Hematopoietic stem cell transplantation in a patient with osteopetrosis and mutation in CLCN7: long-term follow-up / Trasplante de células progenitoras hematopoyéticas en un paciente con osteopetrosis y mutación en CLCN7: seguimiento a largo plazo

Abstract Background: Osteopetrosis is a rare hereditary bone dysplasia characterized by insufficient osteoclast activity that results in increased bone mineral density. Hematopoietic stem cell transplantation (HSCT) can reverse skeletal abnormalities and restore hematopoiesis. Case report: We present the case of a 3-year and 2-month-old male patient with the diagnosis of osteopetrosis. The patient underwent allogeneic HSCT (Allo-HSCT) using 100% compatible bone marrow from a related donor and received a myeloablative conditioning regimen and a CD34 cell dose (4.7 × 107/kg). In the early post-transplant, frequent complications such as pneumonitis, hypercalcemia, and hyperphosphatemia ocurred. With a suitable granulocytic graft and chimerism of 100%, it was considered a successful transplant. However, the patient showed a delayed platelet graft treated with a platelet-stimulating factor for 6 months. The patient is currently disease-free, outpatient follow-up, with no data on graft-versus-host disease, and no progressive neurological damage. Conclusions: Osteopetrosis is a childhood disease that requires clinical suspicion and early diagnosis. HSCT is necessary at an early age to prevent disease progression and sensorineural, hematological, and endocrinological functions damage that can lead to death.

Resumen Introducción: La osteopetrosis es una displasia ósea hereditaria poco común, caracterizada por una actividad osteoclástica deficiente que aumenta la densidad mineral ósea. Se considera que el trasplante de células progenitoras hematopoyéticas (TCPH) puede revertir las anormalidades esqueléticas y restaurar la hematopoyesis. Caso clínico: Se presenta el caso de un paciente de sexo masculino, de 3 años y 2 meses de edad, con diagnóstico tardío de osteopetrosis. Se realizó un TCPH alogénico de donador relacionado 100% compatible con médula ósea. Se utilizaron un régimen de acondicionamiento mieloablativo y una dosis celular de CD34 de 4.7 × 107/kg de peso. En el postrasplante temprano, el paciente desarrolló complicaciones como neumonitis, hipercalcemia e hiperfosfatemia. Con un injerto granulocítico adecuado y quimerismo del 100% se consideró un trasplante exitoso. Sin embargo, el paciente presentó retraso en el injerto plaquetario, por lo que se administró factor estimulante de plaquetas por 6 meses. Actualmente el paciente se encuentra libre de enfermedad, en seguimiento ambulatorio, sin datos de enfermedad del injerto contra el hospedero y con pruebas de neurodesarrollo sin deterioro neurológico progresivo. Conclusiones: La osteopetrosis es una enfermedad infantil que requiere una sospecha clínica y un diagnóstico temprano, ya que es necesario un TCPH a corta edad como tratamiento para evitar la progresión de la enfermedad y el deterioro de las funciones neurosensoriales, hematológicas y endocrinológicas que puede derivar en la defunción del paciente.

SNX10 gene mutation in infantile malignant osteopetrosis: A case report and literature review / 中南大学学报(医学版)

A case of SNX10 gene mutation in a patient with infantile malignant osteopetrosis (IMO) was admitted to Department of Pediatrics, Third Xiangya Hospital, Central South University. The patient had the symptom of anemia, hepatosplenomegaly and growth retardation. The X-ray examination suggested extensive increase of bone density throughout the body, which was clinically diagnosed as IMO. The homozygous mutation of SNX10 gene c.61C>T was found via gene sequencing. We reviewed the relevant literatures and found that anemia, visual and hearing impairment, hepatosplenomegaly are the main clinical symptoms of IMO, SNX10 gene mutation is a rare cause of IMO, and hematopoietic stem cell transplantation is an effective treatment.

Autosomal recessive osteopetrosis type I: description of pathogenic variant of TCIRG1 gene / Osteopetrosis infantil maligna: descripción de una nueva mutación patogénica de TCIRG1

Abstract Background: Autosomal malignant osteopetrosis is a rare condition arising from dysfunction of bone-resorbing osteoclasts, in which diagnosis requires a high suspicion index. Treatment of choice is allogeneic stem cell transplantation. Best outcomes occur if the procedure is carried out before damage to cranial nerves ensues; nonetheless, patients improve their clinical condition. Case report: An 8-month-old infant was referred for hematology consultation for cytopenias, hepatomegaly, and growth failure. Autosomal malignant osteopetrosis was diagnosed on the basis of physical findings, alteration in calcium and phosphorus metabolism, and hyperdensity of bone. DNA was obtained from the patient and parents; compound heterozygosity of the TCIRG1 gene with a previously non-described deletion (c.1809_1818del) was identified. Conclusions: A new pathogenic mutation of TCIRG1 was identified in a Mexican osteopetrotic patient. Hematopoietic stem cell transplantation was offered as the best available treatment but declined by the parents. An early recognition and wider access to this procedure should be implemented.

