Genetic Disease/Headache

Educational Objectives

The goal of this program is to improve diagnosis and management of genetic diseases and headaches in children and adolescents. After hearing and assimilating this program, the clinician will be better able to:

1.   Recognize the diagnostic features of Williams syndrome, Marfan syndrome, neurofibromatosis type 1, Beck­with-Wiedemann syndrome, DiGeorge/22q11 spectrum disorder, Klinefelter syndrome, and Turner syndrome.

2.   Explain the general principle of metabolic disease and list symptoms that suggest the presence of a metabolic disorder.

3.   Discuss the role of newborn screening in the early detection of genetic conditions.

4.   List the steps for evaluation of pediatric headache, including the recommended medical history, elements of a quick neurologic examination, and indications for brain imaging.  

5.   Describe the recommended approaches for management of pediatric migraine, tension, secondary gain, and caffeine withdrawal headaches.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning com­mittee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose. In their lec­tures, Drs. Sacharow and Willis discussed off-label or investigational use of therapies, products, or devices.

Acknowledgements

Dr. Sacharow spoke at Masters of Pediatrics Leadership Conferences, held January 28 to February 2, 2009, in Miami Beach, FL, and sponsored by the University of Miami, Miller School of Medicine, Department of Pediatrics, and De­partment of Dermatology and Cutaneous Surgery. Dr. Willis lectured at 5th Annual Gulf Coast Update in Pediatrics, held August 14-16, 2009, in Biloxi, MS, and sponsored by Ochsner for Children.  The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

A Genetics Primer for the Primary Care Physician

Stephanie Sacharow, MD, Assistant Professor, Dr. John T. Macdonald Foundation Department of Human Ge­netics, University of Miami, Miller School of Medicine, Miami, FL

Syndromes Associated with Significant Morbidity

Williams syndrome (WS): main features  —  cardiovascular disease  (CVD; most characteristic defect supravalvular aortic stenosis); mental retardation (usually mild); “cocktail conversation” personality (hypersocial, very gregari­ous, empathetic); may have sensitivity to sound and musical ability; distinctive “elfin” facies; endocrine abnormal­ities (particularly hypercalcemia); CVD significant and progressive in many cases); children with WS should not take multivitamins, as excess calcium and vitamin D should be avoided

Marfan syndrome (MS): features  —  ocular (myopia; displacement of lens); skeletal (bony overgrowth resulting in long extremities; inward or outward overgrowth of ribs; scoliosis; joint laxity); CVD (main concerns dilatation of aorta and predisposition for aortic tear and rupture; also mitral and tricuspid prolapse and regurgitation); neonatal presentation of MS  —  many features present at birth, whereas in classic MS, features develop over time; severe and rapidly progressive; causes disease in multiple organ systems; unless treated, patients die in first few years of life due to heart failure from grossly incompetent valves; treatment of classic MS  —  aims to slow progression of heart disease; initial treatment with b-blockers; treated with aortic graft surgery after progression; losartan  —  new treat­ment; angiotensin II receptor blocker; reduces inflammatory effects of transforming growth factor (TGF)-b, which weaken tissues and cause features of MS

Neurofibromatosis type 1 (NF1): diagnostic criteria  —  ³2 features (café au lait macules; neurofibromas; freckling of axillary or inguinal regions; optic glioma; ³2 Lisch nodules; osseous lesions [sphenoid dysplasia or tibial pseudoarthrosis]; positive family history); often inherited from parents; plexiform neurofibromas (PNs)  —  less common, but can cause disfigurement and may compromise function or jeopardize life; primarily internal, as­ymptomatic, and unsuspected on physical examination (PE); PNs of head and neck usually develop at <1 yr of age; PNs in other sites  usually develop before adolescence

Beckwith-Wiedemann syndrome (BWS)/hemihypertrophy: features  —  macrosomia; anterior linear ear lobe crease; macroglossia; omphalocele (form of umbilical hernia); visceromegaly; embryonal tumor; hemihypertrophy; renal abnormalities; minor features include neonatal hypoglycemia (major cause of mortality in these patients); recommended surveillance  —screening for embryonal tumors by abdominal ultrasonography (US) of liver and kid­neys approximately every 3 mo until »8 yr of age; measurement of serum alpha fetoprotein (AFP) concentration in first few years of life for early detection of hepatoblastoma; children with hemihypertrophy but without other fea­tures of BWS may have similar risks for embryonal tumors; majority of BWS caused by abnormalities in methyla­tion (difficult to detect on chromosome testing or fluorescence in situ hybridization [FISH])

