Consideration of intravenous immunoglobulin to prenatally mitigate the development of chondrodysplasia punctata in children born to mothers with autoimmune disease
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Features of chondrodysplasia punctata (CDP) can be noted prenatally by ultrasound or by radiographic imaging and physical exam after birth (1). It is important to distinguish between non-genetic and genetic causes of CDP as genetic causes often have a severe clinical course. Among the non-genetic causes of CDP, warfarin embryopathy and maternal autoimmune disease (MAD) have been described (2, 3, 4). Transplacental maternal antibody transfer results in abnormal fetal bone and cartilage development (2). Several antibodies have been implicated in previous cases including anti-RNP, anti-La, anti-Ro, and ANA antibodies (2, 3, 4). We present two siblings of a mother with MAD who were born with features of CDP with the goal of considering prenatal treatment with intravenous immunoglobulin (IVIG) to mitigate features of CDP in the newborn.
Case Presentation
We report a now 2-year-old male who was born at 30 weeks to a G1P1 22- year-old mother. Pregnancy complications included maternal lupus (positive anti-RNP antibodies). Anatomy scan at 18.1 weeks showed short long bones, fetal growth restriction (FGR), and micrognathia. Birth complications included severe maternal pre-eclampsia and premature delivery. Birth weight was 1095 grams. His newborn course was complicated by respiratory insufficiency and extended need for CPAP. Significant mid-face hypoplasia and shortened limbs were noted.
Our proband’s sister was born at 37.1 weeks. Pregnancy complications included FGR and elevated anti-RNP antibodies. Mild mid-face hypoplasia was noted. She was discharged after a routine stay in the nursery.
Diagnostic Workup
For our first patient, genetics was consulted on day of life 4 due to concern for skeletal dysplasia. X-ray imaging showed unusual punctate densities in epiphyses of multiple extremities and shortened humeri. A complete skeletal survey redemonstrated these findings. Lab workup included very long chain fatty acids and plasmalogens to rule out peroxisomal spectrum disorders (resulted as normal). A custom gene panel was negative at 3 months of age. Neither molecular nor biochemical testing was pursued for our second patient. X-ray did show CDP lesions at 1 month of age.
Treatment and Management
Our first patient required CPAP support from birth until 2.5 months. Both patients have followed with genetics since birth and neither has required treatment.
Outcome and Follow-Up
The first patient has more discernable dysmorphic features including mid-face hypoplasia, short fingers, and broad thumbs. At 35 months he is in the 3rd percentile for weight (Z = -1.83) and 6th percentile for height (Z = -1.6). Our second patient is 6 months old with weight in the 15th percentile (Z = -1.0) and length in the 7th percentile (Z = -1.46). Both patients have appropriate development.
Discussion
Physicians caring for mothers with MAD should be aware of the potential for CDP in offspring. Geneticists have an important role in distinguishing between the causes of CDP. Children with non-genetic CDP likely have a better prognosis compared to genetic CDP, but these children can still have severe problems related to prematurity, respiratory insufficiency, and skeletal dysplasia (1,2,3,4). We highlight the spectrum of severity that can be seen. The radiographic signs of CDP usually diminish with age as cartilage calcifies. There is limited literature regarding long-term effects. Prenatal use of IVIG has been previously proposed for mothers with MAD (5,6,7), but this has not been described to mitigate CDP.
Conclusion
We hypothesize that prenatal treatment with IVIG may lessen antibody burden and thus mitigate the development of CDP in the offspring of mothers with MAD. Future directions to explore include the specific antibody involved, implications for subsequent pregnancies, as well as the dose, timing, and frequency of IVIG treatment. Prenatal intervention may lessen the health problems related to this diagnosis, lessen healthcare costs, reduce the diagnostic workup, optimize medical care, and reduce psychological burden.
Features of chondrodysplasia punctata (CDP) can be noted prenatally by ultrasound or by radiographic imaging and physical exam after birth (1). It is important to distinguish between non-genetic and genetic causes of CDP as genetic causes often have a severe clinical course. Among the non-genetic causes of CDP, warfarin embryopathy and maternal autoimmune disease (MAD) have been described (2, 3, 4). Transplacental maternal antibody transfer results in abnormal fetal bone and cartilage development (2). Several antibodies have been implicated in previous cases including anti-RNP, anti-La, anti-Ro, and ANA antibodies (2, 3, 4). We present two siblings of a mother with MAD who were born with features of CDP with the goal of considering prenatal treatment with intravenous immunoglobulin (IVIG) to mitigate features of CDP in the newborn.
Case Presentation
We report a now 2-year-old male who was born at 30 weeks to a G1P1 22- year-old mother. Pregnancy complications included maternal lupus (positive anti-RNP antibodies). Anatomy scan at 18.1 weeks showed short long bones, fetal growth restriction (FGR), and micrognathia. Birth complications included severe maternal pre-eclampsia and premature delivery. Birth weight was 1095 grams. His newborn course was complicated by respiratory insufficiency and extended need for CPAP. Significant mid-face hypoplasia and shortened limbs were noted.
Our proband’s sister was born at 37.1 weeks. Pregnancy complications included FGR and elevated anti-RNP antibodies. Mild mid-face hypoplasia was noted. She was discharged after a routine stay in the nursery.
Diagnostic Workup
For our first patient, genetics was consulted on day of life 4 due to concern for skeletal dysplasia. X-ray imaging showed unusual punctate densities in epiphyses of multiple extremities and shortened humeri. A complete skeletal survey redemonstrated these findings. Lab workup included very long chain fatty acids and plasmalogens to rule out peroxisomal spectrum disorders (resulted as normal). A custom gene panel was negative at 3 months of age. Neither molecular nor biochemical testing was pursued for our second patient. X-ray did show CDP lesions at 1 month of age.
Treatment and Management
Our first patient required CPAP support from birth until 2.5 months. Both patients have followed with genetics since birth and neither has required treatment.
Outcome and Follow-Up
The first patient has more discernable dysmorphic features including mid-face hypoplasia, short fingers, and broad thumbs. At 35 months he is in the 3rd percentile for weight (Z = -1.83) and 6th percentile for height (Z = -1.6). Our second patient is 6 months old with weight in the 15th percentile (Z = -1.0) and length in the 7th percentile (Z = -1.46). Both patients have appropriate development.
Discussion
Physicians caring for mothers with MAD should be aware of the potential for CDP in offspring. Geneticists have an important role in distinguishing between the causes of CDP. Children with non-genetic CDP likely have a better prognosis compared to genetic CDP, but these children can still have severe problems related to prematurity, respiratory insufficiency, and skeletal dysplasia (1,2,3,4). We highlight the spectrum of severity that can be seen. The radiographic signs of CDP usually diminish with age as cartilage calcifies. There is limited literature regarding long-term effects. Prenatal use of IVIG has been previously proposed for mothers with MAD (5,6,7), but this has not been described to mitigate CDP.
Conclusion
We hypothesize that prenatal treatment with IVIG may lessen antibody burden and thus mitigate the development of CDP in the offspring of mothers with MAD. Future directions to explore include the specific antibody involved, implications for subsequent pregnancies, as well as the dose, timing, and frequency of IVIG treatment. Prenatal intervention may lessen the health problems related to this diagnosis, lessen healthcare costs, reduce the diagnostic workup, optimize medical care, and reduce psychological burden.
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