Case Report: Idiopathic hypoparathyroidism presenting as Secondary myelofibrosis : A rare disease association.

Dr.Jithesh.K. PG student calicut medical college*
Prof.P.K. Sasidharan; Dept. of General medicine calicut medical college**
(*=First author;**=Second author)

Key words
Myelofibrosis , Idiopathic hypoparathyroidism , Secondary Myelofibrosis.


Abstract
Myelofibrosis occurring both in childhood and adulthood is most commonly idiopathic, followed by neoplastic infiltration of the bone marrow. We are reporting an extremely rare association of Idiopathic hypoparathyroidism associated with stable secondary Myelofibrosis.

Introduction

Myelofibrosis or fibrosis (MF) of bone marrow is an uncommon condition in children. Fewer than 100 cases of myelofibrosis in children have been described in medical literature 1 . Most cases in children arise secondary to other disease processes. In adults it is not a rare disorder but most cases are idiopathic and if secondary, they are mostly due to neoplastic infiltration of bone marrow. Secondary causes in the adults include infections, carcinomatous metastases to the marrow, Hodgkin’s and Non Hodgkin’s lymphomas, Chronic Myeloid leukemia, Hairy cell Leukemia, Polycythemia Rubra Vera, SLE, Systemic mastocytosis etc.2. We are reporting an extremely rare association of Idiopathic hypoparathyroidism with stable and untreated Myelofibrosis in an adult patient on treatment from the age of 9 years with a diagnosis of Indian Childhood Cirrhosis, which was probably a wrong diagnosis.

Case Report

29-year-old mentally challenged female was admitted in our ward with insidious and progressive upper abdominal distention with easy bruisability, bleeding from gums and ecchymosis since childhood. Her previous treatment records showed that she was under regular medical treatment with haematinics and repeated fresh blood transfusions for bleeding from gums and echymosis due to thrombocytopenia presumptively due to hypersplenism for past 20 years. Previously she was erroneously treated as a case of Indian childhood cirrhosis and was under regular use of diuretics also for the ascites. Recently she presented with easy bruising and on evaluation she was found to have pancytopenia as per her complete haemogram Hb – 6.4 gm/dl ,TC – 3,800 cell/mm3 , DC – P72 L 28 , Platelet count – 48,000/mm3 , MCV-78.5 fl,MCH - 29.3 pg, MCHC- 24 gm/dl , ESR – 34mm/I hour thought to be due to hyperspelnism. The bone marrow biopsy done during the work up for pancytopenia, in our department, showed hyperplasic phase of myelofibrosis. The cause of myelofibrosis was considered to be due to secondary cause in view of her age and onset of symptoms since childhood and a detailed evaluation for various secondary causes for myelofibrosis was done. Her family history was not contributory . On examination , there was facial dysmorphism with prominent malars , pinched up nose and narrow upper lip ( Figure)

Her hands showed abnormal dermatoglyphics with clinodactyly of the little fingers.

There was extensive caries of teeth with malocclusion in spite of a good oral hygiene and absence of gingivitis (Figure 4)
She was short statured and was having genu valgum and pes planus (Figure 5)
Abdomen showed massive splenomegaly with asymmetrically enlarged liver and ascites. Repeat haemogram also showed pancytopenia.
Bone marrow trephine biopsy showed hyperplastic phase of myelofibrosis (Figure 6) and peripheral smear showed teardrop cells. Because of the skeletal abnormalities and caries teeth and also because of the mention of hypoparathyroidism as a cause for myelofibrosis in medical literature, we wanted to rule out that, or another disorder of calcium homeostasis, though she had no symptoms or signs of hypocalcaemia. Serum calcium was 7.8 mg/dl, serum phosphate was 11.4 mg/dl and alkaline phosphatase was 124 IU/ml with normal renal function tests, which suggested the possibility of hypoparathyroidism . PTH assay was done which was 6.5 ngm/ml ( Normal :9-15 ngm/ml ) with TmP / GFR of 1.4mmol/L which confirmed primary hypoparathyroidism . Radiological survey of skeletal system did not show any features of extra skeletal calcifications . USG abdomen showed massive splenomegaly with liver echogenicity suggestive of cirrhosis. Liver biopsy or further studies to evaluate the cause of hepatosplenomegaly was not possible in this patient considering the risk of bleeding due to thrombocytopenia, her poor general condition and the unwillingness of parents for such procedures. Cirrhosis in this patient with Myelofibrosis was due to the chronic presentation of Budd chiari syndrome. The association of Chronic Budd chiari syndrome with Myelofibrosis is well established and reported and probably due to the extramedullary haematopoesis occurring in the liver. The possibility of transfusion associated chronic viral hepatitis by HBV and HCV has been excluded by viral marker studies and serum ferritin and transferrin levels were within the normal range. Again the possibility of cirrhosis as suggested by the radiologist USG might be a misinterpretation of the nodularity seen in liver echogenicity by the ectopic haemopoetic tissue in liver.
Ascitic fluid study showed a transudate fluid with a SAAG of 1.6. Subsequently the patient was put on calcium supplementation along with 1,25 dihydroxycholecalciferol and Calcium carbonate as calcium supplement and as phosphate binder, and is under follow up.