DiGeorge/22q11 spectrum disorder: hypocalcemia, aplastic thymus/immune deficiency, and conotruncal cardiac anomaly considered classic triad of features; actually find wide variability of symptoms, including palatal anoma­lies, characteristic facial features, other developmental anomalies (eg, scoliosis), hernias, variable cognition, and mental illness; important to diagnose early; must test parents (as they may carry 22q11 chromosomal deletion and have few or no appreciable manifestations)

Sex chromosome anomalies: important to diagnose early; Klinefelter syndrome  —  features include poor beard growth, gynecomastia, underdeveloped testes; early diagnosis and treatment with testosterone replacement therapy avoids gynecomastia and promotes normal development of secondary sexual characteristics and sexual function; Turner syndrome  —  patients may or may not have characteristic facial features; other features include aortic steno­sis, poor breast development, and underdeveloped ovaries; early growth hormone therapy recommended to increase height; estrogen replacement therapy  allows normal secondary sexual characteristics to develop in puberty; test for Y chromosome to rule out XO/XY mosaicism; remove gonadal tissue if Y present to avoid gonadoblastoma

Metabolic disease: general principle  —  enzyme to convert substrate to product missing; when to suspect  —  catastrophic neonatal presentation; biochemical disturbances; liver disease or dysfunction; neurologic features; myopathy or cardiomyopathy; signs of storage disease; symptoms usually occur in child otherwise healthy at birth; however, prenatal onset of disease and resultant dysmorphology can occur when defect severe and integral to cellu­lar metabolism (eg, Zellweger syndrome, mitochondrial disease)

Storage disease: red flags  —  coarse facial features; corneal clouding or related ocular abnormalities; angiokeratoma; umbilical and inguinal hernias; short stature; developmental delay; joint or skeletal deformities; organomegaly (es­pecially of liver and spleen); muscle weakness or lack of control; neurologic failure and decline; signs of degenera­tive process most significant red flag; treatment options  —  stem cell transplantation (using healthy stem cells from bone marrow or cord blood); enzyme replacement therapy (ERT; newer form of treatment; recombinant form of de­ficient enzyme administered intravenously); substrate inhibition (rate of production of substrate slowed by drug therapy); many new treatments in development

Newborn screening: public health program; aimed at identification of conditions for which early intervention can prevent mortality, morbidity, and disabilities; performed by analysis of diagnostic markers in blood spots collected on filter paper at birth (now collected at »24 hr); extent of program chosen and upgraded by each state indepen­dently; screening now done by tandem mass spectrometry (MS/MS); collective incidence 1 in 2000 to 4000 new­borns; clinical impact £2000 cases per year in United States; many cases of sudden infant death syndrome (SIDS) in past may have been undiagnosed metabolic disorders; speaker recommends metabolic studies for all SIDS and near-SIDS patients; if patient has family history of SIDS, consider metabolic workup of siblings; pearl  —  check that every newborn has screening result in chart by 2 wk of life

What’s New in Genetics

Microarray (array comparative genomic hybridization [CGH]): relatively new procedure; contains »44,000 probes (also version with »252,000 probes); looks for copy number variations (CNVs; contiguous gene deletions or duplications); picks up changes in contiguous genes; does not detect inversions or translocations; in large studies, CNVs identified in 10% to 15% of patients with autism, £28% with syndromic autism, and £12% with unknown cause for mental retardation

Tandem mass spectrometry: quicker and more efficient technology for diagnosing metabolic disease; now used for newborn screening (eg, amino acids, acylcarnitine profile done)

Genomics: refers to study of complex genetic disease, as opposed to Mendelian diseases; phenotypes of complex eti­ology influenced by environmental and genetic factors and modifier genes; genome-wide association study (GWAS)  —  comprehensive scan of genome; unbiased; may use 1,000,000 single nucleotide polymorphisms (SNPs); allows for identification of disease-related genes with only modest increase in risk, and can identify multiple inter­acting disease-related genes; interpreted by comparing prevalence of polymorphisms in patient population with prevalence in control population

