Brown's Pediatric Residency Blog

Category: Endocrine

Metabolism gone wild!

Case: Last week we talked about Jane, an otherwise healthy 2-week old girl. Let’s change the story a bit to hit on another consideration in infants. Instead of simply being febrile and fussy, let’s say that she comes back to the ED, this time afebrile, but lethargic with poor cap refill. How does our differential change now?



Image Credit: Pixabay

What are the important diagnostic considerations for neonates and infants who present very ill?

  1. Infection
  2. Metabolic/Endocrinologic
  3. Trauma
  4. Cardiac
  5. Surgical emergencies

For those of you who like acronyms, consider “THE MISFITS” in neonates and young children presenting with undifferentiated shock (adapted from post on PEM Playbook)

  • Trauma
  • Heart Disease/Hypovolemia
  • Endocrine Emergencies
  • Metabolic
  • Inborn errors of metabolism (to get this acronym to work, there may be some repetition)
  • Seizures
  • Formula problems (think too little or too much water)
  • Intestinal disasters
  • Toxins
  • Sepsis (while this is last, all very sick infants/children should be evaluated/treated for sepsis)


Today we will focus on the emergency management of inborn errors of metabolism (IEM), specifically at the immediate recognition and management.



Epidemiology and Etiology

IEMs are Individually rare, but more common in aggregate- 1/5000 live births for any IEM (Ewing, 2009)

Helpful to lump metabolic deficiencies into 3 broad categories (Saudabray, 2002)

  1. Disorders leading to intoxication (think urea cycle defects)
  2. Disorders involving energy metabolism (think hypoglycemia)
  3. Errors involving synthesis or catabolism of complex molecules (e.g. lysosomal storage disorders)
    • Note: Disorders in this category are rarely treatable in emergency

How do these children present?

  • Deterioration of consciousness is one of the more common presentations of IEMs (El-Hattab, 2015)
    • Other presenting features include vomiting, seizures, apnea, hepatic failure, and cardiac disease (heart failure, cardiomyopathy, arrhythmias)
  • Specific Presentation Patterns (Ewing, 2009)
    • Hypovolemia, hyponatremia, hyperkalemia: Consider adrenal insufficiency
    • Metabolic acidosis, hyperammonemia, ketotic hypoglycemia: Consider an organic acid defect
    • Encephalopathy, respiratory alkalosis, hyperammonemia: Consider a urea cycle disorder
  • Remember, “As the neonate has an apparently limited repertoire  of responses to severe overwhelming illness, the predominant clinical signs and symptoms can be nonspecific like poor feeding, lethargy, failure to thrive, etc.” (Saudabray, 2002)

What is the immediate workup? (El-Hattab, 2015)

Image Credit: Pixabay

  • Primary Workup

    • Glucose
    • Blood Gas with Lactate
    • Serum Chemistry (including BUN/SCr)
    • Urinalysis
    • Complete Blood Count (CBC) and Differential
  • Secondary Workup

    • Specific Findings from Initial Workup and/or Exam
      • Hypoglycemia: insulin, cortisol, growth hormone, β-hydroxybutryate, plasma acylcarnitine profile, plasma amino acids and urine organic acids
      • Encephalopathy: ammonia, Liver “Function” Test (sp. ALT, AST, bilirubin)
      • Suspected galactosemia: urine reducing substances

How do you stabilize? (Note: Do not wait for labs to return to begin stabilization!)

Image Credit: Pixabay

  • ABCs (patients can present altered, apneic and/or in shock)
  • Recall the 2 main categories leading to emergencies: IEMs leading to intoxication and those resulting in energy defects (Ewing, 2009)
    1. Give Energy
      • Dextrose
        • Bolus as needed to treat hypoglycemia
        • Maintenance with D10 solutions
    2. Remove Toxins
      • Make NPO
      • Intravenous Fluids
        • D10 Half-normal saline run at 1-1.5x maintenance rate
      • Hemodialysis if indicated
        • Severe Hyperammonemia (Urea Cycle defects)

Next Steps?

Consultation with a metabolic specialist is essential!

  • Will help direct further diagnostic workup
  • Will help determine if further medical interventions (medications, vitamins, cofactors, etc)



  1. Inborn errors of metabolism present non-specifically
  2. Always consider IEM when presented with unwell neonate or infant
  3. For critically ill presentations, IEMs can be broken down into 2 main categories: Toxin Accumulation and/or Deficient Energy
    • Emergent Treatment (following ABCs) are directed at these two issues

Faculty Reviewer: Chanika Phornphutkul, MD


  • El-Hattab AW. “Inborn Errors of Metabolism.” Clinc Perinatol. 2015;1-27
  • Ewing, PH et al. “Evidence-Based Management Of Metabolic Emergencies In The Pediatric Emergency Department.” Pediatric Emergency Medicine Practice. 2009;6(10)1-16
  • Horeczko, Tim. “The Undifferentiated Sick Infant.” PEM Playbook. Accessed: 5/3/2017
  • Saudabray JM et al. ” Clinical approach to inherited metabolic disorders in neonates: an overview.” Semin Neonatol. 2002;7(1)3-15


What’s that smell?

Post developed by Lynae Conyers, MD

Case: A 6yo previously healthy girl presents to clinic with her mother with the complaint of body odor and concerns that patient is “developing too early”. Mom reports onset of body odor a few months ago now requiring daily deodorant. Your exam reveals Tanner stage II to III pubic hair and a small amount of axillary hair. What might be going on in this patient? What other information should be obtained from history and physical exam and what are the next steps?


