Concurrent hypopituitarism and leukemic retinopathy in a child with B-precursor acute lymphoblastic leukemia and isolated central nervous system relapse

Hypopituitarism in leukemia is very rare. In addition, central nervous system (cns) relapse and leukemic retino­ pathy in childhood acute lymphoblastic leukemia (all) have declined with the use of modern systemic chemo­ therapy that includes cns prophylaxis. Here, we report the case of a 4­year­old girl who received chemotherapy and intrathecal therapy without cns radiation after a diagnosis of B­precursor all without cns involvement. Three months after chemotherapy completion, she presented with lower­extremity weakness and was diagnosed with an isolated cns relapse. Concurrent hypopituitarism and leukemic retinopathy were also found. After receiving craniospinal radiotherapy and systemic chemotherapy, her retinopathy and vision improved. She is now in com­ plete remission, and she is still on chemotherapy according to the guideline from the Pediatric Oncology Group. Although rare, hypopituitarism and leukemic retinopathy should be taken into consideration in patients with cns involvement by leukemia.


INTRODUCTION
Acute lymphoblastic leukemia (all) is the most common malignancy in children 1 .With advances in systemic poly chemotherapy and the introduction of preventive central nervous system (cns) therapy, the incidence of cns relapse has declined to less than 5%-10%.Hypopituitarism has been reported as the initial presentation or relapse in acute myeloid leukemia 2,3 or as the initial presentation in chronic lymphocytic leukemia 4 .Primary lymphoma in the pituitary gland has also been noted 5 .Hypopituitarism in children with all appears to be quite rare, having been reported in only 1 child, and is associated with radiation 6,7 .Like cns relapse, the incidence of leukemic retinopathy has declined with the progression of cnsdirected treatment.
Here, we report the case of a child with cns relapse of all that manifested as weakness together with concur rent hypopituitarism and leukemic retinopathy.Written informed consent was obtained from the patient and her parents for publishing her individual details and any accompanying images in this manuscript.

CASE DESCRIPTION
A 4yearold girl originally displayed symptoms of fever for 7 days.An elevated leucocyte count (28.78×10 9 /L), with anemia (hemoglobin: 6.8 g/dL) and thrombocytopenia (92×10 9 /L), was noted in peripheral blood.Bone marrow examination showed markedly hypercellular marrow with diffused infiltration by blasts.Flow cytometric analyses of the blasts was consistent with Bprecursor all.The karyo type of the blast cells was 45,XX.No nucleated cells were found in the cerebrospinal fluid (csf).
Given the diagnosis of Bprecursor all without cns involvement, the patient received chemotherapy accord ing to the Taiwan Pediatric Oncology Group all2002 standardrisk protocol 8 (  6mercaptopurine, and methotrexate.For cns prophylaxis, triple intrathecal chemotherapy with methotrexate, hy drocortisone, and cytarabine was administered.No pro phylactic cranial irradiation was given.No lumbar puncture was traumatic.Remission was achieved at the end of induction therapy, and the patient remained in complete remission after finishing 2.5 years of chemotherapy.Weakness of both legs, with a limping gait, were found 3 months after completion of chemotherapy.A neurologic examination demonstrated intact cranial nerves.No ev idence of relapse was found in a bone marrow aspiration and biopsy, but in csf, white cells 3.464×10 9 /L, of which 95% were blasts, were found.Flow cytometric analysis of the csf blasts showed them to be of Bprecursor lineage.Magnetic resonance imaging of the spine showed an abnormal infiltrative mass with heterogeneous enhance ment in the S1-2 epidural space, suggesting leukemic involvement.Isolated cns relapse of all was diagnosed, and the patient received chemotherapy according to the Pediatric Oncology Group guideline 9 . At the time of cns relapse, edema was noticed in the girl's upper and lower extremities.Investigations for an endocrine cause revealed low T3 (38.01 ng/dL; reference: 90-230 ng/dL), low total T4 (3.68 μg/dL; reference: 4.5-10.0μg/dL), low free T4 (0.58 ng/dL; reference: 0.7-2.0ng/ dL), and low thyroidstimulating hormone (0.27 IU/mL; reference: 0.5-4.5 IU/mL).When a single low growth hormone (gh) level of 0.065 ng/mL (reference: >7 ng/mL) after exercise was found, the patient underwent 2 separate gh provocation tests using clonidine and insulin hypo glycemia to assess gh response 10 .On both tests, all peak gh levels were found to be less than 7 ng/mL, indicating gh deficiency.Very low, and even undetectable, levels of adrenocorticotropic hormone (<5.00 pg/mL; reference: 7.2-63.3pg/mL), low morning fasting cortisol (<0.4 μg/ dL; reference: 6.7-22.6 μg/dL), and low evening cortisol (<0.4 μg/dL; reference: 2.5-12.5 μg/dL) all indicated a central origin of hypocortisolism.Serum prolactin and insulinlike growth factor 1 were within their normal ranges.Urinary specific gravity, plasma and urinary os molarities, and urine and serum sodium levels were all within their normal ranges.Magnetic resonance imaging of brain showed thickening and increased bilateral en hancement in the hemispheric dura, indicating dural involvement of the leukemia.Additionally, a focal nodu lar enlargement about 7×4 mm at the left lateral aspect of pituitary gland was found (Figure 1).
After hypopituitarism was found, the patient was treated with cortisone acetate (10 mg/m 2 in divided doses twice daily) and lthyroxine (2 μg/kg daily).No gh replace ment was given because gh replacement has been reported to be associated with leukemia 11 .
The patient's cortisol level returned to the normal range 2 months after initiation of treatment with cortisone acetate; replacement therapy was subsequently tapered and then discontinued.High free T4 was noted after the supplementation with lthyroxine and that replacement therapy was also tapered and discontinued.
During the reinduction chemotherapy after cns re lapse, the patient complained of bilateral blurred vision and progressive visual loss.Her corneas were clear and the anterior chambers and vitreous were silent; however, funduscopic examination revealed severely swollen optic discs, blurred disc margins, tortuous and sheathing ret inal vessels in the posterior poles radiating from disc to FIGURE 1 Magnetic resonance imaging of brain.A focal nodular enlargement about 7×4 mm at the left lateral aspect of pituitary gland was noted (arrows).Bilateral dilated ventricles were also found.macula areas, and flameshaped hemorrhage in both eyes (Figure 2).She was diagnosed with leukemic retinopathy, and craniospinal irradiation to a total dose of 24 Gy was immediately begun.At the end of radiotherapy, visual findings were all improved, but not completely resolved.At present, her csf is negative for disease.Her weakness and vision have improved.

