What Are Common Inherited Thrombophilias?

Patient Presentation
A 6-month-old female came to clinic for her health maintenance visit. She was growing well physically. Her mother had several questions regarding her normal development which were easily answered. The mother was most concerned because the family history was now positive for her sister (patient’s maternal aunt) having a recent deep venous thrombosis during pregnancy. The aunt’s evaluation showed Factor V Leiden and the mother was in the process of being tested. She wanted to know if the patient should also be tested. The past medical history showed no abnormal bruising/bleeding or other problems with the patient or other family members.

The pertinent physical exam showed a smiling infant with growth parameters in the 75-95% for age. Her examination was normal. The diagnosis of a healthy infant was made. The pediatrician recommended that first the mother finish her own evaluation and re-iterated that there were several things the mother could already do to decrease her own risk of blood clots including being active and a non-smoker. The physician said, “Being pregnant like your sister is also a risk, and one you need to discuss with your doctor and your husband about. Once we know if you have Factor V Leiden then we can talk about the baby’s risks. Usually we wait until the child is older to discuss testing, but we can have you talk with the genetic counselor if you would like to. The good news is that infants and children are at low risk for getting blood clots.”

Discussion
Thrombophilia is the increased risk of thromboembolic disease due to a disorder. Thrombophilia can be inherited or acquired (such as antiphospholipid syndrome). The risk of thromboembolic events is much lower in children than adults.

At-risk patients should avoid:

  • Dehydration
  • Sitting for prolonged time periods during travel
  • Obesity
  • Smoking
  • Estrogen containing oral contraceptives

Common inherited thrombophilias include:

  • Prothrombin (Factor II mutation)
    • Second most common
    • Genetics: 1-2% prevalence is variable depending on location and ethnic background.
    • Cause: Abnormal point mutation of the prothrombin gene that causes increased levels of prothrombin, the precursor of thrombin.
  • Protein C
    • Relatively common
    • Genetics and epidemiology – 0.2% prevalence of general population. Heterozygous state is most common. Can occur in homozygous state but has severe thromboembolic events mainly in neonatal period.
    • Cause: Protein C becomes activated (activated Protein C = APC) and combines with Protein S. This complex then normally inactivates Factors Va and VIIIa. Protein C is Vitamin K dependent.
    • Two types:
      • Type 1 – antigen and activity levels are low (quantitative deficiency, 85% of cases)
      • Type 2 – antigen levels are normal and activity levels are low (qualitative deficiency, 15% of cases)
  • Protein S
    • Relatively uncommon
    • Genetics and epidemiology – 0.03-.13% prevalence of general population. Heterozygous state is most common. Can occur in homozygous state but has severe thromboembolic events mainly in neonatal period.
    • Cause: Free Protein S combines with Protein C. This complex then normally inactivates Factors Va and VIIIa. Protein S is Vitamin K dependent. Protein S is 60% protein bound.
    • Three types:
      • Type 1 – free antigen and total antigen is low (quantitative deficiency)
      • Type 3 – free antigen is low but total antigen is normal (quantitative deficiency)
      • Type 2 – normal free and total antigen levels but activity is low (qualitative deficiency)
  • Antithrombin
    • Least common
    • Genetics and epidemiology: 0.02% prevalence of Caucasian population, Autosomal dominant so heterozygous state is most common. Homozygous Type 1 is incompatible with life.
    • Cause: Acts to inhibit several coagulation factors including IIa, IXa, Xa, XIa, and XIIa.
    • Two types:
      • Type I – low antigen and activity levels (quantitative deficiency)
      • Type II – normal antigen but low activity levels (qualitative deficiency)

Learning Point
Factor V Leiden

  • Most common thrombophilia, named for the city of Leiden, Netherlands where it was discovered.
  • Genetics and epidemiology – Prevalence is variable depending on location and ethnic background. 1% in African American population, 2% in Hispanic population and 5% in European background. Mainly occurs in heterozygous state. Homogygotes have a high risk with thrombosis in up to 80/1000.
  • Cause: Factor V Leiden is an abnormal activated Protein C (APC) caused by a point mutation replacing arginine with glutamine at position 1691 which changes the amino acid at position 506 of the protein. Normally APC inactivates coagulation Factor V which then slows down the clotting process and prevents the clots from becoming too large. Is usually inactivated by activated protein C. Factor V Leiden doesn’t allow the APC to work, so the coagulation Factor V continues to allow the clot to grow.
  • Screening is controversial – Prior to a known thrombotic event, many people recommend to wait until children are adolescent age for screening so patients can make informed choices particularly as epidemiology in children is much different than adults. Screening after a thromboembolic event is less clear and most people would evaluate the patient and screen for thrombophilias as this will also help with treatment decisions.