Image Credit: Pixabay

Precocious Puberty



  • Precocious puberty is the development of secondary sexual characteristics prior to age 8 in girls and prior to age 9 in boys



  • Peripheral (gonadotropin-independent) precocious puberty (PPP): adrenal or ovarian source of excess sex hormone production
  • Benign pubertal variants: non-progressive, isolated development (e.g. premature thelarche, premature adrenarche)
  • Central (gonadotropin-dependent) precocious puberty (CPP): early maturation of hypothalamic-pituitary-gonadal axis (Note: The discussion in this entry will focus on central precocious puberty.)


Before we discuss precocious puberty lets review normal puberty:



Figure 1: The hypothalamic-pituitary-gonadal axis

Image adapted from: Dixon JR et al, 2007


What physical exam findings herald the onset of puberty?

  • In girls puberty typically begins with thelarche (breast bud development).
  • In boys puberty typically begins with testicular enlargement.

When does puberty begin?

  • The onset of puberty is affected by many factors. Puberty typically occurs earlier in girls with early maternal menarche, obesity, and low birth weight. Racial and ethnic background also appears to play a role in the timing of puberty. Several cross-sectional studies in the US have noted earlier onset of puberty in African-American girls as compared to Caucasian girls. (Carel and Lager 2008)


Now that we’ve reviewed normal, let’s return to precocious puberty



How common is precocious puberty?

  • Precocious puberty is ten times more common in girls than boys.
  • In the US, the incidence is estimated at 1 in 5,000 to 10,000 girls. (Latronico et al. 2016)


What causes Central Precocious Puberty?

  • Early activation of pulsatile GnRH secretion. In other words, central precocious puberty is gonadotropin-dependent
    • Therefore, features include presence of breast buds, increased growth velocity, vaginal bleeding, pubic and axillary hair
    • Early GnRH secretion can be due to many causes (Figure 2):

Note: In girls, more than two-thirds of cases of central precocious puberty are idiopathic. An identifiable cause is much more common in boys. (Muir 2006)




  • Premature thelarche: presence of breast buds without any other signs of pubertal development; common in toddlers and often regresses
  • Premature adrenarche: presence of pubic hair, axillary hair, acne, and adult-type body odor without other features of puberty; may have some bone age advancement
  • Non-classical congenital adrenal hyperplasia: presence of pubic hair, axillary hair, acne and adult-type body odor, mild virilization
  • Peripheral causes: E.g. ovarian follicular cyst, McCune-Albright, hCG-secreting tumor, exogenous steroid exposure




  • Inquire about which features of puberty are present
  • Establish the timing of symptoms
  • Perform a neurologic ROS, including visual disturbances
  • Ask about family history of pubertal onset
  • Ask about exposure to estrogen or testosterone products and lavender or tea tree oil

Physical Exam

  • Assess linear growth
  • Evaluate for presence of breast buds (requires palpation in addition to inspection to help discern between adipose tissue and true breast buds)
  • Perform testicular exam in boys (enlargement greater than 3 ml is indicative of puberty)
  • Perform external vaginal exam to look for signs of estrogenization of the vaginal mucosa (bright pink/red is non-estrogenized while light, dull pink indicates estrogen exposure
  • Assign Tanner staging

Diagnostic Tests

Case courtesy of Dr Jeremy Jones, From the case rID: 23244

  • Hormone levels
    • If signs of central puberty (breast buds or testicular enlargement) then order LH, FSH and testosterone (boys)/ estradiol (girls)
    • If signs of adrenarche only (hair, body odor) then order DHEAS, testosterone, androstenedione and 17-OH progesterone
  • Bone age xrays
    • Typically advanced by at least two years in patients with precocious puberty
  • GnRH stimulation testing
    • Measurement of LH 15-60 minutes following GnRH stimulation
    • If the central pubertal axis is quiescent, one GnRH injection will not cause an increase in serum gonadotropin concentrations
  • Brain MRI
  • Pelvic ultrasound
  • Adrenal US (only if labs indicate concern for androgen secreting mass)



  • Treatment is dictated by the underlying cause if one is identified.
    • Treatment is particularly important for younger patients, male patients, and for patients whose skeletal age is advancing more than height age.
  • GnRH agonists (such as leuprolide) are the most effective medical therapy. Constant stimulation of the pituitary gland with GnRH agonists initially leads to short term pubertal stimulation followed by downregulation of GnRH receptors and decreased gonadotropin production.
  • Referral to a pediatric endocrinologist is essential. Even those with suspected benign pubertal variants need to be followed over to time to ensure no other evidence of true puberty develops.


Back to our case…

On further questioning, there have been no known exposures to estrogen products or tea tree oil. Review of systems is otherwise negative. Mom reports first menstruating at age 11. In addition the pubic and axillary hair, exam is notable for small breast buds. You review the patient’s growth chart and note she has grown 7cm in the past year. Based on these findings, you are concerned for central precocious puberty. You begin the evaluation with labs (FSH, LH and estradiol) and bone age xrays and arrange for short interval follow-up.


Faculty Reviewer: Bracha Goldsweig, MD



  • Carel JC, Leger J. Precocious puberty. NEJM 2008; 358:2366-77.
  • Dixon JR and Ahmed SF. Precocious puberty. Paediatr Child Health 2007; 17(9):343-48.
  • Latronico AC, Brito VN, Carel JC. Causes, diagnosis and treatment of central precocious puberty.  Lancet Diabetes Endocrinol 2016; 4:265-74.
  • Muir A. Precocious puberty. Pediatr Rev 2006; 27(10):373-81.
  • Neely EK and Crossen SS. Precocious puberty. Curr Opin Obstet Gynecol 2014; 26(5):332-38.


© 2021 Brown Pediatrics

Theme by Anders NorenUp ↑