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Bone Rep. 2016 June; 4: 11–16.
Published online 2015 November 19. doi:  10.1016/j.bonr.2015.11.002
PMCID: PMC4926827

A case of infantile osteopetrosis: The radioclinical features with literature update[star]

Abstract

Background

Osteopetrosis is a rare hereditary metabolic bone disorder characterized by generalized skeletal sclerosis caused by a defect in bone resorption and remodelling. Infantile autosomal recessive osteopetrosis is one of three subtypes of osteopetrosis and the most severe form. The correct and early diagnosis of infantile osteopetrosis is important for management of complications and for future genetic counselling. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable.

Methods

Therefore, in this case study the classical clinical and radiological signs of a boy with infantile osteopetrosis will be presented with a comprehensive literature update. The differentiating signs from other causes of hereditary osteosclerosing dysplasias are discussed.

Results

This case study and review of available literature show that there tends to be a highly unique clinical and skeletal radiographic pattern of affection in infantile osteopetrosis.

Conclusion

Although tremendous advances have been made in the elucidation of the genetic defect of osteopetrosis over the past years, the role of accurate clinical and radiological assessment remains an important contributor to the diagnosis of infantile osteopetrosis.

Keywords: Malignant autosomal recessive, Skeletal imaging, Osteosclerosing dysplasia, Osteoclasts

1. Introduction

Osteopetrosis is a rare hereditary metabolic bone disorder characterized by generalized skeletal sclerosis caused by a defect in bone resorption and remodelling. The defect in bone turnover characteristically results in skeletal fragility despite increased bone mass, and it may also cause haematopoietic insufficiency. The actual incidence is unknown but it is estimated to be 1 case per 100,000–500,000 population (Stark and Savarirayan, 2009). Three distinct clinical forms of the disease—infantile, intermediate, and adult onset—are identified based on age and clinical features. Infantile autosomal recessive osteopetrosis is the more severe form that tends in the first few months of life. Hence, it is referred to as “infantile” and “malignant” compared to the autosomal dominant adult osteopetrosis (Stark and Savarirayan, 2009). The correct and early diagnosis of infantile osteopetrosis (IO) is important for management of complications and for future genetic counselling. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable (Sit et al., 2015). It is therefore important to be familiar with the radiological features of IO. Therefore, in this case study the classical clinical and radiological signs of a boy with infantile osteopetrosis will be presented and a comprehensive literature update. The differentiating signs from other causes of hereditary osteosclerosing dysplasias are discussed.

2. Case report

A one and a half year old boy was brought to our outpatient clinic with complains of delayed milestones. He was first in order to a first cousin parents. Birth and family history were unremarkable.

Clinical examination revealed macrocephaly with opened anterior fontanel, frontal bossing, nystagmus of left eye and retromicrognathia, near normal stature and proportions and abnormal dentition. He had small chest cavity with ptosed liver and mildly enlarged spleen. The boy was only able to ambulate with parents' assistance.

Radiographic examination of the axial and appendicular skeleton revealed generalized osteosclerosis within the medullary portion of the bone with relative sparing of the cortices. Detailed radiographic abnormalities are depicted in Figs. 1A, B and and2A,2A, B, C, D. The pelvi-abdominal sonography revealed splenomegaly with no focal lesions. The blood picture revealed moderate anaemia. Our patient's parents were informed that data concerning the case would be submitted for publication. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. No financing was received for this study. The study was authorized by the local ethical committee.

Fig. 1
Anteroposterior and lateral radiographs of the skull (A) and the spine (B) demonstrating an overall increased density of the bones with fundamental involvement of the medullary portion. Note the classic endobone or “bone-within-bone” appearance ...
Fig. 2
Radiographs showing antero-posterior (A) and lateral views (B) of the pelvis and both lower limbs. Antero-posterior view of the chest wall and both upper limbs (C) and left hand (D). Note the uniform sclerosis of the pelvis and long bones of the lower ...

3. Discussion

The principals of clinical assessment of skeletal dysplasias include accurate history regarding time of onset of short stature prior to physical examination. Some dysplasias have prenatal onset, while others may only present either as newborns or beyond 2 to 3 years of age. Nonetheless some generalized bone mineralization abnormalities such as osteogenesis imperfects, some osteosclerotic disorders as osteopetrosis, and hypophosphatasia may present with near normal proportions (Krakow and Rimoin, 2010). Our patient presented with near normal stature and proportions, but other associated symptoms and radiologic findings presented in infancy. These findings go in line with those reported by the previous authors.

