Neurofibromatosis with Autoimmune hemolytic anemia: Bystander or intriguer

Kiran Araballi1, Jyoti M2, Yashaswini K3

1Junior consultant – Pediatric critical care medicine, Kauvery Hospital – Electronic City

2Visiting consultant – Pediatric hemato oncologist, Kauvery Hospital – Electronic City

3Lead Consultant Dept. of Paediatric Critical Care, Kauvery Hospital – Electronic City

Abstract

Antibody production against RBC cell membrane is known in Autoimmune hemolytic anemia, but the pathogenesis of antibody production is uncertain. Cold agglutinin disease is less common in children than in adults. There are some established associations between NF1 and leukemias, lymphomas, gliomas and there are some case reports on autoimmune causes. Our index child had a respiratory infection and infection triggered hemolytic anemia unlike the autoimmune association reported so far.

Introduction

Autoimmune hemolytic anemia (AIHA) has been noted as an unusual but significant association with neurofibromatosis type 1 (NF1) in pediatric patients. Autoimmune hemolytic anemias may occur in either of 2 general clinical patterns. An acute transient type lasting 3-6 months and occurring predominantly in children age 2-12 yr-accounts for 70–80% of patients. It is frequently preceded by an infection, usually respiratory. Cold agglutinin disease is less common in children than in adults and more frequently results in an acute, self-limited episode of hemolysis. There are some established associations between NF1 and leukemias, lymphomas, gliomas and there are some case reports with autoimmune causes. Despite these associations, it is important to note that the prevalence of AIHA in NF1 patients remains low, and further research is needed to clarify the underlying mechanisms and clinical implications of this relationship.

Case Presentation

A 3year old male child, with language delay, and suspected autistic spectrum disorder was brought with c/o fever, cough – 4 days, vomiting – 2 episodes.

At OPD, he was found to be pale, icteric, no organomegaly, tachycardia with gallop. He also had two out- patient visits in the last 48hrs for pallor and jaundice.

Investigations showed severe anemia, with mildly deranged liver functions [Bilirubin was elevated].

After admission, child was being treated as severe anemia with congestive cardiac failure, pending all labs. Packed red blood cell transfusion was planned in small aliquots (5ml/kg) under diuretics as child was in congestive cardiac failure.

Lab reports showed Hb to be 4 Gm %, with high indirect bilirubin and LDH, Reticulocyte count was pending.

Child was started on ceftriaxone and azithromycin considering hemolysis secondary to infection. But child continued to have severe pallor despite transfusion, tachycardia, tachypnea and dropping sensorium, hence was intubated.

Blood investigation was suggestive of severe anemia and hemolysis – possibility of autoimmune hemolytic anemia was thought of (low hb, high bilirubin, high LDH, retic pending) and Direct Coombs Test (DCT) was sent and hence pulsed with Inj.Methylprednisolone (10mg/kg).

Paediatric hemato oncologist opined as Autoimmune haemolytic anemia in view of Low Hb, high LDH, increased Bilirubin, positive DCT, absence of organomegaly, however retic was low.

Subsequently child had high coloured urine and decreased urine output with increasing Sr. creatinine , child was in stage 1 Acute kidney injury as per KDIGO. Child was hydrated well and oral bicarbonate supplements was started in concurrence with the nephrologist. USG KUB was done reported as normal. Pediatric neurologist opinion was sought, MRI was advised as father had nodules all over the face and child also had multiple café au lait spots – meeting 2/6 criteria, >6 cafe au lait macules and 1st degree relative with neurofibromas . MRI was reported as normal. Advised follow up. Fundus examination was normal. Methylprednisolone was given for 3 days and followed with oral steroids. Autoimmune hemolytic workup was done in which cold agglutinin was positive, Autoimmune profile [ANA, Ani ds DNA, AntiRo Anti La was negative. The patient was continued on oral steroids and had a decreasing trend in LDH levels.

The patient was discharged in a stable condition with a comprehensive discharge plan, including medication instructions, growth monitoring, and follow-up appointments.

Table 1. Investigations

DATEHBRETICLDHD.BILI/I.BILIU/CREATBICARB
16/112.81.218634.1/3.532/.216.4
17/115.20.21307-67/0.419
18/115.7-699-56/.316.4
19/115.6-490-54/0.318.7
19/116.1-448-35/0.3-
20/115.9-377--17

Discussion

The development of autoimmune hemolytic anemia (AIHA) in patients with neurofibromatosis type 1 (NF1) is influenced by genetic mechanisms primarily involving the NF1 gene and its role in immune regulation. The NF1 gene encodes neurofibromin, a protein that negatively regulates the Ras signaling pathway, which is crucial for hematopoietic cell function. Aberrant Ras signaling due to NF1 mutations can lead to dysregulated immune responses, contributing to the pathogenesis of AIHA.

Autoimmune hemolytic anemia (AIHA) has been noted as an unusual but significant association with neurofibromatosis type 1 (NF1) in paediatric patients. While the literature on this connection is limited, several cases highlight the potential for autoimmune disorders to co-occur with NF1, suggesting a complex interplay between genetic predisposition and immune dysregulation. Reports indicate that AIHA can manifest in patients with NF1, although it is rare. Autoimmune hemolytic anemias may occur in either of 2 general clinical patterns. An acute transient type lasting 3-6 months and occurring predominantly in children age 2-12 year patients. It is frequently preceded by an infection, usually respiratory. Cold agglutinin disease is less common in children than in adults and more frequently results in an acute, self-limited episode of hemolysis.

Our index child had a respiratory infection and was Mycoplasma infection triggered hemolytic anemia unlike the autoimmune association reported so far. Child was further evaluated for genetic analysis and came positive for heterozygous pathogenic variant in the NF1 gene. There are no case reports so far with an infection triggered Hemolytic anemia with NF1 association to the best of our knowledge.

Conclusion

Current study sheds light on association between NF1 and infection triggered AIHA in paediatric population.

References

[1]V.C.Williams,J.Lucas,M.A.Babcock,D.H.Gutmann,B.Bruce,andB.L.Maria,“Neurofibromatosistype1 revisited,”Pediatrics,vol.123,no.1,pp.124–133,2009.

[2] Z. Zaka-ur-Rab and K. Chopra, “Diabetes mellitus in neurofibromatosis I: an unusual presentation,” Indian Pediatrics,vol.42,no.2,pp.185–186,2005.

[3] F. Tekin, O. Ozutemiz, S. Carcurgan, and T. Ilter, “Autoimmune haemolysis as an unusual cause of anaemia in von Reckling-hausen’s disease,” Netherlands Journal of Medicine, vol.62, no.9, pp. 337–339,2004.

[4] J. Schwarz and A. J. Belzberg, “Malignant peripheral nerve sheath tumors in the setting of segmental neurofibromatosis. Case report,” Journal of Neurosurgery, vol.92, no.2, pp.342–346, 2000.

[5] B. Yalc¸in, G. G. Toy, E. Tamer et al., “Increased expression of segmental neurofibromatosis with bronchoalveolar lung carcinoma,” Dermatology, vol.209, no.4, p.342,2004.

 

Dr. Kiran Araballi
Junior consultant – Pediatric critical care medicine

Dr. Yashaswini K
Lead Consultant Dept. of Paediatric Critical Care

Kauvery Hospital