Osteopetrosis describes a heterogeneous group of diseases characterised by increased bone density due to impaired osteoclast. The malignant infantile autosomal recessive (MIOP) form caused by mutations in OSTM1 is the most severe form of osteopetrosis. Children with this phenotype exhibit multisystemic complications, of which the neuropathic manifestations are the most severe. Infants with MIOP may present with pain and irritability that are likely to become continuous and debilitating as the disease progresses. There is limited understanding of the aetiology and management of pain in MIOP. Here, we describe a 2 month-old infant with OSTM1 mutation-related MIOP presenting with severe irritability and pain. This case provides the opportunity to discuss the cause and management of these distressing symptoms. We also review similar cases and the possible underlying mechanisms of pain and irritability to help provide a conceptual framework for the management of these symptoms in infants with OSTM1 MIOP.
Mutation in OSTM1 give rise to the rarest and most lethal subtype of malignant infantile osteopetrosis (MIOP), and an improved understanding of OSTM1‐associated MIOP would help with informed decision‐making regarding symptom management and early palliative care referral. This retrospective study describes the clinical and laboratory features of patients with a genetic diagnosis of OSTM1 MIOP made between January 2011 and December 2021 in the Department of Pediatrics, Al‐Adan Hospital, Kuwait. Twenty‐two children had confirmed homozygous deletion in OSTM1 (13 females, nine males). Consanguinity was reported in almost all parents. 72.7% were diagnosed before the age of two months, most commonly incidentally with a high clinical suspicion. All 22 patients developed upper respiratory symptoms, hepatosplenomegaly, poor feeding, and had severe developmental delay. 80% of patients developed pain and/or irritability, and 40.9% were diagnosed with primary seizures. Bone fractures developed in 27% of patients, most likely iatrogenic, and some patients had hernia and gum abnormalities. The mean survival was 10.9 months. The clinical presentation, symptomatology, and mortality of our cohort were compared with other cases of OSTM1 MIOP identified through a comperhensive search of the PubMed database. The findings conclude that OSTM1 MIOP is a multi‐systemic disease with distinct clinical features, of which neurological complications are the most severe and include nociplastic pain and irritability. Although orthopedic complications influence the trajectory of most patients with other forms of osteopetrosis, OSTM1 MIOP is driven by its neurological complications. Hence, OSTM1 should be regarded as a neurodegenerative disease with osteopetrosis as a comorbidity that warrants early palliative care referral.
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