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Autosomal Recessive Osteopetrosis Type 5

Infantile Malignant Osteopetrosis Type 3

Autosomal recessive osteopetrosis 5 (OPTB5) is a severe form of infantile osteopetrosis. Patients may die in utero or be born at full-term after an uneventful pregnancy. Notwithstanding, they soon develop a broad range of neurological symptoms that result from anomalies of the skull interfering with brain development and neurodegeneration due to a lysosomal storage disorder. Lack of bone resorption eventually causes the bone marrow spaces to be filled up with dense osseous tissue, which results in bone marrow failure and pancytopenia. The majority of patients dies within their first two years of life.


Presentation

OPTB5 is a congenital disorder, and symptom onset may occur before birth. Extensive disturbances of bone remodeling render the child's bones fragile and prone to pathological fractures. Such fractures may be observed in prenatal imaging, and they may be induced peri- and postnatally by trivial traumas. Anomalies of skeletal growth may interfere with the development of the central nervous system and be incompatible with life, leading to intrauterine death and stillbirth. Hydrocephalus is a common consequence of malformations of the skull and may develop in utero or postnatally, giving rise to seizures and a broad spectrum of neurological symptoms. Children may be irritable, feed poorly, vomit, and present a low muscle tone [1] [2] [3].

OPTB5 is related to postnatal retardation of growth and the development of dysmorphic facial features. Patients may have a triangular or squared face, prominent forehead, exophthalmia, low-set ears, micrognathia, and retrognathia [4]. Over the course of the disease, the abnormal growth of the cranial bones provokes the narrowing of cranial nerve foramina. The compression of the second and eighth cranial nerve causes progressive visual and hearing impairment and eventually leads to blindness and deafness, where loss of vision is further accelerated by retinal atrophy. Less frequently, trigeminal and facial neuropathies are observed [1] [2].

Eventually, excessive bone compromises bone marrow spaces, leading to bone marrow failure. Laboratory analyses of blood samples may reveal pancytopenia, and affected children may present the corresponding symptoms: Anemia is associated with fatigue, pallor, and possibly cyanosis. Hypoxia may ensue tachypnea. Leukopenia reflects in increased susceptibility to infections, and thrombocytopenia renders OPTB5 patients prone to bleed. Because of chronic bone marrow failure, hematopoiesis shifts to liver and spleen, and hepatosplenomegaly may be noted in the clinical examination.

