The NYTimes for several years has run a column on puzzling diagnostics, by Lisa Sanders MD. This week's case is a 39 year old man with abdominal pain and a strong yellow skin color. While the general problem was easy (bilirubin disorder and gallstones), the specific genetic diagnosis took the team and consultants several weeks.
I put the first 95% of the article into GPT4, and it immediately offered the correct genetic diagnosis as choice #1. (This was at the point in the article where the medical team was slowing down, having come up empty handed on their first ideas.)
The article is here:
The patient's symptoms point to some sort of hemolytic anemia and hyperbilirubinemia, both of which are contributing to his jaundice. The most common genetic causes of these conditions, such as sickle cell disease, G6PD deficiency, and thalassemia, have been ruled out. The jaundice is further exacerbated by the gallstones blocking the flow of bilirubin into the gastrointestinal tract.
Given these symptoms, the physicians should consider testing for the following genetic disorders:
Hereditary Spherocytosis (HS): [CORRECT]
This is a genetic disorder characterized by anemia, jaundice, and splenomegaly. It is caused by defects in red blood cell (RBC) membrane proteins leading to spherical-shaped red blood cells which are broken down prematurely leading to hemolysis. Spherocytosis can present with very small RBCs, known as microspherocytes. It could account for the patient's anemia, jaundice, and small blood cell size. It's usually diagnosed with a peripheral blood smear, osmotic fragility test, or EMA-binding test, and the genetic basis can be confirmed with molecular genetic testing.
Pyruvate Kinase Deficiency (PKD): This is an inherited metabolic disorder of the enzyme pyruvate kinase, which affects the survival of red blood cells. A deficiency in pyruvate kinase impairs the energy metabolism of the red blood cells, causing them to be destroyed prematurely (hemolysis). The chronic hemolysis can cause recurrent jaundice, gallstones, and splenomegaly.
Hereditary Elliptocytosis (HE): In this condition, the red blood cells are elliptical rather than round and are prone to breakdown, leading to hemolytic anemia. It's less common, but it can lead to jaundice and gallstones.
Hereditary Stomatocytosis (overhydrated or dehydrated): This group of rare disorders is characterized by the presence of stomatocytes (mouth-shaped cells) on a blood film and is associated with hemolysis. It can cause recurrent jaundice and gallstones.
In conclusion, further testing, including a peripheral blood smear and specific enzyme assays, might be warranted to pinpoint the exact genetic condition this patient is experiencing. Next-generation sequencing panels for hereditary hemolytic anemias could be considered to provide a more comprehensive analysis of potential genetic causes. It's important to identify the exact condition because the treatment and management options can differ. For example, splenectomy can be beneficial in hereditary spherocytosis but can have deleterious effects in conditions such as hereditary stomatocytosis.
By the way, this puzzle is a little less puzzling online, since the NYT puts the final diagnosis in the HTML link!