18p deletion syndrome is a rare chromosomal disease caused by deletion of the short arm of chromosome 18. By using cytogenetic and SNP array analysis, we identified a girl with 18p deletion syndrome exhibiting craniofacial anomalies, intellectual disability, and short stature. G-banding analysis of metaphase cells revealed an abnormal karyotype 46,XX,del(18)(p10). Further, SNP array detected a 15.3-Mb deletion at 18p11.21p11.32 (chr18:12842-15375878) including 61 OMIM genes. Genotype-phenotype correlation analysis showed that clinical manifestations of the patient were correlated with LAMA1, TWSG1, and GNAL deletions. Her neuropsychological assessment test demonstrated delay in most cognitive functions including impaired mathematics, linguistic skills, visual motor perception, respond speed, and executive function. Meanwhile, her integrated visual and auditory continuous performance test (IVA-CPT) indicated a severe comprehensive attention deficit. At age 7 and 1/12 years, her height was 110.8 cm (-2.5 SD height for age). Growth hormone (GH) treatment was initiated. After 27 months treatment, her height was increased to 129.6 cm (-1.0 SD height for age) at 9 and 4/12 years, indicating an effective response to GH treatment.

Keywords:
Cytogenetics, Genotype, Growth hormone, Neuropsychological test, 18p deletion syndrome, Phenotype, SNP array
1.
Abdel Razek AA, Castillo M: Magnetic resonance imaging of malformations of midbrain-hindbrain. J Comput Assist Tomogr 40:14-25 (2016).
2.
Aldinger KA, Mosca SJ, Tétreault M, Dempsey JC, Ishak GE, et al: Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy. Am J Hum Genet 95:227-234 (2014).
3.
Avasthi P, Scheel JF, Ying G, Frederick JM, Baehr W, Wolfrum U: Germline deletion of Cetn1 causes infertility in male mice. J Cell Sci 126:3204-3213 (2013).
4.
Balboa-Beltran E, Duran G, Lamas MJ, Carracedo A, Barros F: Long survival and severe toxicity under 5-fluorouracil-based therapy in a patient with colorectal cancer who harbors a germline codon-stop mutation in TYMS. Mayo Clin Proc 90:1298-1303 (2015).
5.
Bellfield EJ, Chan J, Durrin S, Lindgren V, Shad Z, Boucher-Berry C: Anterior pituitary aplasia in an infant with ring chromosome 18p deletion. Case Rep Endocrinol 2016:2853178 (2016).
6.
Billington CJ Jr, Schmidt B, Marcucio RS, Hallgrimsson B, Gopalakrishnan R, Petryk A: Impact of retinoic acid exposure on midfacial shape variation and manifestation of holoprosencephaly in Twsg1 mutant mice. Dis Model Mech 8:139-146 (2015).
7.
Brenk CH, Prott EC, Trost D, Hoischen A, Walldorf C, et al: Towards mapping phenotypical traits in 18p-syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation. Eur J Hum Genet 15:35-44 (2007).
8.
Bryan CD, Chien CB, Kwan KM: Loss of laminin alpha 1 results in multiple structural defects and divergent effects on adhesion during vertebrate optic cup morphogenesis. Dev Biol 416:324-337 (2016).
9.
Carvalho CA, Carvalho AV, Kiss A, Paskulin G, Götze FM: Keratosis pilaris and ulerythema ophryogenes in a woman with monosomy of the short arm of chromosome 18. An Bras Dermatol 86:S42-45 (2011).
10.
Chen CP, Huang JP, Chen YY, Chern SR, Wu PS, et al: Chromosome 18p deletion syndrome presenting holoprosencephaly and premaxillary agenesis: prenatal diagnosis and aCGH characterization using uncultured amniocytes. Gene 527:636-641 (2013).
11.
Cheng D, Yan X, Gao Z, Xu K, Zhou X, Chen Q: Neurocognitive profiles in childhood absence epilepsy. J Child Neurol 32:46-52 (2017).
12.
DasBanerjee T, Middleton FA, Berger DF, Lombardo JP, Sagvolden T, Faraone SV: A comparison of molecular alterations in environmental and genetic rat models of ADHD: a pilot study. Am J Med Genet B Neuropsychiatr Genet 147B:1554-1563 (2008).