Splenomegaly
  • Optic disc pallor 0000543 Osteopetrosis Harder, denser, fracture-prone bones 0011002 Pancytopenia Low blood cell count 0001876 Respiratory failure 0002878 Short stature Decreased body height Small stature [ more ] 0004322 Spastic tetraplegia 0002510 Splenomegaly[rarediseases.info.nih.gov]
Short Stature
  • Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia.[malacards.org]
  • […] trunk 0008936 Nystagmus Involuntary, rapid, rhythmic eye movements 0000639 Optic atrophy 0000648 Optic disc pallor 0000543 Osteopetrosis Harder, denser, fracture-prone bones 0011002 Pancytopenia Low blood cell count 0001876 Respiratory failure 0002878 Short[rarediseases.info.nih.gov]
Pallor
  • [ more ] 0000252 Micrognathia Little lower jaw Small jaw Small lower jaw [ more ] 0000347 Muscular hypotonia of the trunk Low muscle tone in trunk 0008936 Nystagmus Involuntary, rapid, rhythmic eye movements 0000639 Optic atrophy 0000648 Optic disc pallor[rarediseases.info.nih.gov]
Increased Susceptibility to Infections
  • Leukopenia reflects in increased susceptibility to infections, and thrombocytopenia renders OPTB5 patients prone to bleed.[symptoma.com]
Tachypnea
  • Hypoxia may ensue tachypnea. Leukopenia reflects in increased susceptibility to infections, and thrombocytopenia renders OPTB5 patients prone to bleed.[symptoma.com]
Hepatomegaly
  • Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. 0001290 Generalized-onset seizure 0002197 Gingival overgrowth Gum enlargement 0000212 Hepatic failure Liver failure 0001399 Hepatomegaly[rarediseases.info.nih.gov]
Gingival Overgrowth
  • overgrowth Gum enlargement 0000212 Hepatic failure Liver failure 0001399 Hepatomegaly Enlarged liver 0002240 Hydrocephalus Too much cerebrospinal fluid in the brain 0000238 Hyperbilirubinemia High blood bilirubin levels 0002904 Hypocalcemia Low blood[rarediseases.info.nih.gov]
Cyanosis
  • Laboratory analyses of blood samples may reveal pancytopenia, and affected children may present the corresponding symptoms: Anemia is associated with fatigue, pallor, and possibly cyanosis. Hypoxia may ensue tachypnea.[symptoma.com]
Visual Impairment
  • OPTB5 patients manifest primary central nervous system involvement in addition to the classical stigmata of severe bone sclerosis, growth failure, anemia, thrombocytopenia and visual impairment with optic atrophy.[uniprot.org]
  • impairment, and bone marrow insufficiency.[iofbonehealth.org]
  • impairment Impaired vision Loss of eyesight Poor vision [ more ] 0000505 Showing of 33 Last updated: 1/1/2020 Making a diagnosis for a genetic or rare disease can often be challenging.[rarediseases.info.nih.gov]
Low Set Ears
  • Patients may have a triangular or squared face, prominent forehead, exophthalmia, low-set ears, micrognathia, and retrognathia.[symptoma.com]
  • Dysarthria Ptosis Hearing impairment Carious teeth Photophobia Headache Cryptorchidism Rod-cone dystrophy Anemia Cataract Wide mouth Prominent nasal bridge Thin upper lip vermilion Abnormality of the genital system Delayed speech and language development Low-set[mendelian.co]
Fracture
  • Extensive disturbances of bone remodeling render the child's bones fragile and prone to pathological fractures. Such fractures may be observed in prenatal imaging, and they may be induced peri- and postnatally by trivial traumas.[symptoma.com]
  • Phenotype Severe form, loss of trabecular structure, poor/no definition between cortical and medullary bone, fractures, increased bone density (sclerosis) and generalized high bone mass, in utero fractures, and skeletal hyperdensity, hepatosplenomegaly[iofbonehealth.org]
  • Other major manifestations include failure to thrive, pathologic fractures, and increased infection rate.[malacards.org]
