Bone Abstracts

Background: Parathyroid hormone-like hormone (PTHLH) is an important regulator of endochondral bone development. Mutations of the PTHLH gene can cause a variety of different skeletal dysplasias, with duplications of the PTHLH gene resulting in a phenotype characterized by endochrondomatosis, metaphyseal dysplasia and osteolysis.

Presenting problem: Our patient presented at the age of 4 months, given concerns regarding lower limb deformities and ribcage asymmetry. A skeletal survey revealed multiple rib abnormalities, metaphyseal concavities of the long bones and osteolytic changes. Bone histomorphometry demonstrated increased bone turnover with significantly increased osteoid, areas of woven osteoid and bone marrow fibrosis; features in keeping with hyperparathyroid-bone disease. Serum calcium, phosphate, ALP, PTH and PTHrP concentrations however were all normal. Microarray demonstrated a de novo chromosomal microdeletion on chromosome 12 (12p11.22-p11.21), located near the PTHLH gene. No other known causative mutations or mutations involving the PTH pathway were found on exome sequencing.

Clinical management: Our patient’s clinical course was complicated by significant progressive deformities, of both upper and lower limbs. He had bilateral tibial pseudarthroses and went on to develop other deformities requiring long bone rodding as well as restrictive lung disease secondary to limited chest wall growth. He was commenced on bisphosphonate treatment. Subsequently there has been a significant improvement in ambulation, in the non-operated forearm deformities as well as the operated lower limb deformities. Using qPCR, PTHLH expression in fibroblasts was increased in our patient compared to controls. Analysis of the microdeletion demonstrated that it includes PTHLH regulatory sites and results in a distal limb-enhancer being brought into close proximity to the PTHLH gene.

Discussion: We hypothesize that this novel chromosome 12 microdeletion results in a combination of loss of normal PTHLH regulators and gain of a foreign enhancer, resulting in a phenotype similar to patients with PTHLH duplications.

Disclosure: The authors declared no competing interests.