Questions for Further Discussion
1. What are the Vitamin K dependent coagulation factors?
2. What is the role of imaging in evaluation and treatment of thromboembolic events?
3. What is the role of genetic counseling in thromboembolic events?

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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Blood Clots and Bleeding 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.

Varga EA, Moll S. Prothrombin 20210 Mutation (Factor II Mutation). Circulation. 2004; 110: e15-e18.

Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child. 2005 Apr;90(4):402-5.

Kenet G, Nowak-Gottl U. Venous thromboembolism in neonates and children. Best Pract Res Clin Haematol. 2012 Sep;25(3):333-44.

Heleen van Ommen C, Middeldorp S. Thrombophilia in childhood: to test or not to test. Semin Thromb Hemost. 2011 Oct;37(7):794-801.

Kalpatthi, RV, Kirkland KR, Tarantino CA. Screening for Factor V Leiden Mutation. The Link – Kansas City Mercy Infectious Disease. 2015; April 7(4).

Author

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

When Do Hemorrhoids Occur in Children?

Patient Presentation
A 3-year-old male came to clinic because of rectal bleeding. He was toilet training and had had some constipation. His parents noted that morning that he had some streaked blood on the toilet tissue and were concerned. They said they had not seen any blood in the toilet or on the stools. They denied any mucous in the stool, but said that it was hard. The past medical history was non-contributory. The pertinent physical exam showed a well-appearing male in no distress with normal vital signs and growth parameters. His abdomen examination was negative. His genitourinary examination showed a posterior midline fissure of his anus.

The diagnosis of an anal fissure was made. The senior resident physician recommended conservative treatment including Sitz baths if he had more pain. She also gave several suggestions for constipation treatment and toilet training. When staffing the patient, the resident and attending discussed the differential diagnosis of rectal bleeding and at one point asked, “When do hemorrhoids occur in kids?” The attending wasn’t exactly sure but knew that it didn’t occur very often in her clinical practice. They decided to try to find an answer in the medical literature.

Discussion
Common anorectal problems come to the attention of clinicians because of blood, pain or a mass lesion. These include anal fissures, perianal abscess and fistulas and hemorrhoids.

Anal fissures are tears of the distal anus usually in the midposterior line that often occur in toilet training children and those with constipation. Rectal bleeding and pain are common. Treatment is conservative.

Perianal abscess and fistulas present as masses that are firm or fluctuant. Treatment is antibiotics along with various types of incision and drainage. Recurrence is high and may require additional surgery. Crohn’s disease should be considered if a perianal fistula occurs.

Hemorrhoids are swollen vein in the anus. Symptoms include bleeding, pain, prolapse and itching. External hemorrhoids can be noted by external examination but internal hemorrhoids require anoscopy. External hemorrhoids occur below the dentate line (the mucocutaneous junction that occurs at the upper 2/3 and lower 1/3 of the anal canal) and are covered by skin. Thrombosis causes pain because of their cutaneous innervation. Thrombosis generally resolves in 2-3 days with regression around 1-2 weeks. A skin tag may remain. Internal hemorrhoids are covered by columnar epithelium. They generally are painless if thrombosed because of their visceral innervation. Bleeding and prolapse are more common.

Hemorrhoid treatment is conservative with increasing fluids and dietary fiber along with Sitz baths. Cooling packs also provide direct relief for pain. When conservative measures fail rubber band ligation, staple hemorrhoidectomy or surgical hemorroidectomy can provide treatment.

The differential diagnosis of gastrointestinal bleeding can be found here and the differential diagnosis of constipation can be found here.

Learning Point
There are few articles that document the incidence or prevalence of hemorrhoids occur children.

In a review article from 2007, the authors state ‘hemorrhoids are extremely uncommon in children with prevalence increase in adolescents and adults.” They also state that patients with portal hypertension have them more often but are rarely symptomatic.

A 2013 paper used nationwide insurance data to investigate the risk of cancer over time in patients who initially presented with benign anal lesions. They found 3,299 patients from 0-19 years old had hemorrhoids. They had a total patient population of 70,513 patients with hemorrhoids most of which occurred in the 20-59 year old age group. Data from Wikipedia, cites a total population of Taiwan at 23,374,000 persons in 2013. Of these 0-14 year olds comprised 15.65%. If all 3299 patients were attributed to the 0-14 year old age group, then the pediatric population in Taiwan would have a rate of .0022% of hemorrhoids. This rate would obviously be lower if the additional adolescents 15-19 year olds were added. Hemorrhoids in the pediatric population are rare.

