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Journal of Pediatric Neurology 2024; 22(02): 140-148
DOI: 10.1055/s-0044-1786776
Review Article

Microcephaly and Its Related Syndromes: Classification, Genetic, Clinical, and Rehabilitative Considerations

Alessandra Di Nora   *
1   Pediatrics Postgraduate Residency Program, University of Catania, Catania, Italy
,
Daria La Cognata   *
1   Pediatrics Postgraduate Residency Program, University of Catania, Catania, Italy
,
Antonio Zanghì   *
2   Research Center for Surgery of Complex Malformation Syndromes of Transition and Adulthood, Department of Medical and Surgical Sciences and Advanced Technologies, University of Catania, Catania, Italy
,
Michele Vecchio
3   Rehabilitation Unit, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
,
Rita Chiaramonte
3   Rehabilitation Unit, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
,
Francesco Marino
4   Department of Medical Surgical Sciences and Advanced Technologies, University Hospital Policlinico “G. Rodolico-San Marco,” Catania, Italy
,
Stefano Palmucci
5   IPTRA Unit, Department of Medical Surgical Sciences and Advanced Technologies, University Hospital Policlinico “G. Rodolico-San Marco,” Catania, Italy
,
Giuseppe Belfiore
6   Department of Medical Surgical Sciences and Advanced Technologies, Unit of Radiology I University Hospital Policlinico “G. Rodolico-San Marco,” Catania, Italy
,
Agata Polizzi
7   Chair of Pediatrics, Department of Educational Sciences, University of Catania, Catania, Italy
,
Andrea D. Praticò
8   Chair of Pediatrics, Department of Medicine and Surgery, Kore University, Enna, Italy
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Abstract

Microcephaly, a form of cortical cortex malformation, results from abnormal cellular production and proliferation, identified when the occipital frontal head circumference (OFC) falls two or more standard deviations (SDs) below the expected average for age, gender, and population. Severity is classified based on SD: mild (OFC < 2 SD) or severe (OFC < 3 SD). While microcephaly can lead to developmental delay, intellectual disability, epilepsy, and cerebral palsy, not all cases exhibit these issues. Classified as primary/congenital or secondary/postnatal, microcephaly can stem from genetic or acquired factors in both types. Congenital microcephaly origins vary, while secondary microcephaly is characterized by normal OFC at birth, followed by a decrease within the first year, often associated with progressive cognitive and motor impairments. Primary hereditary microcephaly (MCPH), or microcephaly vera, is genetically diverse, with 28 related genes (MCPH1 to MCPH28) encoding proteins linked to centrosomes and progenitor cell mitosis in the brain ventricle's neuroepithelium. Defects in deoxyribonucleic acid (DNA) repair pathways (e.g., NBN, FANCA, ATR, ATM genes) can lead to microcephaly by impairing DNA repair. Enzyme deficiencies in metabolic pathways may also contribute, causing toxic metabolite accumulation or essential metabolite loss (microcephaly of metabolic origin). Acquired congenital microcephaly may result from ischemic or infectious processes, drugs, radiation, maternal diseases during pregnancy, with damage influenced by fetal genetics, environmental interactions, developmental stage, and exposure intensity/duration. Diagnostic workup includes electroencephalogram, ophthalmological, auditory, magnetic resonance imaging, metabolic, echocardiogram, and infection screening tests, alongside genetic evaluations like cytogenetic studies, fluorescence in situ hybridization, comparative genomic microarray-hybridization, single-nucleotide microarray-polymorphism, and exome sequencing. Symptomatic treatment is available, and genetic counseling is crucial for affected families.

Keywords

microcephaly - brain malformations - genetics - causes - childhood

* These authors contributed equally to this article.




Publikationsverlauf

Eingereicht: 11. Dezember 2023

Angenommen: 03. April 2024

Artikel online veröffentlicht:
11. Mai 2024

© 2024. Thieme. All rights reserved.

