What Causes Neutropenia?

Patient Presentation
A 4-month-old female came to the emergency room with fever, poor feeding, fussiness and strong smelling urine. She had not been feeding well for 36 hours, with a decreasing number of diapers and increasing foul-smelling urine. The fever began about 18 hours previously and had ranged from 99.8°F to 102.3°F. Acetaminophen helped but the fever returned. She was crying more, and could be consoled but she appeared overall ill. She had 2 episodes of emesis just before coming to the emergency room but no diarrhea. Her parents denied any cough, rhinorrhea, or rashes other than her eczema.

The past medical history showed a term-infant born without complications who had received appropriate preventative care including vaccinations. She had been diagnosed with atopic dermatitis 2 week previously. The family history was positive for heart disease and diarrhea. They denied any kidney disease or immune problems. The review of systems was otherwise negative.

The pertinent physical exam revealed a tired and fussy infant who would calm with some effort. Her vital signs had a fever of 102.6° with tachycardia to 114 beats/min, respiratory rate of 26/min and an oxygen saturation of 100%. Her weight was down 250 grams from her visit 2 weeks ago, which was at the 50%. Her capillary refill was 2-3 seconds, with slightly dry mucous membranes. Her fontanelle was normal. Her skin showed dry reddened areas in the flexural areas and behind her ears, and general xerosis of her trunk and cheeks. Her examination was otherwise well. Her diaper smelled foul.

The laboratory evaluation showed a catheterized urinalysis of 1.025 specific gravity, many white blood cells, some red blood cells with positive nitrites and leukocyte esterase. Her complete blood count showed a hemoglobin of 10.6 x 1000/mm2, white blood cell count of 5.2 x 1000/mm2 with only 1350 neutrophils. Her platelets were 360 x 1000/mm2. The rest of her complete blood count was normal as a complete metabolic profile. Her C-reactive protein was elevated at 2.7 mg/dl.

The diagnosis of a urinary tract infection and potential bacteremia was made. She was admitted for intravenous fluids, antibiotics and monitoring. The patient’s clinical course showed that she improved with treatment and was discharged at 48 hours. The blood culture was negative. Her urine culture grew Escherichia coli that was pansensitive to antibiotics and she was sent home on oral antibiotics. An ultrasound of her kidneys was normal before discharge. Her complete blood count still showed mild neutropenia at 1475 at discharge. Her C-reactive protein had decreased to 1.8 mg/dl. At her one week followup appointment her neutropenia and complete blood count were normal. At her one year well-child examination, her complete blood count was normal and she had not had any other urinary tract infections.

Neuropenia is defined as a neutrophil count < 1500/µL. It is classified as mild from 1000-1500/µL, moderate from 500-1000/µL, and severe if < 500/µL.

It is not uncommonly seen in the setting of acute self-limited infections, and with re-testing returns to normal. It is also not uncommon at certain ages, such as perinatally, especially in premature infants (up to 6%) . It is also common in certain ethnic groups particularly African American or Arabic populations where up to 10% of the children may have mild neutropenia which does not cause clinical disease. The overall prevalence and incidence are not known but some studies estimate it at 2 per million persons.

Neutropenia can be thought of as an acute problem due to rapid neutrophil use or destruction, or decreased production of neutrophils. Chronic neutropenia is due to decreased production or splenic sequestration.

Neutropenia can also be thought of as a primary or intrinsic problem due to primary myeloid cell production or an intrinsic defects. Secondary or acquired causes of neutropenia are usually due to infections, immune response, bone marrow infiltration or drugs.

Clinical signs or symptoms of potential neutropenia include fever, oral ulcers, upper airway infections (e.g. otitis media, pharyngitis, sinusitis), respiratory (e.g. pneumonias) or perianal infections. Skin infections like cellulitis, paronychia, or furunculosis may also indicate neutropenia. Bacteremia or sepsis are also potential clinical indications. Recurrent or complicated infections or infections with unusual organisms may indicate neutropenia. Other systems can also be affected.

