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CASE REPORT |
https://doi.org/10.5005/jp-journals-10070-8008
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Rare Mucocutaneous (Dermatological) Manifestations of Vitamin B12 Deficiency: A Case Series
1–5Department of General Medicine, Gauhati Medical College and Hospital, Guwahati, Assam, India
Corresponding Author: Asif Mohammed Oleeur Rahman Mazumder, Department of General Medicine, Gauhati Medical College and Hospital, Guwahati, Assam, India, Phone: +91 9864289439, e-mail: mohammedasif315@gmail.com
How to cite this article: Deuri A, Mazumder AMOR, Sarma AK, et al. Rare Mucocutaneous (Dermatological) Manifestations of Vitamin B12 Deficiency: A Case Series. Bengal Physician Journal 2023;10(2):59–68.
Source of support: Nil
Conflict of interest: None
Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.
Received on: 24 April 2023; Accepted on: 25 May 2023; Published on: 04 August 2023
ABSTRACT
Vitamin B12 deficiency is widespread in developing countries, especially in Africa, India, South and Central America. It affects 1–2% of the general population and 10–15% of older adults and hospitalized patients. The evaluation includes a detailed history of associated conditions and symptoms; an examination for gastrointestinal, dermatological, neurological, and other findings, and laboratory testing, including complete blood count (CBC) and vitamin B12 and folate levels. The prevalence of vitamin B12 deficiency is higher in vegans. Less commonly mucocutaneous presentations usually Addisonian-like hyperpigmentation over knuckles palms, and soles, diffuse/symmetric or a few scattered macules can occur. The hypothesis regarding pathophysiology behind these includes the decrease in the reduced form of glutathione increasing the activity of tyrosinase; second defective melanin transfer between melanocytes and keratinocytes and finally disturbed melanin distribution due to megaloblastic changes in keratinocytes.
Here we present a case series of eleven patients ages varying from 22 years to 71 years, who presented with a history of multiple blood transfusions with rare findings of mucocutaneous hyperpigmentation, very prominent in the hard and soft palate, tongue, buccal mucosa and accentuated hyperpigmentation in upper limb and lower limb, all over face. Few cases also presented with whole-body pigmentation. They all presented high mean corpuscular volume (MCV) (>120) with severe anemia with hypersegmented neutrophils, normal cortisol, and very low serum vitamin B12. All related investigations were done. They have previously tried treatment with oral vitamin B12 supplements, but they didn’t respond. Now they were treated with intramuscular vitamin B12 and all patients started to respond with clinical and lab oratorical values. There were also improvements in hyperpigmentation also.
Keywords: Deficiency, Hyperpigmentation, Mucocutaneous, Vitamin B12.
INTRODUCTION
Vitamin B12 plays a vital role in the proper performance of the complex central and peripheral nervous systems and the generation of red blood cells (RBC) in the bone marrow, mainly DNA synthesis.1 Vitamin B12 deficiency is widespread in developing and low-income countries, especially in Africa, India, and mostly in elderly population.2 The deficiency of vitamin (Vit) B12 can cause specific skin manifestations, such as hyperpigmentation, vitiligo, angular stomatitis, and hair and nail changes.3 Dr. Bramwell Cook, in 1944, first noticed a peculiar pattern of macrocytic anemia with hyperpigmentation of the skin, which both showed improvement with ingestion of crude liver extract.4 These mucocutaneous signs can be seen commonly with other diseases and very rarely with vitamin B12 deficiency, causing a roadblock in early diagnosis, leading to an increase in morbidity.5,6 The peculiar mucocutaneous manifestations are hardly reported in the context of vitamin B12 deficiency and are easily missed and confused with other common causes of hyperpigmentation. Here we present 11 cases of mucocutaneous manifestations of vitamin B12 deficiency.
