Demystifying the Mystery of Vitamin B12 Deficiency in an Infant with Developmental Delay

Vitamin B12 is one of the water-soluble vitamins that are present in animal product-derived foods. Risk factors include families with low socioeconomic status, exclusively breastfed infants of vegan mothers, and malabsorption diseases. Vitamin B12 deficiency causes multisystemic involvement. Presentation may include megaloblastic anemia and neuropathy, along with nonspecific symptoms, including hyperpigmentation of the skin, weakness, failure to thrive, developmental delay, afebrile seizures, nystagmus, tremors, and irritability. Late diagnosis and treatment may result in irreversible neurological effects [1]. Clinical and hematological improvement will be observed following vitamin B12 administration [1].

A seven-month-old boy was brought to emergency department of our hospital with 2 days history of bleeding from nose. There was no history of trauma or bleeding from any other part of the body. The parents also raised a concern that he has been less playful and not progressing well with his developmental milestones since the age of 4 months. The birth history was unremarkable and there was no family history of hematological disorders.

On clinical examination, he looked alert but irritable with poor eye contact. There was no significant dysmorphism except for frontal bossing and protruded tongue. The patient had significant pallor, hepatomegaly (around 5–6 cm below right costal margin), splenomegaly (4–5 cm below left costal margin), and acral hyperpigmentation (shown in Fig. 1) and was noted to be alacrimiac. There were no petechial spots or lymphadenopathy. Neurologically he had developmental delay with profound hypotonia. Initial laboratory workup revealed bicytopenia and neutropenia (hemoglobin of 5.8 g/dL, platelets of 28 × 10³/μL, and absolute neutrophil count of 0.5 × 10³/μL), along with normal retic count and raised LDH 2,893 U/L (shown in Table 1), hence admitted for further investigation.

In view of severe anemia with hepatosplenomegaly and developmental delay, he was worked up for hematological and metabolic causes. The acral hyperpigmentation in the setting of developmental delay and anemia raised a possibility of vitamin B12 deficiency. This prompted us to revisit the dietary history of both the patient and his mother. Interestingly, his mother was a pure vegetarian, which is quite unusual in this ethnic group, her vitamin B12 level was 37 pg/mL (reference range 197–771 pg/mL), and she was not adherent to vitamin B12 therapy. The infant was exclusively breastfed with no weaning attempted. A serum vitamin B12 level was sent for our infant, which showed an extremely low value of 82 pg/mL (reference range 187–883 pg/mL). The thyroid function test and hemoglobulin electrophoresis were unremarkable (shown in Table 1). Blood film was consistent with bicytopenia and leucoerythroblastic blood picture indicating bone marrow stress (shown in Fig. 2). The bone marrow study demonstrated megaloblastic erythroid hyperplasia (shown in Fig. 3), supporting the diagnosis of vitamin B12 deficiency. The metabolic panel revealed elevated methylmalonic acid and homocysteine levels along with low methionine levels (shown in Table 1), which further supported our diagnosis of vitamin B12 deficiency.

Hence, the infant was initiated on vitamin B12 therapy with 1,000 μg subcutaneous injections for 4 days. On the 4th day post-initiating vitamin B12 therapy, the infant appeared more interactive and less irritable. He seemed to regain his appetite and started tolerating a mashed diet.

Two weeks later, he was reassessed in the general pediatric clinic. The infant showed significant clinical improvement with progression of developmental milestones and normal physical examination including regression of the previously noted hepatosplenomegaly. The repeated laboratory report showed significant improvement in all blood cell lines (shown in Table 1 ), along with a vitamin B12 level of 349 pg/mL (reference range 187–883 pg/mL).

Vitamin B12 is one of the micronutrients that may be uncommonly deficient in children. Many causes can be attributed to vitamin B12 deficiency. Giving birth to vitamin B12 deficient infants is commonly related to strict vegan mothers or those who consume low amounts of animal products during pregnancy and lactation [2]. A study done in Turkey, including pregnant women consuming a Mediterranean diet (mainly fresh fruits and vegetables) and their term babies, showed an association between maternal and cord blood serum vitamin B12, which was deficient in both mentioned groups [3], supporting the fact that our baby was being exclusively breastmilk fed by a vegan mother who is known to be vitamin B12 deficient and not adherent to vitamin B12 therapy.

Vitamin B12 deficiency is a well-known cause of megaloblastic anemia that has an association with neurocognitive and other complications [4]. Some researchers claim that vitamin B12 does not directly influence the pathophysiology of the nervous system, but it may affect the balance of cytokines responsible for myelin sheath metabolism [5].

The infant in our case presented with complaints of epistaxis, hypotonia, acral hyperpigmentation, and delayed developmental milestones. These presentations were similar to a study done in India on 27 infants with vitamin B12 deficiency. Developmental delay, pallor, skin hyperpigmentation, and hair changes were present in all; the majority of infants were noted to have decreased tone and involuntary movements along with anemia and macrocytosis [6].

Laboratory investigations of our baby showed pancytopenia, raised lactate dehydrogenase, methylmalonic acid, and homocysteine levels along with low methionine, as well as leucoerythroblastic changes in the bone marrow biopsy. Similar findings were found in two reported cases of Syrian refugees with severe vitamin B12 deficiency who presented with pancytopenia, hepatosplenomegaly, raised LDH, and leukoerythroblastosis [7]. Similarly, two asymptomatic newborns with vitamin B12 deficiency were found to have raised methylmalonic acid and propionyl carnitine in the newborn screening test [8].

Treatment with vitamin B12 therapy is the core of management. In a study done in India, it was documented that significant general activity and appetite improvement within 2–3 days after commencing vitamin B12 therapy followed by a catchup of lost milestones [6]. Moreover, in a reported case, regression of hepatosplenomegaly was noted within 7 days, neutrophil count and hemoglobin normalized in 8 weeks, and neurological consequences resolved after 4 months [7]. Our patient demonstrated resolution of hepatosplenomegaly, normalization of cell lines and improvement of neurological symptoms on 14 days of follow-up (Table 1).

Vitamin B12 deficiency is an uncommon but preventable cause of developmental delay in the pediatric population. It can manifest with a wide variety of symptoms. Our case report exemplifies that vitamin deficiencies still prevail even in countries with high socioeconomic status. Therefore, a high index of suspicion should be maintained so as to not overlook these easily treatable conditions.

Informed consent was obtained from parents for the publication of the details of their child’s medical case and any accompanying images. Ethical approval is not required according to the Dubai Ethics Committee policies.

The authors have no conflicts of interest to declare.

The authors did not receive any funding for the publication of this case report.

Heba Aldarawsha – preparing case summary, literature review, and final draft of the manuscript, Sura Ahmed AlDoory – critical reviewing of the manuscript and supervising the publication, Nidheesh Cheeyancheri Chencheri and Shafiqa Mohamed Saleh – critical reviewing of the manuscript.

All data generated or analyzed during this case report are included in this article. Further inquiries can be directed to the corresponding author.

We confirm that this work is original and has not been published elsewhere, nor is it currently under consideration for publication elsewhere.