ESPE Abstracts

Background: Mutations in the ANKH gene affect the cellular transportation of the bone mineralization inhibitor, inorganic pyrophosphate (PPi). Loss-of-function mutations in this gene result in craniometaphyseal dysplasia (CMD), a rare disorder characterized by bone hyperostosis, particularly in the craniofacial bones, and metaphyseal widening of long bones. CMD patients experience impaired transport of PPi to extracellular compartment, leading to excessive bone mineralization. Some reports also noted hypocalcemia, hypophosphatemia, elevated alkaline phosphatase (ALP) and parathyroid hormone (PTH) levels consistent with rickets-like features in CMD patients. One study also reported hypophosphatemic rickets in a CMD patient. Here, we present a case of skeletal hyperostosis and calcipenic rickets, initially diagnosed as infantile osteopetrosis but later identified as CMD.

Method: Patient’s clinical information was reviewed, and whole exome sequencing (WES) was conducted to identify genetic abnormalities.

Result: A 2-year-old boy presented with bowed legs and inability to walk since the age of 1 year. Physical examination revealed faltering growth (weight 7.9 kg [<P3] and height 67.5 cm [<P3]), macrocephaly, frontal bossing, hepatomegaly, and anterolateral bowing of both legs. Left nystagmus with poor visual acuity due to optic neuropathy and bilateral hearing loss were identified. Laboratory investigations revealed marked hypocalcemia (calcium 6.4, phosphate 4.7 mg/dL, albumin 4.5 g/dL), elevated ALP (1381 U/L), high PTH (261 pg/mL) and vitamin D deficiency (25OHD 15.3 ng/mL). Radiographic studies demonstrated diffuse osteosclerosis, a bone-within-bone appearance, and signs of rickets, including fraying and flaring of metaphyses. MRI of the brain revealed ventriculomegaly with optic and internal auditory canal stenosis, diffuse thickening of bony calvaria and facial bones, and cerebellar ectopia. Initial suspicion was for concomitant infantile osteopetrosis and calcipenic rickets. Calcium and vitamin D supplementation was initiated. Subsequent genetic analysis identified a heterozygous in-frame variant, c.1124_1126del (p.Ser375del) in the ANKH gene, leading to the diagnosis of CMD. This variant has been reported and classified as pathogenic, resulting in decreased ANKH expression. Previous functional studies confirmed reduced extracellular PPi levels, leading to loss of inhibition of hydroxyapatite accretion in bones, and subsequently causing osteosclerosis.

Conclusion: CMD is a rare cause of skeletal hyperostosis in children, mimicking osteopetrosis. This case underscores the importance of genetic testing in distinguishing rare disorders associated with osteosclerosis. The clinical course of CMD may complicate with hypocalcemia and elevated ALP and PTH levels due to calcipenic rickets, likely resulting from excessive bone mineralization and increased calcium uptake in bone or occurring concurrently with nutritional rickets.