Gaucher’s disease type III C: Unusual cause of intracardiac calcification

We report a case of intracardiac calci ﬁ cation associated with oculomotor apraxia and corneal deposits in a 12-year-old girl, who presented with dyspnea on exertion, sinusitis, and epistaxis since the age of 6 years. Unusual presentation with multiorgan involvement prompted us to evaluate her in terms of metabolic/storage disorder. The bone marrow aspirate con ﬁ rmed the diagnosis of Gaucher’s disease.


INTRODUCTION
Gaucher's disease is the most common lipid-storage disorder with an autosomal recessive pattern of inheritance. It is characterized by deposition of glucocerebrosides in various organs due to defi ciency of the enzyme glucocerebrosidase. Type III C has been recently identifi ed, and classically, has cardiac valvular manifestations, unlike other forms of Gaucher's disease. We report this rare case wherein the diagnosis was diffi cult due to unusual clinical manifestations. Presence of intracardiac calcification on echocardiography prompted detailed clinical and laboratory evaluation that eventually led us to the diagnosis of type III C Gaucher's disease.

CASE REPORT
A 12-year-old girl, born to consanguineous parents, came to the hospital seeking medical treatment for easy fatigability, dyspnea on exertion, and decreased activity for last 6 months. She also had history of recurrent episodes of sinusitis, epistaxis, and involuntary movements of upper limbs. Similar complaints were observed in one of her maternal fi rst cousin sisters, also born to consanguineous parents, aged 8 years. She had normal growth parameters, intellect, and appearance. Clinical examination revealed pes cavus, blood pressure of 100/60 mm/Hg, and oxygen saturation of 100%. Auscultation of the chest revealed coarse crepitations bilaterally. Restricted movements of both eyeballs in specifi c directions were observed. Cardiac auscultation revealed normal heart sounds with a 2/6 systolic murmur at the apex and left upper sternal border.
Her chest X-ray revealed cardiothoracic ratio of 50% with no evidence of calcifi cation. The lung fi elds were clear. Echocardiogram showed calcifi cation of endocardium, mitral and aortic valves, and aortic root [ Figure 1]. There was moderate mitral regurgitation, mild mitral stenosis, and mild aortic regurgitation. Calcifi cation was also seen surrounding the aortic arch. Fluoroscopy confi rmed calcification in the aortomitral area [ Figure Figure 4] with evidence of sinusitis. Ophthalmic evaluation revealed oculomotor apraxia with corneal dot-like intrastromal deposits. Abdominal sonography showed mild splenomegaly. A bone marrow aspirate performed confi rmed the diagnosis of Gaucher's disease [ Figure 5]. The cousin sister with similar complaints was also evaluated and found to have intracardiac calcifi cation, oculomotor apraxia, corneal opacities, and splenomegaly. Homozygous D409H mutations were confi rmed in both the cousin sisters. The result of enzyme analysis to evaluate fi broblast beta glucocerebrosidase activity is awaited.

DISCUSSION
Intracardiac calcifi cation is commonly known to occur in rheumatic heart disease, myocardial infarction, pseudohypoparathyroidism, end-stage renal disease on chronic hemodialysis, endomyocardial fi brosis, and pseudoxanthoma elasticum. The heart is not frequently involved in Gaucher's disease.
Type III Gaucher's disease is a late onset, slowly progressive, subacute/chronic disorder presenting with anorexia, respiratory problems, hepatosplenomegaly, seizures, impaired coordination, and disorder of extraocular movements. Most of the patients perish before their thirtieth birthday. Type III A is characterized by myoclonus and dementia, while III B has early onset of isolated horizontal supranuclear gaze palsy with aggressive systemic illness. Type III C is associated with cardiovascular manifestations. Presence of intracardiac calcifi cation in Gaucher's III C has been reported. [1][2][3][4][5][6][7] The sites involved are mitral and aortic valves, ascending aorta, aortic arch, and coronary ostia. The calcifi cation in our case had similar distribution, except for the involvement of coronary ostia. Veinot et al., first documented the presence of Gaucher cells in the heart valve tissue and proposed a cell-mediated mechanism involving bone matrix proteins and integrins in the pathogenesis of the valvular injury. [5] The characteristic late onset of presentation with slower progression of complaints in a child born to consanguineous parents, with similar symptoms in a cousin sister, with mild splenomegaly, involuntary movements of the extremities, intracerebral calcifi cations, oculomotor apraxia with corneal deposits, and cardiovascular calcifi cation made us suspect Gaucher's disease type III C and prompted us to perform a bone marrow aspirate.
In all cases reported till date, there is homozygosity for an asp409his (D409H) mutation in the gene encoding acid beta-glucosidase located on chromosome 1q21. [4,[6][7][8][9] This mutation was found in both the cousin sisters. Disordered intracellular traffi cking of glucocerebrosidase is seen with this mutation. Treatment options include enzyme replacement therapy (ERT) and bone marrow transplantation. [6,9] ERT has been described to improve hematological parameters and organomegaly. [10] Our patient was advised ERT, but could not afford it. Affected individuals need close monitoring to decide about the need and timing for valve replacement. Surgery is usually offered to those individuals who have clinically and hemodynamically signifi cant valve lesion. [6] Apart from the valve replacement, patients have been subjected to replacement of the ascending aorta and the aortic arch with a Dacron graft when there is a signifi cant calcifi cation resulting in severe narrowing of the aorta. When coronary ostia are involved, one needs to graft the coronary arteries as well. [11] In conclusion, patients with intracardiac calcifi cation and multiorgan involvement should be investigated for metabolic disorders such as Gaucher's disease as was the case in our patient.