  • […] jaw Small jaw Small lower jaw [ more ] 0000347 Muscular hypotonia of the trunk Low muscle tone in trunk 0008936 Nystagmus Involuntary, rapid, rhythmic eye movements 0000639 Optic atrophy 0000648 Optic disc pallor 0000543 Osteopetrosis Harder, denser, fracture-prone[rarediseases.info.nih.gov]
Decrease in Height
  • […] body height Small stature [ more ] 0004322 Spastic tetraplegia 0002510 Splenomegaly Increased spleen size 0001744 Stillbirth Stillborn 0003826 Thrombocytopenia Low platelet count 0001873 Visual impairment Impaired vision Loss of eyesight Poor vision[rarediseases.info.nih.gov]
Small Head
  • […] fluid in the brain 0000238 Hyperbilirubinemia High blood bilirubin levels 0002904 Hypocalcemia Low blood calcium levels 0002901 Microcephaly Abnormally small skull Decreased circumference of cranium Decreased size of skull Reduced head circumference Small[rarediseases.info.nih.gov]
Recurrent Fractures
  • The susceptibility is variable and in some children recurrent fractures are the most debilitating part of the disease. 4 7-9 13 They tend to occur only after moderate trauma and are thus rare in infancy.[adc.bmj.com]
  • A recurrent fracture in his right humerus with*Correspondence to: Amos Etzioni, M.D., Department of Pediatrics,Meyer Childrens Hospital, Bat-Galim, Haifa, Israel 31096.[documents.tips]
Long Arm
  • This gene is to be found on the long arm of chromosome 6 and encodes for the osteopetrosis-associated transmembrane protein 1.[symptoma.com]
  • PDB4 on the long arm of chromosome 5 and PDB6t arm of chromosome 10 are being investigated.[docslide.com.br]
Neonate-Onset
  • Symptoms and severity can vary greatly, ranging from neonatal onset with life-threatening complications (such as bone marrow failure) to the incidental finding of osteopetrosis on X-ray.[malacards.org]
Seizure
  • Hydrocephalus is a common consequence of malformations of the skull and may develop in utero or postnatally, giving rise to seizures and a broad spectrum of neurological symptoms.[symptoma.com]
  • Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia.[malacards.org]
  • Autosomal recessive osteopetrosis type 5; Osteopetrosis infantile malignant 3 Categories: Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. 0001290 Generalized-onset seizure[rarediseases.info.nih.gov]
Irritability
  • Children may be irritable, feed poorly, vomit, and present a low muscle tone. OPTB5 is related to postnatal retardation of growth and the development of dysmorphic facial features.[symptoma.com]
  • ., A Case of Malignant Infantile Osteopetrosis Presenting with Irritability and Failure to Thrive (2007) Turk Jem, 11, pp. 124-126 Al Mefty, O., Fox, J.L., Al Rodhan, N., Optic nerve de compression in osteopetrosis (1988) J Neurosurg, 68 (1), pp. 80-84[pbn.nauka.gov.pl]
  • […] forehead Scoliosis Failure to thrive Blindness Hypertelorism Nystagmus Feeding difficulties Facial palsy Visual impairment Oxycephaly Gastroesophageal reflux Wide nasal bridge Hepatomegaly Rare Symptoms - Less than 30% cases Hepatosplenomegaly Vomiting Irritability[mendelian.co]
  • Linked Idiopathic Intracranial Hypertension Idiopathic Neonatal Hepatitis Idiopathic Pulmonary Fibrosis Idiopathic Thrombocytopenic Purpura IgA Nephropathy Imperforate Anus Incontinentia Pigmenti Infantile Neuroaxonal Dystrophy IRF6-Related Disorders Irritable[rarediseasesregistryindia.com]
Clonus
  • Affiliated tissues include bone, bone marrow and eye, and related phenotypes are hydrocephalus and clonus Disease Ontology : 12 An osteopetrosis characterized by autosomal recessive inheritance that has material basis in mutation in the OSTM1 gene on[malacards.org]

