medical management.
Conclusion OI is predominantly inherited as an autosomal dominant disorder, and the risk of an affected individual passing the gene to the offspring is 50%. Prenatal level 2 ultrasonog- raphy screening has to be done as early as 16 weeks of gestation as a primary method of assessment of the early fetal malformation. DNA blood testing for detecting gene defects has an accuracy of 60% to 94%. Thus, genetic counseling and prenatal diagnosis with DNA testing has to be done.
References 1. Smith R, Francis MJO, Houghton GR. In: The Brittle Bone
Syndrome: Osteogenesis Imperfecta. 1st ed. Oxford, United Kingdom: Butterworth–Heinemann; 1983:5.
2. Glorieux FH, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res. 2000;15(9):1650–1658.
3. Akiode O, et al. SICOT Online Report 2003 E049: osteogenesis imperfecta congenita in a Nigerian baby. http:// lhcnews.sicot.org/resources/File//IO_reports/12-2003/E049. pdf. Accessed April 2, 2019.
4. Glorieux FH, et al. Osteogenesis imperfecta type V1: a form of brittle bone disease with a mineralization defect. J Bone Miner Res. 2002;17(1):30–38.
5. Mundlos S, et al. Multiexon deletions in the type I collagen COL1A2 gene in osteogenesis imperfecta type IB. Molecules containing the shortened alpha2(I) chains show differential incorporation into the bone and skin extracellular matrix. J Biol Chem. 1996;271(35):21068–21074.
6. Jandl JH. Hereditary disorders of connective tissue: osteogenesis imperfecta. In: Blood Textbook of Haematology. 2nd ed. Massachusetts, MA: Little, Brown and Company; 1996:1285.
7. Lee GR, et al, eds. Hereditary disorders of connective tissue: osteogenesis imperfecta. In: Wintrobe’s Clinical Hematology. Vol 2. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:1637.
8. Engelbert RH, et al. Osteogenesis imperfecta in childhood: treatment strategies. Arch Phys Med Rehabil. 1998;79(12):1590–1594.
9. Behrman RE, Kliegman R, Nelson WE, ed. Inherited osteoporosis: osteogenesis imperfecta. In: Nelson Textbook of Paediatrics. 15th ed. Philadelphia, PA: WB Saunders Ltd; 1996:1978–1980.
10. Sutton D. Textbook of Radiology and Imaging. 7th ed. London, UK: Churchill Livingstone; 2003:72, 74, 411, 423, 476.
11. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16(2):101–116.
12. Fairney A. Metabolic bone disorders: congenital disorders of the bone matrix- osteogenesis imperfecta. In: Harris NH, ed. Postgraduate Textbook of Clinical Orthopedics. Massachusetts, MA: John Wright & Sons Ltd; 1983:311–312.
Author Affiliations
Dr Sahana Devadas, Professor; Dr Rekha Takkalaki Devendrappa, Junior Resident; Dr Sarala Sabhapathy, Head; Dr Manu Malenahalli Ashok, Junior Resident, Department of Pediatrics, Bangalore Medical College and Research Institute, Bengaluru 560002, Karnataka, India
Devadas S, et al. Osteogenesis Imperfecta Type 2
Case Report
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