Discussion
DHS is characterized by alteration of the red blood cell membrane permeability related to alterations of the intracellular cationic content and cell volume.3 Generally, DHS is a group of well-compensated hemolytic anemia diseases manifested by high reticulocyte count, macrocytosis, and mild jaundice.4Because 5 % stomatocytes was seen in our patient’s peripheral smear, hereditary stomatocytosis was not considered initially and other causes of non-immune hemolytic anemia were investigated. Since stomatocytes are rare in the peripheral smears, it is challenging to make the definitive diagnosis of DHS, just like our patient.
DHS is inherited as an autosomal dominant trait. The gene locus was first localized at 16q23–24.5 Several years later, PIEZO1, a mechanosensitive cation channel, was isolated by exome sequencing in the DHS patients and realized that it could cause both syndromic and nonsyndromic DHS. 1,6 The identified mutations are mostly missense and mainly located in the highly conserved C-terminus of the protein. The mutations cause delayed inactivation of the channel and increased cation permeability that leads to erythrocyte dehydration.7 Recently, a novel gene, KCNN4, has been identified as causative of the second form of the DHS, named DHS2, in six different families.8 However, 83 % of DHS patients carried PIEZO1 mutations. A new homozygous missense mutation (c.3364G> A, p.Glu1122Lys) was detected in our patient’s PIEZO1 gene, which is the most common one, using the Whole NGS target sequencing method. Since our patient did not have a history of perinatal edema or hydrops fetalis, it was accepted as nonsyndromic DHS.
Although it has shown that these two forms of DHS have very similar phenotypes, there are also some differences. Especially, while the hemoglobin values and MCV values of DHS patients with KCNN4 mutation were lower, the reticulocyte count was higher. Chronic and mild hemolytic anemia has been shown more frequently in patients with PIEZO1 mutation.8 Our patient was diagnosed at 11 years. Hemoglobin value was 9 g/dl. In the study of Andolfo et al., they reported that the age of onset of symptoms was 13.7 ± 2.2 years and the age of diagnosis was 36.3 ± 3.0 years in patients with PIEZO1 mutation. The onset of symptoms in our case was similar to the findings obtained in previous studies. However, because of studying genetic tests with NGS, the mutation was determined and a definite diagnosis could be made at a much earlier age. Unlike other DHS, there are two significant points in clinical follow-up in DHS: transfusion-independent iron accumulation, especially in the liver and the contraindication of splenectomy. For these reasons, early diagnosis at the onset of symptoms is important for the subsequent clinical management of the patient. In recent years, it has been shown that senicapoc treatment can be effective in DHS patients.9 Thanks to its early diagnosis, it may also allow the use of new treatment methods that are on the agenda in the treatment of the DHS before complications develop.
In conclusion, we here present a new case of DHS diagnosed through the aim of interlaboratory collaboration and the use of advanced technologies as NGS targeted sequencing platforms. Rare anemia can be challenging to diagnose in a developing country due to limited resources, financial constraints, and the disease’s rarity. Expert laboratories are needed for an easier, faster, and more accurate diagnosis.
Financial Disclosure: The authors have no financial relationships relevant to this article to disclose.
Conflict of Interest: The authors have no conflicts of interest to disclose.
Running title: Dehydrated hereditary stomatocytosis