What is the Current Classification for Ehlers-Danlos Syndrome?

Patient Presentation
A 4-year-old female came to clinic for her health supervision visit. Her mother had no complaints except that she was concerned that the child may have Ehlers-Danlos syndrome. “I’m being evaluated now because I’ve always been double-jointed and had some pain now and then. But during my last pregnancy with her brother I had a lot of problems and my doctor is starting to evaluate me more. She complains once in a while about her legs being tired, so it just makes me worried,” the mother explained.

The past medical history was positive for admission for respiratory syncytial virus and 2 otitis media diagnoses. The review of systems was negative for other problems such specific joint pain, problems moving after resting for time, easy bruisability or skin problems, being “double-jointed”, true fatigue, problems playing or keeping up with other children, abnormal muscle strength or dental problems. Her mother also said that she complained of the leg pain after playing for a long period of time and was better after resting. It occurred infrequently.

The pertinent physical exam showed a smiling female with growth parameters in the 25% and was proportional. Her physical examination was normal. Her Beighton score was 3 for bilateral dorsiflexing her 5th metacarpal to 90%, and she could place her hands on the floor with forward flexion of the trunk.

The diagnosis of a healthy female was made. The pediatrician felt that the intermittent leg discomfort was most likely due to exercise but asked the mother to monitor it. She also recommended that the mother let her know about the outcome of the mother’s evaluation. “Depending on if your doctor finds any problems and what type of problems they are, we may need to do something for her and her brother but we’ll see what you find out,” she recommended.

Discussion
As with any potential problem there is a often a range from normal to abnormal and this is true for joint hypermobility. Generalized joint hypermobility is hypermobility in multiple joints with few or no other symptoms. Generalized hypermobility spectrum disorder (also known as joint hypermobility syndrome) has hypermobility along with other symptoms such as pain, reduced muscle strength, and decreased proprioception and balance. Other clinical entities with hypermobility include Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta.

In the office, a 5-point questionnaire with 2 or more “yes” answers has high sensitivity (80-85%) and specificity (89-90%) for joint hypermobility. It includes:

“1. Can you now (or could you ever) place your hands flat on the floor without bending your knees?
2. Can you now (or could you ever) bend your thumb to touch your forearm?
3. As a child, did you amuse your friends by contorting your body into strange shapes
or could you do the splits?
4. As a child or teenager, did your shoulder or kneecap dislocate on more than one
occasion?
5. Do you consider yourself “double-jointed”?””

The most commonly recognized scoring system for joint hypermobility on physical examination is the Beighton score which can be reviewed here. Children have more joint mobility therefore they have a higher cutoff score than adults (Beighton score = 5-6 versus adults with score of 4-5).

Learning Point
Although recognized since ancient times, Ehlers-Danlos syndrome (EDS) was first named in 1936 after Ehlers and Danlos who were both dermatologists. EDS is a genetic connective tissue disorder with heterogeneous clinical characteristics that include joint hypermobility, tissue fragility and skin hyperextensibility. Because of newer genetic research and testing and increased recognition of the problems, several classification systems for EDS have evolved over the past 40 years. As this involves soft tissue or related structures, it is not surprising that EDS has various clinical patterns. The most recent international classification includes 13 different patterns which are:

  • Classic
  • Abbreviation: cEDS
  • Genetic Pattern: Autosomal Dominant
  • Major criteria are skin hyperextensibility and aulophic scarring, and generalized joint hypermobility
  • Classic-like
  • Abbreviation: cIEDS
  • Genetic Pattern: Autosomal Recessive
  • Major criteria are skin hyperextensibility and aulophic scarring, and generalized joint hypermobility, and easy bruisability skin / spontaneous ecchymoses
  • Hypermobile
  • Abbreviation: hEDS
  • Genetic Pattern: Autosomal Dominant
  • Is a clinical diagnosis with major criteria being generalized joint hypermobility, several criterion and features within the criterion. These include various skin, joint, soft tissue, vascular and other features and also genetic risk
  • Cardio-valvular
  • Abbreviation: cvEDS
  • Genetic Pattern: Autosomal Dominant
  • Major criteria are progressive cardiac-vascular problems, skin involvement and joint hypermobility
  • Vascular
  • Abbreviation: vEDS
  • Genetic Pattern: Autosomal Dominant
  • Major criteria are family history of vEDS, arterial rupture, spontaneous sigmoid colon perforation, uterine rupture, carotid-cavernous sinus fistula
  • Arulochalasia
  • Abbreviation: aEDS
  • Genetic Pattern: Autosomal Dominant
  • Dermatosparaxis
  • Abbreviation: dEDS
  • Genetic Pattern: Autosomal Recessive
  • Kyphoscoliotic
  • Abbreviation: kEDS
  • Genetic Pattern: Autosomal Recessive
  • Brittle Cornea syndrome
  • Abbreviation: BEDS
  • Genetic Pattern: Autosomal Recessive
  • Spondylodysplastic
  • Abbreviation: spEDS
  • Genetic Pattern: Autosomal Recessive
  • Musculoconulactural
  • Abbreviation: mcIEDS
  • Genetic Pattern: Autosomal Recessive
  • Myopathic
  • Abbreviation: mIEDS
  • Genetic Pattern: Autosomal Dominant or Autosomal Recessive
  • Periodontal
  • Abbreviation: pIEDS
  • Genetic Pattern: Autosomal Dominant