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Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Cox J, Jackson AP, Bond J, Woods CG. What primary microcephaly can tell us about brain growth. Trends Mol Med 2006; 12 (08) 358-366
    CrossrefPubMedSuche in Google Scholar
  • 2 Barbagallo M, Ruggieri M, Incorpora G. et al. Infantile spasms in the setting of Sturge-Weber syndrome. Childs Nerv Syst 2009; 25 (01) 111-118
    CrossrefPubMedSuche in Google Scholar
  • 3 Pavone P, Rizzo R, Conti I. et al. Primary headaches in children: clinical findings on the association with other conditions. Int J Immunopathol Pharmacol 2012; 25 (04) 1083-1091
    CrossrefPubMedSuche in Google Scholar
  • 4 Pavone P, Pappalardo XG, Praticò AD. et al. Primary microcephaly with novel variant of MCPH1 gene in twins: both manifesting in childhood at the same time with Hashimoto's thyroiditis. J Pediatr Genet 2020; 9 (03) 177-182
    Thieme ConnectPubMedSuche in Google Scholar
  • 5 Pavone P, Praticò AD, Falsaperla R. et al. Congenital generalized hypertrichosis: the skin as a clue to complex malformation syndromes. Ital J Pediatr 2015; 41: 55
    CrossrefPubMedSuche in Google Scholar
  • 6 Praticò AD, Pavone P, Scuderi MG. et al. Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report. Cases J 2009; 2: 7394
    PubMedSuche in Google Scholar
  • 7 Pavone P, Praticò AD, Ruggieri M, Rizzo R, Falsaperla R. Resuming the obsolete term “small head”: when microcephaly occurs without cognitive impairment. Neurol Sci 2017; 38 (09) 1723-1725
    CrossrefPubMedSuche in Google Scholar
  • 8 Pavone V, Signorelli SS, Praticò AD. et al. Total hemi-overgrowth in pigmentary mosaicism of the (hypomelanosis of) ito type: eight case reports. Medicine (Baltimore) 2016; 95 (10) e2705
    CrossrefPubMedSuche in Google Scholar
  • 9 Pavone P, Falsaperla R, Ruggieri M. et al. Clinical course of N-methyl-D-aspartate receptor encephalitis and the effectiveness of cyclophosphamide treatment. J Pediatr Neurol 2017; 15: 84-49
    Thieme ConnectPubMedSuche in Google Scholar
  • 10 Faheem M, Naseer MI, Rasool M. et al. Molecular genetics of human primary microcephaly: an overview. BMC Med Genomics 2015; 8 (suppl 1): S4
    CrossrefPubMedSuche in Google Scholar
  • 11 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
    CrossrefPubMedSuche in Google Scholar
  • 12 Pavone P, Praticò AD, Gentile G. et al. A neurocutaneous phenotype with paired hypo- and hyperpigmented macules, microcephaly and stunted growth as prominent features. Eur J Med Genet 2016; 59 (05) 283-289
    CrossrefPubMedSuche in Google Scholar
  • 13 Naveed M, Kazmi SK, Amin M. et al. Comprehensive review on the molecular genetics of autosomal recessive primary microcephaly (MCPH). Genet Res 2018; 100: e7
    CrossrefPubMedSuche in Google Scholar
  • 14 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
    CrossrefPubMedSuche in Google Scholar
  • 15 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
    CrossrefPubMedSuche in Google Scholar
  • 16 Baxter PS, Rigby AS, Rotsaert MH, Wright I. Acquired microcephaly: causes, patterns, motor and IQ effects, and associated growth changes. Pediatrics 2009; 124 (02) 590-595
    CrossrefPubMedSuche in Google Scholar