Workup

First indications of a disorder of bone metabolism are generally obtained during pregnancy or shortly thereafter. OPTB5 is associated with severe general osteosclerosis, osseous hyperdensity and poorly defined boundaries between cortical and medullary spaces. Most of the skeleton is uniformly affected [4]. The appearance of "bone within a bone" is regularly described, as is the striation of appendicular bones [5]. With regard to the head, calvarial hyperostosis and consequent cerebral atrophy may be observed as well as narrowing foramina of the cranial nerves [1].

Bone biopsy samples obtained from OPTB5 patients reveal an increased number of osteoclasts possessing a poorly developed ruffled border and disrupted cytoskeleton [5]. Additionally, evidence of a lysosomal storage disease may be gathered: Electron-dense, osmiophilic material with an amorphous, granular or, infrequently, lamellar ultrastructure may be deposited in neuronal perikarya. Within the central nervous system, neurodegenerative features are accompanied by microgliosis and astrogliosis. Storage material, however, cannot only be found in the brain and retina, but also in several organs and tissues [6].

Finally, the tentative diagnosis of OPTB5 is to be confirmed by the identification of the underlying mutation in the OSTM1 gene.

Increased Bone Density
  • Osteopetrosis is a disorder of increased bone density due to defects in bone resorption.[ctgt.net]
  • Phenotype Severe form, loss of trabecular structure, poor/no definition between cortical and medullary bone, fractures, increased bone density (sclerosis) and generalized high bone mass, in utero fractures, and skeletal hyperdensity, hepatosplenomegaly[iofbonehealth.org]
  • NIH Rare Diseases : 54 Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth.[malacards.org]
  • Title Other Names: OPTB5; Autosomal recessive osteopetrosis type 5; Osteopetrosis infantile malignant 3 Categories: Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth.[rarediseases.info.nih.gov]
Enlargement of the Liver
  • The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as … Previous 1 2 3 4 ... 7 Next Last[checkrare.com]
  • Consequently, children with ARO1 may have severe anemia, problems with immune system function that lead to an increased risk for infections, and enlargement of the liver and spleen.[myriadwomenshealth.com]
  • In addition, abnormal enlargement of the liver and spleen (hepatosplenomegaly); abnormal hardening of some bones (osteosclerosis); fractures, usually of the ribs and long bones; inflammation of the lumbar vertebrae (osteomyelitis); increased density of[rarediseases.org]
  • Abdominal ultrasonography detected an enlarged spleen and liver. His liver margin was 4.0 cm below the right costae and the spleen margin was 6 cm below the left costae.[nature.com]
Cytopenia
  • Corticosteroids may be administered as a means of palliative therapy to stimulate hematopoiesis, transfusions may be realized to compensate for cytopenias, and further pharmacotherapy may be applied according to the individual needs of the patient.[symptoma.com]
  • The abnormal expansion of cortical and trabecular bone physically limits the availability of medullary space for hematopoietic activity, leading to life-threatening cytopenia and secondary expansion of extramedullary hematopoiesis at sites such as the[mendelian.co]
Gliosis
  • Some Features of Basic Reactions Characteristic for Immature Nervous Tissue.- Reaction of Immature Nervous Tissue to Necrosis.- Age-Dependent Variation in Anoxic Tissue Damage.- Anoxic Neuronal Necrosis.- Myelination Gliosis.- Reactive Gliosis.- Fibrillary[amazon.it]

Treatment

Hematopoietic stem cell transplantation may offer a chance for cure but is contraindicated in patients with severe neurological impairment [1] [2] [7]. The surgical decompression of nervous structures may buy some time and prevent further deterioration of vision but offers no solution to other aspects of the disease. Moreover, it is at least questionable whether the lysosomal storage disorder leading to neurodegeneration and blindness - independent of bone metabolism - would respond to stem cell transplantation [6], and some experts even go so far as to state that OPTB5 patients are no candidates for stem cell transplantation at all [7]. Either way, specific data regarding the outcome of stem cell transplantations in OPTB5 patients are not available, and even though it has been speculated that stem cell transplantation in utero may suffice to prevent fatal defects, the prenatal diagnosis of the disease most commonly entails the decision to terminate the pregnancy [5].

With regards to the entire group of autosomal recessive osteopetrosis, the rate of success of hematopoietic stem cell transplantation is <50%, and damage to the nervous system or skeleton have largely proven irreversible. What's more, disease progression has been observed in as much as one-fourth of the patients who successfully underwent the procedure [8].

Corticosteroids may be administered as a means of palliative therapy to stimulate hematopoiesis, transfusions may be realized to compensate for cytopenias, and further pharmacotherapy may be applied according to the individual needs of the patient [1] [2]. None of these measures will significantly delay disease progression and improve survival, though.

Prognosis

OPTB5 patients have a poor prognosis. Most patients succumb to the disease, to bone marrow failure and severe infections or hemorrhages during their first two years of life [7]. Hematopoietic stem cell transplantation is still associated with mortality rates >50% but constitutes the only chance for cure. For better results, it should be carried out as early as possible [8].