Questions for Further Discussion
1. What is included in the differential diagnosis of joint pain? A review can be found here
2. What are indications for referral to genetics, rheumatology or orthopaedics for potential hypermobility?
3. What are treatments for hypermobility with associated musculoskeletal problems?

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: Ehlers-Danlos Syndrome and Connective Tissue 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.

Baeza-Velasco C, Grahame R, Bravo JF. A connective tissue disorder may underlie ESSENCE problems in childhood. Research in Developmental Disabilities. 2017;60:232-242. doi:10.1016/j.ridd.2016.10.011

Scheper MC, Juul-Kristensen B, Rombaut L, Rameckers EA, Verbunt J, Engelbert RH. Disability in Adolescents and Adults Diagnosed With Hypermobility-Related Disorders: A Meta-Analysis. Arch Phys Med Rehabil. 2016;97(12):2174-2187. doi:10.1016/j.apmr.2016.02.015

Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):8-26. doi:10.1002/ajmg.c.31552

van Meulenbroek T, Huijnen IPJ, Simons LE, Conijn AEA, Engelbert RHH, Verbunt JA. Exploring the underlying mechanism of pain-related disability in hypermobile adolescents with chronic musculoskeletal pain. Scand J Pain. 2021;21(1):22-31. doi:10.1515/sjpain-2020-0023

Ehlers-Danlos syndrome. Accessed October 10, 2022. http://www.whonamedit.com/synd.cfm/2017.html

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

How is Endometriosis Diagnosed?

Patient Presentation
A 16-year-old female came to clinic with a history of pelvic pain that was adversely affecting her daily activities. A couple days before menstruation she had constipation but during menstruation would have the pelvic pain associated with diarrhea and frequent urination. She intermittently took some ibuprofen with variable success. Some months she would need to miss school, but generally the pain would subside within 2 days of menses. Her menses were regular, lasting about 5 days but with heavy bleeding for the first couple of days. She also would have similar pains at other times that usually would last for < 24 hours, but would be associated with constipation and/or diarrhea. Again sometimes she would need to miss school or other activities. She denied any increased gas or bloating, dysuria, fever, or worsening with particular food. She denied any sexual activity and otherwise was doing well at school, in her activities and with friends. The pain could awaken her at night if it coincided with her menses but the non-menstrual associated pain would not awaken her at night. She says that she passed stools every 2 days and would occasionally clog the toilet or have harder stools. The family history was positive for a maternal aunt with endometriosis and her mother said she had painful periods as well but they did not cause functional problems.

The pertinent physical exam showed a healthy female with normal vital signs and growth parameters in the 50-75% range. Her general physical examination was normal. Her abdominal examination was soft, non-tender with no organomegaly but some noticeable stool burden in the lower left quadrant. Her musculoskeletal examination was normal. Genitourinary examination showed a Tanner V female for pubic hair with normal vulvar structures and intact hymen. Her anus was patent with normal anal wink. She declined a vaginal or rectal/abdominal examination.