Questions for Further Discussion
1. What are pilonidal cysts and how are they treated?
2. What causes rectal prolapse and how is it treated?

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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Hemorrhoids

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.

Stites T, Lund DP. Common anorectal problems. Semin Pediatr Surg. 2007 Feb;16(1):71-8.

Lee PC, Hu YW, Hung MH, et. al. The risk of cancer in patients with benign anal lesions: a nationwide population-based study. Am J Med. 2013 Dec;126(12):1143.e9-18.

Demographics of Taiwan. Wikipedia.
Available from the Internet at http://en.wikipedia.org/wiki/Demographics_of_Taiwan (cited 4/1/15).

Author

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

How Common Are Tremors in Childhood?

Patient Presentation
A 19-year-old male came to clinic with a 2 month history of tremor in both hands. He first noticed it when doing homework late at night, but now notices it more throughout the day. There are times when it is better (after sleeping) but also worse (when sleep deprived or stressful times). It generally does not bother him, but he has noticed that his homework is somewhat messier but still more than legible and functional to use in his college classes. He denies any new drugs (prescribed, illicit or complimentary/alternative), but did notice that the tremor gets worse with increased caffeine and is better after drinking a beer. He says otherwise he feels fine but this was making him nervous. The past medical history was non-contributory. The family history is positive for a paternal grandfather with hand tremors. The review of systems showed no fevers, chills, weight loss/gain, night sweats, changes in hair or nails, or rashes.

The pertinent physical exam showed a healthy male with normal vital signs. HEENT showed normal hair texture and no thyroid enlargement or nodules. His neurological examination showed a rest tremor in both hands that had moderate frequency and low amplitude. The tremor continued in different positions but did not increase in frequency or amplitude. If he put one hand on top of the other, this decreased the tremor. He said that he noticed that he just did this instinctively sometimes when he was working on handwritten homework at different times. The work-up included a normal complete blood count, electrolytes, calcium, magnesium, phosphorus, glucose and thyroid stimulating hormone and T4. A ceruloplasmin level was later negative. The diagnosis of a probable essential tremor was made. Because of the recent onset and that he was living out-of-state from his family who were also concerned, a neurology appointment was made. The neurologist confirmed the diagnosis of an essential tremor and he was offered functional recommendations. He was to re-contact the neurologist if his symptoms worsened and were interfering with his life and work.

Discussion
Tremor is one of several movement disorders in childhood including tics, dystonia, chorea, myoclonus, and sterotypy. Tremors are a rhythmic oscillating involuntary movement across a joint axis. They are the result of normal or accentuated postural or muscular processes. They are categorized as follows:

  • Rest tremor – occurs during rest and stops with movement
  • Action tremor- occurs during a voluntary activity
    • Kinetic tremor- occurs when limb is moving
    • Postural tremor – occurs when the limb is stationary but held against gravity
    • Isometric tremor – occurs when limb is stationary but is exerting a force against a stationary object

Causes of tremors including those that are benign (jitteriness, shuddering attacks, spasmus nutans), hereditary (fragile X premutation, essential), neurological (brain lesions, strokes, mitochondrial encephalopathy, peripheral neuropathy), endocrinopathies (hyperthyroid, hyperadrenergic states), metabolic (low calcium, glucose, or magnesium, B12 deficiency and inborn errors of metabolism), drugs (many including anti-epileptic, asthma, nicotine, alcohol, caffeine) and psychogenic.

Essential tremor (ET) is the most common movement disorder in adults. Up to 50% of adults report onset of their tremor in childhood and it appears to be the most common movement disorder in children. ET is a hereditary action tremor that is autosomal dominant with variable penetrance. Penetrance appears to increase with increasing age. Young children may not report it as it does not functionally cause problems, but adolescents may report tremor more as it affects their school, social and personal habits than younger children. Most children present with a high frequency tremor of the upper limbs that is postural or kinetic and only rarely causing disability. Usually difficulties are with eating and handwriting. Assuming an otherwise normal child with hand tremor as the only problem, then the child most likely has ET. A moderate amount of alcohol also improves ET in some families (i.e. ET is alcohol responsive). The differential diagnosis for ET mainly includes drugs and medication, hyperthyroidism, Wilson disease and psychogenic tremor.

Psychogenic tremor occurs suddenly but is inconsistent regarding the frequency and amplitude of the tremor as well as the affected muscle groups. Unusual combinations of rest and action tremors occur. Although psychological stressors and psychiatric disease may be more common, up to 30% of subjects with psychogenic movement disorders have no psychiatric diagnosis.

