The Importance of Karyotyping in an Age of Sequencing: A Rare Cause of Campomelic Dysplasia
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Campomelic dysplasia (CD) is a rare, potentially lethal skeletal dysplasia caused primarily by pathogenic variants in SOX9. However, 5% of cases are due to an interstitial deletion or reciprocal translocation of 17q24.3-q25.1 involving SOX9 or its regulatory region. We present a case of CD caused by a reciprocal translocation outside of the previously reported regulatory region. This case also highlights the importance of phenotyping and the value of a karyotype during a time in which exome sequencing (ES) is commonly recommended.
Case Presentation
A two-week-old female presented due to Pierre Robin sequence (PRS) with cleft palate and failed newborn hearing screen. Physical exam was significant for relative macrocephaly. Trio exome sequencing was initiated. While pending, patient underwent imaging during an admission for respiratory failure at five months of age, and hypoplastic scapula and thoracic vertebral pedicles were identified. Additional features at that time included mild bowing of lower extremities, bilateral mild talipes equinovarus, and midface hypoplasia, all consistent with a diagnosis of CD.
Diagnostic Workup
Exome sequencing reported a hemizygous variant of uncertain significance in FANCB; mother was heterozygous and father was negative. Due to concern for CD and the presence of Y chromosome material, further workup included karyotype and SNP microarray. She was identified to have a balanced translocation between chromosomes 5 and 17 (t(5;17)(q22;q23.1)) with a complete XY sex chromosome complement and no other copy number variants. While this chromosome 17 breakpoint is outside of the previously reported SOX9 regulatory region, this patient’s features are consistent with a diagnosis of CD with XY sex reversal. DEB studies were completed and normal.
Treatment and Management
Following diagnosis, it was recommended that patient continue following with ENT/Pulmonology, Cleft Craniofacial, and Orthopedics. Lateral radiographs of the cervical spine were completed and normal. Due to the presence of Y chromosome material, she was evaluated by Endocrinology and Urology. External genitalia was typical female. Pelvic ultrasound found a typical uterus, but gonads were unable to be visualized. Bilateral laparoscopic gonadectomy was completed and pathology was significant for streak gonads with bilateral gonadoblastoma. Palatoplasty is planned. Hearing loss resolved after bilateral myringotomy and tube placement. Parental karyotypes were completed and normal.
Outcome and Follow-Up
When the patient was last seen in Medical Genetics clinic at 14 months of age, she was making excellent developmental progress. Because of her mild phenotype and novel genetic test results, the diagnosis of CD has been questioned by other providers, which has led to frustration for the family. However, a genetic diagnosis has allowed family and the genetics team to advocate for appropriate care.
Discussion
One previous report describes a phenotypically female individual with tetralogy of Fallot, skeletal anomalies, and PRS. She was identified to have a 46,XY,t(2;17)(p15;q24.2) karyotype and diagnosed with CD (PMID:30012910). Combined with our case, these reports indicate that translocations outside of the previously reported SOX9 regulatory region can cause CD. Additionally, breakpoints a long distance from SOX9 may lead to milder phenotypes, suggesting that CD is underrecognized. However, it is important to recognize CD to reduce the risk of gonadoblastoma and provide appropriate multisystemic monitoring.
Conclusion
This case highlights that CD due to a translocation a long distance from SOX9 can present with milder phenotype. Further research is needed to better characterize a potential genotype-phenotype correlation. Additionally, ES is unable to detect translocations. Until optical genome mapping becomes more clinically available, karyotypes remain a valuable diagnostic tool. Finally, phenotyping is important in the diagnostic process. Although karyotype is not a phenotype driven test, combining our patient’s clinical features with their genetic test results allowed for an appropriate diagnosis that is used to guide care.
Campomelic dysplasia (CD) is a rare, potentially lethal skeletal dysplasia caused primarily by pathogenic variants in SOX9. However, 5% of cases are due to an interstitial deletion or reciprocal translocation of 17q24.3-q25.1 involving SOX9 or its regulatory region. We present a case of CD caused by a reciprocal translocation outside of the previously reported regulatory region. This case also highlights the importance of phenotyping and the value of a karyotype during a time in which exome sequencing (ES) is commonly recommended.
Case Presentation
A two-week-old female presented due to Pierre Robin sequence (PRS) with cleft palate and failed newborn hearing screen. Physical exam was significant for relative macrocephaly. Trio exome sequencing was initiated. While pending, patient underwent imaging during an admission for respiratory failure at five months of age, and hypoplastic scapula and thoracic vertebral pedicles were identified. Additional features at that time included mild bowing of lower extremities, bilateral mild talipes equinovarus, and midface hypoplasia, all consistent with a diagnosis of CD.
Diagnostic Workup
Exome sequencing reported a hemizygous variant of uncertain significance in FANCB; mother was heterozygous and father was negative. Due to concern for CD and the presence of Y chromosome material, further workup included karyotype and SNP microarray. She was identified to have a balanced translocation between chromosomes 5 and 17 (t(5;17)(q22;q23.1)) with a complete XY sex chromosome complement and no other copy number variants. While this chromosome 17 breakpoint is outside of the previously reported SOX9 regulatory region, this patient’s features are consistent with a diagnosis of CD with XY sex reversal. DEB studies were completed and normal.
Treatment and Management
Following diagnosis, it was recommended that patient continue following with ENT/Pulmonology, Cleft Craniofacial, and Orthopedics. Lateral radiographs of the cervical spine were completed and normal. Due to the presence of Y chromosome material, she was evaluated by Endocrinology and Urology. External genitalia was typical female. Pelvic ultrasound found a typical uterus, but gonads were unable to be visualized. Bilateral laparoscopic gonadectomy was completed and pathology was significant for streak gonads with bilateral gonadoblastoma. Palatoplasty is planned. Hearing loss resolved after bilateral myringotomy and tube placement. Parental karyotypes were completed and normal.
Outcome and Follow-Up
When the patient was last seen in Medical Genetics clinic at 14 months of age, she was making excellent developmental progress. Because of her mild phenotype and novel genetic test results, the diagnosis of CD has been questioned by other providers, which has led to frustration for the family. However, a genetic diagnosis has allowed family and the genetics team to advocate for appropriate care.
Discussion
One previous report describes a phenotypically female individual with tetralogy of Fallot, skeletal anomalies, and PRS. She was identified to have a 46,XY,t(2;17)(p15;q24.2) karyotype and diagnosed with CD (PMID:30012910). Combined with our case, these reports indicate that translocations outside of the previously reported SOX9 regulatory region can cause CD. Additionally, breakpoints a long distance from SOX9 may lead to milder phenotypes, suggesting that CD is underrecognized. However, it is important to recognize CD to reduce the risk of gonadoblastoma and provide appropriate multisystemic monitoring.
Conclusion
This case highlights that CD due to a translocation a long distance from SOX9 can present with milder phenotype. Further research is needed to better characterize a potential genotype-phenotype correlation. Additionally, ES is unable to detect translocations. Until optical genome mapping becomes more clinically available, karyotypes remain a valuable diagnostic tool. Finally, phenotyping is important in the diagnostic process. Although karyotype is not a phenotype driven test, combining our patient’s clinical features with their genetic test results allowed for an appropriate diagnosis that is used to guide care.