Treatment depends on the underlying cause with antibiotics, general support, discontinuation of potential iatrogenic causes, and granulocyte stimulating medications if appropriate.

Learning Point
The differential diagnosis of neutropenia includes:

  • Age or ethnic-related
    • Premature infant
    • Newborn infant
    • African American or Arabic ethnicity
  • Infection
  • Congenital or hereditary neutropenia
    • ELANE mutations
      • Cyclic neutropenia – generally 21 day cycles between normal and abnormal neutrophil counts
      • Severe congenital neutropenia
    • Non-syndromic
      • Autosomal dominant severe congenital neutropenia
        • Kostman syndrome
      • Autosomal recessive severe congential neutropenia
        • Wiskott Aldrich syndrome
      • X-linked neutropenia
    • Other syndromic
      • G6PC3 deficiency
      • Barth syndrome
      • Cohen syndrome
    • Bone marrow insufficiency
      • Dyskeratosis congenital
      • GATA2 deficiency
      • Fanconi anemia
    • Combined immunodeficiency
      • XHIGMS
      • WHIM syndrome
      • Reticular dysgenesis
    • Metabolic disease
      • Glycogen storage disease 1b
      • Isovaleric acidemia
      • Methylmalonic acidemia
      • Propionic acidemia
    • Oculocutaneous hypopigmentation
      • Chediak-Higashi syndrome
      • Griscell syndrome type 2
      • Hermansky Pudlak syndrome type 2
      • p14 deficiency
    • Pancreatic insufficiency
      • Schwachman-Diamond syndrome
      • Pearson marrow syndrome
  • Drug related
    • Antibiotics
    • Alcohol
    • Chemotherapy
  • Immune mediated
    • Neonatal alloimmune – transplacental transfer of maternal antibodies to paternal antigen
    • Neonatal isoimmune neutropenia – transplacental transfer of existing maternal IgG antibodies
    • Autoimmune – probably triggered by viral infections or environmental antigens
    • AIDS
  • Myelodysplasia
    • Bone marrow infiltration or replacement
      • Leukemias
      • Dysgammaglobulinemia
  • Other
    • Folate or Vitamin B12 deficiency
    • Hypersplenism or splenic sequestration

Questions for Further Discussion
1. What are common presentations for primary immunodeficiencies? A review can be found here

2. What are different fever patterns and what are their potential problems? A review can be found here

3. What is in the differential diagnosis of lymphocytosis? A review can be found here
4. What are potential complications of acute pyelonephritis? A review can be found here
5. How do you treat fever and neutropenia due to chemotherapy?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Urinary Tract Infections, Blood Disorders and Immune System and Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Neutropenia – Hematology and Oncology. Merck Manuals Professional Edition. https://www.merckmanuals.com/professional/hematology-and-oncology/leukopenias/neutropenia?query=neutropenia. Accessed December 3, 2019.

Dale DC. How I manage children with neutropenia. Br J Haematol. 2017;178(3):351-363. doi:10.1111/bjh.14677

Kebudi R, Kizilocak H. Febrile Neutropenia in Children with Cancer: Approach to Diagnosis and Treatment. Curr Pediatr Rev. 2018;14:204-209.

Spoor J, Farajifard H, Rezaei N. Congenital neutropenia and primary immunodeficiency diseases. Crit Rev Oncol Hematol. 2019;133:149-162. doi:10.1016/j.critrevonc.2018.10.003

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

What Safety Guidance Should Farm Families Be Aware Of?

Patient Presentation
A 6-year-old male and a 9-year-old male came to clinic with their mother for their health supervision visits. The boys both had attention deficit disorder (with hyperactivity and inattention) and were using stimulant medication without side effects. Their mother reported they were doing well in school. The 9-year-old reported that the medicine “helped my brain stay calmer.” The social history showed that the parents were a firefighter and a nurse who also ran a farm with animal stock and crops.

The pertinent physical exam showed healthy boys with growth parameters in the 10-50% for the 6-year-old and 25-50% for the 9-year-old. Their examinations were normal.

