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Microcephaly: A clinical genetics approach

Geoff Woods, ChB, MB, MD, FRCP, FMedSci
Section Editor
Helen V Firth, DM, FRCP, DCH
Deputy Editor
Mary M Torchia, MD


Microcephaly is an important neurologic sign. Deviations from normal head growth may be the first indication of an underlying congenital, genetic, or acquired problem. Many genetic conditions are associated with an abnormal pattern of head growth; the earlier these conditions are detected, the earlier appropriate treatment, services, and genetic counseling can be provided [1].

A clinical genetics approach to microcephaly in infants and children will be presented here. At the heart of this approach is an attempt in each case to formulate an etiological diagnosis that gives at least an indication of the sibling recurrence risk. The etiology and primary care evaluation of microcephaly in infants and children and microcephaly related to Zika virus are discussed separately. (See "Microcephaly in infants and children: Etiology and evaluation" and "Zika virus infection: An overview", section on 'Children'.)


The definition of microcephaly is not standardized. It is sometimes defined as an occipitofrontal circumference (OFC) more than 3 standard deviations (SD) below the mean for a given age, sex, and gestation. Other times, it is defined as an OFC more than 2 SD below the appropriate mean (ie, less than the 3rd percentile).

OFC measurements at birth are necessary to establish a diagnosis of primary microcephaly (see 'Primary microcephaly and its syndromes' below). It can be difficult to measure OFC accurately in children with severe microcephaly without the landmark of the occiput. It is important to record measurements rather than percentiles – as head circumference charts vary, especially up to the age of three years, and to use the most recent culturally and ethnically relevant charts to determine percentiles [2].

If microcephaly is defined as a head size less than 3 SD below the appropriate mean, it is more likely to be associated with genetic and non-genetic disorders affecting brain development. In contrast, if microcephaly is defined as more than 2 SD below the mean, many intellectually normal individuals who have a head circumference at the low end of the population distribution will be included.

