Background

Insulin-like growth factor I (IGF-I) is the effector of growth induced by growth hormone (GH). IGF-I deficiency can be the result of GH resistance or insensitivity due to genetic disorders of the GH receptor causing GH receptor deficiency (GHRD, Laron syndrome) or postreceptor defects, including the principal transduction agent STAT5b, the IGF-I/IGFBP3 stabilizer acid labile subunit (ALS), the IGF-I gene, or the IGF-I receptor.Acquired forms of GH insensitivity include the rare GH1 mutation (in which GH inhibiting antibodies develop after a few months of replacement therapy with recombinant GH) and, far more commonly, malnutrition, hepatic disease, renal disease, and diabetes.

Pathophysiology

The GH molecule binds to its specific cell surface receptor (GHR), which dimerizes with another GHR molecule so that the single GH molecule is enveloped by 2 GHR molecules. The intact receptor lacks tyrosine kinase activity, but binding of GH and dimerization results in association with JAK2, a member of the Janus kinase family, which results in self-phosphorylation of the JAK2 and a cascade of phosphorylation of cellular proteins. The most critical of these proteins is the signal transducer and activator of transcription 5b (STAT5b), which couples GH binding to the activation of gene expression that leads to the intracellular effects of GH, including synthesis of IGF-I, insulin-like growth factor binding protein 3 (IGFBP3), and ALS.

Hepatic IGF-I circulates almost entirely bound to IGF binding proteins (IGFBPs), with less than 1% being free. The IGFBPs are a family of 6 structurally related proteins with a high affinity for binding IGF. The principal BP, IGFBP3, binds approximately 90% of circulating IGF-I in a large (150-200 kD) ternary complex consisting of IGFBP3, ALS, and the IGF molecule. The ALS stabilizes the IGF–IGFBP3 complex, reduces the passage of IGF-I to the extravascular compartment, and extends its half-life.

IGF binding involves 3 types of receptors: the structurally homologous insulin receptor and type 1 IGF receptor and the distinctive type 2 IGF-II/mannose-6-phosphate receptor. Although the insulin receptor has a low affinity for IGF-I, IGF-I is present in the circulation at molar concentrations that are 1000 times those of insulin. Thus, even a small insulin-like effect of IGF-I could be more important than that of insulin itself, were it not for the IGFBPs that control the availability and activity of IGF-I. In fact, intravenous infusion of recombinant human IGF-I (rhIGF-I) can induce hypoglycemia, especially in the IGFBP3 deficient state.

Clinical Presentation

The clinical features of GHRD are not different than those of severe GH deficiency. Postreceptor Continue reading »

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Chronic anemia has no precise definition. Anemia that persists for 6 months or more (eg, hereditary spherocytosis [HS]) is clearly chronic; however, anemia that lasts only 2 months (eg, iron deficiency that is being treated) should also be considered chronic anemia, and other explanations must be sought.

Chronic anemia can be primary or secondary.

Primary chronic anemia

Primary chronic anemias are the true chronic anemias, in which anemia (defined as a hemoglobin level more than 2 standard deviations below the mean reference value for age) is part of the basic disease process. The basic disease process is hematologic (eg, sickle cell disease, HS), and the degree of anemia varies markedly from etiology to etiology and from patient to patient, even with the same etiology. (See Etiology and Workup.)

Secondary chronic anemia

Secondary chronic anemias are chronic anemias that may provide a diagnostic clue to an underlying pathology. They are the consequence of a nonhematologic problem (eg, chronic blood loss, chronic renal failure, osteomyelitis, inflammatory bowel disease, tuberculosis).

Etiology

Chronic anemia is classified into the following 3 primary categories:

  • Decreased red cell production
  • Increased red cell destruction (hemolysis)
  • Blood loss

Clinical Presentation

Patients with chronic anemia are usually asymptomatic, even with remarkably low levels of hemoglobin. Symptoms more often relate to the underlying cause.

Hemoglobin levels as low as 5-6 g/dL are well tolerated in most patients, and patients do not require transfusion. Parents, however, frequently note that patients become much more active following a transfusion.

Inquire carefully regarding any evidence of blood loss (eg, hemoptysis, hematochezia, melina, hematuria, menorrhagia). In endemic areas, a history of papulovesicular skin lesions on the feet may suggest a diagnosis of hookworm infestation.

Age is always an important consideration. Nutritional iron deficiency is seen in older infants and toddlers (aged 6 mo to 3 y), whereas iron deficiency due to blood loss occurs in menstruating girls. The deficiency can be surprisingly severe, but transfusion is indicated only in the rare circumstance of impending high-output cardiac failure.

The patient’s sex must always be considered in hemolytic anemias. Severe G-6-PD deficiency may be seen as a chronic nonspherocytic anemia, usually in males.

Dietary history is important with regard to the amount and source of milk ingested by infants and toddlers and to their risk of chronic iron deficiency (24 oz of milk/d or more is a clear risk factor for nutritional iron deficiency in infants and young children). Continue reading »

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Like other herpesviruses, human herpesvirus 6 causes an initial infection, a life-long latency, and a clinical reactivation, especially in hosts who are immunocompromised

Pathophysiology

The infectious agent in roseola infantum/exanthem subitum was demonstrated to be present in blood by inoculating healthy infants with serum from ill infants, a procedure considered very dangerous by today’s standards.

Clinical Presentation

Human herpesvirus 6 (HHV-6) is the single most common cause of hospital visits in infants with fever.

Roseola is characterized by an initial febrile phase of 3-5 days, with temperatures reaching 40°C.

With the fever, some children exhibit bilateral periorbital edema in the prodrome.

At or near the period of defervescence, a maculopapular rash is observed on the infant’s trunk and neck; however, this rash is found in the minority of patients (10%).

Children can contract primary human herpesvirus 6 without manifesting a rash.

Human herpesvirus 6 can be isolated from the blood for the first 5 days and later is found intermittently or persistently in saliva, stool, and, rarely, urine.

Physical Examination

High-grade fever higher than 39.5°C (103°F) persists for 3-5 days and then resolves abruptly.

Rash appears after 12-24 hours of resolution of fever. In many incidents of human herpesvirus 6, rash appears during defervescence or within a few hours.

Rash of roseola is erythematous, nonpruritic, mildly elevated, and consists of rosepink papules (roseola meaning pink-colored rash). The rash blanches on pressure and mainly is distributed on the trunk, arms, and neck.

The rash fades in 1-2 days.

Most children are playful despite high-grade fever; however, anorexia, irritability, and listlessness Continue reading »

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