  • 17 Vitaliti G, Praticò AD, Cimino C. et al. Hepatitis B vaccine in celiac disease: yesterday, today and tomorrow. World J Gastroenterol 2013; 19 (06) 838-845
    CrossrefPubMedSuche in Google Scholar
  • 18 Leonardi S, Praticò AD, Lionetti E, Spina M, Vitaliti G, La Rosa M. Intramuscular vs intradermal route for hepatitis B booster vaccine in celiac children. World J Gastroenterol 2012; 18 (40) 5729-5733
    CrossrefPubMedSuche in Google Scholar
  • 19 Sniderman A. Abnormal head growth. Pediatr Rev 2010; 31 (09) 382-384
    CrossrefPubMedSuche in Google Scholar
  • 20 Vitaliti G, Cimino C, Coco A, Praticò AD, Lionetti E. The immunopathogenesis of cow's milk protein allergy (CMPA). Ital J Pediatr 2012; 38: 35 Erratum in: Ital J Pediatr. 2014;39:82
    CrossrefPubMedSuche in Google Scholar
  • 21 Palano GM, Praticò AD, Praticò ER. et al. Intossicazione accidentale da alcol etilico in un lattante di 30 giorni. Quadro clinico e follow-up neurologico. Minerva Pediatr 2007; 59 (03) 275-279
    PubMedSuche in Google Scholar
  • 22 Gilmore EC, Walsh CA. Genetic causes of microcephaly and lessons for neuronal development. Wiley Interdiscip Rev Dev Biol 2013; 2 (04) 461-478
    CrossrefPubMedSuche in Google Scholar
  • 23 Fiumara A, Lanzafame G, Arena A. et al. COVID-19 pandemic outbreak and its psychological impact on patients with rare lysosomal diseases. J Clin Med 2020; 9 (09) 2716
    CrossrefPubMedSuche in Google Scholar
  • 24 Praticò AD, Leonardi S. Immunotherapy for food allergies: a myth or a reality?. Immunotherapy 2015; 7 (02) 147-161
    CrossrefPubMedSuche in Google Scholar
  • 25 Heald-Sargent T, Muller W. Zika virus: a review for pediatricians. Pediatr Ann 2017; 46 (11) e428-e432
    CrossrefPubMedSuche in Google Scholar
  • 26 Pratico AD, Salafia S, Barone P, La Rosa M, Leonardi S. Type II autoimmune hepatitis and small duct sclerosing cholangitis in a seven years old child: an overlap syndrome?. Hepat Mon 2013; 13 (12) e14452
    CrossrefPubMedSuche in Google Scholar
  • 27 Praticò AD, Ruggieri M. COVID-19 vaccination for children: may be necessary for the full eradication of the disease. Pediatr Res 2021; 90 (06) 1102-1103
    CrossrefPubMedSuche in Google Scholar
  • 28 Jean F, Stuart A, Tarailo-Graovac M. Dissecting the genetic and etiological causes of primary microcephaly. Front Neurol 2020; 11: 570830
    CrossrefPubMedSuche in Google Scholar
  • 29 Praticò AD, Polizzi A, Salafia R. et al. Megalencephaly capillary malformation syndrome. J Pediatr Neurol 2018; 16: 328-337
    Thieme ConnectPubMedSuche in Google Scholar
  • 30 Praticò AD, Mistrello G, La Rosa M. et al. Immunotherapy: a new horizon for egg allergy?. Expert Rev Clin Immunol 2014; 10 (05) 677-686
    CrossrefPubMedSuche in Google Scholar
  • 31 Becerra-Solano LE, Mateos-Sánchez L, López-Muñoz E. Microcephaly, an etiopathogenic vision. Pediatr Neonatol 2021; 62 (04) 354-360
    CrossrefPubMedSuche in Google Scholar
  • 32 Praticò AD. COVID-19 pandemic for pediatric health care: disadvantages and opportunities. Pediatr Res 2021; 89 (04) 709-710
    CrossrefPubMedSuche in Google Scholar
  • 33 Fiévet A, Bellanger D, Zahed L. et al. DNA repair functional analyses of NBN hypomorphic variants associated with NBN-related infertility. Hum Mutat 2020; 41 (03) 608-618
