Iron deficiency is the most common nutritional deficiency in children [1]. In young children after infancy, diet-ary problems, such as insufficient intake of iron through food or obesity, are the most common causes of iron deficiency anemia (IDA). In rare cases, diseases that cause gastrointestinal (GI) blood loss or malabsorption also cause IDA [2].
Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare autosomal dominant disorder caused by germline
Herein, we present the case of an 8-year-old girl diagnosed with BRRS during treatment for recurrent IDA. Therefore, we emphasize the importance of esophago-gastroduodenoscopy (EGD) in pediatric patients with IDA.
This study was approved by Seoul St. Mary’s Hospital Institutional Review Board (IRB No. KC24ZASI0200).
An 8-year-old girl was treated at the outpatient clinic of the hematology department with recurrent IDA for 5 years. The following were revealed based on blood tests performed at her first visit to the hospital: white blood cell (WBC), 8,440/mL; hemoglobin (Hb), 5.0 mg/dL; platelets, 448,000/mL; mean corpuscular volume (MCV), 53.6 fL; reticulocyte count, 2.82%; iron, 9 mg/dL; and total iron-binding capacity (TIBC), 456 mg/dL were confirmed. Additional tests, including reticulocyte count, peripheral blood smear, and stool occult blood tests, showed no abnormalities; therefore, oral iron supplementation was initiated. However, even after taking oral iron supplementation for 18 months, Hb level was not maintained stably within normal range. Therefore, additional intravenous iron supplementation was attempted for 4 months. Then the Hb level was well maintained without iron supplementation, thus the treatment was discontinued. Unfor-tunately, the patient’s condition got worsened again. Oral iron supplementation was given for 10 months. Hb level was not recovered and intravenous iron supplement was admitted again. This wax and wane pattern of patient’s Hb level was continued to show fluctuations for a year.
Despite iron supplementation, IDA recurred, and poor weight gain, hypoproteinemia, and hypoalbuminemia were also recently observed; therefore, she was referred to the pediatric GI department. At the time of hospitalization, the height was 127.4 cm (25th percentile) and body weight was 22.5 kg (5th percentile). A head circumference of 57.4 cm, which was superior to 97p, meeting the macrocephaly criteria. The laboratory exam revealed the following: WBC, 8,360/mL; Hb, 11.6 mg/dL; platelets, 525,000/mL; MCV, 83.1 fl; MCH, 25.5 pg; iron, 46 mcg/dL; TIBC, 271 mcg/dL; ferritin, 91.7 ng/mL; LDH, 289 U/L; total protein, 4.6 g/dL; and albumin, 2.7 g/dL. The stool occult blood test results were positive.
EGD was performed for a basic evaluation, and numerous polyps of various shapes and sizes were identified in the stomach and duodenum. Polyps were not observed on colonoscopy and no other unusual findings were observed. Capsule endoscopy was performed for an additional evaluation of the small intestine, and polyposis was confirmed in the duodenum and jejunum (Fig. 1). Biopsy confirmed a hyperplastic polyp. Considering the possibility of PHTS, brain MRI was performed, and FLAIR imaging showed enlarged perivascular spaces and abnormal signals in both the posterior periventricular and deep white matter (Fig. 2).
Next-generation sequencing was performed for the GI polyposis. Targeted panel sequencing of Cancer 151 genes, the c.389G>A, p.(Arg130Gln) mutation, classified as pathogenic in
The patient had macrocephaly, lipomas, and GI hamar-tomatous polyps, and a PTEN mutation was confirmed by genetic testing, leading to a diagnosis of BRRS. After-wards, polyps larger than 2 cm were removed through EGD, and cancer screening for several organs was planned according to the PHTS management guidelines. IDA, hypoalbuminemia, and low body weight were monitored regularly and iron and nutritional supplements were ad-ministered.
IDA is the most common hematological disorder in children; however, gastroduodenal polyposis is a very rare cause of IDA [2]. In this case, polyposis was identified in the stomach and duodenum during evaluation of the cause of recurrent IDA in a young child, and BRRS was later diagnosed through additional examinations, including genetic testing.
Among the patients who visited the hospital with IDA in late infancy and early childhood, the peak incidence occurred between age 9 and 12 months [6]. If IDA occurs in children over 3 years of age and there are no dietary risk factors for iron deficiency, it is considered an atypical case, and it is necessary to determine whether there is a disease that causes blood loss or reduces intestinal iron absorption [7]. The evaluation is carried out step-by-step, starting with additional laboratory examinations such as complete blood count with indices, reticulocyte count, peripheral blood smear, stools for occult blood, and checking for clinical findings that may suggest other diseases [2].
PHTS is a rare disease with a prevalence of 1:200,000-1:250,000; BRRS is even rarer [8]. Therefore, there are only clinical diagnostic criteria for Cowden syndrome, the most common PHTS, which are difficult to apply directly to children [9]. BRRS has not yet been established with clear diagnostic criteria and is diagnosed based on clinical findings, such as macrocephaly and cutaneous lipomas, GI hamartomatous polyps, developmental deformity, and pigmented macules on the glans penis in males. Confirmation of
Early diagnosis of BRRS is important because similar to other patients with PHTS, there is a high risk of developing benign and malignant tumors. There are no management guidelines specifically for BRRS, but PHTS management guidelines are currently recommended. It is important to conduct an appropriate initial evaluation and regular cancer screening of various organs, such as the breast, thyroid, kidney, endometrium, and colon [3,4]. Therefore, it is clinically important to diagnose BRRS in a timely manner and continue follow-up thereafter.
In the evaluation of IDA, EGD is often performed when GI diseases are suspected owing to distinct GI symptoms or when a positive result is obtained in a stool occult blood test [12]. However, even if there are GI diseases, such as in the patient in this case, the GI symptoms are often unclear, especially in children, and it is difficult to rule out GI diseases through stool examination alone. Therefore, in cases where IDA is atypical, frequently recurs after treatment, or does not respond to treatment, it may be necessary to perform EGD more actively to differentiate between GI diseases, including BRRS.
In this case, the patient’s clinical findings were check-ed after the diagnosis of BRRS, and there was no developmental delay; however, characteristic macrocephaly and lipomas of BRRS were present, and there was a history of treatment for a benign breast mass. Although IDA is not a representative clinical symptom of BRRS, if BRRS was suspected, EGD could have been performed sooner, even if the patient had no GI symptoms and no abnormalities in the stool test. Although BRRS is not common, clinicians should be aware of its clinical characteristics.
In conclusion, nutritional IDA is the most common cause of pediatric IDA; however, it can also occur for various reasons. If IDA is atypical or recurrent, additional aggressive testing, including EGD, may be necessary.
The authors have no conflict of interest to declare.