The diagnosis of chronic constipation and dysmenorrhea seemed most likely. The mother and patient were very concerned about potential endometriosis and wanted a referral to a gynecologist. The pediatrician recommended that she be screened for alternative problems and for possible anemia given the heavier bleeding. She would begin with daily treatment for constipation using Miralax® and increased fiber. He also discussed menstrual hormone therapy but the family did not want to start anything until they had seen a gynecologist. He did recommend using ibuprofen starting before her periods and for the first couple of days until the pain seemed to subside. “It would also be very helpful to me and the gynecologist if you could keep a pain diary so we can look for patterns in your pain,” he explained. The laboratory testing that day included a complete blood count, inflammatory markers, complete metabolic profile and urinalysis and pregnancy testing which were all normal. When the patient saw the gynecoloogist about 6 weeks later, she reported much improved non-cyclical pain, but only some mild improvement with her last period using the ibuprofen. The gynecologist recommended to start hormonal suppression therapy and to followup. If the patient did not improve then they could consider potential laparoscopy. At followup 4 months later, the patient had had marked improvement with her pain overall, including one break through menstrual period that lasted only 2 days.

Discussion
Endometriosis is classically defined as endometrial tissue occurring outside the uterine lining. It is a common cause of chronic pelvic pain and dysmenorrhea in adolescents. It can present differently in adolescents than adult women and usually can appear like many other common problems such as chronic constipation or gastrointestinal dysmotility. It is estimated that ~25-38% of adolescents with chronic pelvic pain have endometriosis. Use of clinical criteria versus laparoscopic documentation of disease makes the epidemiology of this problem more challenging.

The cause is not wholly agreed upon but many believe the idea of retrograde menstruation through the fallopian tubes with seeding of the peritoneal cavity, and with implantation and growth of the endometrial tissue as the cause. Yet, many women (up to 90%) can have retrograde menstruation, implying that other factors probably are involved and it is likely multifactorial. There are rare cases of premenarchal girls also being diagnosed with endometriosis. Adolescents present with pelvic pain that can be cyclic, acyclic or both with about 2/3s of adolescents presenting with both types of pain whereas adult women usually have cyclic pain. Other common symptoms include constipation, diarrhea, dysuria or urgency, dyspareunia in sexually active teens, and adolescents with endometriosis also have a higher migraine headache prevalence. Adolescents also report an inferior quality of life compared with normal teens.

Medical therapy usually starts with non-steroidal anti-inflammatory drugs and menstrual hormonal regulation using oral contraceptives including continuous hormonal suppression. Some patients may not respond to this treatment and may need laparoscopy and/or other therapy including hormonal or surgical therapies.

There is no cure for endometriosis but it can be managed. The nature history can include continued pain, fibrosis/adhesions, and infertility.

Chronic pelvic pain in adolescents includes:

  • Gynecological problems
    • Adnexal cysts – both functional and non-functional
    • Ovarian cysts
    • Endometrioma
    • Pelvic inflammatory disease
    • Reproductive tract anomies
  • Non-gynecological problems
    • Abuse and/or neglect
    • Abdominal/pelvic adhesions
    • Abdominal migraine
    • Celiac disease
    • Cystitis
    • Diabetic ketoacidosis
    • Food insensitivity/intolerance
    • Inguinal hernia
    • Irritable bowel syndrome
    • Inflammatory bowel syndrome
    • Musculoskeletal problems – back or pelvic bone or myofascial pain
    • Pancreatitis
    • Peptic ulcer disease
    • Pregnancy
    • Psychological stress – depression, anxiety
    • Sickle cell disease
    • Urolithiasis

Learning Point
History is one key to diagnosis of endometriosis. Pain diaries which document the frequency, duration, pain character, and alleviating/provoking factors are helpful. Physical examination to help with alternative diagnosis especially a reproductive tract anomaly or pelvic mass is also helpful. Pelvic examination is not always necessary, as a rectal-abdominal examination may yield as much information. Attention to the musculoskeletal system looking for bony tenderness, difficulties with spine or hip motion may indicate alternative problems. Laboratory testing usually looks for alternative diagnoses such as appendicitis, inflammatory bowel disease, cystitis etc. Pregnancy and sexually transmitted infection testing should also be considered. Imaging does not always need to be completed but ultrasound of the pelvis to assess for endometrioma, reproductive tract anomaly or ovarian cyst and/or adnexal torsion again can be helpful. Abdominal ultrasound could also be considered in the proper circumstances. Laproscopy is considered the standard but may or may not be used for diagnosis depending on the circumstances, and patients may be diagnosed clinically. When used it is usually intended to diagnose and for treatment. Laproscopy is commonly used if patients do not respond to a trial of medical therapy.

Questions for Further Discussion
1. What causes acute pelvic pain? A review can be found here
2. What causes constipation? A review can be found here
3. What are the ROME criteria used for? 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: Constipation and Endometriosis.

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.

Smorgick N, As-Sanie S. Pelvic Pain in Adolescents. Sem Reprod Med. 2018;36:116-122.

