An 18-year-old sexually active black male presents to your department feeling weak, tired, and a bit confused. He was seen 2 days earlier for burning on urination and treated with TMP-SMX and phenazopyridine. Laboratory studies reveal hemoglobin of 95 g/L and reticulocytes 21%. Rapid fluorescent blood spot test fails to fluoresce under ultraviolet light.
Which one of the following is most likely to be the cause of this clinical presentation?
Correct Answer E:
This patient’s clinical presentation is suggestive of hemolytic anemia. The patient has an acute presentation with hemoglobin of 95 g/L and reticulocytes 21%. He is also black and was recently treated with TMP-SMX and pyridium (phenazopyridine) - two drugs known to cause oxidative stress in patients with glucose-6-phosphate dehydrogenase deficiency (choice E). The G6PD enzyme catalyzes the oxidation of glucose-6-phosphate to 6- phosphogluconate while concomitantly reducing the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP+) to nicotinamide adenine dinucleotide phosphate (NADPH).This is why this condition can be confirmed by a positive rapid fluorescent spot test, as seen in this patient. This test detects the generation of NADPH from NADP and is positive if the blood spot fails to fluoresce under ultraviolet light.
→ Sickle cell disease (choice A) is also increased in blacks. It is not associated with high risks of hemolytic anemia after treatment with TMP-SMX or phenazopyridine such as seen in G6PD patients.
→ Thrombotic thrombocytopenia purpura (choice B) presents with classic pentad of thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, kidney failure, and fever.
→ Beta thalassemia (choice C) is caused by mutations in the globin genes. It affects 1 or both of the beta-globin genes. Hemolytic anemia seen after treatment with TMP-SMX in this patient is not commonly seen in beta-thalassemia; besides the results of the rapid fluorescent blood spot test point to G6PD.
→ Hemolytic uremic syndrome (choice E) is characterized by the involvement of widespread occlusive microvascular thromboses resulting in thrombocytopenia, microangiopathic hemolytic anemia, and variable signs and symptoms of end-organ ischemia. E. coli serotype O157:H7 has been associated with more than 80% of infections leading to hemolytic uremic syndrome. The rapid fluorescent blood spot test that is positive in this patient points to a diagnosis of G6PD deficiency.
Key point:
A 5-year-old girl is referred to a cardiologist because of a murmur heard during a routine examination. Which one of the following clinical characteristics is consistent with an innocent murmur?
Correct Answer D:
Heart murmurs is a common finding on routine examination of infants and children. 50% of normal children have an innocent heart murmur. Murmurs which are attenuated with changing body position are usually innocent.
Abnormal findings indicating a pathological origin of a heart murmur include: shortness of breath, easy fatigue, failure to thrive, cyanosis. All diastolic murmurs are pathological murmurs.
During a routine physical examination of a 2-year-old child, a grade 3/6 early systolic vibratory murmur is heard. The mother reports no signs or symptoms of illness. The child is otherwise asymptomatic. Physical examination is normal.
The most appropriate next step is to:
Correct Answer A:
This patient most likely has Still#s murmur, which is the most common innocent murmur in children between the ages of 2 and 6 years, though it may be present at extremes of age (adolescence and infancy). It is an early systolic, grade 1 to 3 (usually grade 2), low to medium pitched murmur, best heard at the lower left sternal edge and extending to the apex and loudest in the supine position. It changes on sitting or standing. It has a distinctive vibratory quality or a twanging sound, which gives it a musical character. The origin of the murmur is not clear. This has been attributed to various causes including vibration of the pulmonary valves during systolic ejection, physiologic narrowing of the left ventricular outflow tract and presence of ventricular false tendons. Still’s murmur is diagnosed by physical examination. Additional testing is not necessary in absence of additional signs and symptoms. Still’s murmur is not associated with any sort of cardiovascular pathology.
A six-day-old boy was brought to hospital because of episodes of vomiting, cyanosis, and jitteriness and hepatomegaly. His mother was not diabetic and he was a full-term baby of normal birth weight and he was exclusively breast-fed. With appropriate work-up, the diagnosis of hypoglycemia was established. Urinalysis showed presence of reducing substance but no ketonuria.
Which of the following disorders is the most likely cause of hypoglycemia in this patient?
Correct Answer B:
Galactosemia (choice B) typically presents in the second half of the first week of life with features of hypoglycemia including vomiting, jaundice, cyanosis, jitteriness, and seizures. The liver is usually enlarged. Urine of patients with galactosemia usually contains reducing substances (galactose) but is devoid of ketone bodies. Our patient showed most of these features and galactosemia is the most likely cause of hypoglycemia.
