Bone/Parathyroid Case 7

A 19-year-old Caucasian male presented for assessment of subacute right knee pain and bilateral hip discomfort with exertion during military recruit training. He reported a history of foot and wrist fractures during childhood and chronic backache. The patient’s family history was notable for two brothers with a constellation of fractures including clavicular, foot, and wrist fractures. Radiographs of the right knee and pelvis demonstrated femoral meta-diaphyseal widening and cortical thickening, respectively. Radiographs of the cervical, thoracic, and lumbar spine showed diffuse vertebral body endplate sclerosis “rugger jersey spine appearance.”  Initial laboratory studies including serum calcium, alkaline phosphatase, albumin, 25-hydroxy vitamin D, parathyroid hormone and complete blood count were all normal. DXA scan showed Z-scores of + 0.5 at femoral neck, + 1.4 total hip, and 0.0 at lumbar spine.

Erlenmeyer flask deformity X-ray of knee (left), pelvis x-ray with cortical thickening and sclerosis (center), rugger jersey spine x-ray (right).


Palagano E, Menale C, Sobacchi C, Villa A. Genetics of Osteopetrosis. Curr Osteoporos Rep. 2018;16:13-25. 

Wu CC, Econs MJ, DiMeglio LA, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017;102(9):3111-3123.  

Moore JB, Hoang TD, Shwayhat AF.  Osteopetrosis. Mil Med. 2017;182(3): e1886-e1888.   

Question 1

What is the diagnosis?

A. Renal osteodystrophy
B. Paget disease of bone
C. Osteopetrosis
D. Fluorosis
Correct Answer
C. Osteopetrosis

Osteopetrosis (C) is an inherited connective tissue disease resulting in abnormally dense bones prone to fracture. Mutations in more than a dozen known genes result in dysfunctional osteoclasts and accumulation of old bone normally resorbed. In severe cases, malfunctioning endochondral bone replaces the marrow space, resulting in inadequate hematopoiesis. Resultant pancytopenia can lead to opportunistic infection and death in childhood. Compensatory hepatosplenomegaly ensues as a result of extramedullary hematopoiesis. Cranial nerve deficits can manifest as blood cell production in concert with ongoing hypertrophy enlarges bony structures of the skull. The continued production of abnormal endochondral bone also results in brittleness predisposing to fracture, which occurs even in patients with less severe forms and normal life expectancy.   

A diagnosis of osteopetrosis is based on a thorough clinical evaluation, detailed medical history, X-ray imaging, and bone mineral density measurements.  Genetic testing can identify the mutation in 90% of cases. In our patient, genetic testing revealed 2 heterozygous PLEKHM1 mutations (exon 4 and exon 7).  PLEKHM1 gene is important to endosomal and lysosomal vesicular function.  Defects within the PLEKHM1 gene result in defective osteoclastic ruffled border formation and consequential inadequate bone resorption. This patient’s lack of hematologic deficiencies and survival into adulthood portend an improved long-term prognosis.  

Renal osteodystrophy (A) refers to specific changes in bone morphology associated with chronic kidney disease and was excluded in our patient who does not have chronic kidney disease. The serum alkaline phosphatase was normal, making paget disease of bone (B) unlikely.  Our patient did not have a history of excess fluoride consumption, thus, fluorosis (D) is unlikely.