This issue of eMedRef provides information to clinicians on the pathophysiology, diagnosis, and therapeutics of microcephaly

Michels, Thomas C.

Morris, Monica

Myers, Tammy

University of Missouri: MOspace

Microcephaly Page 1 of 7    10.9.09 Microcephaly Background 1. Definition varies  o Head circumference [occipito-frontal circumference (OFC)]   <2 standard deviations (SD) below mean for age (<3rd percentile)   <3 SD (<1st percentile) = severe microcephaly1  o Actual growth charts   http://www.cdc.gov/growthcharts/charts.htm#set1  o Some definitions adjust for prematurity and parental head size 2. General information  o May require serial measurements (crossing several percentile lines); in utero antenatal diagnosis requires multiple measures less than 3 or 4 SD  3. CDC growth charts based on US population are slightly different than WHO charts  o http://www.who.int/childgrowth/standards/hc_for_age/en/index.html   Pathophysiology 1. Pathology of disease  o Lack of brain development from variety of causes or insult to a previously normal brain 2. Incidence, prevalence  o By definition 1-3% of population; individual etiologies much less common 3. Risk factors / etiology  o Genetic   Isolated vs. syndromic microcephaly   Several genes and multiple syndromes with associated anomalies  Microcephalia vera (MV) and microcephaly with simplified gyral pattern (MSG) are genetic forms of isolated congenital microcephaly with no extracerebral malformation  Well-known associated genetic syndromes   Down syndrome, Trisomy 18, Trisomy 13, Cri-du-chat  o Neuroanatomic abnormalities   Neural tube defects, holoprosencephaly, others  See http://www.merck.com/mmpe/sec19/ch292/ch292b.html#sec19-ch292-ch292b-2567 o Metabolic   Aminoacidurias, urea cycle disorders, organic acidurias, storage dz o Infection   TORCH   Toxoplasmosis  Hepatitis B  Syphilis  Herpes zoster  Rubella  Cytomegalovirus (CMV)  Herpes simplex virus  Microcephaly Page 2 of 7    10.9.09 o Drug / toxin exposure in utero   Fetal alcohol syndrome, maternal opioid use o Acquired brain injury   Hypoxic-ischemic insult, intraventricular hemorrhage o Systemic disease   Renal failure, biliary atresia, etc o Severe malnutrition o Hyperthermia   Associated with significant fever in 1st trimester with seizures and facial anomalies o Abnormal fusion of cranial sutures   Craniosynostosis 4. Morbidity / mortality  o Most cases associated with some degree of mental retardation o Severity correlates with degree of microcephaly  o Craniosynostosis morbidity depends on severity and if treated early (referred by 8-12 months)  o Most conditions   Prognosis depends on cause, severity, and associated abnormalities  Diagnosis 1. History  o Prenatal history   Maternal medical illness, medications, tobacco, substance abuse  Findings on prenatal lab tests and ultrasounds o Birth history   Infections, medications, complications o Family history   Similar conditions, consanguinity, syndromes  Parental head size o Developmental and neurologic history   Milestones, seizures 2. Physical examination  o Technique of measurement   http://www.simulconsult.com/resources/ftemp20.html o Compare height, weight, OFC percentiles o Genetic influences   Weaver curve compares child's OFC to that expected based on parental OFC2  o OFC trajectory; height and weight trajectories o General appearance   Dysmorphic features o Head   Sutures and fontanelles  Head symmetry o Eyes   Chorioretinitis, cataracts  Microcephaly Page 3 of 7    10.9.09 o Mouth   Midline defects with holoprosencephaly and related conditions o Skin   Petechiae, jaundice, eczema (infection, metabolic or systemic dz) o Abdomen   Hepatosplenomegaly with infection, metabolic dz o Neurologic   Reflexes, symmetry, muscle tone 3. Diagnostic testing  o Physical findings can be used to identify syndromes, for example entering findings into OMIM database   http://www.ncbi.nlm.nih.gov/omim/  o Especially if dysmorphic features, short stature   Consider karyotype, genetic analysis o Maternal serum phenylalanine level o Fasting plasma and urine amino acids o Serum ammonia o Thyroid stimulating hormone o Infection   TORCH titers  Urine CMV culture  Maternal and infant HIV o Diagnostic imaging   MRI esp if abnormal development or neuro exam  CT or cephalometric radiography if craniosynostosis suspected 4. Diagnostic criteria  o OFC   <2 SD from mean for age  <3 SD severe; or   Decreasing head growth, crossing 2 or 3 major percentile lines on growth curve 5. Recommendations  o Neuroimaging is recommended in a child with global developmental delay   As presence of physical findings (e.g., microcephaly, focal motor findings) increases, the yield of making a specific diagnosis increases, and scan has higher yield3  o Every child (birth through 24 months of age) found to have microcephaly should be followed and periodically screened for late-onset congenital or acquired hearing loss4   Differential Diagnosis 1. Key DDx  o Craniosynostosis  2. Extensive DDx  o Primary   Genetic   Isolated Microcephaly: present at birth, no other anomalies  Microcephaly Page 4 of 7    10.9.09 o Receding forehead, normal-sized face, and relatively large-appearing ears  Autosomal dominant: normal stature, normal intelligence or mild MR   X-Linked: severe MR   Syndromic   Trisomy 13  Trisomy 18 syndrome   Cornelia de Lange's syndrome   Rubinstein-Taybi syndrome   Prader-Willi syndrome  Neuroanatomic   Neural tube defects   Holoprosencephaly  o Incomplete development and septation of midline CNS