Cartilage-Hair Hypoplasia: Expanding the Association of Severe Prenatal Skeletal Findings
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Introduction: Cartilage-hair hypoplasia (CHH) is an autosomal recessive ribosomal disorder with variable multisystemic effects including immune dysfunction, skeletal abnormalities, increased incidence of anemia, Hirschsprung disease, and malignancy. Characteristic metaphyseal dysplasia and hair hypoplasia with immunodeficiency are well recognized features in children. However, prenatal skeletal findings of CHH are rarely reported. This report expands the fetal skeletal phenotype and provides information on postnatal extra-skeletal features and the clinical course of siblings with distinctly severe prenatal skeletal findings.
Case Presentation
Case Presentation: The proband, a now 4-year-old female, presented prenatally with short and bowed long bones and decreased FL:AC ratio, leading to clinical suspicion for thanatophoric dysplasia. She was born at term with birth length of -7 SD, weight at -2.34 SD, and OFC -0.54 SD. Her newborn screen had no T-cell receptor excision circles. Short-segment Hirschsprung disease was diagnosed at age 22 months and resected without complication. Her growth remains exceedingly slow with height -10 SD, weight -6 SD, and OFC -2 SD.
The proband’s younger sister was noted to have micromelia with long bone bowing by time of second trimester ultrasound. Pregnancy was complicated by polyhydramnios and sibling was delivered at 37 weeks gestation with birth length of -7 SD, weight at -0.61 SD, and OFC of +0.95 SD. She had similar skeletal findings, did not require respiratory support, and also had no T-cell receptor excision circles on newborn screen.
Diagnostic Workup
Diagnostic Workup: Xrays of the proband as a neonate were notable for micromelia with bowing of the radius and ulna, bell-shaped thorax, short and gracile ribs, and distinctively prominent distal femoral epiphyses. Flow cytometry demonstrated profound B- and T- cell lymphopenia with absent naive T-cells with low to absent IgG, IgA, and IgM. Genetic testing with a skeletal dysplasia NGS panel identified biallelic variants in RMRP (n.-19-3dup and n.223C>T). Limited evaluation has been done to date on the affected newborn sibling, but radiographs have similar features. Flow cytometry is again notable for profound lymphopenia. Targeted familial variant testing confirmed the same biallelic RMRP variants as the proband.
Treatment and Management
Treatment and Management: Hematopoietic stem cell transplantation is not performed universally in individuals with CHH although immune dysregulation is a consistent feature. Given the profound lymphopenia, HSCT was completed in the proband as a neonate. The younger sister is currently undergoing preparation for HSCT.
Outcome and Follow-Up
Outcome and Follow-up: At age four, the proband does not have long-term complications from HSCT and no longer requires antibiotic prophylaxis. She had colostomy for Hirschsprung disease and remains G tube fed for dysphagia but does not require respiratory support. Metaphyseal dysplasia is now more apparent, but she is making developmental progress, communicates easily and operates a power wheelchair independently.
Discussion
Discussion: These siblings represent a distinctively severe prenatal skeletal presentation of CHH. Rare reports describe fetuses with similar findings, described as thanatophoric dysplasia, Glasgow variant and later as recessive lethal chondrodysplasia, round femoral inferior epiphysis type. Subsequent publications of similarly affected individuals with a perinatally lethal course were eventually characterized as severe CHH. These siblings are the first reported to have severe prenatal skeletal features and prolonged postnatal survival.
Conclusion
Conclusion: This report expands skeletal findings of CHH, including suggestive prenatal findings. Early consideration of this diagnosis allows for protective precautions at time of delivery while awaiting newborn screening results and early HSCT. This intervention has resulted in the longest surviving child with severe prenatal skeletal features of CHH, and prevention of interval infection in her affected sibling as she awaits HSCT.
Introduction: Cartilage-hair hypoplasia (CHH) is an autosomal recessive ribosomal disorder with variable multisystemic effects including immune dysfunction, skeletal abnormalities, increased incidence of anemia, Hirschsprung disease, and malignancy. Characteristic metaphyseal dysplasia and hair hypoplasia with immunodeficiency are well recognized features in children. However, prenatal skeletal findings of CHH are rarely reported. This report expands the fetal skeletal phenotype and provides information on postnatal extra-skeletal features and the clinical course of siblings with distinctly severe prenatal skeletal findings.
Case Presentation
Case Presentation: The proband, a now 4-year-old female, presented prenatally with short and bowed long bones and decreased FL:AC ratio, leading to clinical suspicion for thanatophoric dysplasia. She was born at term with birth length of -7 SD, weight at -2.34 SD, and OFC -0.54 SD. Her newborn screen had no T-cell receptor excision circles. Short-segment Hirschsprung disease was diagnosed at age 22 months and resected without complication. Her growth remains exceedingly slow with height -10 SD, weight -6 SD, and OFC -2 SD.
The proband’s younger sister was noted to have micromelia with long bone bowing by time of second trimester ultrasound. Pregnancy was complicated by polyhydramnios and sibling was delivered at 37 weeks gestation with birth length of -7 SD, weight at -0.61 SD, and OFC of +0.95 SD. She had similar skeletal findings, did not require respiratory support, and also had no T-cell receptor excision circles on newborn screen.
Diagnostic Workup
Diagnostic Workup: Xrays of the proband as a neonate were notable for micromelia with bowing of the radius and ulna, bell-shaped thorax, short and gracile ribs, and distinctively prominent distal femoral epiphyses. Flow cytometry demonstrated profound B- and T- cell lymphopenia with absent naive T-cells with low to absent IgG, IgA, and IgM. Genetic testing with a skeletal dysplasia NGS panel identified biallelic variants in RMRP (n.-19-3dup and n.223C>T). Limited evaluation has been done to date on the affected newborn sibling, but radiographs have similar features. Flow cytometry is again notable for profound lymphopenia. Targeted familial variant testing confirmed the same biallelic RMRP variants as the proband.
Treatment and Management
Treatment and Management: Hematopoietic stem cell transplantation is not performed universally in individuals with CHH although immune dysregulation is a consistent feature. Given the profound lymphopenia, HSCT was completed in the proband as a neonate. The younger sister is currently undergoing preparation for HSCT.
Outcome and Follow-Up
Outcome and Follow-up: At age four, the proband does not have long-term complications from HSCT and no longer requires antibiotic prophylaxis. She had colostomy for Hirschsprung disease and remains G tube fed for dysphagia but does not require respiratory support. Metaphyseal dysplasia is now more apparent, but she is making developmental progress, communicates easily and operates a power wheelchair independently.
Discussion
Discussion: These siblings represent a distinctively severe prenatal skeletal presentation of CHH. Rare reports describe fetuses with similar findings, described as thanatophoric dysplasia, Glasgow variant and later as recessive lethal chondrodysplasia, round femoral inferior epiphysis type. Subsequent publications of similarly affected individuals with a perinatally lethal course were eventually characterized as severe CHH. These siblings are the first reported to have severe prenatal skeletal features and prolonged postnatal survival.
Conclusion
Conclusion: This report expands skeletal findings of CHH, including suggestive prenatal findings. Early consideration of this diagnosis allows for protective precautions at time of delivery while awaiting newborn screening results and early HSCT. This intervention has resulted in the longest surviving child with severe prenatal skeletal features of CHH, and prevention of interval infection in her affected sibling as she awaits HSCT.