Balkan Journal of Medical Genetics

OSTEOPETRORICKETS IN AN INFANT WITH COEXISTENT CONGENITAL CYTOMEGALOVIRUS INFECTION
Katsafiloudi M, Gombakis N, Hatzipantelis E, Tragiannidis A
*Corresponding Author: Athanasios Tragiannidis, M.D., Ph.D., Assistant Professor of Pediatrics, Pediatric Hematology-Oncology Unit, 2nd Pediatric Department, AHEPA Hospital, Aristotle University of Thessaloniki, S. Kiriakidi 1 str., Thessaloniki, Greece. Tel: +306-944-944-777. Fax: +302-310-994-803. E-mail: atragian@ auth.gr; atragian@hotmail.com
page: 107

DISCUSSION

Osteopetrosis seems to be related to defects in the acidification process of resorption lacuna, mainly caused by mutations in the TCIRG1, CLCN7 and CAII genes coding for a 3-subunit of proton pump, chloride channel and carbonic anydrase II, respectively. Mutation in the TCIRG1 or CLCN7 gene is found in nearly 70.0% of all patients with autosomal recessive osteopetrosis [4,8]. The TCIRG1 gene mutation was also detected in our patient. Mutations in the TCIRG1 gene present clinically as malignant autosomal recessive osteopetrosis in early infancy. Severe anemia, thrombocytopenia, neutropenia, hepatosplenomegaly, susceptibility to fractures, cranial nerve anomalies, visual impairment and deafness, are the prominent manifestations. Meanwhile, CMV infection is the most frequent congenital infection in humans and shares common clinical features including pancytopenia, hepatosplenomegaly, intrauterine growth retardation, sensorineural hearing loss and intracranial calcifications. Our patient was assessed for common causes of pancytopenia and hepatosplenomegaly including CMV and other congenital and acquired infections. Infantile leukemia and myeloproliferating diseases were excluded by bone marrow aspiration. Inborn errors of metabolism and chromosomal anomalies were ruled out by metabolic control and karyotype, respectively. Evaluation for congenital infections revealed a CMV infection, which was regarded as a coincidence, as radiological findings raised the suspicion of osteopetrosis. Other inherited and acquired conditions with sclerotic skeletal appearance such as pyknodysostosis, progressive diaphyseal dysplasia, renal osteodystrophy, hypervitaminosis A and D, chemical poisoning and transient hypersclerosis of infancy were excluded by bone biopsy and genetic analysis that confirmed the diagnosis of autosomal recessive osteopetrosis [5,10]. Remarkable in this case, was the biochemical and radiological evidence of rickets, which is a paradoxical complication of osteopetrosis. Despite a positive total body calcium balance, patients with osteopetrosis tend to develop rickets because the dysfunctional osteoclasts are unable to maintain a normal calcium-phosphorus balance in the extracellular fluid [9]. In osteopetrorickets the serum calcium-phosphate product decreases (<30.0 mg2/dL2) so that the mineralization of growing bones is insufficient [4]. The diagnostic radiological findings of rickets superimposed on the osteopetrosis are changes in metaphyses of long bones and in costochondral junctions (rachitic rosary), which was also noticed in our patient, along with the biochemical markers of rickets [4]. Treatment of rickets with calcitriol and calcium supplementation improves the overall condition of these patients and is essential for successful BMT. At present, hematopoietic stem cell transplantation offers the only chance of cure for malignant infantile osteopetrosis (MIOP), and ideally, it should be performed early, before the irreversible neurologic impairment [7]. Hematopoietic stem cell transplantation (HSCT) using HLA identical donors results in 73.0% 5-year disease-free survival [3]. The purpose of transplantation is to provide hematopoietic stem cells from which normal osteoclasts can differentiate. However, BMT cannot cure patients with osteopetrorickets, as normal osteoclasts cannot resorb the hypomineralized osteoid. Therefore, it is important to diagnose and treat the rickets before BMT [4]. Another therapeutic option is interferon γ-1b, mainly recommended in non infantile osteopetrosis or as a bridge to transplantation [3,5]. Hatzipantelis et al. [11] have reported a case of malignant infantile osteopetrosis treated with IFN-γ with subsequent improvement in bone resorption and hematopoietic function but the patient died from sepsis 4 months later. Finally, the therapeutic spectrum includes supportive blood transfusions, treatment of infections and regular assessment of the patient by a multidisciplinary team consisting of specialists in hematology, endocrinology, ophthalmology, neurology-neurosurgery, orthopedics, dentistry, otolaryngology and nephrology. Gene therapy would be the optimum future direction to a radical cure of osteopetrosis. Given the fact that parents of MIOP patients are at 25.0% risk of having further affected children in each pregnancy, genetic counseling is of utmost importance for the families in whom a mutation has been identified.

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