Etiology

OPTB5 is caused by mutations of the OSTM1 gene. This gene is to be found on the long arm of chromosome 6 and encodes for the osteopetrosis-associated transmembrane protein 1. This protein functions as the β subunit of chloride channel 7 and is crucial to the maturation and function of osteoclasts [9]. To date, about five mutations have been described. They are mostly null mutations that result in the synthesis of a dysfunctional truncated protein [2] [10].

Epidemiology

OPTB5 is inherited in an autosomal recessive manner and is most frequently diagnosed in children born to consanguineous parents. Accordingly, most cases are reported where consanguineous marriage is common: in the Middle East and Mediterranian region. Here, the incidence of autosomal recessive osteopetrosis has been estimated at >5 in 100,000 live births, whereas the global incidence of this group of disorders may range around 1 in 250,000 live births [4] [5]. In any case, OPTB5 accounts for <6% of these cases, with about half a dozen families described in the literature [3] [7] [10].

Sex distribution
Age distribution

Pathophysiology

OPTB5 develops due to severe impairments of osteoclast function. In detail, osteoclasts carrying dysfunctional OSTM1 genes are unable to resorb immature bone and to adapt bone structures to changing physical demands. The progressive increase of bone density is associated with proneness to fractures, narrowing of skull base foramina, and the partial or complete obliteration of marrow cavities [1]. Bone resorption requires the dissolution of bone minerals in acidic resorption lacunae, and chloride channel 7 is involved in this process. Chloride channel 7 is a chloride-proton exchanger localized in the lysosomes of osteoclasts, where it serves as an electrical shunt for the electrogenic V-type ATPase that acidifies the lysosomal lumen and - once inserted into the ruffled border of bone-attached cells - the resorption lacuna. Unless a countercurrent is assured that avoids the build-up of a positive potential on the luminal or lacunar side, this proton pump would soon stop working. In the presence of cytosolic chloride, chloride channel 7 fulfills this function by mediating chloride transport across the ruffled border into the extracellular space. It thus sustains the acidification of the underlying resorption lacuna [11] [12].

In line with the role of chloride channel 7 in bone remodeling, mutations of the CLCN7 gene, which encodes for the α subunit of this same channel, may also cause osteopetrosis [9]. Both gene products maintain a closely dependent relationship: In the absence of the α subunit, the β subunit of chloride channel 7 cannot exit the endoplasmatic reticulum and traffic to lysosomes, whereas deficiencies of the β subunit result in loss of stability and function of the α subunit [11]. Those variants of the disease related to CLCN7 mutations are autosomal dominant osteopetrosis 2 and autosomal recessive osteopetrosis 4.

Malformations of cranial bones have long since been considered the main cause of neurological impairment in OPTB5 patients. Notwithstanding, the OSTM1 gene has also been shown to be expressed in the brain, retina, and other organs and tissues, like liver, spleen, kidney, thymus, and skin [12] [13]. The degeneration of these tissues is now generally explained by lysosomal storage due to OSTM1 mutations, and pathogenetic mechanisms similar to those observed in neuronal ceroid lipofuscinosis are assumed [6].

Prevention

Families known to harbor pathogenic mutations of the OSTM1 gene may benefit from genetic counseling. If both parents of an unborn child are identified as carriers, the genotype of the child can be determined during pregnancy. This may help to avoid diagnostic delays and shorten the time until the patient can undergo hematopoietic stem cell transplantation, possibly in utero [5]. Still, complications may occur prenatally, and parents should be informed about the option of medical termination of pregnancy.

Beyond the management of families, education is the key to the avoidance of consanguineous marriage and thus the reduction of the incidence of OPTB5 and many other hereditary disorders.