Case 1
A 34-year-old daily wage worker, nonvegetarian male patient with a history of chronic weakness with progressive generalized hyperpigmentation for the last 9 months. Previously he had no problems. There is also hyperpigmentation of the hard palate and lateral aspect of the tongue. A Similar patch of hyperpigmentation was noted on the flexor aspect of forearm and neck area near clavicle (Fig. 1A). He also complained of a tingling sensation over both lower limbs. There was also grayish discoloration of hair. The tongue was smooth with loss of papilla. There was also severe pallor noticed over the conjunctiva, and nail beds. Hemodynamically patient was stable. Lab investigations at presentation revealed the blood routine with Hb 5.5 g/dL, MCV 135 fL, WBC 4290/cumm, RBC 1.17 million/cumm, PLT 100,000/cumm. On peripheral blood smear examination, white blood cells (WBC) of normal count and morphology with occasional hypersegmented neutrophils, RBC predominantly macrocytic cells with severe anisocytosis, platelet is mildly reduced on smear and normal morphology. The corrected retic count was 1.25%. Serum vitamin B12 level was <159 pg/mL (239–931 pg/mL), folic acid was 7.1 ng/mL (normal >5.38 ng/mL) and lactate dehydrogenase (LDH) >1000 (140–280 U/L). The 8 a.m. serum adrenocorticotropic hormone (ACTH) and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. The liver and kidney profile, thyroid profile, and ultrasound whole abdomen were within normal limits. Stool examination for occult blood and parasites was also negative. Colonoscopy was normal. Upper gastrointestinal (UGI) endoscopy showed atrophic gastric mucosa with loss of gastric folds and scalloped duodenal folds. Multiple biopsies were taken from the body, pylorus, antrum of the stomach, and the first part of the duodenum. History was suggestive of chronic gastritis. Antiparietal cell antibody came out to be positive with high titer. Skin biopsy was taken from a hyperpigmented patch over the left cubital fossa and histopathology revealed an increased pigmentation in the stratum basale. It was at last diagnosed as a case of severe pernicious anemia and treated with intramuscular vitamin B12 1500 mcg and folic acid 0.7 mg daily for six doses, then weekly for four doses, then monthly thereafter. He also received injection FCM 1000 mg two doses 1 month apart.
Figs 1A and B: (A) Hyperpigmentation of skin, tongue, oral cavity and gray hair; (B) Reversion of pigmentation after 3 months of treatment
He started to improve after 1 month. After 3 months, his hemoglobin raised to 10.1 g/dL, MCV was 91 fL and serum vitamin B12 (>1000) level also increased. He also gained weight and the tingling sensation has improved. His pigmentation also started to faint (Fig. 1B). He is taking monthly doses of intramuscular vitamin B12 and folic acid regularly.
Case 2
A 22-years-old, non-married, non-vegetarian male, presented with easy fatigability and generalized hyperpigmentation with pigmentation over the tongue and soft and hard palate for the last 1 year, and it’s progressing (Fig. 2). No history of chronic medication intake or any other comorbidity. His Hb was 5.1 g/dL with MCV 128 fL and hypersegmented neutrophils and macrocytes in peripheral blood smear (PBS). Serum vitamin B12 level was 105 pg/mL, folic acid was 8.2 ng/mL, and LDH – 987 u/L. The 8 a.m. serum ACTH and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. The liver and kidney profile, thyroid profile, and ultrasound whole abdomen was within normal limits. Stool examination for occult blood and parasites were also negative. Colposcopy and UGI endoscopy were normal. Antiparietal cell antibody came out to be positive with high titer and finally diagnosed as pernicious anemia. Parenteral vitamin B12 and folic acid were given according to the above regimen and his parameters are improving.
Fig. 2: Hyperpigmentation of tongue, oral cavity, palms and knuckles
Case 3
A 71-years-old married, non-vegetarian female presented with a repeated history of blood transfusions with palmoplantar hyperpigmentation and also in the tongue and palates for the last 10 years (Fig. 3). She also complained of a tingling sensation in all four limbs. There was the history of weight loss. No other comorbidity was reported. No history of chronic medication intake. Her CBC was suggestive of pancytopenia with Hb 3.9 g/dL with MCV 138 pg/dL and hypersegmented neutrophils in PBS. Serum vitamin B12 level was 59 pg/mL, folic acid was 4.5 ng/mL, and LDH - 686 u/L (140–280 U/L). She is a known case of hypothyroidism on Tablet Thyronorm 50 µg once daily. The 8 a.m. serum ACTH and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. The liver and kidney profile, thyroid profile, and ultrasound whole abdomen were within normal limits. Stool examination for occult blood and parasites was also negative. Colonoscopy was normal and UGI endoscopy was suggestive of gastric mucosal atrophy with loss of gastric folds. Antiparietal cell antibody came out to be positive with high titer and finally diagnosed as pernicious anemia. Parenteral vitamin B12 and folic acid were given according to the above regimen and her parameters are improving.