Shim JY, Laufer MR. Adolescent Endometriosis: An Update. J Pediatr Adolesc Gynecol. 2020;33(2):112-119. doi:10.1016/j.jpag.2019.11.011.

Lax Y, Singh A. Referred Abdominal Pain. Ped in Rev. 2020;41(8):430-433.

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

Is This Primary Exertional Headache?

Patient Presentation
A 20-year-old female came to clinic with a history of headache. She was performing leg presses with increased weight and had a sudden onset of throbbing bilateral headache. She continued to do the leg presses but the pain increased and she became more nauseous. She went home and slept for about 90 minutes and woke up tired but without the headache. This occurred a second time later in the week but she stopped her workout and the headache duration was only a few minutes and she did not have nausea. She denied any other problems including numbness, tingling, aura, vision changes, etc. Her mentation and balance were normal at all times. She denied any fainting or palpitations. She said that possibly she was dehydrated the first time but she had been specifically drinking more the second time and usually had 2 liters of fluid daily. She denied any drugs, medications, or disordered eating patterns.

The past medical history was positive for migraine. She had about 2-3 episodes per year that were usually associated with decreased sleep or dehydration. The family history was positive for an older uncle who had some type of vascular surgery. The review of systems was normal.

The pertinent physical exam showed a healthy appearing female with weight in the 25% and height at the 50%. Blood pressure was 102/66 and pulse was 70. Her physical examination was normal including her neurological examination.

The diagnosis of a sudden onset of headache associated with exertion was made. After reading about these types of headaches and the potential risk of vascular abnormalities and the unknown problem with the uncle, a pediatric neurologist was consulted who agreed with brain imaging. The radiologic evaluation of a brain magnetic resonance imaging was normal. The diagnosis of a primary exertional headache was made and the patient counseled regarding natural history and methods to decrease the possible recurrence.

Discussion
Commonly occurring primary headaches include tension, cluster and migraine headaches. “Other primary headaches” are often situational. Patients can have more than 1 type of these “other” headaches along with more common headaches. Other primary headaches as a group tend to be self-limited with long remission periods. Some other primary headaches include:

  • Thunderclap headache
    • Explosive sudden onset with maximum intensity in less 1 minute and resolution within 5 minutes usually
    • 43/100,000 persons in adults
    • Primary or secondary
    • Secondary causes include intracranial hemorrhage, stroke, thromboembolism, hypertensive encephalopathy etc.
  • Cough headache
    • Associated with or brought on by cough or other Valsalva maneuvers and lasts < 48 hours
    • Valsalva maneuvers can include straining, bending over, laughing, sneezing etc.
    • Note that a migraine headache is different as it is worsened not precipitated by Valsalva
    • 1% lifetime prevalence
    • In pediatric population has been associated with Chiari I malformation but appears to have benign outcome for most patients
    • Treatment with indomethacin
  • Headache associated with sexual activity
    • Occurs during or brought on by sexual activity with either or both of: increased intensity with sexual excitement or explosive intensity around orgasm
    • Lasts 1 minute to 72 hours
    • Treatment with indomethacin or beta blockers
  • Other types include cardiac, cold stimulus, external pressure, hypnic, or nummular headaches

Learning Point
Primary exercise headache (PEH) is a headache occurring during or immediately after exercise that has no known intercranial pathology

  • Occurs during or brought on by strenuous physical exercise (within 30 minutes) and lasts < 48 hours
  • Usually throbbing-type headache
  • About 1% of the general population
  • More common in young with average age of ~40 years with studies mixed on gender occurrence
  • Often co-morbid with migraine with aura (up to 50% have some type of co-morbid migraine)
  • Dysregulated cerebral vasculature is the presumed cause but is not well understood
  • Usually this is benign but differential diagnosis includes:
    • Cervical artery dissection
    • Chiari malformation
    • Idiopathic intracranial hypertension
    • Reversible cerebral vasoconstriction syndrome
    • Pheochromocytoma
    • Subarachnoid hemorrhage
    • Space occupying lesions
    • Cardiac cephalgia
  • Treatment includes avoidance of precipitating activity levels, increasing activities over a long time period (weeks to months), long warmups, ensuring headgear is not restrictive, avoiding hot weather, high altitude or dehydration.
    Medical treatment is with indomethacin or beta blockers.

Questions for Further Discussion
1. What are common treatments for headaches? A review can be found here
2. What are common recommendations for athletic injury prevention?
3. What are indications for imaging for headache?