structures  Varying degrees of brain separation, hypotelorism, facial clefts, and nasal malformations  Atelencephaly  o Absence of cerebrum and associated structures  Lissencephaly  o Surface of the brain appears completely or partially smooth with loss or reduction of sulci  Schizencephaly  o Asymmetric infolding of cortical gray matter   Polymicrogyria  o Excessive gyri on surface of brain   Macrogyria  o Reduction in number of sulci of cerebrum and is often seen in lissencephaly   Fetal brain disruption sequence  o Severe microcephaly of prenatal onset (average OFC 5.8 SD below the mean), overlapping cranial sutures, prominence of the occipital bone, and scalp rugae o Secondary   Metabolic disorders   PKU  o Part of Newborn screen in all 50 states, District of Columbia, Puerto Rico, US Virgin Islands and Guam  Methylmalonic aciduria  o Typically have severe metabolic acidosis with an increased anion gap, ketosis, and hyperammonemia  Citrullinemia  o Quantitative plasma amino acid analysis  Environmental factors   TORCH infections: Toxoplasmosis, Other (syphilis), Rubella, CMV, HSV  In utero toxin exposure (ie ETOH, illicits, solvents) Microcephaly Page 5 of 7    10.9.09  Hypoxic-ischemic insults  Intraventricular hemorrhage or stroke  Malnutrition  Therapeutics 1. Acute treatment  o Not an urgent condition unless associated metabolic or systemic illness present 2. Further management  o If severe and congenital, evaluation and consultation indicated o If OFC is low-normal, can be followed serially o Management depends on etiology   Craniosynostosis   Referral to craniofacial team by age 8-12 months  Dietary modification for certain metabolic syndromes  Treatment if specific infection identified  Treat underlying medical illness, as appropriate (thyroid, renal, hepatic)  Neurosurgical referral for neural tube defects, neuroanatomic anomalies  Genetics, developmental pediatrics referral if genetic syndrome identified 3. Long-term care  o Family and patient typically need long term psychological support o Medical social work involvement for support and resources5   Follow-Up 1. Return to office  o Newborn   Depends on etiology and severity o Declining OFC in older child: repeat exam in 1-2 months if developmentally normal o Recommendations for earlier follow-up   Vomiting, delayed milestones, focal neurologic symptoms 2. Refer to specialist  o Newborn   Genetics, developmental pediatrics, neurosurgery as indicated o Older child   Depends on suspected cause, consider developmental pediatrics o Craniosynostosis   Craniofacial team (neurosurgery, plastic surgery, otolaryngology, speech therapy, audiology, radiology, orthodontics, etc.) 3. Admit to hospital  o Concern regarding increased intracranial pressure (vomiting, altered awareness)    Microcephaly Page 6 of 7    10.9.09 Prognosis 1. Poor postnatal head growth in preterm infants becomes more evident by 2 years and is strongly associated with poor neurodevelopmental outcome and cerebral palsy6  2. Otherwise prognosis depends on underlying cause  Prevention  1. Women who use heroin should be maintained on an opioid agonist other than heroin during pregnancy; use of long-acting morphine is superior to methadone in abstention rates during pregnancy7  2. Identify women who use alcohol in pregnancy and counsel regarding cessation8  3. Ensure needed immunizations in women prenatally  Patient Education 1. National Institute of Neurological Disorders and Stroke  o http://www.ninds.nih.gov/disorders/microcephaly/microcephaly.htm 2. National Library of Medicine: Medline Plus  o http://www.nlm.nih.gov/medlineplus/ency/article/003272.htm 3. Foundation for Children with Microcephaly  o http://www.childrenwithmicro.org/  References 1. Kinsman SL, Johnston MV. Chapter 592: Congenital anomalies of the central nervous system. In: Kliegman RM, Behrman, RE, Jenson, HB, Stanton, BF. Kliegman: Nelson Textbook of Pediatrics, 18th ed. Philadelphia: Saunders-Elsevier 2007.  2. Weaver, DD, Christian, JC. Familial variation in head size and adjustment for parental head circumference. J Pediatr 1980; 96:990.  3. Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, Majnemer A, Noetzel M, Sheth RD. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2003 Feb 11;60(3):367-80.  4. Cunningham M, Cox EO. Hearing assessment in infants and children: recommendations beyond neonatal screening. Pediatrics 2003 Feb;111(2):436-40.  5. Wise, PH. Chapter 38: Developmental disabilities and chronic disease. In: Kliegman RM, Behrman, RE, Jenson, HB, Stanton, BF. Kliegman: Nelson Textbook of Pediatrics, 18th ed. Philadelphia: Saunders-Elsevier 2007.  6. Cheong JL, Hunt RW, Anderson PJ, Howard K, Thompson DK, Wang HX, Bear MJ, Inder TE, Doyle LW. Head growth in preterm infants: correlation with magnetic resonance imaging and neurodevelopmental outcome. Pediatrics. 2008 Jun;121(6):e1534-40  7. Minozzi S, Amato L, Vecchi S, Davoli M. Maintenance agonist treatments for opiate dependent pregnant women. Cochrane Database of Systematic Reviews 2008, Issue 2.  8. May P. A multiple-level, comprehensive approach to the prevention of fetal alcohol syndrome (FAS) and other alcohol related birth defects (ARBD). Int J Addictions, 1995; 30(12): 1549-1602. Microcephaly Page 7 of 7    10.9.09  Authors:  Thomas Michels, MD, Monica Morris, MD, & Tammy Myers, MD, University of Colorado FMR, Denver, CO  Editor:  Vince WinklerPrins, MD, Georgetown University-Providence Hospital, Washington DC 

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