Resumen Introducción: La osteopetrosis infantil maligna es una condición rara cuyo origen es la deficiente reabsorción ósea por parte de los osteoclastos. Su diagnóstico requiere un alto índice de sospecha. El tratamiento de elección es el trasplante alogénico de células hematopoyéticas. Los mejores desenlaces ocurren si el procedimiento se lleva a cabo antes de que ocurra daño a los nervios craneales. Caso clínico: Paciente masculino de 8 meses de edad fue referido a la consulta de hematología por citopenias, hepatomegalia y falla para crecer. Se diagnosticó osteopetrosis infantil maligna basándose en los hallazgos de la exploración física, la alteración del metabolismo del calcio y el fósforo y la hiperdensidad del hueso. Se obtuvo ADN del paciente y ambos padres; se demostró un heterocigosidad compuesta del gen TCIRG1 con una deleción (c.1809_1818del) no descrita previamente. Conclusiones: Una nueva mutación patogénica de TCIRG1 se identificó en un paciente mexicano con osteopetrosis. Se ofreció trasplante de células progenitoras hematopoyéticas como el mejor tratamiento disponible, pero fue rechazado por los padres. Se necesita un reconocimiento temprano y la implementación del acceso generalizado a este procedimiento.

Malignant infantile osteopetrosis.

Osteopetrosis, a rare congenital genetic disease characterized by increased bone density due to impaired bone resorption by osteoclasts. It is classified into three forms: Infantile malignant autosomal recessive (AR) osteopetrosis, intermediate (AR) osteopetrosis and autosomal dominant (AD) osteopetrosis. Incidence of infantile malignant AR is 1/2,00,000 and if untreated has a fatal outcome. The condition is commonly diagnosed in infancy with symptoms of significant hematologic abnormalities with bone marrow failure, hepatosplenomegaly, macrocephaly with frontal bossing and bone fractures. Because of rarity of this type of malignant infantile form of osteopretrosis, we like to report this case of malignant infantile osteopetrosis who presented with bronchopneumonia, anemia with melaena at 2 months 15 days of age.

Autosomal-dominant osteopetrosis: An incidental finding.

Osteopetrosis is a descriptive term that refers to a group of rare, heritable disorders of the skeleton. Osteopetrotic conditions vary greatly in their presentation and severity, from just as an incidental finding on radiographs to causing life-threatening complications such as bone marrow suppression. It is caused by failure of osteoclast development and function. Osteopetrosis can be inherited as autosomal-recessive, autosomal-dominant or as X-linked traits, with the most severe forms being the autosomal-recessive ones. The severity of the disease is mild to moderate in the autosomal-dominant forms, with normal life expectancy. Diagnosis is largely based on clinical and radiographic evaluation. The present paper reports a case of autosomal-dominant osteopetrosis complicated by osteomyelitis with a short review of the condition.

Novel mutations in Indian patients with autosomal recessive infantile malignant osteopetrosis.

Background & objectives: Although clinical reports have described infantile malignant autosomal recessive osteopetrosis (ARO) in Indian patients, no published data are available about the genetic causes of ARO in this population. We investigated the main genetic causes of ARO in eight Indian patients with early postnatal onset and the typical severe clinical course including visual impairment and anaemia. Methods: Mutation screening in the genes CLCN7 and TCIRG1 was done on genomic DNA from 8 affected individuals (diagnosed on the basis of clinical and haematological parameters and characteristic radiological changes of increased bone density) and their parents. In one family, after detection of both mutations in the proband, targeted mutation analysis was also done in chorionic villus samples for prenatal diagnosis. Results: Six patients had mutations in TCIRG1 and two patients harboured mutations in CLCN7 gene. Three of the five different TCIRG1 mutations identified and both CLCN7 mutations were novel mutations. Except for the already known mutation p.Ile720del, all TCIRG1 mutations disrupt conserved splice consensus sequences or lead to premature stop codons. In contrast, both CLCN7 mutations only lead to missense changes of conserved amino acids. In a foetus harbouring TCIRG1 mutations osteopetrosis was visible radiologically at 23 wk of gestation. Interpretation & conclusions: That the CLCN7 mutations provoke a phenotype as severe as the one caused by TCIRG1 loss of function suggests the affected residues to be crucial for the function of the ClC-7 chloride channel or chloride/proton-exchanger. Our data also show that ARO can manifest as early as in the second trimester of pregnancy.