Osteopetrosis is considered to be the prototype of sclerosing dysplasia, it is characterized by wide clinical and genetic heterogeneity with a common end-pathway of failure of normal osteoclastic resorption of bone and increased density in medullary portions of bones with sparing of cortices. The diagnosis also relies greatly on radiographic appearance of the skeleton (Ihde, LL, et al., 2011, Vanhoenacker, FM, et al., 2000).

Panda and colleagues described in their recent review article, a radiographic approach and review of common non-lethal skeletal dysplasias (Panda et al., 2014). They reported the essential radiological features of IO. These include; diffuse sclerosis involving both the skull vault, multiple limb fractures despite increased density, metaphyseal flaring leading to (Erlenmeyer flask deformity), and “Bone-within-bone” appearance typically noted in spine, pelvis and short tubular bones. In spine, this is termed as a sandwich vertebrae appearance due to end-plate sclerosis and relative lucency of center of body. In the pelvis, they appear as multiple dense white lines parallel to the iliac crest. There is a clear agreement between the radiographic findings reported in the previous study and those reported in our case. Nonetheless our patient lacked any pathologic fractures. The use of internal fixation in treatment of pathologic fractures in osteopetrosis has been reported in adults (Aslan, A, et al., 2014, Benichou, OD, et al., 2000).

Erlenmeyer flask bone deformity (EFD) is a long-standing term used to describe a specific abnormality of the distal femora. The deformity consists of lack of modelling of the diaphysis and metaphysis with abnormal cortical thinning and lack of the concave diaphyseal metaphyseal curve. Utilizing a literature review and cohort study of 12 skeletal dysplasias, Faden and colleagues classified EFD into three groups and determined which skeletal dysplasias or syndromes were highly associated with that specific deformity (Faden et al., 2009). They associated IO with the second group characterized by absence of normal diaphyseal metaphyseal modelling with abnormal radiographic appearance of trabecular bone. The description of the distal femoral deformities in IO offered by the previous authors is in accordance with radiographic findings demonstrated in our case.

Ihde and colleagues conducted an excellent review article on sclerosing bone dysplasias and their differential diagnosis (Ihde et al., 2011). The radiographic findings of IO reported by the previous study was similar to those described in our case. Table 1 provides a summary of the differential diagnosis of hereditary sclerosing bone dysplasias presenting in childhood, in regards to pathogenetics and radioclinical features.

Table 1
Differential diagnosis of hereditary sclerosing bone dysplasias in children and adolescents (Stark, Z and Savarirayan, R, 2009, Ihde, LL, et al., 2011, Maranda, B, et al., 2008, Steward, CG, 2003, Jacquemin, C, et al., 1998, Whyte, MP, 1993, Guerrini, ...

3.1. Genetic profiling

Nearly half of cases infantile autosomal recessive osteopetrosis involve mutation of TCIRG1 gene. This is followed by mutations of CLCN7 which is responsible for 13% of cases. The clinical picture of both is similar but patients with CLCN7 mutations have more developmental delay and convulsions (Frattini et al., 2003). Nearly 4% of cases of autosomal recessive osteopetrosis involves mutations in SNX10 gene. Although the clinical picture seems to be milder, loss of vision, anaemia and bone fragility is more common (Aker et al., 2012). OSTM1 gene causes a very severe form of the disease with frequent CNS manifestations, the mutation of which is responsible for 2% of cases of infantile autosomal recessive osteopetrosis (Pangrazio et al., 2006). A very mild phenotype that can regress with age is caused by mutation of PLEKHM1 gene (Van Wesenbeeck et al., 2007).

All these genes are involved in the acid secretion mechanism of osteoclasts, the mechanism by which osteoclasts causes bone resorption through its “extracellular lysosomes” (Teitelbaum and Ross, 2003). For example, the CLCN-7 gene encodes the chloride channel that resides in lysosomal vesicles and is thought to transport negative charge in parallel to the proton pumped into the resorption lacunae by the membrane H-ATpase. TCIRGI gene encodes an important subunit of this H-ATPase (Kornak et al., 2001). Molecular diagnosis was not conducted in our patient. Nevertheless we suggest that testing of TCIRG1 gene at first is appropriate, because of the mild developmental delay and absence of other manifestations as; convulsions, and loss of vision.

4. Conclusion

Although tremendous advances have been made in the elucidation of the genetic defect of osteopetrosis over the past years, the role of accurate clinical and radiological assessment remains an important contributor to the diagnosis of infantile osteopetrosis.

Footnotes

[star]The authors of the current study declare that no conflict of interest exists. No financing was received for research on which our study is based.

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Articles from Bone Reports are provided here courtesy of Elsevier