The diagnosis of healthy boys with attention deficit disorder was made.
When discussing anticipatory guidance the pediatrician asked about safety rules they had for the farm. The mother asked the 6 year old, “When you’re outside, where can you play?” He said, “I have to stay on the grass, I can’t go in the road.” “And what if you are by the barns with Dad or Grandpa?” she went on. “I can’t go in the barns without them. If I am by the barns and something is moving then I have to put my hand on the barn, the fence or a tree,” he replied. The mother said that the grass was by the house and most of it was fenced off. The driveway separated the house from the barns and they had taught the children if they were in the barn area with adults and a car, tractor, or large animals were moving, then they had to go next to something big and sturdy like the barn itself or a tree. The 9-year-old said, “We can’t be in the barn by ourselves. I’m still too little to be by the steers, but this summer Dad says I can help him with the goats,” the 9-year-old said proudly. “I get to help with the baby goats, though” the 6-year old protested. “Yes but I get to do that AND be with the big goats,” he again said proudly. “We’re pretty strict about the rules. Grandpa wanted to let them drive the golf cart with him. I even vetoed that one. With their ADHD I’m not sure when I am going to let them drive anything with wheels,” the mother said.

“The agriculture industry is consistently ranked as one of the most hazardous industries in the United States with some of the highest rates of work related injuries and deaths. Agriculture is a unique profession in that children who live on farms are exposed to, and in participate in, the family business of farming. Moreover, children who work on their family farm fall outside the regulation of governmental safety and labor practices….There is often little separation between work areas and play or living areas, thus children living on or visiting a farm may be in close proximity to safety hazards.

The rates of agriculture-related injuries are decreasing. Children have overall fewer injuries but their injuries are more severe. A study of 0-19 year olds with agricultural-related injuries from 2001-2006 found an annual incidence of ~26,600 injuries. Of these 29% were work-related, 0.32% were fatal (n=84), with falls (35.2%), machinery (3.7%), transportation (14.4%), assaults and self-harm (11.7%), and fire and explosions (0.63%) being the most common causes of injuries. Of the fatalities, machinery (21.4%), fire and explosions (14.2%), transportation (10.7%) and drowning (9.5%) were the most common causes. Boys report more exposure to potential hazards and are injured more than girls.

Farming is a heterogeneous industry and the activities vary widely. It is important to ask the family the type of farming they engage in when assessing the safety risk factors.

Potential exposures on a farm include:

  • Tractors, machinery, cars/trucks, small vehicles (e.g. Gator® utility vehicles, all-terrain vehicles, motorcycles, golf carts, snowmobiles etc.).
  • Water hazards – ponds, drainage ditches, water tanks, etc.
  • Falls – buildings, machinery and equipment (e.g. hayloft, silos)
  • Chemicals, petroleum and pesticide product exposures
  • Animal exposures – large animals, domestic animals, wild animals, rodent/insect, etc.
  • Farm product exposure – grain dust, raw milk, product holding areas such as grain bins
  • Recreational activities – horse-back riding, hunting, shooting, archery, snowmobiling, rodeo, fishing, boating, camping
  • Temperature and weather related exposures

Tractors injuries are the leading cause of trauma on the farm for all age groups. This includes operating or being a passenger on a tractor. Tractors and other farm machinery including lawn mowers are designed for adults. The throttles, gears, pedals, and steering wheels are designed for adults and may be beyond the reach of children and youth (anyone < 19 years old), and they often take more strength to operate properly than a child has. As children are not as tall, they can have a reduced field of view. Children and youth also have poorer executive function and lack experience. Impulse control may not occur until adulthood.

Learning Point
Methods to decrease all workplace injuries are the 3 E’s of industrial safety, which are engineering, education and enforcement.

  • Engineering design eliminates or reduces the potential hazard. For example, separation from the hazard such as fencing around the home to make a safe area for children to play in.
    Understanding ergonomic loads on children to determine if, and how, a child or youth can safely perform a specific farm task.

