Are the symptoms in this 17-year-old girl medical or psychiatric?
Ehlers-Danlos Syndrome: An Unexpected Genetic Finding
A 17-year-old girl presented to her pediatrician with a request for reevaluation of her numerous symptoms that she believed had been misdiagnosed as anxiety disorder and chronic fatigue syndrome.
She had been a colicky infant who had required numerous formula changes; in later childhood, she had developed constipation and a sensitive stomach, which were diagnosed as gastroesophageal reflux and were relieved somewhat by proton-pump inhibitors. Daily knee and foot pain developed in junior high school, when she became active in cheering, dance, and soccer. This pain first was dismissed as growing pains, and then later was attributed to Osgood-Schlatter osteochondritis. Competitive soccer in high school had led to a succession of knee injuries, the last of which required ligament repair and plica resection and caused her to stop competitive athletics.
This past summer, she was slow to recover from a flulike illness with dizziness, fainting on two occasions, spells of tachycardia with anxiety, and chronic fatigue. She was unable to return to school in the fall. At presentation, she was on medication for anxiety and depression without symptom relief. She and her parents had consulted the Internet and believed that she has a medical disorder rather than a psychiatric disorder.
The pediatrician noted a number of key physical examination findings, including wrist hypermobility, skin elasticity, and white-surfaced scars. Referrals to specialists in cardiology and genetics provided insight, including informative findings from a whole-exome sequencing (WES) test. She received a diagnosis of hypermobility due to connective tissue dysplasia (specifically, Ehlers-Danlos syndrome) with secondary bowel dysmotility and orthostatic intolerance.
JOINT MOBILITY ASSESSMENT
Assessment of joint mobility is a relatively easy and high-yield component of the adolescent physical examination that can prevent injury and lead to the recognition of a broad category of diseases. The Beighton score1 is most widely used, assigning 1 point for each of 4 bilateral maneuvers (bending back the fifth finger beyond 90° on the dorsal hand, touching thumbs to forearms with bended wrists, hyperextending the elbows with arms stretched horizontal, and hyperextending the knees backward while standing), plus 1 more point for touching the palms to the floor with the knees extended. A positive Beighton score of 4 or 5 out of 9 points will be obtained in 20% of adolescent girls, 10% of adolescent boys, and 40% of preadolescent children.
Even though most flexible adolescents have benign hypermobility,2,3 they have an increased risk of injury (eg, anterior cruciate ligament tears in adolescent girls) that can be lessened by teaching them to recognize joint stress and to use specific warm-up and training routines.4 In other cases, hypermobility is accompanied by more serious signs and symptoms (Table), placing the patient’s condition in the broad category of CTD. The most common are on the Ehlers-Danlos syndrome (EDS) spectrum5; the milder but distinctive pattern of symptoms in EDS often can be overlooked when physicians look for dramatic CTD conditions such as osteogenesis imperfecta or Marfan syndrome.6 The clinical diagnosis of CTD is based on joint pain and injuries, hypermobility on physical examination, and a distinctive pattern of accessory symptoms.
A DISTINCTIVE CLINICAL PATTERN
A clinical diagnosis of CTD, gathered from an informed history and a physical examination, allows for appropriate referral and management without worrying about specific disease types or eponyms. Skeletal signs and symptoms often present first, with infants and toddlers exhibiting unusual postures such as holding bottles with their feet, sitting in a W position, turning over ankles, or walking pigeon-toed with a clumsy gait and frequent falls.
“Growing pains” usually occur at night, so recurring daytime arthralgia should be taken seriously as possible evidence of wear-and-tear joint injury. Frequent sprains, dislocations, or fractures may reveal diminished joint protection by lax tendons and ligaments, the latter also contributing to deformities of the palate (high with crowded teeth needing orthodontics), eye globes (requiring early glasses for myopia or astigmatism), scoliosis, concave or convex sternum (pectus excavatum or pectus carinatum), or flat arches.
Many flexible people believe themselves to be the norm and may not perceive themselves as “double-jointed” until their flexibility is displayed by the Beighton maneuvers. Figure 1 demonstrates the classic wrist hypermobility of CTD. Other maneuvers include having a patient join hands with one over the shoulder and the other around the back, or having a patient reach a hand around the back to touch the umbilicus. I have found the Metenier sign (easy eversion of eyelids) and the Gorlin sign (touching the nose with the tongue) to be unreliable indicators of CTD, but the Walker-Murdoch sign (overlap of fifth finger and thumb around wrist) and the thumb-through-fist sign are useful to show arachnodactyly and digital flexibility, which raise suspicion for Marfan syndrome.6 Most people with CTD recognize that their joints “pop” with movement (like Rice Krispies) and experience spontaneous or intentional (to relieve stress) dislocation of their shoulders or hips. Many can “wing” their scapulae.
