Background: Ghosal Type Hematodiaphyseal Dysplasia is an autosomal recessive disorder characterized by refractory anemia and diaphyseal bone dysplasia. Case characteristics: A 3 y 9 mo-old male child presented with progressive anemia and bowing of thighs. Child was found to have a previously reported homozygous point mutation c.1238G>A, (p.Arg413Glu) in Exon 16 of TBXAS1 gene. Outcome: Low dose steroid therapy resulted in normalization of hemoglobin and prevented further progression of bony changes. Message: Refractory anemia in association with bony deformities should prompt pediatricians to investigate for inherited bony dysplasia.

Keywords: Anemia, Diaphyseal dysplasia, Engelmann disease.

A 3 y 9 mo-old boy born to a third degree consanguineous couple was referred for genetic evaluation for progressive abdominal distension and pallor since the age of 1 year. The child first presented to the hospital at 2 years age with severe pallor. There was no history of bleeding from any site, bony pains, fractures, visual problems, developmental delay, or seizures. Examination revealed hepatomegaly (liver span 8 cm) and firm splenomegaly (10 cm below costal margin). There was no bony deformity, facial dysmorphism, icterus or lymphadenopathy. Cardio-respiratory and central nervous system examination were normal. Initial investigations revealed presence of severe anemia (Hb 46 g/L), and thrombocytopenia (37×109/L) with normal leukocyte count. The reticulocyte count, pre-transfusion hemoglobin electrophoresis, renal and hepatic functions were normal. First hour erythrocyte sedimentation rate was 40 mm. Serum iron studies showed borderline iron deficiency anemia. Bone marrow examination showed reactive marrow, with prominence of mature lymphoid cells, normoblastic maturation without any storage/atypical cells. Possible infectious etiologies were excluded. Enzyme assays for storage disorders were normal. Fundus evaluation was also normal. Skeletal survey was unremarkable. He was treated with packed red cell transfusion. By 30 months of age, there was a gradual increase in the blood transfusion requirement to almost every month. Platelets count ranged from 100-150×109/L. There was no history of bleeding.

At 3 years 6 months, he developed progressive and painful limping with deformity of both thighs. His growth parameters at 3 years 9 months were below 5th percentile. Examination showed presence of bowing of both thighs without any tenderness or fracture. He had severe pallor. Liver and spleen size were 2.5 cm and 2 cm, respectively. His hemoglobin and platelets were 56 g/L and 111×109/L respectively without any leucopenia. Radiograph of both femurs showed evidence of increased cortical density with diaphyseal involvement (Fig. 1). Rest of the bones were normal.

Fig. 1 Radiograph of both femurs showing diaphyseal involvement with increased bone density.

A diagnosis of Ghosal Type Hematodiaphyseal Dysplasia was made in view of the involvement of diaphyses of long bones with refractory anemia. After obtaining an informed consent, mutation analysis of the TBXAS1 gene was performed by Sanger sequencing of all the 13 exons and exon-intron boundaries as previously described [2]. It showed presence of a previously reported homozygous mutation c.1238G>A (p.Arg413Glu) located in exon 16 (NM_001130966.2). Carrier testing of parents could not be done due to non-availability. The child was initiated on 1 mg/ kg/ day of oral prednisolone with subsequent rise of hemoglobin to 88 gm/L after one month of therapy. There was a decrease in the transfusion requirement. Presently, child is on low dose prednisolone (0.5 mg/kg/day) and is maintaining his hemoglobin between 80 to 100 g/L.

Genevieve, et al. [2] identified the mutations in TBXAS1, which encodes thromboxane synthase (TXAS). Regulation of expression of arachidonic acid pathway and genes of tumour necrosis factor families provides a logical explanation for anemia and increased bone density associated with this dysplasia. Till date, 24 cases have been reported worldwide [1-10] (Web Table I). Of these, total 17 cases are from India and Middle East indicating a common racial background and probably shared gene pool. Thrombocytopenia was present only in 50% of the patients. The time lag between hematological symptoms and bony involvement ranged from 0-60 months with a mean duration 14.5 months. Our case presented with anemia, mild thrombocytopenia and splenomegaly initially followed by diaphyseal involvement of lower limbs. There was a gap of approximately 2 years for bony changes to become obvious as the initial skeletal survey was normal initially resulting in delay in the diagnosis and treatment in our patient.

Four different mutations (c.1463T>C p.Leu488Pro; c.248T>C p.Leu83Pro; c.1444G>T p.Gly482Trp; c.1238G>A p.Arg413Glu) have been reported in the 10 cases from 4 different families [2]. Our patient had c.1238G>A, p.Arg413Glu, mutation which has been reported by this group in a Pakistani family. This might represent a founder effect and require mutation analysis of more patients of Indian and Pakistani origin for further elucidation.

Based upon the underlying molecular basis and evidence from previous reports, child was initiated on steroid therapy to which he responded well by maintaining the hemoglobin and cessation of further progression of bony symptoms. This case illustrates that in the presence of refractory anemia, thrombocytopenia, hepatosplenomegaly and bone manifestations, one should further investigate for uncommon inherited bony dysplasia for timely diagnosis and effective treatment.