MG-109 Revisiting a clinical diagnosis 15 years later with the aid of whole exome sequencing: Osteopetrosis versus harderophorphyria
Bibliographic record
Abstract
<h3></h3> The advent of whole exome sequencing (WES) has revolutionised gene discovery and led to the identification of atypical phenotypes for well-known syndromes. Our case illustrates the phenotypic overlap between very different syndromes, harderoporphyria and infantile osteopetrosis, which was only resolved by WES. We report two siblings, both born with severe hepatosplenomegaly, jaundice, thrombocytopenia and anaemia. The eldest child had increased bone density on radiographs and was diagnosed with infantile osteopetrosis. Both children responded well to bone marrow transplant (BMT). Molecular testing was negative for genes involved in infantile osteopetrosis: <i>CLCN7, TCIRG1, OSTM1, TNFSF11A </i>and <i>PLEKHMI1</i>. Many years later, the family was offered whole exome sequencing to clarify the underlying molecular aetiology. The siblings were found to harbour a homozygous mutation (p. K404E) in the <i>CPOX</i> gene confirming a diagnosis harderoporphyria. No mutations were found in any known genes causing infantile osteopetrosis. Defects of heme biosynthesis enzymes result in porphyrias. Harderoporphyria is caused by homozygous mutations in the <i>CPOX</i> gene which encodes coproporphyrinogen oxidase. Individuals with harderoporphyria exhibit neonatal hyperbilirubinemia, hemolytic anaemia, hepatosplenomegaly and photosensitivity. Infantile osteopetrosis presents with increased bone density, reduction of bone marrow spaces leading to anaemia, hepatosplenomegaly, cranial nerves compression and severe growth failure. It is a lethal condition, but responds well to BMT. Given that both children had undergone BMT, their own hematopoietic precursors would have been replaced by those of the donor. Thus, they would not be expected to manifest a harderoporphyria phenotype. To our knowledge, there have been no reports of increased bone mineral density in patients with harderoporphyria. An initial clinical presentation suggesting a diagnosis infantile osteopetrosis was only challenged after the WES data returned. Since the siblings received BMT in the first year of life, it remains unknown whether increased bone density was a persistent finding. This case report illustrates the clinical utility of WES and the importance of establishing a definitive molecular diagnosis for appropriate genetic counselling and medical management.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".