Infantile osteopetrosis; bone marrow transplantation from a cousin donor.

Taylor, G. M.; Dearden, S.; Will, Andrew; Evans, D. I. K.; Stevens, Robert G.; Simon, Sybil; Super, Maurice; Morrell, G.; Fergusson, William; Brown, I. H.

doi:10.1136/adc.73.5.453

Cited by 7 publications

(2 citation statements)

References 8 publications

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“…17,18 The role of BMT for osteopetrosis secondary to CAII deficiency, a condition that may have very significant morbidity but an ill-defined mortality risk, has not been previously described. We have demonstrated that BMT does benefit these patients because it reversed osteopetrosis and, in doing so, stabilized vision and hearing and improved their growth potential.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow transplantation corrects osteopetrosis in the carbonic anhydrase II deficiency syndrome

McMahon

Will

et al. 2001

Blood

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Carbonic anhydrase II (CAII), found in renal tubules, brain, and osteoclasts, is critical in acid-base homeostasis and bone remodeling. Deficiency of CAII gives rise to a syndrome of osteopetrosis, renal tubular acidosis (RTA), and cerebral calcification with associated developmental delay. It is inherited in an autosomal recessive fashion and found most frequently in the Mediterranean region and the Middle East. We report 2 related Irish families with clinically severe CAII deficiency in whom the gene mutation has been fully elucidated. Two children, one from each family, have undergone allogeneic bone marrow transplantation because of severe progressive visual and hearing loss. The older 2 children had already developed cerebral calcification and marked visual loss at the time of diagnosis and were treated symptomatically. Post-transplantation evaluation at 2 and 3 years demonstrates histologic and radiologic resolution of their osteopetrosis with stabilization of hearing and vision. Both children remain developmentally delayed and continue to have RTA, and the older child has now developed cerebral calcification. Allogeneic bone marrow stem cell replacement cures the osteoclast component of CAII deficiency and retards the development of cerebral calcification, but it appears to have little or no effect on the renal lesions. IntroductionThe carbonic anhydrases (CA) have important physiologic functions in the body to accelerate the association of CO 2 and H 2 O to form H 2 CO 3 , which dissociates to H ϩ and HCO 3 Ϫ . Carbonic anhydrase II (CAII) is the most catalytically active of the group, with the widest tissue distribution being found in bone, kidney, brain, and erythrocytes, with osteoclasts being particularly rich in CAII. Deficiency of CAII impairs the production of H ϩ by the osteoclast and, thus, bone resorption is blocked, leading to the development of osteopetrosis. 1 The CA gene has been defined and located on chromosome 8. 2 CAII deficiency is an autosomal recessive inherited condition that gives rise to osteopetrosis, renal tubular acidosis (RTA), and cerebral calcification. 3 Short stature, fractures, cranial nerve compression, and developmental delay are variable findings. 1 Severe mental retardation occurs in the Arabic 4 and Japanese 5 populations, but normal or only mildly abnormal development has been reported in some American kindreds. 6 There are 12 described mutations of the CAII gene. However, 3 mutations (His107Tyr, 2971G3a, and 744delA) account for more than 90% of the reported patients with CAII deficiency. 7 Autosomal recessive "malignant" osteopetrosis is a more aggressive form of osteopetrosis. The failure of osteoclasts to reabsorb immature bone results in more severe impairment of bone remodeling, causing bony narrowing of the cranial nerve foramina with cranial nerve, especially optic nerve, compression; abnormal bone marrow cavity formation, resulting in bone marrow failure; and abnormal remodeling of primary, woven bone to lamellar bone, giving rise to "brittle" bone that is...

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Section: Discussionmentioning

confidence: 99%

Bone marrow transplantation corrects osteopetrosis in the carbonic anhydrase II deficiency syndrome

McMahon

Will

et al. 2001

Blood

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“…This can lead to immune recovery, bone remodeling, improved growth and survival. [5][6][7][8][9][10][11][12] In this study we report the outcomes of 10 patients with infantile osteopetrosis, transplanted at the University of Minnesota between 1978 and 1997. The data indicate that allogeneic HCT can be an effective therapeutic option for these children.…”

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Hematopoietic stem cell transplantation for infantile osteopetrosis

Eapen

Davies

Ramsay

et al. 1998

Bone Marrow Transplant

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Summary:Infantile osteopetrosis is a lethal disorder resulting from a severe defect in the ability of osteoclasts to resorb bone. The only therapy shown to be capable of providing lasting benefit is allogeneic hematopoietic stem cell transplantation (HCT). We report the outcome of 10 patients with infantile malignant osteopetrosis treated with HCT from an HLA A, B, DRB1 matched (n = 6) or A or B locus mismatched (n = 4) family member or unrelated donor at the University of Minnesota between 1978 and 1997. Eight of 10 patients achieved primary engraftment; secondary graft failure was seen in two patients. Five of 10 patients survive; three with full or partial donor chimerism and two with autologous hematological recovery. Transient or partial donor chimerism can be sufficient to correct the hematological manifestations of osteopetrosis. We recommend early referral for consideration of HCT with a related or unrelated donor as neurosensory manifestations of osteopetrosis are generally not reversible. Donor engraftment may be easier to achieve early in the course of the disease.

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