DISCUSSION
With advances in therapy, the cure rate in childhood all has reached approximately 80%-90% 1,12,13 .The cns is the most common site of leukemic extramedullary invasion.On the basis of our Taiwan Pediatric Oncology Group all2002 report, only 3.0% of children with all experience isolated cns relapse 8 .In all, cns relapse is reported to be associated with Tcell lineage, a high white blood cell count at diagnosis, and traumatic punctures 14,15 .Our patient had none of those risk factors, but presented with neurologic changes that signalled cns relapse.A cns relapse should be considered in any patient with leukemia who has neu rologic symptoms or signs, even those at lower risk of cns relapse.A cns relapse can manifest in many ways, but the occurrence of hypopituitarism and leukemic retinopathy in our patient were unusual and are highlighted in this report.
Except for radiationinduced hypopituitarism 6 , only Nishi et al. 7 have reported a child with hypopituitarism in all.Our patient was diagnosed with hypopituitarism because of her low thyroidstimulating hormone, low gh after gh provocation tests, and low adrenocorticotropic hormone.It is interesting that the hypopituitarism required only temporary replacement therapy and resolved with craniospinal irradiation.
All ocular structures have been found to be involved in patients with cns leukemia 16 .Overt leukemic infiltration of the eye is uncommon at presentation and is usually associated with leukemic relapse 17,18 .It suggested that, like the cns and testes, the eye could be a sanctuary site in all 19 .In leukemic retinopathy, leukemic infiltrations and hemorrhage can be found in the retinal area by funduscopic examination 20 .Although the prognosis for restoration of vision is poor, visual recovery after emergent radiotherapy has been reported 21 .In our patient, unlike the patient reported by Nishi et al 7 , a typical leukemic retinopathy with cns relapse was found, together with hypopituitar ism.Because visual changes might not be appreciated or expressed by young children, funduscopic examination should be routine in patients with all and cns relapse.

SUMMARY
A cns relapse in childhood all is uncommon, but can man ifest in many ways.All patients with relapse should undergo evaluation of the eyes, because visual changes might not be appreciated by young children.Endocrine dysfunction occurs only rarely with cns relapse, but should be investi gated in patients with symptoms or findings suggesting a possible endocrine origin.

CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology's policy on dis closing conflicts of interest, and we declare that we have none.
AUTHOR AFFILIATIONS *School of Post Baccalaureate Chinese Medicine, College of Chi nese Medicine, China Medical University, Taichung; † Division of Pediatric Hematology-Oncology, Children's Hospital, China Medical University, Taichung; ‡ Division of Pediatric General Medicine, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan; § College of Medicine, Chang Gung University, Taoyuan; || Department of Ophthalmology, China Medical Univer sity Hospital, Taichung; # Department of Medical Research, China Medical University Hospital, Taichung; **Division of Genetics and Metabolism, Children's Hospital, China Medical University, Taichung; † † Department of Radiology, China Medical University Hospital, Taichung; ‡ ‡ Department of Biotechnology and Bioin formatics, Asia University, Taichung; § § Department of Pediatrics, Chung Shan Medical University Hospital, Taichung; and ## School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

TABLE I Chemotherapy protocol used Treatment stage and drug Dose Schedule
2 Vincristine 2 mg/m 2 Dexamethasone plus vincristine every 4 weeks until week 100 Dexamethasone 12 mg/m 2 Triple intrathecal therapy a a Methotrexate 12 mg, hydrocortisone 24 mg, and cytarabine 36 mg.