Migraine in Children

John Willis, MD, Section Head, Pediatric Neurology, Ochsner Children’s Health Center, New Orleans, LA

Introductory remarks: by »15 yr of age, »80% of people have headaches (HAs); only »4% of HAs migraines; most childhood HAs benign; if seeing child for another condition, speaker does not ask whether he or she has HAs with­out specific reason for investigating

HA history: date of onset (new-onset HAs of greater concern than chronic HAs); location; duration (lengthier HAs more worrisome); severity (based on disruption of daily activities); auras and antecedents; other symptoms (any neurologic change cause for concern); precipitants (eg, fasting, stress, social situations, exposure to sun or over­heating, red wine, foods); relieved by sleep; family’s treatment; caffeine intake; previous work-up or treatment

Quick neurologic examination: gait (running better than walking; look for decorticate posture or ataxia); fundi (look for evidence of papilledema); eye and facial movements; speech and swallowing

Pain-sensitive structures: periosteum (but not bone); basal meninges and vessels (but not brain); all soft tissues above shoulders (including teeth); cranial nerves 5, 7, and 9; occipital nerves (rarely problematic in childhood)

Common conditions associated with HA: fever; upper respiratory infections; dental abscess; meningitis and en­cephalitis; ocular inflammation or pressure (but not visual acuity changes); caffeine withdrawal; evaluate by exam­ining “everything from shoulders up” and doing quick neurologic examination

Localization of HA: above tentorium anterior; below tentorium posterior; migraine in children usually bifrontal; ten­sion HAs usually in cervical or bitemporal muscles

Arnold Chiari type I malformation: recent problem in pediatric practice (easily seen on magnetic resonance imag­ing [MRI]); cerebellar tonsils protrude down into foramen magnum; if protrusion <7 mm, rarely symptomatic; if >12 mm, usually symptomatic; symptoms  —  spasticity, ataxia, or lower cranial nerve findings; if compression or obliteration of cerebrospinal fluid spaces around brainstem (syrinx) seen on MRI, neurosurgery required

Indications for brain imaging: any focal neurologic finding on history or physical examination (PE); new HAs (ex­perienced <4 mo); progressive course (patient says HA different or worst ever); computed tomography (CT) usu­ally adequate, but MRI superior for evaluating posterior fossa or anterior temporal regions; imaging not required for chronic migraine or tension HA if PE unremarkable

Features of migraine: occur in patients of all ages, including infants, who may present with cyclic vomiting; severe HA stops activities and causes tears; objective distress; diagnosis requires ³1 associated symptom of nausea, vom­iting, photophobia, or phonophobia (auras rare in children); periodic (do not occur all day, every day; patient well between HAs); relieved by sleep; family history positive »75% of the time; PE normal between attacks; common for first attack to occur after minor head trauma

Migraine pathogenesis: great vessels at base of brain, trigeminal system, deep brain nuclei, and serotonin and other neurotransmitters all suspected to be involved; probably involves multifactorial genetics

Pediatric migraine: usually bifrontal; aggravated by caffeine withdrawal; development of severe HA and vomiting, followed by resolution in »30 min to 1 hr common pattern in children; for management of cyclic vomiting, speaker recommends low-dose phenobarbital maintenance

Migraine neurology: focal deficits (eg, aphasia, visual field defects, motor and sensory defects) may occur at begin­ning of HA, but usually resolve; often associated with infrequent migraine attacks; usually benign; can see transient slowing on electroencephalograpy (EEG) slowing; if persistent, imaging indicated to rule out masses as well as vas­cular problems; imaging also indicated if possible history of seizure (suggesting postictal HA)

Migraine home remedies: avoid triggers; consumption of caffeine therapeutic at time of HA, but caffeine with­drawal state can aggravate migraines; wear hat in sun and avoid overheating

Acute migraine therapy: ibuprofen and caffeine; sleep and sedation; combination medications (butalbital/acetamin­ophen/caffeine [Fioricet]; isometheptene mucate/dichloralphenazone/acetaminophen [Midrin]); dihydroergotamine (nasal or IV); nasal lidocaine; triptans  —  very effective (speaker’s first choice if mild medication like ibuprofen not effective); no serious side effects in children, but contraindicated in adults with coronary artery disease; higher doses more effective; should be taken at onset of HA