  • Education for both parents and children to understand risks and ways to mitigate them. Various methods can be used including school, organizations, community events and educational materials such as farm safety camps, safety certification programs, etc.
  • Enforcement by both parents and children again can help to mitigate problems. Parental and older sibling modeling of appropriate safety has been shown to decrease injuries.
  • Appropriate supervision is always necessary for children of any age. Supervision includes the adult’s attention (i.e. listening and watching), proximity (within reach or beyond) and supervision continuity over time (intermittent or continuous).

Risks are increased, as would be expected, when parents are farming, or the child is exposed to equipment or animals. Tractor injuries as noted before carry the highest risk. This includes being the driver or a passenger on a tractor or piece of equipment.

While many of the usual safety suggestions may seem logical, like any environment, they may be difficult to implement on a consistent basis. A permanent fence around a pond may be easier to implement than locking up every small tool in a workshop every time. Injuries will occur in any workplace or home and children must also be taught basic first aid and how to obtain help if needed. Basics such as good sleep hygiene and appropriate rest periods can have big effects on the decisions adults and children make for their own and others safety.

Guidance for farm safety includes:

  • Engineering
    • Make sure children know what areas of the farm are unsafe
    • Keep children away from dangerous equipment and water hazards by fencing in play areas
    • Layout workspaces to encourage safety – chemicals and petroleum products locked up in a separate area, workshop with tools can be locked, etc.
    • Safety equipment should be readily available to encourage their use such as fire extinguishers, first aid kits, respirators, etc.
  • Education
    • Check equipment regularly to ensure safety features are working properly
    • Children should not play on equipment, even with adult supervision
    • Monitor changing weather conditions
    • Children < 16 years of age should not operate farm vehicles. Allow youths ages 16 to 18 years to operate farm vehicles on public roads only if they have a motor vehicle license and are graduates of a state-approved tractor and farm vehicle safety training program.
    • Never allow extra riders on tractors, mowers or ATVs, etc.
    • Seat belts should always be used on tractors or any other vehicle
    • Limit young children’s access to large animals
    • Teach children not to run or speak loudly around animals
    • Participate in farm safety events and certificate training programs (e.g. farm vehicle safety, hunter safety, boating safety, etc.)
    • Teach and practice a safety plan for common problems that do occur. For example, what to do when they are near a barn when a tractor drives into the area, or animal is startled, or they find a potentially dangerous tool, or need to get emergency help, etc.
  • Enforcement
    • Children should be adequately supervised at all times
    • Make sure children know how and use all safety equipment properly
      • Use basic safety equipment – seat belts, eye and ear protection, respirators, clothing, etc.
      • Specialized safety equipment should be used appropriately and with additional supervision
    • Children should be properly attired for the work
      • Appropriate clothing that provides comfort while working yet is protective such as closed toed shoes, long sleeve-shirts, pants, hats
      • Hair should be kept short or tied back
      • No loose clothing or hair
    • Encourage children to ask for help when they encounter problems

Questions for Further Discussion
1. What professional organizations offer farm safety education and training?
2. What is the extension? Program information can be found here and a specific example in the State of Iowa can be found here
3. What diseases are related to livestock exposure?
4. When can a child mow a lawn? A review can be found here

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Farm Health and Safety

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Rasch H. Down on the farm: Don’t let children fall victim to injuries. AAP News. 2012;33(8):25-25. doi:10.1542/aapnews.2012338-25d

Zaloshnja E, Miller TR, Lawrence B. Incidence and Cost of Injury Among Youth in Agricultural Settings, United States, 2001-2006. Pediatrics. 2012;129(4):728-734. doi:10.1542/peds.2011-2512

Schwebel DC, Pickett W. The role of child and adolescent development in the occurrence of agricultural injuries: an illustration using tractor-related injuries. J Agromedicine. 2012;17(2):214-24. doi: 10.1080/1059924X.2012.655120.