Summary

There are distinct types of autosomal recessive osteopetrosis, all of which are characterized by osteoclast failure and impaired bone resorption [5]. Skeletal anomalies associated with autosomal recessive osteopetrosis include an increase in bone density that leads to the distinctive radiological appearance of "marble bones". Yet, patients with milder forms of the disease may be asymptomatic. The more severe variants of autosomal recessive osteopetrosis may be fatal in infancy or be incompatible with life, and OPTB5 belongs to the latter group. There is no effective treatment, and while hematopoietic stem cell transplantation may eventually be performed, advanced neurological impairment usually contraindicates this measure. The life expectancy of OPTB5 patients is below two years, and thus, most parents opt for medical termination of pregnancy when the disease is confirmed in their unborn child.

Patient Information

Under physiological conditions, osseous tissue is continuously build up and resorbed, which allows for normal growth and the adaptation of bone structures to changing physical demands. If bone remodeling is disturbed, the patient's bone density may decrease, as in osteoporosis, or increase, as in osteopetrosis. Autosomal recessive osteopetrosis 5 (OPTB5) is indeed a rare disorder of bone resorption, where affected individuals suffer from additional metabolic disturbances. The disease is caused by mutations of the OSTM1 gene and is characterized by early-onset proneness to fractures, neurodegeneration, visual and auditory deterioration, and bone marrow failure.

OPTB5 may be diagnosed prenatally. On the one hand, families known to harbor pathogenic mutations of the OSTM1 gene may seek genetic counseling and opt for genetic testing of unborn children. On the other hand, OPTB5 is associated with anomalies of the skeleton that may be recognized in prenatal imaging. To date, there is no chance for cure. Prenatal hematopoietic stem cell transplantation has been discussed as a possible treatment option but has never been carried out. If OPTB5 is confirmed prenatally, parents should consider the option of medical termination of pregnancy.

If the pregnancy is carried to term, symptoms will manifest shortly after birth. The child's bones are very fragile, rendering them prone to fractures. They may be irritable, feed poorly, vomit, present a low muscle tone and seizures. Visual and hearing impairment are common and follow a progressive course. Eventually, excessive bone compromises bone marrow spaces, leading to bone marrow failure. This condition is related to anemia, leukopenia, and thrombocytopenia, which entail chronic fatigue, susceptibility to infections, and an increased propensity to bleed. Most children with OPTB5 succumb to the disease, to severe infections and sepsis or hemorrhages within their first two years of life.

References

Article

  1. Castellano Chiodo D, DiRocco M, Gandolfo C, Morana G, Buzzi D, Rossi A. Neuroimaging findings in malignant infantile osteopetrosis due to OSTM1 mutations. Neuropediatrics. 2007; 38(3):154-156.
  2. Maranda B, Chabot G, Decarie JC, et al. Clinical and cellular manifestations of OSTM1-related infantile osteopetrosis. J Bone Miner Res. 2008; 23(2):296-300.
  3. Pangrazio A, Poliani PL, Megarbane A, et al. Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. J Bone Miner Res. 2006; 21(7):1098-1105.
  4. Souraty N, Noun P, Djambas-Khayat C, et al. Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis. Eur J Med Genet. 2007; 50(3):188-199.
  5. Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone. 2008; 42(1):19-29.
  6. Kasper D, Planells-Cases R, Fuhrmann JC, et al. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. Embo j. 2005; 24(5):1079-1091.
  7. Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013; 9(9):522-536.
  8. Driessen GJ, Gerritsen EJ, Fischer A, et al. Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. 2003; 32(7):657-663.
  9. Lange PF, Wartosch L, Jentsch TJ, Fuhrmann JC. ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature. 2006; 440(7081):220-223.
  10. Ott CE, Fischer B, Schröter P, et al. Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1. Bone. 2013; 55(2):292-297.
  11. Graves AR, Curran PK, Smith CL, Mindell JA. The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature. 2008; 453(7196):788-792.
  12. Poroca DR, Pelis RM, Chappe VM. ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies. Front Pharmacol. 2017; 8:151.
  13. Chalhoub N, Benachenhou N, Rajapurohitam V, et al. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med. 2003; 9(4):399-406.

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Last updated: 2019-07-11 20:01