Dr Shivanee Shah

A one-year-old female child was brought to a tertiary case hospital in Mumbai with fever, pallor, and conjunctival and intracranial hemorrhage. Blood tests revealed low platelet counts and hypothyroidism. Bone marrow aspirates indicated the presence of platelet precursors, and suggested that the platelets were being destroyed. An MRI was also done and showed multifocal hemorrhagic areas in the cerebral parenchyma and cerebellum. The patient was thought to have immune thrombocytopenic purpura (ITP) and was treated with packed RBCs, platelets, intravenous immunoglobin (IVIg), methylprednisolone and dapsone for ITP, and for hypothyroidism with L-thyroxine. Steroids and dapsone were tapered and stopped after 6 months along with L-thyroxin. The patient did well for a few months and then returned to the hospital at age 2 with fever, cough, cold, and thrombocytopenia. This time she was treated with antibiotic therapy, oral steroids and dapsone. The patient had a 3rd admission to the hospital at age 3 with purpura and she was started on cyclosporine syrup and discharged. This treatment regime was effective for a few years.

However, at age 4, the child was brought to Lilawati Hospital and Research Center, Mumbai, to consult with Dr. Swati Kanakia, a pediatric hemato-oncologist. The patient presented with bleeding in the skin, another intracranial hemorrhage, and low platelet count. An MRI showed calcification in the basal ganglia and evidence of the previous intracranial bleeding. Based on the history, the patient was started on IVIg for treating low platelets. Further, even though normally platelets are not given as therapy in such cases as they would be expected to be destroyed in the body, this patient was again given platelets as well because of the intracranial hemorrhage, and started with cyclosporine syrup.

In addition, Dr. Kanakia observed certain morphological abnormalities including short stature, high arched palate, low set ears, and wider wrists than normal. Wider wrists are typical signs of rickets and an X-ray of the wrist was done which indeed showed typical signs of rickets. Blood tests for vitamin D, calcium, and phosphorous however did not corroborate with the clinical findings for rickets.

This was indeed an atypical case where the patient
had an early onset of ITP, was not responsive to treatment over long periods of time, had two intracranial hemorrhages, calcification of basal ganglia and showed signs of
abnormal facies. In addition to these, she was strongly positive for alloantibodies against red blood cells as evidenced in a direct Coomb’s test and thyroid antibodies causing hypothyroidism. Such autoantibodies are
evidence of autoimmunity. Dr. Kanakia was not satisfied
with the diagnosis and treatment being offered to the
patient, and continued to search for a more accurate diagnosis and better treatment options. She searched the OMiM database for other similar cases, but was not able to come up with anything similar. During discussions with other doctors, she realized that perhaps her choice of keywords was not correct. She was including the keyword ‘rickets’ due to the wider wrists that are characteristic of rickets. However, once she replaced ‘rickets’ with ‘metaphyseal dysplasia’, she was able to find a very similar condition called spondyloenchondrodysplasia with immune dysregulation (SPENCDI). As per the description, ‘SPENCDI is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement’ The patient’s condition seemed to fit well with the description.

SPENCDI is caused by a homozygous mutation in the APC5gene on chromosome 19p13. Genetic testing was carried out, and consistent with the clinical symptoms, the patient was found to carry a homozygous deletion in the APC gene that results in a truncated protein. The patient’s parents also underwent genetic testing, and they were found to carry the heterozygous mutations. Based on this genetic identification, the patient had a confirmed diagnosis of SPENCDI and was accordingly continued on cyclosporine. The dosage of cyclosporine was kept at a minimum dose just to maintain the platelet levels at a safe count of 30,000-40,000/uL. The patient is doing well as of now.

The genetic identification was not only important for adequate treatment and management of the patient, but would also be important in case the parents decided to have another child. Prenatal testing can be used to determine whether the child would be homozygous or heterozygous, allowing for the option to terminate the pregnancy if required. Such prenatal testing may therefore prevent another child with the same genetic disorder. Genetic testing can also be done for close family members to assess hereditary mutations.

“Accurate diagnosis gives the patient/patient’s family a sense of closure and helps them prepare for their next child. Even in this age of technological advances, clinical judgement is extremely important. To be able to diagnose accurately, it is important to understand which tests to run,” Dr. Kanakia shares her learnings from this case.

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