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Literature review current through: Nov 2017. | This topic last updated: Apr 20, 2016.
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  1. Nard JA. Abnormal head size and shape. In: Common & Chronic Symptoms in Pediatrics, Gartner JC, Zitelli BJ (Eds), Mosby, St. Louis 1997.
  2. Woods CG, Parker A. Investigating microcephaly. Arch Dis Child 2013; 98:707.
  3. Lorenz JM, Whitaker AH, Feldman JF, et al. Indices of body and brain size at birth and at the age of 2 years: relations to cognitive outcome at the age of 16 years in low birth weight infants. J Dev Behav Pediatr 2009; 30:535.
  4. Räikkönen K, Forsén T, Henriksson M, et al. Growth trajectories and intellectual abilities in young adulthood: The Helsinki Birth Cohort study. Am J Epidemiol 2009; 170:447.
  5. Gale CR, O'Callaghan FJ, Bredow M, et al. The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years. Pediatrics 2006; 118:1486.
  6. Heinonen K, Räikkönen K, Pesonen AK, et al. Prenatal and postnatal growth and cognitive abilities at 56 months of age: a longitudinal study of infants born at term. Pediatrics 2008; 121:e1325.
  7. Woods CG, Bond J, Enard W. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 2005; 76:717.
  8. Yang YJ, Baltus AE, Mathew RS, et al. Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation. Cell 2012; 151:1097.
  9. Mahmood S, Ahmad W, Hassan MJ. Autosomal Recessive Primary Microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum. Orphanet J Rare Dis 2011; 6:39.
  10. Kelley RI, Robinson D, Puffenberger EG, et al. Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am J Med Genet 2002; 112:318.
  11. Rajab A, Manzini MC, Mochida GH, et al. A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A 2007; 143A:2761.
  12. Spiegel R, Shaag A, Edvardson S, et al. SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis. Ann Neurol 2009; 66:419.
  13. Baxter PS, Rigby AS, Rotsaert MH, Wright I. Acquired microcephaly: causes, patterns, motor and IQ effects, and associated growth changes. Pediatrics 2009; 124:590.
  14. Abuelo D. Microcephaly syndromes. Semin Pediatr Neurol 2007; 14:118.
  15. Opitz JM, Holt MC. Microcephaly: general considerations and aids to nosology. J Craniofac Genet Dev Biol 1990; 10:175.
  16. Vargas JE, Allred EN, Leviton A, Holmes LB. Congenital microcephaly: phenotypic features in a consecutive sample of newborn infants. J Pediatr 2001; 139:210.
  17. Almgren M, Källén B, Lavebratt C. Population-based study of antiepileptic drug exposure in utero--influence on head circumference in newborns. Seizure 2009; 18:672.
  18. Hanley WB. Finding the fertile woman with phenylketonuria. Eur J Obstet Gynecol Reprod Biol 2008; 137:131.
  19. Prick BW, Hop WC, Duvekot JJ. Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies. Am J Clin Nutr 2012; 95:374.
  20. Rollins JD, Collins JS, Holden KR. United States head circumference growth reference charts: birth to 21 years. J Pediatr 2010; 156:907.
  21. Weaver DD, Christian JC. Familial variation of head size and adjustment for parental head circumference. J Pediatr 1980; 96:990.
  22. Garshasbi M, Motazacker MM, Kahrizi K, et al. SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly. Hum Genet 2006; 118:708.
  23. Perche O, Menuet A, Marcos M, et al. Combined deletion of two Condensin II system genes (NCAPG2 and MCPH1) in a case of severe microcephaly and mental deficiency. Eur J Med Genet 2013; 56:635.
  24. Pfau RB, Thrush DL, Hamelberg E, et al. MCPH1 deletion in a newborn with severe microcephaly and premature chromosome condensation. Eur J Med Genet 2013; 56:609.
  25. Comeaux MS, Wang J, Wang G, et al. Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes. Mol Genet Metab 2013; 109:260.
  26. Williams SR, Mullegama SV, Rosenfeld JA, et al. Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Eur J Hum Genet 2010; 18:436.
  27. Jacob FD, Ramaswamy V, Andersen J, Bolduc FV. Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature. Eur J Hum Genet 2009; 17:1577.
  28. Bahi-Buisson N, Nectoux J, Girard B, et al. Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant. Neurogenetics 2010; 11:241.
  29. Gilfillan GD, Selmer KK, Roxrud I, et al. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet 2008; 82:1003.
  30. Zweier C, Peippo MM, Hoyer J, et al. Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet 2007; 80:994.
  31. Gitiaux C, Ceballos-Picot I, Marie S, et al. Misleading behavioural phenotype with adenylosuccinate lyase deficiency. Eur J Hum Genet 2009; 17:133.
  32. Willemsen MH, Rensen JH, van Schrojenstein-Lantman de Valk HM, et al. Adult Phenotypes in Angelman- and Rett-Like Syndromes. Mol Syndromol 2012; 2:217.