Fig. 3: Hyperpigmentation of tongue, oral cavity and palms
Case 4
A 27-years-old married, non-vegetarian female presented with generalized weakness and pigmentation over her tongue and palates for the last 7 months (Fig. 4). There was no history of fever, loose stools, or any significant symptoms. Although she complained of a burning sensation in both feet. Her Hb was 5.0 g/dL with MCV 122 fL, and hyper-segmented neutrophils with macrocytes in PBS at presentation. Serum vitamin B12 level was <159 pg/mL, Folic acid was 5.5 ng/mL and LDH - 884 U/L. The 8 a.m. serum ACTH and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. The liver and kidney profile, thyroid profile, and ultrasound whole abdomen was within normal limits. Stool examination for occult blood and parasites were also negative. Colonoscopy and upper GI endoscopy were normal. Antiparietal cell antibody was found to be positive in her case and finally diagnosed as pernicious anemia. Parenteral vitamin B12 and folic acid were given according to the above regimen and her parameters are improving.
Fig. 4: Hyperpigmentation in oral cavity, tongue and palmar and dorsal aspect of hand
Case 5
A 37-years-old married, non-vegetarian female patient with a history of progressive easy fatigability with the pigmentation of the tongue and mucosa of the oral cavity for the last 2 years. She had pigmentation over her face (Fig. 5). There was a history of night cramps in both lower limbs for the last 6 months for which she is taking multiple oral vitamin supplements which mainly had vitamin B12. Her Hb was 6.0 g/dL with MCV 127 fL, and hyper-segmented neutrophils with macrocytes in PBS. Serum vitamin B12 level was <159 pg/mL, folic acid was 5.4 ng/mL and LDH - 691 U/L. She was hypothyroid and taking Tab Thyronorm 25 mcg/day. The 8 a.m. Serum ACTH and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. The liver and kidney profile, thyroid profile, and ultrasound whole abdomen were within normal limits. Stool examination for occult blood and parasites was also negative. Colonoscopy and upper GI endoscopy were apparently normal. Antiparietal cell antibody in her case was positive with a high titer. Parenteral vitamin B12 and folic acid were given according to the above regimen and his parameters are improving.
Fig. 5: Facial hyperpigmentation and also in tongue and knuckles
Case 6
A 47-years-old married, non-vegetarian male patient with a history of Type 2 diabetes mellitus presented to us with a history of repeated hospitalization for blood transfusion for the last 7 years. He complained of a tingling sensation and cramping pain in both of his lower limbs, but no history suggestive of postural hypotension. He is also a hypothyroid patient on thyroid hormone supplements for the last 5 years. There was generalized pigmentation on the tongue and mucous membrane of the oral cavity (Fig. 6). At presentation, his blood parameters are suggestive of pancytopenia with Hb 3.7 g/dL with MCV 133 fL and macro-ovalocytes and hypersegmented neutrophils in PBS. Serum VIT B12 level was <100 pg/mL, folic acid was 8.2 ng/mL, and LDH - 711 U/L. The 8 a.m. serum adrenocorticotropic hormone (ACTH) and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. Liver and kidney profile, thyroid profile, and ultrasound whole abdomen were within normal limits. Stool examination for occult blood and parasites were also negative. Colonoscopy and upper GI endoscopy was apparently normal. Antiparietal cell antibody report came out to be positive strongly and we finally labeled as a case of pernicious anemia. Parenteral vitamin B12 and folic acid were given according to the above regimen and his parameters are improving. There is no further history of blood transfusions till now and improvement of pigmentation.
Fig. 6: Hyperpigmentation of tongue, oral cavity and hands
Case 7
A 59-years elderly married female came with complaints of easy fatigability with a tingling sensation in both lower limbs for the last 10 months. She has not taken non-veg meals for the last 10 years due to religious practice. There was no history of fever or loose stool. She had pigmentation over her tongue and oral cavity (Fig. 7). Her Hb at the time of presentation was 6.7 g/dL with MCV - 119 fL and oval macrocytes with few hypersegmented neutrophils in PBS with normal hemoglobin type on Hb electrophoresis. Serum vitamin B12 level was <100 pg/mL, folic acid was 3.1 ng/mL, and LDH >1000. The 8 a.m. serum ACTH and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. The liver and kidney profile, thyroid profile, and ultrasound whole abdomen was within normal limits. Stool examination for occult blood and parasites were also negative. Colonoscopy and UGIE were also normal apparently. She was diagnosed with severe dietary deficiency and was supplemented initially intramuscularly, followed by orally. She has responded with clinical and biochemical improvement.