→ Transient neonatal hypoglycemia (choice A) is not the correct choice. Hepatomegaly and demonstration of reducing substance in urine make the diagnosis of transient neonatal hypoglycemia unlikely. Urine of patients with transient neonatal hypoglycemia is not expected to contain any reducing substance (sugars) because blood glucose is low i.e. much lower than renal threshold for glucose reabsorption. Also hepatomegaly is not a feature of transient neonatal hypoglycemia because the basic etiology of this disorder is reduced liver glycogen stores due to immaturity of the responsible enzyme systems.
→ Type I Glycogen Storage Disease (choice C) is not the correct choice. Type I glycogen storage disease usually presents at the age of three to four months. Urine of patients with this disease is not expected to contain reducing substances because blood glucose is low i.e. much lower than renal threshold for glucose reabsorption.
→ Hereditary Fructose Intolerance (HFI) (choice D) is not the correct choice. Patients with HFI remain asymptomatic until foods containing fructose like table sugar or fruits are introduced. Our patient is exclusive breast-fed.
→ Hyperinsulinism (choice E) is not the correct choice. Hepatomegaly and presence of reducing substances in urine make hyperinsulinism an unlikely cause of hypoglycemia in this patient. Urine of patients with this disorder is not expected to contain reducing substances because blood glucose is low i.e. much lower than renal threshold for glucose reabsorption.
Demonstration of a reducing substance in urine of a neonate with hypoglycemia makes galactosemia a highly likely diagnosis.
A woman brings her one-week-old son to the pediatrician because of vomiting and poor weight gain. The neonate is exclusively breastfed and frequently vomits after feeding. His mother also notes that his stools are almost always loose. Physical exam reveals jaundice, a slightly sunken anterior fontanelle, and bilateral opacification of the lenses.
Which of the following enzymes is likely deficient in this patient?
Correct Answer E: The presence of jaundice, cataracts, vomiting, diarrhea, and poor weight gain in a breastfed neonate is highly suggestive of classic galactosemia.
Galactosemia is caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (choice E). This enzyme converts galactose-1-phosphate to uridine diphosphate (UDP) galactose, which can then either be converted to glucose, or used for biosynthesis of glycolipids, glycoproteins, or glycosaminoglycans. When this enzyme is deficient, there is an excess of galactose-1-phosphate. The only other pathway for galactose-1-phosphate is conversion to galactitol via aldose reductase, since the addition of phosphate to galactose traps it inside the cell.
The excess galactose-1-phosphate and galactitol accumulates in liver, kidney, lens, and nervous tissue, causing cirrhosis, cataracts, mental retardation, and failure to thrive. The source of galactose in this patient is from lactose, which is broken down into glucose and galactose. Breastfeeding is contraindicated in patients with galactosemia for this reason. Rapid diagnosis, and removal of galactose is the best treatment for galactosemia, but neonatal screening can prevent it.
→ Glucose-6-phosphatase (choice A) is incorrect, since a deficiency in this enzyme would cause Von Geirke's disease, a glycogen storage disease characterized by fasting hypoglycemia, hepatosplenomegaly, lactic acidosis, and hyperuricemia.
→ Fructokinase (choice B) is incorrect. A fructokinase deficiency leads to essential fructosuria, a clinically benign condition resulting in fructosuria without major symptoms.
→ Fructose-1-phosphate aldolase deficiency (choice C) is incorrect. Deficiency of this enzyme causes Hereditary fructose intolerance, resulting in severe hepatotoxicity, since causes accumulation of fructose-1-phosphate by preventing it's conversion to glyceraldehyde and dihydroxyacetone. While jaundice, vomiting, and hepatomegaly are expected, cataracts are not, and this disease usually manifests after switching from breast milk to formula, as that is when fructose is often introduced to the diet for the first time.
→ Galactokinase (choice D) is incorrect. Galactokinase deficiency results in the accumulation of galactose. However, since galactose cannot be phosphorylated, it is not trapped inside of cells, and can leave, being excreted in the urine (galactosuria). While it is possible that it can cause cataracts by way of conversion of galactose to galactitol, it does not affect other tissues. This disease mechanism is similar to fructokinase deficiency. Both of these diseases result in excretion of their respective sugar in the urine without major systemic symptoms.
Galactosemia is caused by a deficiency of galactose-1-phosphate uridyltransferase, and can be recognized by vomiting, diarrhea, jaundice, cataracts and failure to thrive in a neonate. Rapid removal of galactose is essential for treatment.
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