The skin often is elastic; in extreme cases, the dermal layer, rather than subcutaneous layer, can be stretched several centimeters on the jaw or forearm (Figure 2). Characteristic keloidal (purplish borders with callous plaque) or white-surfaced (“cigarette-paper”) scars occur (Figure 3). Some individuals have early and numerous striae, while others are spared the development of striae, even after pregnancy. Easy bruising and slow healing occur, with surgeons sometimes commenting that sutures will not hold. Reactivity to insect bites and transient erythematous rashes might prompt a diagnosis of mastocytosis, and many patients with CTD will be unusually sensitive or resistant to certain medications, including anesthetics. Elastic tissues can lead to uterine and/or bladder prolapse, frequent urogenital infections, hernias, Chiari malformations, or disk disease. Pooling of blood in dependent vessels can contribute to migraines, metrorrhagia, lower extremity swelling, and, most disabling of all, dysautonomia.7
The CTD spectrum moves from nuisance to disability when low blood pressure and poor cephalic perfusion activate the sympathetic nervous system, causing irritable bowel syndrome (IBS) and paroxysmal or postural orthostatic tachycardia (POTS).7-9 Early colic and formula changes may predict the low motility of IBS with later constipation/diarrhea, bloating, and reflux, which often is misdiagnosed as Crohn disease, even leading to bowel resection.
Dizziness on arising or sudden standing, coupled with spells of tachycardia (“panic attacks”), can be misdiagnosed as vertigo, supraventricular tachycardia, or anxiety disorder. Psychiatric medications and even cardiac ablation might address the symptoms but not the underlying cause. Often, an infectious illness, a first pregnancy, or another trigger brings the patient to medical attention as a result of disabling POTS with its associated chronic fatigue, mental dysfunction (described by many patients as “brain fog”), and sleep disruption from intermittent tachycardia.
A history of hypotension, a salt fancy, and heat sensitivity (eg, “My friends laugh at my tomato face”) facilitates recognition of adrenal hormone imbalance, but many adolescents’ conditions are written off as anxiety disorder, chronic fatigue syndrome, or functional abdominal pain when tilt-table and gastric motility tests can reveal the true diagnoses.7-9 Causal therapies can then be initiated, rather than symptomatic suppression with psychiatric medicines.10
Much needs to be learned about this complex disease spectrum, including why 95% of patients with severe dysautonomia are female, and why these patients almost always have deficient or insufficient vitamin D levels.
CLINICAL DIAGNOSIS or GENETIC TESTING
Clinical suspicion of CTD allows counseling for joint protection strategies, while genetic testing can diagnose unusual CTD types with significant cardiovascular and pregnancy risks, such as Marfan syndrome or EDS type IV. Cardiologists who are familiar with CTD can evaluate for structural changes such as mitral valve prolapse or aortic dilation and institute nutritional therapy (abundant fluids, salt, vitamin D), exercise therapy (supine position, swimming to minimize joint stress, appropriate weight-lifting to build muscles around joints), biofeedback (training with appropriate exercise can moderate tachycardia and lessen anxiety), and medications (β-blockers or clonidine at bedtime for sleep; fludrocortisone along with fluids and salt to increase intravascular volume).7-9 Many patients will need follow-up by orthopedics specialists for joint injury or bony deformity; physical therapists can teach about appropriate exercises that avoid joint stress and about specific training and warm-up techniques that can forestall arthralgia, joint injuries, and early osteoarthritis. The diverse symptoms listed in the accompanying table emphasize the importance of the pediatrician’s coordination of subspecialty visits using the medical home model.5
While clinical recognition is paramount, pediatricians can benefit families by being aware of the sea change in medicine that will come from the ability to sequence all 23,000 genes in our genome using WES.11,12 Until recently, only single-gene (Mendelian) genetic disorders were amenable to laboratory diagnosis, first by examining proteins or enzymes, then by targeting particular gene (DNA) sequences. If a specific form of CTD such as osteogenesis imperfecta, Marfan syndrome, or EDS type IV is suspected, then particular genes (collagen type I, fibrillin type I, or collagen type III, respectively) can be targeted at costs of $300 to $1,200. Panels of genes relating to specific clinical entities (eg, epilepsy, CTD, spinal muscular atrophy) also can be ordered at higher costs (approximately $3,600 for panels of 12 genes such as the key fibrillin or collagen genes causing CTD).
The problem with targeted gene testing for complex and overlapping disease spectra such as the CTD spectrum is that the same gene mutation, such as those altering the collagen I chains, can cause multiple fractures typical of osteogenesis imperfecta in one family, and symptoms more typical of EDS in another family.
