Clinical and genetic features, surgical management, and longitudinal follow-up in two children with progressive osseous heteroplasia

Background Progressive osseous heteroplasia (POH) is an ultrarare disorder characterized by heterotopic ossification that progresses from the skin and subcutaneous tissues into deeper connective tissues. Most affected individuals harbor heterozygous inactivating variants in GNAS , whereas postzygotic mosaic variants have rarely been described. Evidence to guide surgical management remains limited. Methods We retrospectively characterized two children with clinically diagnosed POH who underwent genetic testing and surgical treatment. Whole-exome sequencing was performed on peripheral blood and, when available, resected tissue, followed by PCR-Sanger sequencing and T-vector cloning. Case 1 underwent clinical and radiographic follow-up for 5 years; follow-up for Case 2 was limited to family-provided radiographs obtained at 2 years. Results Case 1 harbored a possible postzygotic mosaic GNAS variant, NM_000516.7:c.-1_2del, with variant allele frequencies of 14.7% in peripheral blood and 40.56% in bone lesion tissue. The predominantly localized wrist lesion was macroscopically excised. A small radiographic recurrence appeared by the second postoperative year but progressed slowly thereafter; active wrist flexion was 5–10 ° at 5 years. Case 2 harbored NM_000516.7:c.565_568del (p. (Asp189MetfsTer14)), detected as a heterozygous variant in peripheral blood. The lesion diffusely involved neurovascular structures, tendon sheaths, the joint capsule, and adjacent bones, precluding complete excision. Family-provided radiographs at 2 years showed an extent of ossification broadly similar to that before surgery; no in-person clinical assessment was available. Conclusion These cases provide additional clinical, molecular, and longitudinal information on POH and illustrate the importance of lesion distribution and resectability when interpreting surgical outcomes. The available postoperative findings cannot establish a causal relationship between variant status and prognosis because the patients differed in baseline disease extent, completeness of excision, follow-up duration, and outcome ascertainment. A possible association between mosaic burden and lesion distribution remains a hypothesis that requires evaluation in larger cohorts.