  33. McDonell LM, Mirzaa GM, Alcantara D, et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nat Genet 2013; 45:556.
  34. Reardon W, Donnai D. Dysmorphology demystified. Arch Dis Child Fetal Neonatal Ed 2007; 92:F225.
  35. Shen J, Eyaid W, Mochida GH, et al. ASPM mutations identified in patients with primary microcephaly and seizures. J Med Genet 2005; 42:725.
  36. Desir J, Cassart M, David P, et al. Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally. Am J Med Genet A 2008; 146A:1439.
  37. Passemard S, Titomanlio L, Elmaleh M, et al. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. Neurology 2009; 73:962.
  38. Nicholas AK, Swanson EA, Cox JJ, et al. The molecular landscape of ASPM mutations in primary microcephaly. J Med Genet 2009; 46:249.
  39. Awad S, Al-Dosari MS, Al-Yacoub N, et al. Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Hum Mol Genet 2013; 22:2200.
  40. Bundey S, Carter CO. Recurrence risks in severe undiagnosed mental deficiency. J Ment Defic Res 1974; 18:115.
  41. Tolmie JL, McNay M, Stephenson JB, et al. Microcephaly: genetic counselling and antenatal diagnosis after the birth of an affected child. Am J Med Genet 1987; 27:583.
  42. Nicholas AK, Khurshid M, Désir J, et al. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 2010; 42:1010.
  43. Poulton C, Oegema R, Heijsman D, et al. Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations. Neurogenetics 2013; 14:43.
  44. O'Driscoll M, Jackson AP, Jeggo PA. Microcephalin: a causal link between impaired damage response signalling and microcephaly. Cell Cycle 2006; 5:2339.
  45. Klingseisen A, Jackson AP. Mechanisms and pathways of growth failure in primordial dwarfism. Genes Dev 2011; 25:2011.
  46. Ogi T, Walker S, Stiff T, et al. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome. PLoS Genet 2012; 8:e1002945.
  47. Kalay E, Yigit G, Aslan Y, et al. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet 2011; 43:23.
  48. Stiff T, Alagoz M, Alcantara D, et al. Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of Meier-Gorlin syndrome. PLoS Genet 2013; 9:e1003360.
  49. Perry LD, Robertson F, Ganesan V. Screening for cerebrovascular disease in microcephalic osteodysplastic primordial dwarfism type II (MOPD II): an evidence-based proposal. Pediatr Neurol 2013; 48:294.
  50. Daber RD, Conlin LK, Leonard LD, et al. Ring chromosome 20. Eur J Med Genet 2012; 55:381.
  51. Guerrini R, Parrini E. Neuronal migration disorders. Neurobiol Dis 2010; 38:154.
  52. Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain 2009; 132:3199.
  53. Namavar Y, Barth PG, Poll-The BT, Baas F. Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia. Orphanet J Rare Dis 2011; 6:50.
  54. Namavar Y, Barth PG, Kasher PR, et al. Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain 2011; 134:143.
  55. Najm J, Horn D, Wimplinger I, et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet 2008; 40:1065.
  56. Hackett A, Tarpey PS, Licata A, et al. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes. Eur J Hum Genet 2010; 18:544.
  57. Moog U, Kutsche K, Kortüm F, et al. Phenotypic spectrum associated with CASK loss-of-function mutations. J Med Genet 2011; 48:741.
  58. Takanashi J, Okamoto N, Yamamoto Y, et al. Clinical and radiological features of Japanese patients with a severe phenotype due to CASK mutations. Am J Med Genet A 2012; 158A:3112.
  59. Tanyalçin I, Verhelst H, Halley DJ, et al. Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: case study and literature review. Eur J Paediatr Neurol 2013; 17:666.
  60. Mir A, Kaufman L, Noor A, et al. Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet 2009; 85:909.
  61. Philippe O, Rio M, Carioux A, et al. Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation. Am J Hum Genet 2009; 85:903.
  62. Mochida GH, Mahajnah M, Hill AD, et al. A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. Am J Hum Genet 2009; 85:897.
  63. Stephenson JB. Aicardi-Goutières syndrome (AGS). Eur J Paediatr Neurol 2008; 12:355.
  64. Briggs TA, Wolf NI, D'Arrigo S, et al. Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct "pseudo-TORCH" phenotype. Am J Med Genet A 2008; 146A:3173.
  65. Hobson EE, Thomas S, Crofton PM, et al. Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy. Eur J Pediatr 2005; 164:655.
  66. Hoffmann C, Ben-Zeev B, Anikster Y, et al. Magnetic resonance imaging and magnetic resonance spectroscopy in isolated sulfite oxidase deficiency. J Child Neurol 2007; 22:1214.
  67. van Straaten HL, van Tintelen JP, Trijbels JM, et al. Neonatal lactic acidosis, complex I/IV deficiency, and fetal cerebral disruption. Neuropediatrics 2005; 36:193.
  68. Samson JF, Barth PG, de Vries JI, et al. Familial mitochondrial encephalopathy with fetal ultrasonographic ventriculomegaly and intracerebral calcifications. Eur J Pediatr 1994; 153:510.
