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

Abstract

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.

Novel CLCN7 mutation identified in a Han Chinese family with autosomal dominant osteopetrosis-2

“…1 Generally, osteopetrosis is a rare monogenic heritable bone condition characterized by increased bone density due to defective osteoclastic bone resorption, 2–4 exhibiting variable clinical signs with an incidence of about 5/100,000. 2,5 It is an autosomal dominant or recessive inherited disorder possibly caused by mutations in the genes involved in the bone formation or resorption. 4,6 The present literature describes at least nine disease-causing genes, including the low-density lipoprotein receptor-related protein 5 gene ( LRP5 , MIM 603506), the chloride channel 7 gene ( CLCN7 , MIM 602727), the T cell immune regulator 1 gene ( TCIRG1 , MIM 604592), the tumor necrosis factor ligand superfamily, member 11 gene ( TNFSF11 , MIM 602642), the carbonic anhydrase II gene ( CA2 , MIM 611492), the osteopetrosis-associated transmembrane protein 1 gene ( OSTM1 , MIM 607649), the pleckstrin homology domain-containing protein, family M, member 1 gene ( PLEKHM1 , MIM 611466), the tumor necrosis factor receptor superfamily, member 11A gene ( TNFRSF11A , MIM 603499), and the sorting nexin 10 gene ( SNX10 , MIM 614780).…”

Afghan Mutation of Ca-Ii Gene

“…Recurrent infections and growth retardation may also be seen .This disease is usually fatal in infancy. 7 Intracranial calcifications and renal tubular acidosis is not seen in these patients, however in our patient these two are the key manifestations.…”

Health assessment in patients with autosomal recessive osteopetrosis before and after allogeneic hematopoietic stem cell transplantation

“…При неродственных аллогенных ТГСК при кондиционировании с иммуносупрессивной целью вводился антитимоцитарный глобулин. Большинство исследователей отмечают высокий риск миелоаблативного кондиционирования при данной нозологии [1] из-за высокого риска развития синдрома эндотелиального повреждения с поздним, отсроченным дебютом [10,11]. В то же время при использовании режимов сниженной интенсивности отмечается высокий процент отторжения или первичного неприживления трансплантата [1].…”

“…ТГСК от неродственных 10/10 HLA-идентичных доноров проведена у 4 пациентов и от родственного 10/10 HLA-идентичного донора -у 1 больного. Распределение по полу мальчики:девочки составило 2:3, на момент трансплантации медиана возраста составила 7 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11) лет. У всех пациентов после ТГСК определялся полный донорский химеризм.…”