An Atypical Case of Pseudohypoparathyroidism 1b due to Uniparental Hetero- and Isodisomy Detected by Genome Sequencing
Clinical Genetics and Therapeutics
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Primary Categories:
- Genomic Medicine
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Secondary Categories:
- Genomic Medicine
Introduction
Pseudohypoparathyroidism type 1b (PHP1b) is a disorder of hormone resistance associated with imprinting at the GNAS locus. Multiple cases of sporadic PHP1b have been attributed to paternal uniparental disomy (UPD) of chromosome 20. While isodisomy is readily detectable by clinical genome sequencing (cGS), heterodisomy can often go undetected. Here, we present a case of PHP1b caused by mixed hetero- and isodisomy that was detected by trio cGS testing.
Case Presentation
The 27 year-old male proband presented to the orthopedics clinic for treatment of skeletal anomalies following a childhood diagnosis of multiple epiphyseal dysplasia. Clinical features include recurrent bone fractures, genu valgum, osteoarthritis, levocurvature of the thoracolumbar spine, mild dysmorphic facial features, and dental anomalies. X-ray of the lower extremities showed serpentine fibulae, a finding not consistent with multiple epiphyseal dysplasia and suggestive of either Hajdu-Cheney syndrome or serpentine fibula-polycystic kidney syndrome (SFPKS), both of which are associated with variants in NOTCH2. Further, preoperative bloodwork at age 21 showed markedly elevated parathyroid hormone (PTH) (612 pg/mL; normal range: 15-65 pg/mL) and low-normal levels of calcium and 25-hydroxy vitamin D, consistent with pseudohypoparathyroidism. Aside from the noted skeletal anomalies, development was otherwise normal. No family history relevant to the proband’s clinical presentation was reported.
Diagnostic Workup
Previous targeted testing performed by an external laboratory was negative for variants in GNAS and NOTCH2. Trio cGS was provided through Illumina Laboratory Services as part of the iHope program. Large regions of homozygosity encompassing ~2/3 of the length of chromosome 20 (20p13-p11.21 and 20q11.21-q13.12) were detected in the proband, indicative of partial UPD. Notably, this region does not contain the imprinted GNAS locus. Genotype analysis in the apparently heterozygous distal region failed to detect maternally-inherited SNVs. Taken together, these results suggested a pattern of mixed paternal UPD20. Additional testing performed at outside laboratories confirmed the finding of UPD via microsatellite marker analysis and detected altered methylation patterns at the GNAS locus consistent with the diagnosis of PHP1b. No pathogenic variants were detected in NOTCH2 or in candidate genes involved in Notch signaling.
Treatment and Management
Multiple surgical interventions were employed to correct the proband’s skeletal anomalies, including hip, knee, and ankle plate surgery at age 12, and a right proximal femoral intertrochanteric valgus osteotomy with internal fixation as well as a right tibial and fibular osteotomy for correction of genu valgum. The proband is being treated with calcium carbonate, calcitriol, and cholecalciferol (vitamin D-3). Renal ultrasound was normal.
Discussion
Uniparental isodisomy is routinely detected by trio cGS based on the presence of large regions of homozygosity, while heterodisomy is not as readily apparent and is therefore less likely to be detected. In this case, mixed hetero- and isodisomy was suspected based on the diagnosis of PHP and the genomic location of GNAS outside of the observed isodisomic region in the proband. Given the initial suspicion of Hajdu-Cheney syndrome or SFPKS, this finding does not fully explain the proband’s phenotype and may warrant further genetic investigation.
Conclusion
The molecular genetic findings in this case demonstrate that trio cGS is suitable for the detection of mixed UPD, which can inform the diagnosis of imprinting disorders, even when the presentation is atypical. In addition to informing the wider medical genomics community, these data may potentially aid in the development of automated callers which can recognize UPD using short read DNA sequencing technology.
Pseudohypoparathyroidism type 1b (PHP1b) is a disorder of hormone resistance associated with imprinting at the GNAS locus. Multiple cases of sporadic PHP1b have been attributed to paternal uniparental disomy (UPD) of chromosome 20. While isodisomy is readily detectable by clinical genome sequencing (cGS), heterodisomy can often go undetected. Here, we present a case of PHP1b caused by mixed hetero- and isodisomy that was detected by trio cGS testing.
Case Presentation
The 27 year-old male proband presented to the orthopedics clinic for treatment of skeletal anomalies following a childhood diagnosis of multiple epiphyseal dysplasia. Clinical features include recurrent bone fractures, genu valgum, osteoarthritis, levocurvature of the thoracolumbar spine, mild dysmorphic facial features, and dental anomalies. X-ray of the lower extremities showed serpentine fibulae, a finding not consistent with multiple epiphyseal dysplasia and suggestive of either Hajdu-Cheney syndrome or serpentine fibula-polycystic kidney syndrome (SFPKS), both of which are associated with variants in NOTCH2. Further, preoperative bloodwork at age 21 showed markedly elevated parathyroid hormone (PTH) (612 pg/mL; normal range: 15-65 pg/mL) and low-normal levels of calcium and 25-hydroxy vitamin D, consistent with pseudohypoparathyroidism. Aside from the noted skeletal anomalies, development was otherwise normal. No family history relevant to the proband’s clinical presentation was reported.
Diagnostic Workup
Previous targeted testing performed by an external laboratory was negative for variants in GNAS and NOTCH2. Trio cGS was provided through Illumina Laboratory Services as part of the iHope program. Large regions of homozygosity encompassing ~2/3 of the length of chromosome 20 (20p13-p11.21 and 20q11.21-q13.12) were detected in the proband, indicative of partial UPD. Notably, this region does not contain the imprinted GNAS locus. Genotype analysis in the apparently heterozygous distal region failed to detect maternally-inherited SNVs. Taken together, these results suggested a pattern of mixed paternal UPD20. Additional testing performed at outside laboratories confirmed the finding of UPD via microsatellite marker analysis and detected altered methylation patterns at the GNAS locus consistent with the diagnosis of PHP1b. No pathogenic variants were detected in NOTCH2 or in candidate genes involved in Notch signaling.
Treatment and Management
Multiple surgical interventions were employed to correct the proband’s skeletal anomalies, including hip, knee, and ankle plate surgery at age 12, and a right proximal femoral intertrochanteric valgus osteotomy with internal fixation as well as a right tibial and fibular osteotomy for correction of genu valgum. The proband is being treated with calcium carbonate, calcitriol, and cholecalciferol (vitamin D-3). Renal ultrasound was normal.
Discussion
Uniparental isodisomy is routinely detected by trio cGS based on the presence of large regions of homozygosity, while heterodisomy is not as readily apparent and is therefore less likely to be detected. In this case, mixed hetero- and isodisomy was suspected based on the diagnosis of PHP and the genomic location of GNAS outside of the observed isodisomic region in the proband. Given the initial suspicion of Hajdu-Cheney syndrome or SFPKS, this finding does not fully explain the proband’s phenotype and may warrant further genetic investigation.
Conclusion
The molecular genetic findings in this case demonstrate that trio cGS is suitable for the detection of mixed UPD, which can inform the diagnosis of imprinting disorders, even when the presentation is atypical. In addition to informing the wider medical genomics community, these data may potentially aid in the development of automated callers which can recognize UPD using short read DNA sequencing technology.