Endocrine Abstracts

JOINT1752

Hereditary xerocytosis (HX), or dehydrated hereditary stomatocytosis, is a rare haemolytic anaemia caused by gain-of-function mutations in the PIEZO1 gene, located on chromosome 16q23-24. The PIEZO1 gene encodes the PIEZO1 protein, a mechanosensitive cation channel that regulates cell volume and is highly expressed in the red blood cell (RBC) plasma membrane. In HX, mutations disrupt ion transport, causing excessive calcium influx. Elevated intracellular calcium activates the Gardos channels, leading to significant potassium efflux and water loss. These changes cause RBC dehydration, reduced deformability, shortened lifespan, and eventual apoptosis. We report the case of a 22-year-old male with a complex medical history. At 16 years old, he was referred to the endocrinology department for delayed puberty. Laboratory investigations revealed low levels of luteinizing hormone, follicle-stimulating hormone, and testosterone, alongside a negative response to the gonadotropin-releasing hormone agonist stimulation test. He was diagnosed with hypogonadotropic hypogonadism and prescribed testosterone therapy. His medical history also included haemolytic anaemia, initially diagnosed as hereditary spherocytosis at the age of 6, which required intermittent red blood cell transfusions. He underwent splenectomy at the age of 9, followed by cholecystectomy at 13 due to cholelithiasis and mechanical jaundice. Despite the splenectomy, haemolysis persisted, and sporadic transfusion requirement continued. At 22 years old, the patient developed non-autoimmune diabetes mellitus and growth hormone deficiency, prompting an evaluation for iron overload. Laboratory investigations revealed ferritin levels exceeding 700 ng/ml and a transferrin saturation of 81%. Given the atypical progression of haemolysis and the new endocrine complications, genetic testing was subsequently performed, identifying a heterozygous mutation in PIEZO1 c.7483_7488dup, p.(Leu2495_Glu2496dup), affecting the C-terminal region of the PIEZO1 gene. This confirmed a diagnosis of HX, providing a unifying explanation for the patient’s hematologic and endocrine findings. Assessement by T2* magnetic resonance imaging (MRI) showed significant iron overload in the heart, liver and pancreas. Iron chelation therapy and annual MRI evaluation are advised. The phenotypic variability of rare haemolytic anaemias may lead to misdiagnosis and suboptimal treatment. Accurate diagnosis is critical, as it directly impacts patient management. HX, as demonstrated in this case, can be misdiagnosed as hereditary spherocytosis due to overlapping clinical features. However, unlike hereditary spherocytosis, in which splenectomy is a cornerstone of treatment, splenectomy is contraindicated in HX because of the increased risk of thromboembolic complications. This highlights the importance of molecular diagnostics in guiding personalized management, helping to prevent therapeutic missteps, and improving long-term outcomes.