Related Cases

    Disease: Primary Exertional Headache | Headache

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: Headache

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.

Sandoe CH, Kingston W. Exercise Headache: a Review. Curr Neurol Neurosci Rep. 2018;18(6):28. doi:10.1007/s11910-018-0840-8

Upadhyaya P, Nandyala A, Ailani J. Primary Exercise Headache. Curr Neurol Neurosci Rep. 2020;20(5):9. doi:10.1007/s11910-020-01028-4

Bahra A. Other primary headaches – thunderclap-, cough-, exertional-, and sexual headache. J Neurol. 2020;267(5):1554-1566. doi:10.1007/s00415-020-09728-0

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

What Are the Potential Benefits and Risks of Premasticated Foods?

Patient Presentation
A 3-month-old female came to clinic to recheck her weight. She had been seen at 2.5 months and had a weight at the 3rd percentile, length at 15% and head circumference at the 25%. Because of a recent formula shortage her mother had been feeding her almond milk for the past month, which she said she liked more than formula. She also had been prechewing a variety of foods such as macaroni and cheese, chicken, pizza, and some different fruits which she said she ate well without choking. She also said she gave her some of whatever she was eating. She denied any emesis, diarrhea, or rashes. The past medical history showed a term infant born without complications at the 25% for growth parameters. The parents were both of average size and weight.

The pertinent physical exam showed an interactive female with a normal examination but was small without a lot of subcutaneous fat.

The diagnosis of a healthy but small infant with concern for inadequate nutrition was made. The mother was counseled that almond milk did not provide all the necessary nutrition for the infant and help was given to obtain formula. She also was counseled about introduction of complementary foods and the choking hazard risks, dental caries and other potential problems. The patient’s clinical course at followup the following month, the mother had switched her to formula but was still giving her premasticated foods. The infant’s weight had increased to the 5th percentile, with length and head circumference at the 25%.

Discussion
Premastication is the prechewing of foods or medicines by another person before feeding to an infant. It is also used to pretaste or temperature test foods. It was a common practice for millennia, especially before modern food technology, as a way to transition an infant from a solely liquid based diet to a mixed diet mainly of solid food. Rates of premastication vary, with less developed countries having an increased incidence/prevalence (up to 50%) but it is not uncommon in developed countries (in the US 14% is reported).

Saliva is also used to clean other people, treat cuts/itches or insect bites as well. Placement of an avulsed tooth in the patient’s or another person’s mouth is also one of the preferred ways to transport avulsed teeth before treatment.

Learning Point
Premastication has potential benefits and risks which include:

  • Potential benefits
    • Makes a wider variety of foods available and more affordable
    • May help with immunotolerance and immunosensitization potentially decreasing allergy
    • Can be an important cultural practice
    • Saliva
      • Has bactericidal effects which could be transferred to infant
      • Has digestive enzymes to help break down food
    • Protective effect against
      • Respiratory syncytial virus
  • Potential risks for
    • Choking hazard
    • Group A Streptococcus
    • Streptococcus mutans and dental caries
    • Helicobacter pylori
    • Cytomegalovirus
    • Epstein-Barr virus
    • Hepatitis B
    • Human herpes virus 8
    • Human immunodeficiency virus (HIV) – appears to need blood exposure not just saliva

Questions for Further Discussion
1. How common is premastication in your practice?
2. What anticipatory guidance do you offer for infants with first teeth?
3. When are complimentary foods usually introduced and how do you know if the infant is ready for them?

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: Growth Disorders and Child Nutrition.

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.

Centers for Disease Control and Prevention (CDC). Premastication of food by caregivers of HIV-exposed children–nine U.S. sites, 2009-2010. MMWR Morb Mortal Wkly Rep. 2011;60(9):273-275.

Maritz ER, Kidd M, Cotton MF. Premasticating food for weaning African infants: a possible vehicle for transmission of HIV. Pediatrics. 2011;128(3):e579-590. doi:10.1542/peds.2010-3109

Pelto GH, Zhang Y, Habicht JP. Premastication: the second arm of infant and young child feeding for health and survival? Matern Child Nutr. 2010;6(1):4-18. doi:10.1111/j.1740-8709.2009.00200.x

Zhao A, Zheng W, Xue Y, et al. Prevalence of premastication among children aged 6-36 months and its association with health: A cross-sectional study in eight cities of China. Matern Child Nutr. 2018;14(1). doi:10.1111/mcn.12448

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