Fig. 7: Hyperpigmentation tongue and oral cavity
Case 8
A 62-year-old, non-vegetarian male patient with a history of right hemicolectomy due to perforation 7 years back, presented with anorexia, weakness, weight loss, and ataxia for the last 2 years. He also got three units of blood transfusions during that time period also. He also had angular stomatitis and glossitis. There was also pigmentation over oral mucosa and hands and feet (Fig. 8). At presentation, his CBC was suggestive of pancytopenia with Hb 2.9 g/dL with MCV 130 fL. His PBS showed macrocytes along with few microcytes and hypersegmented neutrophils, reduced platelet counts with normal morphology. Serum vitamin B12 level was 89 pg/mL, folic acid was 2.3 ng/mL, LDH >1000, iron 56 mcg/mL, and ferritin 763 ng/mL. The 8 a.m. serum ACTH and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. Liver and kidney profile, thyroid profile, and ultrasound whole abdomen were within normal limits. Stool examination for occult blood and parasites was also negative. Colonoscopy and UGIE are also normal apparently. He was diagnosed with dietary deficiency and was supplemented initially intramuscularly, followed by orally. He also received iron infusions. He has responded with treatment with improvements in clinical and biochemical parameters.
Fig. 8: Generalized hyperpigmentation and also in oral cavity and tongue, also smooth tongue with angular stomatitis
Case 9
A 35-year-old, married, non-vegetarian male patient presented with a history of repeated blood transfusions for the last 6 years with generalized skin hyperpigmentation and also in palates (Fig. 9). There was no history of fever, or loose stools, but complained of a burning sensation in both feet for the last 2 years, for which he took lots of oral vitamin B12 and IFA supplements, but without any improvement. At presentation, his Hb was 4.0 g/dL with MCV 117 fL and hyper-segmented neutrophils and oval macrocytes in PBS. Serum vitamin B12 level was <159 pg/mL, folic acid was 5.0 ng/mL, ferritin was 1011 ng/mL, serum Iron was 102 µg/dL, and LDH - 633 U/L. The 8 a.m. serum ACTH and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. Liver and kidney profile, and thyroid profile were within normal limits. Ultrasound whole abdomen was suggestive of cholelithiasis. Stool examination for occult blood and parasites was also negative. Colonoscopy and upper GI endoscopy were apparently normal. Antiparietal cell antibody was strongly positive and was diagnosed as pernicious anemia. Parenteral vitamin B12 and folic acid were given according to the above regimen and his parameters are improving. There is no further history of blood transfusions till now.
Fig. 9: Hyperpigmentation with involvement of face, palms, oral cavity with severe tongue pallor
Case 10
A 28-years-old married female, strict vegetarian presented with easy fatigability for the last 2 years and tingling and burning sensation in both limbs for the last 2 months for which she did not any medication. She noticed generalized hyperpigmentation and pigmentation on tongue (Fig. 10). No history of fever, or loose stools. Her Hb was 5.9 g/dL with MCV 124 fL and hyper-segmented neutrophils in PBS with a normal Hb electrophoresis report. Serum vitamin B12 level was 189 pg/mL, Folic acid 5.6 ng/mL, LDH - 733 U/L, serum iron 112 mcg/dL, and ferritin 410 ng/mL. The 8 a.m. serum adrenocorticotropic hormone (ACTH) and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. Liver and kidney profile, thyroid profile, and ultrasound whole abdomen were within normal limits. Stool examination for occult blood and parasites was also negative. Colonoscopy and upper GI endoscopy were apparently normal. Antiparietal cell antibody was negative in her case. Initially, parenteral vitamin B12 and folic acid supplements were given for 4 months, followed by orally. She clinically improved and also her blood parameter also improved.
Fig. 10: Pigmentation on tongue and knuckles
Case 11
A 45-years-old, married, non-ethanolic, non-vegetarian male patient presented with generalized pigmentation, most prominent over the face since last 7 months (Fig. 11). He also complained of easy fatigability and anxiety for the last 1 year. He also had angular stomatitis and glossitis. At presentation, his Hb was 7.1 g/dL, MCV 125 fL, and macrocytes with hypersegmented neutrophils in PBS. Serum vitamin B12 level was 208 pg/mL, folic acid was 4.1 ng/mL, LDH - 613 U/L, serum iron 94 mcg/dL, and ferritin 507 ng/mL. The 8 a.m. serum adrenocorticotropic hormone (ACTH) and 8 a.m. serum cortisol levels were within normal limits. There was no dyselectrolytemia or raised blood sugar. Liver and kidney profile, thyroid profile, and ultrasound whole abdomen were within normal limits. UGIE and colonoscopy were apparently normal. Antiparietal cell antibody report revealed high titer positive. He was diagnosed with pernicious anemia and was treated with intramuscular vitamin B12 1500 mcg and folic acid 0.7 mg daily for six doses, then weekly for four doses, then monthly thereafter. After 2 months, his symptoms improved and his blood parameters also improved.