Morrongiello BA, Zdzieborski D, Stewart J. Supervision of children in agricultural settings: implications for injury risk and prevention. J Agromedicine. 2012;17(2):149-62. doi: 10.1080/1059924X.2012.655127.

Gallagher SS. Characteristics of evaluated childhood agricultural safety interventions. J Agromedicine. 2012;17(2):109-26. doi: 10.1080/1059924X.2012.664033.

McCallum DM, Murphy S, Reed DB, Claunch DT, Reynolds SJ. What we know about the effectiveness of farm safety day programs and what we need to know. J Rural Health Off J Am Rural Health Assoc Natl Rural Health Care Assoc. 2013;29(1):20-29. doi:10.1111/j.1748-0361.2012.00426.x

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

What Are the Different Types of Myasthenia Gravis?

Patient Presentation
A 6-year-old male came to clinic for a cough and runny nose for 4 days. He initially had a low grade fever but this had resolved. He continued to cough more at night which was disturbing his sleep. He had no pain. The past medical history was positive for ocular myasthenia gravis that had been diagnosed at age 3. He took pyridostigmine. The review of systems was otherwise negative.

The pertinent physical exam showed a somewhat tired appearing male, wearing glasses and tilting his head backward. His vital signs were normal without a measured fever. His growth parameters were around the 50th percentile. He had bilateral ptosis, moderate clear rhinorrhea, with normal pharynx and ear examinations. He had coarse upper airway sounds but no wheezing or other adventitial breath sounds on lung examination. He had no rashes. His neurological examination showed no other obvious muscle weakness.

The diagnosis of an upper respiratory tract infection was made. The physician commented on the ptosis to the family. The mother said that it seemed to get worse with minor infections but then improved. “He always has some droopiness, so this is just part of being sick,” she noted. The physician discussed symptomatic treatment and reiterated signs of respiratory distress with the family. The mother indicated that she was always looking for respiratory distress and knew when to call neurology or go to the emergency room.

Myasthenia gravis (MG) is a problem of the neuromuscular junction which causes muscle weakness. It can occur in all ages and have a range of symptoms from mild localized disease to mortality-threatening respiratory failure. MG occurs in 1.7-30 cases/million, with a prevalence of 77.7 cases/million. Pediatric patients comprise 10-15% of all patients with MG. In various Asian populations, the juvenile MG can be up to 50% of all of the MG cases. Fluctuations in muscle weakness is a hallmark of the disease.

As a reminder, “[i]n normal synaptic transmission in the neuromuscular junction, the axon is depolarized and this depolarization travels to the axon terminal. Voltage-gated calcium channels open, leading to acetylcholine containing vesicles to fuse to the cell membrane. Acetylcholine is then released from synaptic vesicles into the synaptic cleft from the axon terminal. The acetylcholine travels across the synaptic cleft to the AChR [acetylcholine receptor] sites where binding causes sodium channels to open, depolarizing the motor end plate of the muscle fiber. Acetylcholinesterase degrades the acetylcholine, and the sodium channels close, allowing repolarization of the muscle fiber.”

The diagnosis of MG is made by history of fatiguable weakness, clinical examination trying to fatigue muscles such as continuous upward gaze (patients worsen with this activity), physiological testing such as the Tensilon test (which has improved symptoms when the drug is given), electrophysiological testing (worsening with repeated muscle stimulation) and serological testing for antibodies. Treatment varies from none, to acetylcholinesterase inhibitors, immunosuppressive medications, intravenous immunoglobulin and plasmapheresis. Surgical treatment by thymectomy is also used as there appears to be an association with thymomas. Prognosis depends on the type of MG and remissions do occur.

MG is worsened by “systemic illness, pregnancy, the menstrual cycle, drugs that affect neuromuscular transmission,…, increase temperature, hyperthyroidism or hypothyroidism and emotional upset.”

