Primary Microcephaly with Novel Variant of MCPH1 Gene in Twins: Both Manifesting in Childhood at the Same Time with Hashimoto's Thyroiditis

Abstract

This study is a clinical report on twin females affected by primary microcephaly who displayed at molecular analysis of heterozygous novel MCPH1 variant. The twins at the age of 10 years developed, in coincidental time, a diagnosis of autoimmune juvenile thyroiditis. The main clinical features presented by the twins consisted of primary microcephaly with occipitofrontal circumference measuring −2 or −3 standard deviation, facial dysmorphism, typical nonsyndromic microcephaly, and mild intellectual disability. Molecular analysis of the major genes involved in primary microcephaly was performed and the following result was found in the twins: MCPH1; chr8.6357416; c.2180 C > T (rs 199861426), p.Pro727. Leu; heterozygous; missense; variant of uncertain significance (class 3). At the age of 10 years, the twins started to have, in coincidental time, marked asthenia and episodes of emotiveness, and laboratory exams disclosed a high level of antithyroid peroxidase leading to the diagnosis of autoimmune juvenile thyroiditis with normal thyroid function. The novel heterozygous MCPH1 variant found in the twins may be directly or indirectly involved in the onset of the primary microcephaly. The thyroid disorder in the twins and its onset, in a coincidental time, confirmed the effect of genetic predisposition on the pathogenesis of the immune thyroiditis.

Keywords

MCPH1 variants - twins - primary microcephaly - autoimmune juvenile thyroiditis - Hashimoto's thyroiditis

Note

Written informed consent was obtained from the patient's guardian/parent/next of kin for the publication of this report and any accompanying images.

• References

• 1 Sniderman A. Abnormal head growth. Pediatr Rev 2010; 31 (09) 382-384
• 2 Hanzlik E, Gigante J. Microcephaly. Children (Basel) 2017; 4 (06) E47
• 3 Abdel-Salam G, Czeizel AE. The second unrelated case with isolated microcephaly and normal intelligence (microcephalia vera). Clin Dysmorphol 2000; 9 (02) 151-152
• 4 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
• 5 Gilmore EC, Walsh CA. Genetic causes of microcephaly and lessons for neuronal development. Wiley Interdiscip Rev Dev Biol 2013; 2 (04) 461-478
• 6 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 (05) 717-728
• 7 Van Den Bosch J. Microcephaly in the Netherlands: a clinical and genetical study. Ann Hum Genet 1959; 23 (02) 91-116
• 8 Rizzo R, Pavone L. Autosomal-recessive microcephaly in two siblings, one with normal IQ and both with protruding mandible, small ears, and curved nose. Am J Med Genet 1995; 59 (04) 421-425
• 9 Jackson AP, McHale DP, Campbell DA. , et al. Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet 1998; 63 (02) 541-546
• 10 Zaqout S, Morris-Rosendahl D, Kaindl AM. Autosomal recessive primary microcephaly (MCPH): an update. Neuropediatrics 2017; 48 (03) 135-142
• 11 Ashwal S, Michelson D, Plawner L, Dobyns WB. ; Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Practice parameter: evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2009; 73 (11) 887-897
• 12 Yu TW, Mochida GH, Tischfield DJ. , et al. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 2010; 42 (11) 1015-1020
• 13 Passemard S, Verloes A, Billette de Villemeur T. , et al. Abnormal spindle-like microcephaly-associated (ASPM) mutations strongly disrupt neocortical structure but spare the hippocampus and long-term memory. Cortex 2016; 74: 158-176
• 14 Gul A, Hassan MJ, Hussain S, Raza SI, Chishti MS, Ahmad W. A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly. J Hum Genet 2006; 51 (09) 760-764
• 15 Minelli R, Gaiani F, Kayali S. , et al. Thyroid and celiac disease in pediatric age: a literature review. Acta Biomed 2018; 89 (9-S): 11-16
• 16 Pyzik A, Grywalska E, Matyjaszek-Matuszek B, Roliński J. Immune disorders in Hashimoto's thyroiditis: what do we know so far?. J Immunol Res 2015; 2015: 979167
• 17 Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmun Rev 2014; 13 (4-5): 391-397
• 18 von der Hagen M, Pivarcsi M, Liebe J. , et al. Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Dev Med Child Neurol 2014; 56 (08) 732-741
• 19 Shanske A, Marion R. Central nervous system anomalies in Seckel syndrome: report of a new family and review of the literature. Am J Med Genet 1998; 77 (03) 250
• 20 Verloes A, Drunat S, Gressens P, Passemard S. Primary autosomal recessive microcephalies and Seckel syndrome spectrum disorders 2009. In: Adam MP, Ardinger HH, Pagon RA. , eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. –2018
• 21 Stevenson RE. Alpha-thalassemia X-linked intellectual disability syndrome 2000. In: Adam MP, Ardinger HH, Pagon RA. , eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. –2018
• 22 Pavone P, Taibi R, Lionetti E, Incorpora G, Fisher CA. First case of dizygous twins with X-linked alpha-thalassemia/mental retardation syndrome showing wide clinical variability. Pediatr Int 2010; 52 (02) e72-e75
• 23 Weemaes CM, Hustinx TW, Scheres JM, van Munster PJ, Bakkeren JA, Taalman RD. A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatr Scand 1981; 70 (04) 557-564
• 24 Mlody B, Wruck W, Martins S, Sperling K, Adjaye J. Nijmegen breakage syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants. Sci Rep 2017; 7 (01) 7516
• 25 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
• 26 Pilaz LJ, McMahon JJ, Miller EE. , et al. Prolonged mitosis of neural progenitors alters cell fate in the developing brain. Neuron 2016; 89 (01) 83-99
• 27 Trimborn M, Bell SM, Felix C. , et al. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet 2004; 75 (02) 261-266
• 28 Neitzel H, Neumann LM, Schindler D. , et al. Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition. Am J Hum Genet 2002; 70 (04) 1015-1022
• 29 Jackson AP, Eastwood H, Bell SM. , et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 2002; 71 (01) 136-142
• 30 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
• 31 Zhou ZW, Tapias A, Bruhn C, Gruber R, Sukchev M, Wang ZQ. DNA damage response in microcephaly development of MCPH1 mouse model. DNA Repair (Amst) 2013; 12 (08) 645-655
• 32 Faheem M, Naseer MI, Rasool M. , et al. Molecular genetics of human primary microcephaly: an overview. BMC Med Genomics 2015; 8 (Suppl. 01) S4
• 33 Naseer MI, Rasool M, Abdulkareem AA. , et al. Novel compound heterozygous mutations in MCPH1 gene causes primary microcephaly in Saudi family. Neurosciences (Riyadh) 2018; 23 (04) 347-350
• 34 Cheon CK, Lim SH, Kim YM. , et al. Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene. Sci Rep 2017; 7 (01) 12527
• 35 Hotchkiss L, Donkervoort S, Leach ME. , et al. Novel de novo mutations in KIF1A as a cause of hereditary spastic paraplegia with progressive central nervous system involvement. J Child Neurol 2016; 31 (09) 1114-1119
• 36 Coppedè F. Epigenetics and autoimmune thyroid diseases. Front Endocrinol (Lausanne) 2017; 8: 149
• 37 De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet 2016; 388 (10047): 906-918
• 38 Kust D, Matesa N. The impact of familial predisposition on the development of Hashimoto's thyroiditis. Acta Clin Belg 2020; 75 (02) 104-108