Enhanced Diagnostic Precision: A Case Study Supporting Broad Genetic Testing in the Evaluation of Skeletal Disorders
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Our patient presented to specialty care with orthopedics at age 11 years for a scoliosis evaluation. Kyphotic curvature of 56.3 degrees with wedge deformity of L1, short pedicles, and absent creases and motion of the PIP joints were noted. Imaging also identified symmetric small epiphyses in the proximal femur, proximal tibia, and distal tibia. Patient was also seen by neurosurgery for cervical and thoracic spinal cord syrinx. Further imaging and follow up with both specialists increased suspicion for spondyloepiphyseal dysplasia or possible multiple epiphyseal dysplasia, and a referral was placed to genetics.
Case Presentation
Family history was significant for father and other paternal family members with joint pain and various skeletal concerns. Physical exam findings consistent with macrocephaly, tall/prominent forehead, bilateral prominent helices, pear-shaped nose, thin lips, bilateral brachydactyly with swelling of proximal interphalangeal joints with short metacarpals, bilateral long second toes in comparison to others, and waddling gait.
Diagnostic Workup
Due to previous imaging consistent with findings related to multiple epiphyseal dysplasia, panel was ordered including the following genes: CANT1, COL2A1, COL9A1, COL9A2, COL9A3, COMP, DDR2, MATN3, SLC26A2, UFSP2. This resulted as nondiagnostic. Reflex to larger skeletal disorders panel containing 358 genes was then pursued, which resulted with the following pathogenic variants: NOG: c.665A>G(p.Tyr222Cys), TRPS1: Gain (Exons 2-4) copy number = 3, AND TRPS1: Deletion (exon 5). Parental testing revealed paternal inheritance of the NOG variant and TRPS1 variants likely de novo. Other variants from this panel not included here due to being nondiagnostic or of uncertain significance.
Treatment and Management
Upon confirmation of these gene variants, we ordered additional skeletal imaging indicated based on these findings, as well as a baseline echocardiogram and audiology evaluation.
Outcome and Follow-Up
NOG is associated with autosomal dominant NOG-related symphalangism spectrum disorder. The primary symptom is variable fusions of the joints in the hands and feet, but affected individuals can also present with brachydactyly, limited range of motion due to joint contractures, distinctive facial features, and sometimes conductive hearing loss due to abnormalities of the bones in the middle ear. Vertebral anomalies and spinal canal stenosis have also been described.
TRPS is associated with autosomal dominant trichorhinophalangeal syndrome. TRPS is a skeletal dysplasia characterized by a distinctive facial appearance, skeletal abnormalities and short stature. Patients have sparse, slowly growing scalp hair, laterally sparse eyebrows, a bulbous tip of the nose, protruding ears, long flat philtrum and thin upper vermilion border. The most typical radiographic findings in TRPS are cone-shaped epiphyses, predominantly at the middle phalanges, which are often not detectable before 2 years of age. Hip malformations such as coxa plana, coxa magna, or coxa vara are present in >70% of patients. Our patient’s features are consistent with both NOG and TRPS1-related disorders. Curiously, they lacked the characteristic cone-shaped epiphyses of TRPS.
Conclusion
In hindsight, rather than focusing on the radiologic findings consistent with multiple epiphyseal dysplasia, a larger skeletal disorders panel or exome sequencing could have been considered as first-tier testing. Broad genetic testing is superior when assessing skeletal disorders because it provides a comprehensive analysis that captures the genetic complexity underlying these conditions. Broad testing can also incorporate comparator samples from the start and avoid the need for a separate step for parental testing. This is particularly important for skeletal disorders, which often have diverse genetic causes and overlapping clinical features. Broad testing increases diagnostic accuracy, enables earlier interventions, and supports personalized treatment plans by uncovering genetic factors that may influence disease progression or therapeutic response. Thus, broad genetic testing offers a more thorough, efficient, and precise evaluation, ultimately improving patient outcomes.
Our patient presented to specialty care with orthopedics at age 11 years for a scoliosis evaluation. Kyphotic curvature of 56.3 degrees with wedge deformity of L1, short pedicles, and absent creases and motion of the PIP joints were noted. Imaging also identified symmetric small epiphyses in the proximal femur, proximal tibia, and distal tibia. Patient was also seen by neurosurgery for cervical and thoracic spinal cord syrinx. Further imaging and follow up with both specialists increased suspicion for spondyloepiphyseal dysplasia or possible multiple epiphyseal dysplasia, and a referral was placed to genetics.
Case Presentation
Family history was significant for father and other paternal family members with joint pain and various skeletal concerns. Physical exam findings consistent with macrocephaly, tall/prominent forehead, bilateral prominent helices, pear-shaped nose, thin lips, bilateral brachydactyly with swelling of proximal interphalangeal joints with short metacarpals, bilateral long second toes in comparison to others, and waddling gait.
Diagnostic Workup
Due to previous imaging consistent with findings related to multiple epiphyseal dysplasia, panel was ordered including the following genes: CANT1, COL2A1, COL9A1, COL9A2, COL9A3, COMP, DDR2, MATN3, SLC26A2, UFSP2. This resulted as nondiagnostic. Reflex to larger skeletal disorders panel containing 358 genes was then pursued, which resulted with the following pathogenic variants: NOG: c.665A>G(p.Tyr222Cys), TRPS1: Gain (Exons 2-4) copy number = 3, AND TRPS1: Deletion (exon 5). Parental testing revealed paternal inheritance of the NOG variant and TRPS1 variants likely de novo. Other variants from this panel not included here due to being nondiagnostic or of uncertain significance.
Treatment and Management
Upon confirmation of these gene variants, we ordered additional skeletal imaging indicated based on these findings, as well as a baseline echocardiogram and audiology evaluation.
Outcome and Follow-Up
NOG is associated with autosomal dominant NOG-related symphalangism spectrum disorder. The primary symptom is variable fusions of the joints in the hands and feet, but affected individuals can also present with brachydactyly, limited range of motion due to joint contractures, distinctive facial features, and sometimes conductive hearing loss due to abnormalities of the bones in the middle ear. Vertebral anomalies and spinal canal stenosis have also been described.
TRPS is associated with autosomal dominant trichorhinophalangeal syndrome. TRPS is a skeletal dysplasia characterized by a distinctive facial appearance, skeletal abnormalities and short stature. Patients have sparse, slowly growing scalp hair, laterally sparse eyebrows, a bulbous tip of the nose, protruding ears, long flat philtrum and thin upper vermilion border. The most typical radiographic findings in TRPS are cone-shaped epiphyses, predominantly at the middle phalanges, which are often not detectable before 2 years of age. Hip malformations such as coxa plana, coxa magna, or coxa vara are present in >70% of patients. Our patient’s features are consistent with both NOG and TRPS1-related disorders. Curiously, they lacked the characteristic cone-shaped epiphyses of TRPS.
Conclusion
In hindsight, rather than focusing on the radiologic findings consistent with multiple epiphyseal dysplasia, a larger skeletal disorders panel or exome sequencing could have been considered as first-tier testing. Broad genetic testing is superior when assessing skeletal disorders because it provides a comprehensive analysis that captures the genetic complexity underlying these conditions. Broad testing can also incorporate comparator samples from the start and avoid the need for a separate step for parental testing. This is particularly important for skeletal disorders, which often have diverse genetic causes and overlapping clinical features. Broad testing increases diagnostic accuracy, enables earlier interventions, and supports personalized treatment plans by uncovering genetic factors that may influence disease progression or therapeutic response. Thus, broad genetic testing offers a more thorough, efficient, and precise evaluation, ultimately improving patient outcomes.