Most patients with ET do not need treatment. Primodone and propranolol are usual first-line choices but benzodiazepines are also used. In adults other more invasive treatments are also being used such as botulinum A toxin injections or vagal nerve or brain stimulation. Other interventions such as weighting of wrists or other occupational therapy interventions may also assist patients.

Learning Point
Tremor commonly occurs as part of movement disorders in children (10-20% of children with movement disorders). Tremor prevalence studies in children are not common. Two studies evaluated tremor using Archimedes spiral test scoring, which asks the person to draw a spiral shape starting at the center and spiraling outward.

In a cross-section study in Spain of school aged children in 2011, mild tremor in one hand was common (51%) and was less likely in both hands (10.7%). More severe tremor was uncommon. Boys were slightly more affected than girls, the left hand was more affected than the right, and there was an increase in tremor with age.

In a population-based cohort of New York City children ages 9-15 in 2014, mild tremor was seen in 33.1% in one hand and was less common in both hands (9.1%). The dominant hand was affected in 12.6% and non-dominant hand in 29.7%. Boys were more affected than girls. Age was inversely correlated (in the dominant hand) tremor. The authors believe this may be the result of improved motor performance with increasing age because of development and practice. Children using psychiatric medication more often had tremor but interestingly, asthma medication did not appear associated with tremor. Tremor was also associated with poor motor dexterity.

Questions for Further Discussion
1. How is tremor different from other childhood movement disorders?
2. What are indications for evaluation by a neurologist?
3. What are indications for neuroimaging?

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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Tremor and Movement 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.

Keller S, Dure LS. Tremor in childhood. Semin Pediatr Neurol. 2009 Jun;16(2):60-70.

Louis ED, Cubo E, Trejo-Gabriel-Galan JM, Villaverde VA, Benito VD, Velasco SS, Vicente JM, Guevara JC, Benito-Leon J. Tremor in school-aged children: a cross-sectional study of tremor in 819 boys and girls in Burgos, Spain. Neuroepidemiology. 2011;37(2):90-5.

Cardoso F. Movement disorders in childhood. Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S13-6.

Louis ED, Garcia WE, Rauh VA. Tremor in a population-based cohort of children in New York City. Pediatr Neurol. 2015 Feb;52(2):187-91.

Author

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

Date
May 11, 2015

How Do You Treat Adrenal Crisis?

Patient Presentation
A 3-year-old female with septo-optic dysplasia and panhypopituitarism was traveling on vacation. She had become acutely ill with emesis in the early hours of the morning. The emesis became more frequent so her parents brought her to the small community emergency room that was closest to their hotel. In the ER, she was alert and responsive but was mottled with a capillary refill of 4 seconds. Her respiratory rate was 38/minute, temperature of 37.8° and a blood pressure of 72/44. She had a mild dysconjugate gaze which was normal per her parents. Her heart and lungs were normal. She had slightly hyperactive bowel sounds and mildly diffuse abdominal pain and no organomegaly. She denied any suprapubic, costovertebral or McBurney’s point tenderness.

While an IV was established and fluids begun, her parents said that she had had been well and had taken all of her medications the day before. In retrospect her parents said that she probably had been drinking less the day before and seemed more tired, but they had attributed that to the traveling. She had been diagnosed early in life with septo-optic dysplasia and was treated by a multispecialty team at a children’s hospital. She had done relatively well and had not had any major crises so the family had decided to take a car trip across part of the country to visit relatives.

They had brought with them her emergency steroid medicine in case of adrenal crisis. The father said, “We know it’s supposed to be given in her leg muscle, but we’ve never done it and don’t want to do it.” The physician took the box along with an emergency treatment letter from the child’s doctor. He and the hospital pharmacist checked the emergency instructions and the IM hydrocortisone dosing. They calculated an appropriate IV dosing based on the emergency treatment letter and the pharmacist virtually ran back to the emergency room with the medication. In the meantime, the patient’s laboratory evaluation showed a sodium of 128 mEq/L, potassium of 4.4 mEq/L, and a glucose of 53 mg/dL. She also was now febrile and her blood pressure was not increasing. The physician ordered an additional .9 normal saline bolus along with piggyback fluids of D25W. At the same time, the physician was arranging a transfer to the regional children’s hospital. As the child appeared stable but getting sicker, an airflight ambulance was sent. While still in the ER, her blood pressure started to drop and pressor medications were begun which stablized her.

The physician found out a few weeks later that in the patient’s clinical course she had culture-negative sepsis that precipitated her adrenal crisis. She needed vasopressors for 48 hours but responded well to the antibiotics. She finished her course of antibiotics and was released with followup with her regular physicians.

