What is the diagnosis for a newborn with hyperglycemia, elevated cortisol, normal insulin levels, and normal glucose, with considerations for growth hormone levels, and potential conditions including growth hormone deficiency, adrenal insufficiency, or glycogen storage disease?

Diagnosis: Neonatal Monogenic Diabetes (HNF4A-MODY)

The most likely diagnosis is HNF4A-MODY (neonatal diabetes), which characteristically presents with transient neonatal hypoglycemia and large birth weight, not hyperglycemia as stated in the question. 1 The clinical scenario described appears contradictory—if this newborn truly has "high blood sugar" (hyperglycemia), the differential diagnosis shifts entirely away from the options provided, as all three conditions listed (growth hormone deficiency, adrenal insufficiency, glycogen storage disease) cause hypoglycemia, not hyperglycemia.

Resolving the Clinical Contradiction

If the newborn actually has hypoglycemia (not hyperglycemia), the diagnosis depends critically on the insulin level during the hypoglycemic episode:

Scenario 1: Hypoglycemia with Elevated Insulin (Hyperinsulinemic Hypoglycemia)

• HNF4A-MODY is the diagnosis if the infant has large birth weight, transient neonatal hypoglycemia with inappropriately elevated insulin, and normal glucose later in life. 1
• This form of neonatal diabetes presents with transient hyperinsulinemic hypoglycemia in the neonatal period, then transitions to diabetes later in adolescence or early adulthood. 1
• The elevated cortisol mentioned in the question is a red herring—neonates with hyperinsulinemic hypoglycemia paradoxically generate inappropriately LOW cortisol responses to hypoglycemia, not high cortisol. 2, 3
• Research demonstrates that infants with hyperinsulinemic hypoglycemia have mean cortisol levels of only 94.7 ± 83.1 nmol/L during hypoglycemia with inappropriately low ACTH levels (mean 39.4 ± 20 pg/mL), despite normal responses to exogenous ACTH stimulation. 3

Scenario 2: Hypoglycemia with Low/Normal Insulin (Counter-regulatory Hormone Deficiency)

If insulin is appropriately suppressed during hypoglycemia, then isolated cortisol deficiency (adrenal insufficiency) is the primary diagnosis, with apparent growth hormone deficiency being a secondary, reversible phenomenon. 4, 5

Why Cortisol Deficiency Causes Apparent GH Deficiency:

• Physiologic glucocorticoid levels are required for optimal GH secretion and somatotroph development during infancy. 4, 5
• Two case reports demonstrate that infants with primary cortisol deficiency (MC2R mutation and TPIT mutation) had low GH levels during hypoglycemia that completely normalized after 8 months to 3 years of glucocorticoid replacement. 5
• Do not diagnose permanent GH deficiency in the setting of untreated cortisol deficiency—eucortisolism, like euthyroidism, is required for proper evaluation of GH secretory capacity. 5

Diagnostic Algorithm for Cortisol Deficiency:

• Measure cortisol and ACTH at the time of hypoglycemia: undetectable cortisol (<1 μg/dL) with markedly elevated ACTH (>4000 pg/mL) indicates primary adrenal insufficiency. 4
• Perform ACTH stimulation test: undetectable cortisol response confirms adrenal insufficiency. 4
• Look for diffuse hyperpigmentation (elevated ACTH effect) with normal male genitalia. 4
• Genetic testing for MC2R gene mutations confirms the diagnosis and guides genetic counseling. 4

Scenario 3: Glycogen Storage Disease

Glycogen storage disease is excluded by the clinical presentation described:

• GSD causes hypoglycemia, not hyperglycemia. 6, 7, 8
• GSD presents with hepatomegaly, failure to thrive, and specific metabolic derangements (hyperlactatemia in GSD I, elevated CK in GSD III). 6, 7, 8
• The diagnostic workup for suspected GSD requires elevated lactate + elevated uric acid + normal carnitine for GSD I, or elevated CK + muscle weakness for GSD III. 6, 7
• Normal insulin levels during hypoglycemia would be expected in GSD, as insulin appropriately suppresses. 8
• Cortisol levels are typically normal or elevated in GSD as a counterregulatory response, not elevated as a primary finding. 8

Critical Diagnostic Pitfall

The single most important error to avoid is diagnosing permanent growth hormone deficiency in an infant with untreated cortisol deficiency. 5 Always replace glucocorticoids first, wait 8-12 months, then reassess GH secretory capacity with stimulation testing before committing to lifelong GH therapy. 5

Definitive Diagnostic Approach

For any newborn with hypoglycemia, measure glucose, insulin, cortisol, ACTH, beta-hydroxybutyrate, and lactate simultaneously during the hypoglycemic episode. 6, 7, 3

• Elevated insulin (>2 μU/mL) with suppressed ketones (<0.6 mmol/L) during hypoglycemia = hyperinsulinemic hypoglycemia, requiring genetic testing for KATP channel mutations (KCNJ11, ABCC8) or HNF4A-MODY. 1, 9
• Undetectable cortisol with elevated ACTH = primary adrenal insufficiency, requiring MC2R genetic testing. 4
• Appropriately suppressed insulin with elevated lactate and uric acid = GSD I, requiring G6PC or SLC37A4 genetic testing. 6, 7