Discussion
We are reporting this case to draw attention to the rare clinical association of Idiopathic hypoparathyroidism with Myelofibrosis3. Only a single reported case was seen indexed in Pubmed. Though the exact mechanism of myelofibrosis in hypoparathyroidism was previously less well described. In the present case report we are attempting to draw the attention towards the intricate relationship of Parathyroid hormone, osteogenesis and the ontogeny of the bone marrow and its stromal compartment, which is derived from the skeletal stem/progenitor cells. The ontogeny of bone marrow and its stromal compartment, which is generated from skeletal stem/progenitor cells, was investigated in vivo and ex vivo by Kuznetsov SA et al 4, in mice expressing constitutively active parathyroid hormone/parathyroid hormone-related peptide receptor (PTH/PTHrP; caPPR) under the control of the 2.3-kb bone-specific mouse Col1A1 promoter/enhancer. The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis. This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells. Proliferative osteoprogenitors, but not multipotent skeletal stem cells (mesenchymal stem cells), capable of generating a complete heterotopic bone organ upon in vivo transplantation were assayable in the bone marrow of caPPR mice. Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.

From the above study it is clear that disturbances in PTH mediated signaling of PTH/PTHrP receptors have detrimental effects on proper maturation of a functioning bone marrow in addition to disturbances in osteogenesis and osteoid matrix calcification. In the present patient in our case report, idiopathic hypoparathyroidism, which was existent right from birth, as evidenced by the abnormal dentition and genuvarum may be a contributing factor to development of myelofibrosis.
Chronic hypocalcaemia can be asymptomatic which was the case in this patient , the only odd point is the absence of basal ganglia calcifications and cataracts. However the presence of extensive caries teeth inspite of good dental care , with abnormalities of primary and secondary dentitions and presence of genu valgum all points towards a long standing Ca- Po4 metabolic abnormalities .

Although attempts to correct hypocalcaemia and hyperphosphataemia with Calcium and 1,25 dihydroxycholecalcipherol are beneficial, the long-term benefits in this patient are not known. Treatment of hypo parathyroid patients with synthetic parathyroid hormone is controversial and its effectiveness in this patient is questionable as well. The probable outcome of the disease in this patient is not known at present.


References

1. Maj JS, Roslan K, Fic-Sikorska B: ‘Acute myelofibrosis in children: report on two cases’; Acta Haematol Pol 1996; 27(1): 79-84.

2. Manoharan A: ‘Idiopathic myelofibrosis: a clinical review’. ; Int J Hematol 1998 Dec; 68(4): 355-62.

3. Simpson HK, Howden CW, Elliott HL, Thomson TJ; ‘Idiopathic hypoparathyroidism associated with stable untreated myelofibrosis’; Br Med J (Clin Res Ed). 1983 Apr 23; 286(6374): 1316-7.


4. Kuznetsov SA, Riminucci M et al: ‘The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow’; J Cell Biol. 2004 Dec 20; 167(6): 1113-22.