Microcytosis Leads to Niemann-Pick Disease Type C Diagnosis for Toddler

The case required significant testing to get to the correct diagnosis, but the investigators hope their experience helps inform doctors facing similar cases in the future.

A young child with Niemann-Pick Disease type C (NPDC) was diagnosed after first presenting with neurodevelopmental delay and persistent microcytosis, according to a new case report.

Writing in the Journal of Pediatric Hematology/Oncology, the patient’s doctors explain how they finally came to the right diagnosis, and offer insights for other clinicians who might face similar cases.

Corresponding author Aurea Cervera Bravo, MD, PhD, of Móstoles University Hospital, in Spain, and colleagues explained that hypochromic microcytic anemia is a common type of anemia, and is usually easy to diagnose.

“Atypical cases, however, represent a real diagnostic challenge,” the authors wrote. “The reason is that many rare diseases can be the origin of defective hemoglobinization (genetic disorders of iron metabolism or heme synthesis), some of them with neurological manifestations.”

NPDC is one such rare disease, caused by autosomal recessive mutations in the genes NPC1 or NPC2. Thrombocytopenia is the most common type of cytopenia among patients with NPDC, the authors wrote, followed by anemia, though the anemia is typically not considered microcytic.

“However, [lysosomal storage disorders] have a proinflammatory state triggered by the activation of macrophages that can produce hepcidin dysregulation causing iron-deficient erythropoiesis, and, as a consequence, microcytic anemia,” the investigators wrote. Yet, this particular mechanism is not widely understood and “barely” described in existing literature.

In the new case report, Cervera Bravo and colleagues outline the case of a 2-year-old who had been born prematurely, experienced anemia of prematurity, given iron-replacement therapy, and was otherwise considered healthy.

Soon after release from the hospital, however, the child experienced a number of symptoms. He was diagnosed with splenomegaly, and later subclinical hypothyroidism. By 17 months, he was started on thyroid hormone replacement therapy, but it did not spark improvement. By then, the child’s parents had also noticed that he seemed sadder and more tired than usual. By age 2, developmental delay was evident and the patient was referred to pediatric neurology. There, clinicians used brain imaging to identify thinning of the corpus callosum, small subcortical white matter hyper-intensities in the occipital and frontal areas, and significant delay in myelination.

The child’s liver function was normal, cholesterol was low, and triglycerides were normal.

However, the clinicians noticed high plasma chitotriosidase activity and so performed bone marrow aspiration (BMA) and biopsy during a surgical repair of an inguinal hernia. Later, filipin staining and a genetic study confirmed NPDC.

The patient was 8 years old at the time of the case report’s writing.

“Despite specific therapy (miglustat, intrathecal cyclodextrin, acetyl-DL-leucine, thyroid replacement, and iron therapy) he continues with visceromegalies, microcytosis, and altered iron status,” the authors wrote.

In their discussion, the authors explained why they chose to conduct BMA, even though the procedure is considered invasive and is no longer typically recommended for lysosomal storage disorders.

“In our case, isolated microcytosis (without anemia) was the main hematologic manifestation associated with an iron pattern suggesting infection/inflammation that was not clinically apparent,” they wrote. “This, as well as the increased chitotriosidase—as occurs in sphingolipidosis, but also in thalassemia-major and some infections—prompted our decision to conduct BMA.”

The authors added that BMA is widely available in most medical centers, and in this case revealed, “the presence of foamy histiocytes indicating lipidosis, and also showed that the child was iron deficient despite having normal- high ferritin levels.”

In conclusion, the authors said they hope their experience empowers other clinicians to make swifter diagnoses in future cases.

“As this (microcytosis) may be another frequent manifestation of [NPDC], being aware of it may allow for an early diagnosis and thus avoid unnecessary tests,” they wrote.


Cervera Bravo A, Osuna Marco MP, Morán-Jiménez MJ, Martín-Hernández E. Unexpected cause of persistent microcytosis and neurological symptoms in a child: Niemann-Pick disease type C. J Pediatr Hematol Oncol. Published online March 3, 2021. doi:10.1097/MPH.0000000000002135