  69. Longman C, Tolmie J, McWilliam R, MacLennan A. Cranial magnetic resonance imaging mistakenly suggests prenatal ischaemia in PEHO-like syndrome. Clin Dysmorphol 2003; 12:133.
  70. Schram A, Kroes HY, Sollie K, et al. Hereditary fetal brain degeneration resembling fetal brain disruption sequence in two sibships. Am J Med Genet A 2004; 127A:172.
  71. Henneke M, Diekmann S, Ohlenbusch A, et al. RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection. Nat Genet 2009; 41:773.
  72. Bönnemann CG, Meinecke P. Bilateral porencephaly, cerebellar hypoplasia, and internal malformations: two siblings representing a probably new autosomal recessive entity. Am J Med Genet 1996; 63:428.
  73. Behunova J, Zavadilikova E, Bozoglu TM, et al. Familial microhydranencephaly, a family that does not map to 16p13.13-p12.2: relationship with hereditary fetal brain degeneration and fetal brain disruption sequence. Clin Dysmorphol 2010; 19:107.
  74. van Karnebeek CD, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012; 105:368.
  75. van Karnebeek CD, Houben RF, Lafek M, et al. The treatable intellectual disability APP www.treatable-id.org: a digital tool to enhance diagnosis & care for rare diseases. Orphanet J Rare Dis 2012; 7:47.
  76. Jurecka A, Jurkiewicz E, Tylki-Szymanska A. Magnetic resonance imaging of the brain in adenylosuccinate lyase deficiency: a report of seven cases and a review of the literature. Eur J Pediatr 2012; 171:131.
  77. Verrotti A, D'Egidio C, Agostinelli S, Gobbi G. Glut1 deficiency: when to suspect and how to diagnose? Eur J Paediatr Neurol 2012; 16:3.
  78. Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev 2009; 31:545.
  79. Tabatabaie L, Klomp LW, Rubio-Gozalbo ME, et al. Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency. J Inherit Metab Dis 2011; 34:181.
  80. Jones GE, Ostergaard P, Moore AT, et al. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet 2014; 22:881.
  81. Schlögel MJ, Mendola A, Fastré E, et al. No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome. Orphanet J Rare Dis 2015; 10:52.
  82. Stegmann AP, Jonker LM, Engelen JJ. Prospective screening of patients with unexplained mental retardation using subtelomeric MLPA strongly increases the detection rate of cryptic unbalanced chromosomal rearrangements. Eur J Med Genet 2008; 51:93.
  83. Lu XY, Phung MT, Shaw CA, et al. Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics 2008; 122:1310.
  84. Sagoo GS, Butterworth AS, Sanderson S, et al. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med 2009; 11:139.
  85. Shoukier M, Klein N, Auber B, et al. Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants? Clin Genet 2013; 83:53.
  86. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med 2010; 61:437.
  87. Dumas L, Sikela JM. DUF1220 domains, cognitive disease, and human brain evolution. Cold Spring Harb Symp Quant Biol 2009; 74:375.
  88. Firth HV, Richards SM, Bevan AP, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet 2009; 84:524.
  89. Mefford HC, Sharp AJ, Baker C, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 2008; 359:1685.
  90. Brunetti-Pierri N, Berg JS, Scaglia F, et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 2008; 40:1466.
  91. van Bon BW, Koolen DA, Brueton L, et al. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur J Hum Genet 2010; 18:163.
  92. Franco LM, de Ravel T, Graham BH, et al. A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion. Eur J Hum Genet 2010; 18:258.
  93. Kleefstra T, van Zelst-Stams WA, Nillesen WM, et al. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 2009; 46:598.
  94. Nagamani SC, Erez A, Eng C, et al. Interstitial deletion of 6q25.2-q25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss. Eur J Hum Genet 2009; 17:573.
  95. Shinawi M, Liu P, Kang SH, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 2010; 47:332.
  96. Wilson HL, Crolla JA, Walker D, et al. Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development. Eur J Hum Genet 2008; 16:1301.
  97. Dixon-Salazar TJ, Silhavy JL, Udpa N, et al. Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med 2012; 4:138ra78.
  98. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013; 369:1502.
  99. Guernsey DL, Jiang H, Hussin J, et al. Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am J Hum Genet 2010; 87:40.
  100. Genin A, Desir J, Lambert N, et al. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum Mol Genet 2012; 21:5306.
  101. Jamieson CR, Govaerts C, Abramowicz MJ. Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. Am J Hum Genet 1999; 65:1465.
  102. Rump P, Jazayeri O, van Dijk-Bos KK, et al. Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly. BMC Med Genomics 2016; 9:7.