Fig. 11: Generalized hyperpigmentation, more pronounced over face and hands, along with gray hair
DISCUSSION
Vitamin B12 is usually deficient in plant-based diets and we get it mainly from the animal-based diets and milk products, as our body can’t produce it on its own.5 In normal conditions, our body stores about 2–3 mg of vitamin B12, mainly in the liver, which is sufficient for 2–3 years. The prevalence of vitamin B12 deficiency increases with age, approximately 20% in those with age >60 years in the United Kingdom and the United States. The rough estimate of vitamin B12 deficiency is as high as 70% in the Indian population with age >60 years, owing to a huge vegetarian population.7 Vitamin B12 deficiency is usually associated with people who are strict vegetarians, it can also occur from defective functioning of the intrinsic factor or malabsorption due to multiple diseases of the gastrointestinal tract from the stomach to the ileum. The conditions that can lead to deficiency include gastrectomy, wide surgical resection of the terminal ileum due to any cause, Crohn’s disease, chronic alcoholism, parasitic (Diphyllobothrium latum) infestation and medications such as metformin, and colchicine. Malabsorption of vitamin B12 has been associated with prolonged use (usually >4 years) of H2-receptor antagonists and protonpump inhibitors. Among these potential causes for vitamin B12 deficiency, the most common are low dietary intake and malabsorption. Because the strict vegetarian culture has been extensively practiced for several eras in India, much of the population of this country with that belief is at risk of having low vitamin B12 status throughout their life.8 The common Indian vegetarian meal is a very poor source of vitamin B12 and this must be taken into account while analyzing the results of the previous studies from the Northern and Southern parts of India, because of the vast vegetarian population of living in that part, owing to the strictly religious and cultural belief.8,9 In contrast to that, our hospital (Gauhati Medical College and Hospital) is serving a population mainly from Assam and other parts of Northeast India, where the maximum population is strictly non-vegetarian. As most of the population living here are non-vegetarian, the exact cause of vitamin B12 deficiency can’t be diet related to a great extent.
In the year 1963, Baker and his colleagues notified the distinctive reversible hyperpigmentation over the dorsal surface of the small joints of hands and feet in 21 cases of the South Indian population with macrocytic anemia.4 In this case series, malabsorption was found to be the commonest culprit of severe vitamin B12 deficiency; with a mean serum vitamin B12 level was 49 pg/mL.4 In another study from South India, a similar pattern of reversible mucocutaneous hyperpigmentation was reported among nine patients with very low serum vitamin B12 and other signs of vitamin B12 deficiency.10 In the study by Aaron et al., they also found that 41% of the subjects with peripheral neuropathy owing to severe vitamin B12 deficiency had significant mucocutaneous hyperpigmentation.11
The pathophysiological mechanism of this hyperpigmentation due to Vitamin B12 deficiency may be related to the increased synthesis of melanin pigments and the incomplete movement of the melanin pigments from the melanocytes to the adjacent keratinocytes.12 This increased melanin production happens owing to the increased activity of the tyrosinase enzyme.12 This increase in melanin production is thought to be the major mechanism rather than the incomplete shifting of melanin pigments.13 When this hyperpigmented skin sample was seen under Electron microscopy, showed the appearance of the huge number of megaloblastic keratinocytes surrounding the melanosomes carrying melanocytes.14 Besides the above pathogenesis, the role of vascular endothelial growth factor (VEGF) is additionally found to be associated with hyperpigmentation in a few patients.15 The mucocutaneous hyperpigmentation gradually improved in the patients with proper treatment, clinically visible within a few weeks; also the complete resolution of hyperpigmentation in a span of a few months with strict adherence to the treatment.10 Our patients also showed improvement in anemia and reduction of hyperpigmentation with the treatment. Treatment depends on the underlying causes.
CONCLUSION
The mucocutaneous manifestations are hardly reported in the context of vitamin B12 deficiency, so easily missed out. It usually points towards severe and prolonged deficiency of vitamin B12 or some internal diseases, which cause vitamin B12 deficiency, requires detailed examination and series of investigations and beautifully responds with aggressive, and long duration of treatment.
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