Tohoku J. Exp. Med., 2014 December, 234(4)

A Fatal Case of Infantile Malignant Osteopetrosis Complicated by Pulmonary Arterial Hypertension after Hematopoietic Stem Cell Transplantation

YUICHI KUROYANAGI,¹ HIROHIDE KAWASAKI,¹ YUKIHIRO NODA,¹ TAICHI OHMACHI,¹ SHIN-ICHIRO SEKIYA,¹ KEN YOSHIMURA,¹ CHISATO OHE,² TOSHIMI MICHIGAMI,³ KEIICHI OZONO⁴ and KAZUNARI KANEKO¹

¹Department of Pediatrics, Kansai Medical University, Hirakata, Osaka, Japan
²Department of Pathology, Kansai Medical University, Hirakata, Osaka, Japan
³Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan
⁴Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Infantile malignant osteopetrosis (IMO) is a rare and fatal autosomal recessive condition characterized by a generalized increased in bone density. Hematopoietic stem cell transplantation (HSCT) is the only effective and rational therapy with achieving long-term disease-free survival. However, complications with HSCT for IMO remain unclear. Here we describe a male infant with IMO, carrying two novel mutations in the T-cell immune regulator 1 (TCIRG1) gene. The TCIRG1 gene encodes the a3 subunit of vacuolar H⁺-ATPase that plays an essential role in the resorptive function of osteoclasts. Direct sequencing of all 20 exons of the TCIRG1 gene revealed a single nucleotide change in exon 11 (c1305 G > T), which causes the substitution of Asp (GAT) for Glu (GAG) at position 435, and a two-nucleotide deletion in exon 16 (c1952-1953 del CA), causing a frame-shift mutation. However, the functional consequence of each mutation remains to be determined. Allogeneic HSCT was performed in the patient at the age of nine months. Donor engraftment was achieved, and abnormal bone metabolism and extramedullary hematopoiesis were corrected. Graft-versus-host disease was mild (grade I). However, the patient died of complication of pulmonary arterial hypertension at seven months after the HSCT. Postmortem examination revealed prominent vascular wall thickening of the pulmonary artery and macrophage infiltration to alveoli. It should be noted that a patient with IMO has a risk for pulmonary arterial hypertension, and the evaluation of pulmonary arterial flow should be included in the assessment of each patient with IMO even after HSCT.

keywords —— graft versus host disease; hematopoietic stem cell transplantation; infantile malignant osteopetrosis; pulmonary arterial hypertension; T-cell immune regulator 1

© 2014 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2014, 234, 309-312

Correspondence: Hirohide Kawasaki, M.D., Department of Pediatrics, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan.

e-mail: kawasaki@hirakata.kmu.ac.jp