Learning Point
Patients are formally classified by disease severity, but MG has 2 basic forms based on clinical type:

  • Ocular MG
    • Muscles of the eye are preferentially affected in MG and if only ocular muscles are affected it is termed ocular MG (OMG)
    • OMG patients can have ptosis, strabismus or diplopia. Because this is a fatigable muscle disease, patients may have improved symptoms in the morning and worsen throughout the day
    • Patients may complain of difficulty walking not because of affected extremity weakness but because of difficulty seeing where they are walking, particularly with stairs
    • OMG can be unilateral or bilateral
    • Rates of progression to generalized MG are 8-49%. Preadolescents are less likely to progress than adolescents
    • Spontaneous remission with OMG is common
  • Generalized MG
    • Any muscle can be affected
    • Patients will relate various abnormalities in muscular endurance and exercise intolerance
    • Weakness of the respiratory muscles can cause respiratory distress including respiratory failure
    • Patients with bulbar weakness can have problems with chewing or swallowing, which may cause choking including having nasal regurgitation of food
    • Speech can be affected including slurring, quieter voice or having a nasal voice as fatigue worsen even over a day
    • Patients may also have issues with basic hygiene such as toileting, brushing their teeth or washing their hair

MG has 3 forms based on cause:

  • Transient neonatal MG
    • Cause: Maternal antibodies are transplacentally passed to the newborn
    • Occurs in 5-30% of infants of mothers with MG
    • Presents at or shortly after birth
    • Ocular MG or more generalized weakness may occur – weak cry, poor suck, generalized weakness or respiratory distress
    • Diagnosis is by detecting the antibodies
    • Resolves when antibodies are gone
  • Congenital MG
    • Cause: Functional or structural abnormalities in the proteins involved in the neuromuscular junction
    • Most commonly the AChR proteins and function are affected
    • Mutation specific treatment is important as treatment for one type may worsen another
    • It must be distinguished from myopathies or other neurological conditions
    • Fatigable weakness usually at young age even infancy is the usual presentation
    • Ocular MG or more generalized weakness may occur
  • Juvenile MG
    • Cause: Autoimmune disorder causing dysfunction of the AChR
    • Auto antibodies targeted against various structural proteins, mainly the AChR but also muscle-specific kinase (MuSK)
    • Patients with MuSK antibodies have more severe disease

Questions for Further Discussion
1. What causes ptosis? A review can be found here
2. What causes muscle weakness? A review can be found here
3. What causes hypotonia? A review can be found here
4. What causes peripheral neuropathy? A review can be found here

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Myasthenia Gravis and Neuromuscular Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Della Marina A, Trippe H, Lutz S, Schara U. Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. Neuropediatrics. 2014;45(2):75-83. doi:10.1055/s-0033-1364181

Jastrzebska A, Jastrzebski M, Ryniewicz B, Kostera-Pruszczyk A. Treatment outcome in juvenile-onset myasthenia gravis. Muscle Nerve. 2019;59(5):549-554. doi:10.1002/mus.26445

Peragallo JH. Pediatric Myasthenia Gravis. Semin Pediatr Neurol. 2017;24(2):116-121. doi:10.1016/j.spen.2017.04.003

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

When Does Executive Function Happen?

Patient Presentation
A 7-year-old male came to clinic with his mother who was an elementary school teacher for his health supervision visit. He had just gotten a cast off his right arm that was caused by being thrown off a bike he rode down a rock-covered ravine. He had broken the other arm flying off a swing set the previous year. He was doing well overall in school, with his siblings and loved playing soccer. He didn’t have attentional problems in general. His mother called him a daredevil as he seemed to have little fear and said, “He hasn’t got the executive function yet to really stop himself. He actually plans some of this thinking it would be fun like riding down the ravine. He just needs some more time to get some more common sense.”

The pertinent physical exam showed a healthy boy with growth parameters at 25% and normal vital signs. He had multiple scratches and bruises on the extensor surfaces of his arms and legs. The rest of his examination was normal.

