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 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 7  |  Issue : 2  |  Page : 96-98

Hypocalcemia, seizures, and impairment of vision in a neonate


1 Department of Pediatrics, Division of Neonatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
2 Department of Pediatrics, Division of Pulmonology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
3 Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
4 Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA

Date of Web Publication10-Apr-2018

Correspondence Address:
Dr. Sashi Kumar Kona
1 Children's Way, Slot 512-05, Little Rock, AR 72202
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_63_17

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  Abstract 


Osteopetrosis is a rare, heterogeneous group of inherited diseases characterized by increased bone mass and density due to defective osteoclasts, leading to failure in bone resorption. Pathological features are related to increase in bone mass density and altered craniofacial morphology. Cranial nerve compression due to narrowing of cranial foramina can lead to progressive blindness and deafness. Bone marrow failure can lead to pancytopenia and life-threatening infections. Early diagnosis is crucial due to a short window of opportunity for curative treatment and to prevent complications such as visual impairment. We present the case of a late-preterm infant who had recurrent hypocalcemic seizures and visual impairment. Genetic testing confirmed the diagnosis of autosomal recessive osteopetrosis.

Keywords: Autosomal recessive osteopetrosis, hypocalcemia, impaired vision, osteoclasts, seizures


How to cite this article:
Kona SK, Yenduri NJ, Agarwal N, Ramakrishnaiah R, Miller W. Hypocalcemia, seizures, and impairment of vision in a neonate. J Clin Neonatol 2018;7:96-8

How to cite this URL:
Kona SK, Yenduri NJ, Agarwal N, Ramakrishnaiah R, Miller W. Hypocalcemia, seizures, and impairment of vision in a neonate. J Clin Neonatol [serial online] 2018 [cited 2020 Sep 30];7:96-8. Available from: http://www.jcnonweb.com/text.asp?2018/7/2/96/229670




  Introduction Top


Osteopetrosis is a rare, heterogeneous group of diseases characterized by increased bone mass and density due to defective osteoclasts, leading to failure in bone resorption.[1] Two major forms have been identified on the basis of their mode of inheritance: Autosomal dominant osteoporosis which is usually adult onset and a more benign form, whereas the second form ARO, also termed malignant infantile osteopetrosis, presents soon after birth, is often severe, and leads to death if left untreated.[2] As osteoclasts are of hematopoietic origin, HSCT can be curative for forms of ARO stemming from intrinsic osteoclast defects.


  Case Report Top


A female infant was born at 36+5 weeks by C-section to a 38-year-old Caucasian G3P2002. Pregnancy was complicated by preeclampsia and idiopathic polyhydramnios. Prenatal ultrasound scan was significant for lagging length of bilateral femurs and humeri. Initial postnatal X-rays showed irregular and abnormal appearing metaphases of bilateral femurs and humeri, raising the suspicion for a bone disorder. Skeletal survey revealed diffusely increased bone density, most notably throughout the appendicular and axial skeleton including the skull base [Figure 1] and [Figure 2].
Figure 1: Skeletal survey (initial hospitalization): Lateral radiograph of the skull (a) shows increased density of the skull base (white arrows) and diffusely increased density of the temporal bones (black arrow). The radiograph of the chest (b) shows diffusely increased bone density of the spine and the ribs. Notice the normal aeration of the lung and normal configuration of the heart. The frontal radiograph of the skull (c) shows elevated orbital roofs with increased density (arrows). The frontal radiographs of the pelvis and the femurs (d) show diffusely increased density and loss of medullary cavity. The frontal radiograph of the right tibia and fibula (e) shows absent medullary cavity and diffusely increased bone density. Notice the metaphyseal flaring and irregularity (arrows)

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Figure 2: Pretransplant radiographs. Frontal radiographs of the upper extremity (a) and the lower extremity including the pelvis (b) show generalized increased bone density and submetaphyseal lucent bands showing a classic “bone within bone” appearance of the long bones

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At 3 weeks of life, she exhibited generalized seizure activity. Video-electroencephalography did not reveal electrographic seizures but was abnormal due to excessive multifocal sharp waves and excessive sleep discontinuity for age. Laboratory work revealed severe hypocalcemia with total calcium 3.6 mg/dL (8.5–10.7) and ionized calcium 0.55 mmol/L (1.1–1.3); the infant was started on phenobarbital and levetiracetam but subsequently discontinued as the etiology of seizures was hypocalcemia and resolved with calcium supplementation.

A computed tomography scan of the head and upper neck showed diffusely increased bone density, narrowing of the bilateral optic canals, superior and inferior orbital fissures, and symmetric, mild proptosis [Figure 3]. There was diffuse stenosis of the skull base foramina (foramen ovale and rotundum). Magnetic resonance imaging showed thinning and stretching of optic nerves bilaterally with near complete effacement of cerebrospinal fluid signal surrounding the optic nerves and stenosis of auditory canals. The infant was noted to have poor visual fixation and tracking. A visual evoked potential study revealed absent responses bilaterally, concerning for impaired vision.
Figure 3: Computed tomography scan (initial hospitalization): Axial image through the orbital apex (a) shows severe stenosis of bilateral optic canals (arrows). The axial section through the floor of the middle cranial fossa (b) shows severe stenosis of the foramen ovale (arrows) and spinosum. The axial image through the temporal bone (c) shows small caliber middle ear cavity and space available for the ossicular chain (circle). The temporal bone computed tomography also showed severe stenosis of the internal auditory canals (not shown). The axial image through the midface (d) shows complete absence of bilateral maxillary sinus pneumatization (asterisk)

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Genetic testing revealed compound heterozygous mutations in TCIRG1, consistent with a diagnosis of autosomal recessive osteopetrosis (ARO).