    CrossrefPubMedSuche in Google Scholar
  • 34 Praticò AD, Giallongo A, Arrabito M. et al. SCN2A and its related epileptic phenotypes. J Pediatr Neurol 2021; •••
    Thieme ConnectPubMedSuche in Google Scholar
  • 35 Devakumar D, Bamford A, Ferreira MU. et al. Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management. Lancet Infect Dis 2018; 18 (01) e1-e13
    CrossrefPubMedSuche in Google Scholar
  • 36 Praticò AD, Falsaperla R, Comella M, Belfiore G, Polizzi A, Ruggieri M. Case report: a gain-of-function of hamartin may lead to a distinct “inverse TSC1-hamartin” phenotype characterized by reduced cell growth. Front Pediatr 2023; 11: 1101026
    CrossrefPubMedSuche in Google Scholar
  • 37 Ahmed M, Sood A, Gupta J. Toxoplasmosis in pregnancy. Eur J Obstet Gynecol Reprod Biol 2020; 255: 44-50
    CrossrefPubMedSuche in Google Scholar
  • 38 Polizzi A, Pavone P, Ciancio E, La Rosa C, Sorge G, Ruggieri M. Hypertrichosis cubiti (hairy elbow syndrome): a clue to a malformation syndrome. J Pediatr Endocrinol Metab 2005; 18 (10) 1019-1025
    CrossrefPubMedSuche in Google Scholar
  • 39 Picone O, Vauloup-Fellous C, Cordier AG. et al. A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenat Diagn 2013; 33 (08) 751-758
    CrossrefPubMedSuche in Google Scholar
  • 40 Pavone P, Polizzi A, Marino SD. et al. West syndrome: a comprehensive review. Neurol Sci 2020; 41 (12) 3547-3562
    CrossrefPubMedSuche in Google Scholar
  • 41 Marquez L, Levy ML, Munoz FM, Palazzi DL. A report of three cases and review of intrauterine herpes simplex virus infection. Pediatr Infect Dis J 2011; 30 (02) 153-157
    CrossrefPubMedSuche in Google Scholar
  • 42 Trifiletti RR, Incorpora G, Polizzi A, Cocuzza MD, Bolan EA, Parano E. Aicardi syndrome with multiple tumors: a case report with literature review. Brain Dev 1995; 17 (04) 283-285
    CrossrefPubMedSuche in Google Scholar
  • 43 Feldman B, Yinon Y, Tepperberg Oikawa M, Yoeli R, Schiff E, Lipitz S. Pregestational, periconceptional, and gestational primary maternal cytomegalovirus infection: prenatal diagnosis in 508 pregnancies. Am J Obstet Gynecol 2011; 205 (04) 342.e1-342.e6
    CrossrefPubMedSuche in Google Scholar
  • 44 Polizzi A, Coghill S, McShane MA, Squier W. Acute ataxia complicating Langherans cell histiocytosis. Arch Dis Child 2002; 86 (02) 130-131
    CrossrefPubMedSuche in Google Scholar
  • 45 Odeberg J, Wolmer N, Falci S, Westgren M, Seiger A, Söderberg-Nauclér C. Human cytomegalovirus inhibits neuronal differentiation and induces apoptosis in human neural precursor cells. J Virol 2006; 80 (18) 8929-8939
    CrossrefPubMedSuche in Google Scholar
  • 46 Nicita F, Ruggieri M, Polizzi A. et al. Seizures and epilepsy in Sotos syndrome: analysis of 19 Caucasian patients with long-term follow-up. Epilepsia 2012; 53 (06) e102-e105
    CrossrefPubMedSuche in Google Scholar
  • 47 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child 2013; 98 (09) 707-713
    CrossrefPubMedSuche in Google Scholar
  • 48 Ruggieri M, Polizzi A. From Aldrovandi's “Homuncio” (1592) to Buffon's girl (1749) and the “Wart Man” of Tilesius (1793): antique illustrations of mosaicism in neurofibromatosis?. J Med Genet 2003; 40 (03) 227-232