Carbonic anhydrase II deficiency: A novel mutation.

Carbonic anhydrase II (CA II) deficiency is an extremely rare autosomal recessive disorder, characterised by a triad of osteopetrosis, renal tubular acidosis and cerebral calcifications. A 12-year-old boy with classical features of CA II deficiency is reported who was found to be homozygous for the mutation in CA II gene and parents were heterozygous for the same mutation .To the best of our knowledge this is the first case report of mutation proven CA II deficiency from India.

[Recessive osteopetrosis: new mutation]

Autosomal Recessive osteopetrosis [ARO] is a severe bone disease, whose cellular defect is consisting in impaired osteoclast bone resorption, resulting in generalized osteosclerosis and obliteration of marrow. The molecular defect is heterogeneous. 50 per cent of ARO patients show an abnormality in the TCIR1 gene coding for the a3 subunit of vacuolar proton pump that plays a fundamemtal role in acidifying the osteoclast-bone interface. We report a new case with mutation in the TCIRG1 gene. The patient, a 4 months old male infant, presented with exophthalmia, macrocephaly, hepatosplenomegaly, a very severe bone sclerosis,anemia, thrombocytopenia, optic atrophy, with fatal outcome at second year. He has the mutation G11049T in homozygous state in the TCIRG1 gene, this mutation is in heterozygous state in the parents. Prenatal diagnosis was carried out in the mother by amniocentesis performed at 16 weeks of second gestation. The fetal DMA analysis showed that same mutation were present in heterozygous state. A healthy baby with no clinical, radiological or abnormalities was delivered

Familial osteopetrosis in Agouti paca: report of nine cases / Osteopetrose familiar em Agouti paca: relato de nove casos

Nine cases of familial osteopetrosis were studied in Agouti paca rodents maintained in captivity. Animals were distributed in three groups depending on the severity of their skeletal lesions. Based upon clinical, radiological, and microscopic findings, it was concluded that one animal had level I lesions, three animals had level II lesions, and five animals had level III osteopetrosis and osteonecrosis. Throughout the entire axial and appendicular skeleton, there was an increased amount of both trabecular and cortical bone tissue. All analyzed bones showed thickened cortex and reduced medullary canals. Bone trabeculae were thick and confluent. Cortex showed a narrowing of Haversian canals. Numerous cementing lines resulted in typical mosaic patterns. Osteocytes were pycnotic. Osteonecrosis was characterized by the disappearance of osteocytes and bone matrix decomposition.

Descreveram-se nove casos de osteopetrose familiar em Agouti paca mantidas em cativeiro. Os animais foram distribuídos em três grupos de acordo com a gravidade das lesões do esqueleto. Com base nos exames clínico, radiológico e microscópico, foi concluído que um animal apresentou lesões de nível I, três animais tiveram lesões de nível II e cinco animais tiveram osteopetrose de nível III. Por todo o esqueleto axial e apendicular, a quantidade de osso trabecular e osteônico estava aumentada. Todos os ossos analisados mostraram córtex espesso e canais medulares reduzidos. As trabéculas ósseas eram espessas e confluentes. No córtex, verificou-se um estreitamento de canais de Havers. Numerosas linhas de cimentação resultaram em um padrão de mosaico típico. Osteócitos estavam picnóticos e a osteonecrose foi caracterizada pela morte dos osteócitos, com desintegração da matriz óssea.

Three sibs with mild variety of osteopetrosis.

We report three sibs with mild autosomal recessive variety of osteopetrosis. The prominent clinical features were short stature, malocclusion of teeth, hepatosplenomegaly and a typical facial appearance. The only atypical features were microcephaly, a normal upper segment to lower segment ratio and a normal arm span.

Osteopetrose: relato de dois casos e diagnostico por imagem / Osteopetrosis: report of 2 cases and image diagnosis

Os autores apresentam dois casos de osteopetrose com os principais achados imagenologicos do mesmo.

Osteopetrosis: a case report

A woman had clinicoradiological features of osteopetrosis. The dominant and recessive forms of this condition are discussed

Sindrome de Down en una madre afectada de picnodisostosis: reporte de ambos casos

Se presenta 2 casos. Madre e Hijo afectados de Picnodisostosis la primera de etiología Mendeliana y de Síndrome de Down el segundo de etiología Cromosómica. Se comentan las características clínicas de ambos y la posible relación genética entre ambas entidades