The diagnosis of a healthy boy was made. The pediatrician discussed how important it was to use safety equipment for his activities, and to really stop and think if it is a good idea to do some things. “I’m glad you were wearing your helmet, but riding down the ravine probably wasn’t the best idea. How about if you stop and ask yourself, if you think your mother or teacher would think it would be good idea before you do it. If you think they would approve, then you’re probably okay. If you think they might get upset then ask them first,” the pediatrician offered. The mother and the pediatrician laughed together as they both realized that probably only more time would help his insight.

Executive function (EF) is the “…cognitive processes that facilitate goal-directed action and problem solving, such as working memory, cognitive flexibility, inhibitory control, and self-monitoring. EF skills are important for the conscious, effortful control of thoughts and behaviors.”

EF allow us to inhibit ingrained behaviors that could get us into trouble, e.g. shouting out in a classroom, driving the wrong-way down a one-way street. EF also allow us to pay attention to what is meaningful for the time and situation e.g. academic testing, paying attention to traffic and not the radio while driving. Additionally, EF allows us to organize our thoughts in the face of distraction, complexity, and stress, e.g. sports games, figuring out how to drive to a new location, being aware of personal items when walking down a crowded street to avoid theft.

EF are primarily housed in the prefrontal cortex yet have numerous other brain areas that support these skills such as the cingulate cortex, parietal cortex, basal ganglia, amygdala and hippocampus.

EF is distinct from Theory of Mind (ToM) which “is the social-cognitive ability to understand human actions in terms of the psychological states that motivate behavior, such as beliefs, emotions, desires and intentions.” EF and ToM are linked as they seem to develop together and are the neurobiological basis for this shared development. However the exact linking of the two is still not truly understood. Does the motivation influence the behavior, or does the behavior and it consequences influence the motivation, or is it truly a reciprocal/meshed relationship?

Learning Point

EF milestone development includes:

  • 0-2 years
    • Episodic mental representations
    • Episodic thoughts and goals – past experiences and actions are intertwined with current actions
    • Example – put blocks of same shape in a shape-sorter toy
  • 2-4 years
    • Emerging realistic mental representations
    • Automatic self-based actions or instruction-based actions
    • Example – bathing a toy doll or following simple request such as “bring toy here.”
  • 4-6 years
    • Integration of realistic mental representations
    • Control of attentional focus, can shift between actions depending on instructions/situation
    • Example – transitioning between activities, “It’s time to eat now, then you can play.”
  • 6-8 years
    • Emerging rule-based mental representations
    • Rule-based action plans
    • Example – turn-taking in games
  • 8-11 years
    • Integration of rule-based mental representations
    • Flexible shifting across conceptual systems
    • Example – apply rules to mathematical concepts (multiple or divide numbers before adding and subtracting), shift between memory and inference such as “Before, we went to the ice cream store by driving this way, if mom turns down the next road, she probably is taking us to get ice cream.”
  • 11-13 years
    • Emerging principle-based mental representation
    • Automation of conceptual systems
    • Example – Complex everyday plans such as homework planning, organizing errands in local order of execution
  • 14-16 years
    • Integrated principles
    • Inferential relevance of mental representations
    • Example – long-term planning such as life after high school

Questions for Further Discussion
1. What other examples of executive function can you give for the different developmental stages above?
2. What is in the differential diagnosis of attentional problems? A review can be found here
3. What are indications for referral to a psychologist or psychiatrist?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.
Information prescriptions for patients can be found at MedlinePlus for these topics: Child Development and Teen Development.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Blair C. Educating executive function. Wiley Interdiscip Rev Cogn Sci. 2017;8(1-2). doi:10.1002/wcs.1403

Demetriou A, Makris N, Kazi S, Spanoudis G, Shayer M. The developmental trinity of mind: Cognizance, executive control, and reasoning. Wiley Interdiscip Rev Cogn Sci. 2018;9(4):e1461. doi:10.1002/wcs.1461

Wade M, Prime H, Jenkins JM, Yeates KO, Williams T, Lee K. On the relation between theory of mind and executive functioning: A developmental cognitive neuroscience perspective. Psychon Bull Rev. 2018;25(6):2119-2140. doi:10.3758/s13423-018-1459-0

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa