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Neonatal Lethal Osteochondrodysplasia with Low Serum Levels of Alkaline Phosphatase and Osteocalcin

Departments of Pediatrics (M.H.W., C.E.-T., A.L.) and Pathology (C.T.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; Orthopedic Pathology (F.H.G.), Armed Forces Institute of Pathology, Washington, D.C. 20306-6000; Division of Bone and Mineral Diseases (X.Z., S.M., M.P.W.), Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri 63110; and Center for Metabolic Bone Disease and Molecular Research (S.M., M.P.W.), Shriners Hospitals for Children, St. Louis, Missouri 63131

Address all correspondence and requests for reprints to: Dr. Michael P. Whyte, Shriners Hospitals for Children, 2001 South Lindbergh Boulevard, St. Louis, Missouri 63131. E-mail: mwhyte{at}shrinenet.org.

Neonatal lethal skeletal dysplasias are rare and typically involve thoracic malformations and severe limb shortening. We report on a newborn boy manifesting an osteochondrodysplasia associated with fatal respiratory insufficiency who had normal lung volumes and extremity lengths. His disorder featured aberrant skeletal patterning and defective ossification including a severely osteopenic skull, apparent absence of clavicles, and clefting of the mandible and vertebrae. Serum alkaline phosphatase and osteocalcin levels were markedly low. Biochemical studies suggested parathyroid insufficiency probably from critical illness. Histopathology at autopsy excluded impaired mineralization of skeletal matrix, but endochondral bone formation appeared disorganized with growth plate clustering of chondrocytes in hypertrophic zones and in zones of provisional calcification. Parathyroid glands were not found. Despite features of two distinctive heritable entities, hypophosphatasia and cleidocranial dysplasia, the cumulative findings did not match either condition, and no mutations were found in either the tissue nonspecific ALP isoenzyme or core-binding factor genes, respectively, or in the genes encoding osteocalcin or the osteoblast transcription factor osterix. This patient could represent the extreme of cleidocranial dysplasia (a disorder not always associated with structural mutation in core-binding factor A1), but more likely he defines a unique osteochondrodysplasia disrupting both intramembranous and endochondral bone formation.