Migraine prophylaxis: first, eliminate caffeine; recommendations in order of preference, with possible side effects  —amitriptyline 10 to 25 mg nightly (associated with potentially fatal overdose [OD]); verapamil SR 120 mg daily (no significant side effects); phenobarbital 1 to 2 mg/kg nightly  (can cause mood and behavior changes); propranolol 10 to 80 mg/day (can exacerbate asthma and cause depression); topiramate (Topamax; associated with cognition and mood changes); valproic acid (Depakote; associated with many serious side effects; avoid unless absolutely necessary); cyproheptadine (Periactin; modest efficacy; can cause weight gain and problems with mentation)

Tension HAs: seen mostly in teenage girls, most of whom have normal neurologic examination; typical pattern  —  HAs all day, every day, for long period; little objective distress; increase when patient upset or angry; often local­ized to cervical muscles and temples; common stressors  —  for teenage girls, relationship with father; for teenage boys, issues with gender identification or homosexuality; other factors that cause distress (eg, school, family, loss); serious depression common; treatment  —  address problem (inquire about emotional or life problems, especially if parent insists “everything is perfect”); child may need psychiatrist or counselor; avoid opiates; speaker has had suc­cess using low-dose amitriptyline; look for signs of depression

Secondary gain HA: usually seen in school-age children; often follows febrile illness  or HA that generated parental attention and affection; child gets well and no longer receiving extra attention; child complains of headache to re­gain attention; HA frequent; tears common; usually occurs when home with parent involved; treatment  —  eliminate secondary gain; tact important (many parents take offense at suggestion that their behavior perpetuating child’s condition); if HAs persist, pursue with further work-up

Caffeine HA: common in speaker’s practice; children given many caffeinated beverages (eg, Mountain Dew, tea, cof­fee, “brown” sodas); HAs often occur at same time each day; can be fairly intense (may mimic migraine)

Suggested Reading

Aitken LA et al: Chiari type I malformation in a pediatric  population. Pediatr Neurol 40(6):449, 2009; Clin Endocrinol (Oxf) 70:265, 2009; Battistutta S et al: Chronic tension-type headache in adolescents. Clinical and psychological characteristics analyzed through self- and parent-report questionnaires. J Pediatr Psychol 34:697, 2009; Bojesen A, Gravholt CH: Klinefelter syndrome in clinical practice. Nat Clin Pract Urol 4:192, 2007; Clericuzio CL, Martin RA: Diagnostic criteria and tumor screening for individu­als with isolated hemihyperplasia. Genet Med 11:220, 2009; Fan YS et al: Detection of pathogenic gene copy number variations in patients with mental retardation by genome-wide oligonucleotide array comparative genomic hybridization. Hum Mutat 28:1124, 2007; Fernhoff PM: Newborn screening for genetic disorders. Pediatr Clin North Am 56:505, 2009; Hay BN: Deletion 22q11: spec­trum of associated disorders. Semin Pediatr Neurol 14:136, 2007; Hering-Hanit R, Gadoth N: Caffeine-induced headache in chil­dren and adolescents. Cephalalgia 23:332, 2003; Hung RM, MacGregor DL: Management of pediatric migraine: Current concepts and controversies. Indian J Pediatr 75:1139, 2008; Jacquemont ML et al: Array-based comparative genomic hybridisation identi­fies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 43:843, 2006; Lewis DW: Pediatric migraine. Neurol Clin 27:481, 2009; Lewis KS: Chronic daily headaches in children and adoles­cents. Semin Pediatr Neurol 16:31, 2009; Matt P et al: Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan? J Thorac Cardiovasc Surg 135:389, 2008; Waxler JL et al: Williams syndrome: a multidisciplinary approach to care. Pediatr Ann 38:456, 2009; Weksberg R et al: Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 137C:12, 2005; Wilcken B et al: Expanded newborn screening: outcome in screened and unscreened patients at age 6 years. Pediatrics 124:e241, 2009; Williams VC et al: Neurofibromatosis type 1 revisited. Pediatrics 123:124, 2009.