From genotype to phenotype: the impact of early management in pycnodysostosis
Paulo Rafael Gonçalves da Silva Von Zuben1, Sophia Zuppo de Sousa1, Carolina Costa Figueiredo2
1Centro Universitário São Camilo, São Paulo, SP, Brazil.
Insights
Pycnodysostosis (PYCD), a genetic disorder, presents varied skeletal issues. Early treatment with growth hormone, calcium, and cholecalciferol can improve growth, while bisphosphonates may worsen outcomes in PYCD patients.
Area of Science:
- Genetics and Molecular Biology
- Pediatric Endocrinology
- Skeletal Dysplasias
Background:
- Pycnodysostosis (PYCD) is a rare genetic disorder characterized by osteosclerosis and skeletal fragility, typically caused by mutations in the Cathepsin K (CTSK) gene.
- Patients with PYCD often present with short stature, fractures, and other skeletal abnormalities, with significant variability in clinical presentation.
- Understanding the genotype-phenotype correlations and therapeutic responses is crucial for managing PYCD.
Purpose of the Study:
- To describe the clinical progression and therapeutic responses in four pediatric cases of Pycnodysostosis (PYCD).
- To investigate the impact of different treatment modalities, including growth hormone, calcium, cholecalciferol, and bisphosphonates, on growth and bone health in PYCD.
- To highlight the role of CTSK gene mutations in defining PYCD and influencing its phenotypic expression.
Main Methods:
- Case series describing four pediatric patients diagnosed with Pycnodysostosis (PYCD) based on clinical findings and genetic analysis.
- Genetic sequencing to identify mutations in the CTSK gene.
- Clinical monitoring of growth parameters (height, growth velocity, Z-scores) and fracture history.
- Assessment of therapeutic interventions, including growth hormone therapy, calcium, cholecalciferol, and bisphosphonates.
Main Results:
- Four cases of PYCD with distinct CTSK mutations (c.436G>C; p.Gly146Arg, c.721C>T; p.Arg241*, and c.953G>A; p.Cys318Tyr) were analyzed.
- Growth hormone therapy, combined with calcium and cholecalciferol, demonstrated improved growth velocity and stature Z-scores in patients with PYCD.
- One patient treated with bisphosphonates experienced worsened bone integrity and increased fracture risk, suggesting a negative impact of this treatment in PYCD.
- The CTSK c.953G>A (p.Cys318Tyr) variant was associated with severe skeletal manifestations and a variable treatment response.
Conclusions:
- While CTSK mutations define Pycnodysostosis (PYCD), the clinical phenotype can be modulated by early and individualized interventions.
- Growth hormone therapy, calcium, and cholecalciferol are beneficial for improving growth in selected PYCD patients.
- Bisphosphonates may have detrimental effects on bone remodeling and fracture risk in PYCD, necessitating caution in their use.
Summary:
Pycnodysostosis (PYCD) is an osteosclerotic skeletal dysplasia caused by mutations in the CTSK gene. We describe four cases, highlighting their clinical progression and therapeutic responses. Case 1 is a 2-year-old girl with non-consanguineous parents exhibiting short stature (Z-score: -3.23), slow growth (3 cm/year), wide fontanelles, small hands, and no fractures. She received cholecalciferol and calcium. Two CTSK variants (c.436G>C; p.Gly146Arg and c.721C>T; p.Arg241*) were identified. At age three, somatropin was initiated, leading to improved growth (8 cm/year) and a stature Z-score of -2.21, without fractures until age six. Case 2 is a 2-year-old boy, sibling of Case 1, presenting with similar findings (Z-score: -1.81). Carrying the same CTSK variants, he showed improved growth (3 cm/4 months) after growth hormone therapy. Case 3 is a 3-year-old boy with consanguineous parents having short stature (Z-score: -3.75), slow growth (2 cm/year), exophthalmos, bluish sclera, and multiple tibial fractures. A homozygous CTSK variant (c.953G>A; p.Cys318Tyr) was identified. Growth hormone at age six, alongside cholecalciferol and calcium, increased growth (7 cm/year) and improved stature (Z-score: -2.65). Case 4 is an 8-year-old girl with consanguineous parents having multiple fractures, exophthalmos, and severe growth impairment. Misdiagnosed with osteogenesis imperfecta, she received bisphosphonates, further compromising bone integrity. While genotype defines PYCD, early intervention can modulate its phenotype. Growth hormone, calcium, and cholecalciferol improved growth, whereas bisphosphonates negatively impacted bone quality.
Learning Points:
CTSK mutations define PYCD, but patients exhibit diverse skeletal features, necessitating individualized management. Despite normal IGF-1, growth hormone therapy enhances growth velocity and final height in selected PYCD cases. Bisphosphonates may worsen bone remodeling in PYCD, increasing fracture risk and impairing growth. The CTSK c.953G>A (p.Cys318Tyr) variant correlates with severe skeletal manifestations and variable treatment response.
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