WES, deriving from advances in massive parallel sequencing or NextGen sequencing, avoids the need to target specific genes by sequencing approximately 30 million exonic nucleotides repetitively (fivefold to tenfold coverage for accuracy) in 5 to 6 months. This test has a list price of approximately $10,000 and examines the trio of a patient and both parents to sort out which of thousands of DNA variations are benign familial variants and which are pathogenic. WES can cover all of the 40 to 50 genes implicated in CTD and will expand genetics into a more realistic model of multigenic and environmental interaction (multifactorial determination), highlighting causal genetic factors in disorders as diverse as autism, diabetes, and preeclampsia.
WES is becoming increasingly covered by insurance, with low out-of-pocket costs, but the principle of equal access to care (with acceptance of Medicare and Medicaid) is not yet followed in the era of commercial genetic testing.
Case Report Results
In the case of the 17-year-old girl who received a diagnosis of EDS, her insurance coverage allowed WES testing, which showed the unexpected finding of a COL3A1 p.R271Q mutation (changing arginine to glutamine at position 271 of the collagen, type III, α1 protein chain) in her but not in her parents. Such mutations usually are found in EDS type IV, yet this teenager did not have the characteristic tight lower face, translucent skin, or symptoms of aneurysms or bowel perforation.
The benefits of her receiving this definitive diagnosis include confirmation of a medical condition rather than a psychiatric one. The negative aspects include the need for her to seek care immediately for severe bowel, chest, or head pain; avoidance or acknowledgement of high-risk pregnancy; and a 50% chance of transmitting the mutation to each future child (with potential preimplantation genetic or prenatal diagnosis).13
Golder N. Wilson MD, PhD, is a clinical professor of pediatrics at Texas Tech University Health Sciences Center in Lubbock. He also is on staff at KinderGenome Pediatric Genetics in Dallas.
1. Wicks D. Beighton score. Hypermobility Syndromes Association Web site. http://hypermobility.org/help-advice/hypermobility-syndromes/beighton-score/. Published October 2, 2012. Accessed June 26, 2014.
2. Simpson MR. Benign joint hypermobility syndrome: evaluation, diagnosis, and management. J Am Osteopath Assoc. 2006;106(9):531-536.
3. Remvig L, Jensen DV, Ward RC. Epidemiology of general joint hypermobility and basis for the proposed criteria for benign joint hypermobility syndrome: review of the literature. J Rheumatol. 2007;34(4):804-809.
4. Mandelbaum BR, Silvers HJ, Watanabe DS, et al. Effectiveness of a neuromuscular and proprioceptive training program in preventing anterior cruciate ligament injuries in female athletes: 2-year follow-up. Am J Sports Med. 2005;33(7):1003-1010.
5. Wilson GN, Cooley WC. Connective tissue disorders. In: Preventive Health Care for Children with Genetic Conditions: Providing a Primary Care Medical Home. 2nd ed. New York, NY: Cambridge University Press; 2006:413-436.
6. Wilson GN. Tall stature, pectus excavatum, and lax joints in a young boy: are these signs of a genetic disorder? Consultant for Pediatricians Web site. http://www.pediatricsconsultant360.com/content/tall-stature-pectus-excavatum-and-lax-joints-young-boy-are-these-signs-genetic-disorder. Published June 2011. Accessed June 26, 2014.
7. Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med. 2003;115(1):33-40.
8. Bathen T, Hångmann AB, Hoff M, Andersen LØ, Rand-Hendriksen S. Multidisciplinary treatment of disability in Ehlers–Danlos syndrome hypermobility type/hypermobility syndrome: a pilot study using a combination of physical and cognitive-behavioral therapy on 12 women. Am J Med Genet A. 2013; 161A(12):3005-3011.
9. Murray B, Yashar BM, Uhlmann WR, Clauw DJ, Petty EM. Ehlers–Danlos syndrome, hypermobility type: a characterization of the patients’ lived experience. Am J Med Genet A. 2013;161A(12):2981-2988.
10. Pizzo PA. Lessons in pain relief—a personal postgraduate experience. N Engl J Med. 2013;369(12):1092-1093.
11. Mefford HC. Diagnostic exome sequencing—are we there yet? [editorial]. N Engl J Med. 2012;367(20):1951-1953.
12. Wilson GN. Exome analysis of connective tissue dysplasia: death and rebirth of clinical genetics? Am J Med Genet A. 2014;164A(5):1209-1212.
13. Wilson GN. Presymptomatic and preimplantation genetic diagnosis: neurology, NextGenetics, and the next generation [comment]. JAMA Neurol. 2014;71(4):403-404.