Discussion
Septo-optic dysplasia (SOD) is a disorder of midline prosencephalic development early in gestation. It causes agenesis of the septum pellucidum and/or thinning or absence of the corpus callosum and pituitary hormone deficiencies. It has an incidence of 1:10,000 live births. Most cases appear to be due to a combination of genetic and environmental factors but there are rare familial cases which are most often autosomal recessive.

The phenotype is variable and diagnosis can occur at birth with more severe problems or later with milder ones. Patients must have at least 2 of 3 problems for diagnosis including uni- or bi-lateral optic nerve hypoplasia, midline brain defects (e.g. septum pellucidum absence or agenesis of the corpus callosum) and hypopituitarism (which is a hypothalamic hypopituitarism not a primary dysfunction of the gland itself). Patients have poor visual function, developmental delay, sleep problems, seizures and various endocrine deficiencies. The most common endocrinopathy is growth hormone deficiency, then thyroid stimulating hormone deficiency, then adrenocorticotropic hormone (ACTH) deficiency. The endocrinopathies do not have to be present at birth but can develop later. Patients with SOD are at risk for adrenal insufficiency (AI) as they obviously do not have the normal capacity to increase ACTH during stress.

The hypothamic-pituitary-adrenal axis is important for maintaining homeostasis in the metabolic and immune systems. Normally the hypothalamus secrets corticotrophin-release hormone (CRH) and argenine vasopressin (AVP). These stimulate the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH causes the adrenal gland to secrete aldosterone and cortisol along with androgenic steroids. Normally during stress, CRH, AVP and norepinephrine act to increase ACTH release. Cortisol, a glucocorticoid, maintains serum glucose. Aldosterone, a mineralocorticoid, maintains electrolyte balance and catecholamine balance for blood pressure modulation.

Learning Point
Adrenal insufficiency (AI) is defined as “…inadequate cellular corticoisteroid activity for the severity of the patient’s illness, [and] is the result of either a decrease in adrenal steroid production or tissue resistance to glucocorticoids.” In acute adrenal insufficiency or adrenal crisis, patients can have hypoglycemia, hyponatremia, hyperkalemia, hypotension, dehydration, altered mental status and thermodysregulation. Patients may also present with more nonspecific symptoms such as anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, and fever. It is a medical emergency requiring multispecialty treatment often in an intensive care setting in consultation with an endocrinologist.

  • For hypotension and dehydration, aggressive fluid resuscitation with isotonic saline with dextrose (usually D5 .9 normal saline) should be begun. Resuscitation must be carefully monitored to prevent water retention.
  • For hypoglycemia, additional dextrose (D25W) may be needed in addition to the dextrose in the other fluids.
  • Glucocorticoids can be given intravenously or intramuscularly. Intravenous is preferred as intramuscular injection may have a slower uptake because of decreased perfusion and dehydration.
    • Hydrocortisone (cortisol) is recommended because of its mineralocorticoid affect and should be given in stress doses – 50-75 mg/M2 x 1 dose initially, followed by 50-75 mg/M2 given daily divided into 4 doses.

    • Alternatives are methylprednisolone 10-15 mg/M2 and dexamethasone 1.5-2 mg/M2. Dexamethasone does not cross-react with hydrocortisone and so it can be used if AI is suspected and it will not confound confirmatory testing.

Careful monitoring of glucose, sodium, and potassium are needed. Other testing which can help includes cortisol, ACTH, aldosterone and renin levels. Underlying triggers of adrenal crisis need to be aggressively sought and treated.

Questions for Further Discussion
1. What disease processes cause adrenal insufficiency?
2. What triggers can cause adrenal crisis?

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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Adrenal Gland Disorders, Addison’s Disease and Pituitary 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.

Adrenal insufficiency: still a cause of morbidity and death in childhood. Shulman DI, Palmert MR, Kemp SF; Lawson Wilkins Drug and Therapeutics Committee. Pediatrics. 2007 Feb;119(2):e484-94.

The empty sella. Naing S, Frohman LA. Pediatr Endocrinol Rev. 2007 Jun;4(4):335-42.

Adrenal crisis provoked by dental infection: case report and review of the literature. Milenkovic A, Markovic D, Zdravkovic D, Peric T, Milenkovic T, Vukovic R. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Sep;110(3):325-9.

Septo-optic dysplasia. Fard MA, Wu-Chen WY, Man BL, Miller NR. Pediatr Endocrinol Rev. 2010 Sep;8(1):18-24.

Adrenal dysfunction in critically ill children. Karagüzel G, Cakir E. Minerva Endocrinol. 2014 Dec;39(4):235-43.

Author

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