The infant underwent allogeneic hematopoietic stem cell transplantation (HSCT) for definitive therapy of TCIRG1-mutated ARO at 6 months of age. The preparative regimen consisted of myeloablative chemotherapy, and the graft source was T-cell replete, human leukocyte antigen-mismatched paternal bone marrow. Graft-versus-host disease (GvHD) prophylaxis consisted of posttransplant pulse cyclophosphamide, cyclosporine A, and mycophenolate mofetil. Neutrophils recovered at day +21 following allografting; platelets recovered at day +55. Transient hypercalcemia developed at 4 weeks' posttransplantation; eucalcemia has since ensued. Posttransplant complications included polymicrobial bacteremia (resolved), asymptomatic cytomegalovirus viremia (resolved), and low-grade upper gastrointestinal GvHD (resolved). At 6 months following transplantation, the infant shows 100% donor hematopoietic engraftment and radiographic improvement in bony disease [Figure 4] but continued to show no visual function.
Figure 4: Six-month posttransplant radiographs. Frontal radiographs of the upper extremity (a) and the lower extremity including the pelvis (b) show generalized decrease in the bone density and improved submetaphyseal mineralization. Notice the residual “Erlenmeyer flask” deformity of the femora

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  Discussion and Conclusions Top


Infants with ARO have increased bone mass leading to characteristic facial features including macrocephaly, frontal bossing, exophthalmos, hypertelorism, and micrognathia. The increase in bone mass density can result in a variety of clinical manifestations such as hydrocephalus, Chiari I malformation, choanal stenosis, and respiratory difficulties, narrowing of cranial foramina leading to compression of cranial nerves, spinal nerves, and spinal cord. Cranial nerve compression can lead to progressive blindness, deafness, and facial palsy. Hematopoietic failure due to reduction of the bone marrow space may be present, with compensatory but insufficient extramedullary hematopoiesis and hepatosplenomegaly. Mild hypogammaglobulinemia and impairment of peripheral B-cell maturation have been reported. Patients may present with recurrent infections during infancy. Pathological fractures after minor trauma and delayed bone healing have been reported.[3] Defects of tooth eruption are also common.[4]

As osteoclasts are of hematopoietic origin, HSCT can be curative for forms of ARO stemming from intrinsic osteoclast defects. Our patient underwent HSCT for definitive therapy of TCIRG1-mutated ARO at 6 months of age. Although she successfully engrafted with minimal treatment-related complications, her visual function did not improve.

Early diagnosis of ARO is crucial due to a short window of opportunity for curative treatment and to prevent complications such as visual impairment. In a retrospective analysis of infants that received HSCT for ARO, only 14% of the infants older than 6 months had normal vision at the time of evaluation for HSCT, as compared 50% of the infants younger than 6 months.[5] Hypocalcemia can be the presenting feature and is seen in majority of the patients with ARO.[6],[7] Although ARO is a rare disease, it should be considered in the differential diagnosis of any infant with hypocalcemia, particularly if there are abnormal skeletal X-ray findings.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors gratefully acknowledge the family of the child described. They were gracious enough to allow us to report the case as above.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis 2009;4:5.  Back to cited text no. 1
[PUBMED]    
2.
Villa A, Guerrini MM, Cassani B, Pangrazio A, Sobacchi C. Infantile malignant, autosomal recessive osteopetrosis: The rich and the poor. Calcif Tissue Int 2009;84:1-2.  Back to cited text no. 2
    
3.
Landa J, Margolis N, Di Cesare P. Orthopaedic management of the patient with osteopetrosis. J Am Acad Orthop Surg 2007;15:654-62.  Back to cited text no. 3
    
4.
Wise GE, King GJ. Mechanisms of tooth eruption and orthodontic tooth movement. J Dent Res 2008;87:414-34.  Back to cited text no. 4
    
5.
Driessen GJ, Gerritsen EJ, Fischer A, Fasth A, Hop WC, Veys P, et al. Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: An EBMT report. Bone Marrow Transplant 2003;32:657-63.  Back to cited text no. 5
    
6.
Gerritsen EJ, Vossen JM, van Loo IH, Hermans J, Helfrich MH, Griscelli C, et al. Autosomal recessive osteopetrosis: Variability of findings at diagnosis and during the natural course. Pediatrics 1994;93:247-53.  Back to cited text no. 6
    
7.
Srinivasan M, Abinun M, Cant AJ, Tan K, Oakhill A, Steward CG, et al. Malignant infantile osteopetrosis presenting with neonatal hypocalcaemia. Arch Dis Child Fetal Neonatal Ed 2000;83:F21-3.  Back to cited text no. 7
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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