    CrossrefPubMedSuche in Google Scholar
  • 49 Gilbert SL, Dobyns WB, Lahn BT. Genetic links between brain development and brain evolution. Nat Rev Genet 2005; 6 (07) 581-590
    CrossrefPubMedSuche in Google Scholar
  • 50 Salpietro V, Mankad K, Kinali M. et al. Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study. J Pediatr Endocrinol Metab 2014; 27 (1-2): 107-115
    CrossrefPubMedSuche in Google Scholar
  • 51 Pirozzi F, Nelson B, Mirzaa G. From microcephaly to megalencephaly: determinants of brain size. Dialogues Clin Neurosci 2018; 20 (04) 267-282
    CrossrefPubMedSuche in Google Scholar
  • 52 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. SHORT syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
    CrossrefPubMedSuche in Google Scholar
  • 53 Chiaramonte R, Vecchio M. Dysarthria and stroke. The effectiveness of speech rehabilitation. A systematic review and meta-analysis of the studies. Eur J Phys Rehabil Med 2021; 57 (01) 24-43
    CrossrefPubMedSuche in Google Scholar
  • 54 Chiaramonte R, Pavone P, Vecchio M. Speech rehabilitation in dysarthria after stroke: a systematic review of the studies. Eur J Phys Rehabil Med 2020; 56 (05) 547-562
    CrossrefPubMedSuche in Google Scholar
  • 55 Chiaramonte R, Vecchio M. A systematic review of measures of dysarthria severity in stroke patients. PM R 2021; 13 (03) 314-324
    CrossrefPubMedSuche in Google Scholar
  • 56 Ruggieri M, Gabriele AL, Polizzi A. et al. Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics 2013; 14 (02) 89-98
    CrossrefPubMedSuche in Google Scholar
  • 57 Jacobson LI, Bernal G, Lopez GN. Effects of behavioral training on the functioning of a profoundly retarded microcephalic teenager with cerebral palsy and without language or verbal comprehension. A case study. Behav Res Ther 1973; 11 (01) 143-145
    CrossrefPubMedSuche in Google Scholar
  • 58 Salpietro V, Phadke R, Saggar A. et al. Zellweger syndrome and secondary mitochondrial myopathy. Eur J Pediatr 2015; 174 (04) 557-563
    CrossrefPubMedSuche in Google Scholar
  • 59 DeLuca SC, Wallace DA, Trucks MR, Mukherjee K. A clinical series using intensive neurorehabilitation to promote functional motor and cognitive skills in three girls with CASK mutation. BMC Res Notes 2017; 10 (01) 743
    CrossrefPubMedSuche in Google Scholar
  • 60 O'Connor KC, Lopez-Amaya C, Gagne D. et al. Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis. J Neuroimmunol 2010; 223 (1-2): 92-99
    CrossrefPubMedSuche in Google Scholar
  • 61 Salpietro V, Polizzi A, Di Rosa G. et al. Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications. Int J Endocrinol 2014; 2014: 282489
    CrossrefPubMedSuche in Google Scholar
  • 62 Ruggieri M, Polizzi A. Segmental neurofibromatosis. J Neurosurg 2000; 93 (03) 530-532
    PubMedSuche in Google Scholar
  • 63 Salpietro V, Ruggieri M, Sancetta F. et al. New insights on the relationship between pseudotumor cerebri and secondary hyperaldosteronism in children. J Hypertens 2012; 30 (03) 629-630
    CrossrefPubMedSuche in Google Scholar
  • 64 Falsaperla R, Praticò AD, Ruggieri M. et al. Congenital muscular dystrophy: from muscle to brain. Ital J Pediatr 2016; 42 (01) 78
    CrossrefPubMedSuche in Google Scholar