13.
De Grouchy J, Lamy M, Thieffry S, Arthuis M, Salmon CH: Dysmorphie complexe avec oligophrénie: délétion des bras courts d'un chromosome 17-18. C R Acad Sci 258:1028-1029 (1963).
14.
Di Bella D, Lazzaro F, Brusco A, Plumari M, Battaglia G, et al: Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet 42:313-321 (2010).
15.
Dos Santos CO, Masuho I, da Silva-Júnior FP, Barbosa ER, Silva SM, et al: Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function. J Neurol 263:665-668 (2016).
16.
Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, et al: Mutations in GNAL cause primary torsion dystonia. Nat Genet 45:88-92 (2013).
17.
Giordano M, Muratore V, Babu D, Meazza C, Bozzola M: A 18p11.23-p11.31 microduplication in a boy with psychomotor delay, cerebellar vermis hypoplasia, chorioretinal coloboma, deafness and GH deficiency. Mol Cytogenet 9:89 (2016).
18.
Glas J, Wagner J, Seiderer J, Olszak T, Wetzke M, et al: PTPN2 gene variants are associated with susceptibility to both Crohn's disease and ulcerative colitis supporting a common genetic disease background. PLoS One 7:e33682 (2012).
19.
Gondré-Lewis MC, Gboluaje T, Reid SN, Lin S, Wang P, et al: The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18. J Anat 227:255-267 (2015).
20.
Gripp KW, Wotton D, Edwards MC, Roessler E, Ades L, et al: Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet 25:205-208 (2000).
21.
Hasi-Zogaj M, Sebold C, Heard P, Carter E, Soileau B, et al: A review of 18p deletions. Am J Med Genet C Semin Med Genet 169:251-264 (2015).
22.
Huntley R, Davydova J, Petryk A, Billington CJ Jr, Jensen ED, et al: The function of twisted gastrulation in regulating osteoclast differentiation is dependent on BMP binding. J Cell Biochem 116:2239-2246 (2015).
23.
Kauvar EF, Hu P, Pineda-Alvarez DE, Solomon BD, Dutra A, et al: Minimal evidence for a direct involvement of twisted gastrulation homolog 1 (TWSG1) gene in human holoprosencephaly. Mol Genet Metab 102:470-480 (2011).
24.
Kumar N, Rizek P, Jog M: Movement disorders in 18p deletion syndrome: a case report and review of literature. Can J Neurol Sci 44:441-443 (2017).
25.
Laurin N, Ickowicz A, Pathare T, Malone M, Tannock R, et al: Investigation of the G protein subunit Galphaolf gene (GNAL) in attention deficit/hyperactivity disorder. J Psychiatr Res 42:117-124 (2008).
26.
Lemmers RJ, van den Boogaard ML, van der Vliet PJ, Donlin-Smith CM, Nations SP, et al: Hemizygosity for SMCHD1 in facioscapulohumeral muscular dystrophy type 2: consequences for 18p deletion syndrome. Hum Mutat 36:679-683 (2015).
27.
Masuho I, Fang M, Geng C, Zhang J, Jiang H, et al: Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. Neurol Genet 2:e78 (2016).
28.
McGoey RR, Gedalia A, Marble M: Monosomy 18p and immunologic dysfunction: review of the literature and a new case report with thyroiditis, IgA deficiency, and systemic lupus erythematosus. Clin Dysmorphol 20:127-130 (2011).
29.
Micalizzi A, Poretti A, Romani M, Ginevrino M, Mazza T, et al: Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome). Eur J Hum Genet 24:1262-1267 (2016).
30.
Ning L, Kurihara H, de Vega S, Ichikawa-Tomikawa N, Xu Z, et al: Laminin α1 regulates age-related mesangial cell proliferation and mesangial matrix accumulation through the TGF-β pathway. Am J Pathol 184:1683-1694 (2014).
31.
Ohnishi T, Yamada K, Ohba H, Iwayama Y, Toyota T, et al: A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. Neuropsychopharmacology 32:1727-1737 (2007).
32.
Rao VB, Kerketta L, Korgaonkar S, Ghosh K, Mohanty D: 18p deletion syndrome with a 45,XY,t(14;18)(p11;q11.2),-18 karyotype. Ann Genet 44:187-190 (2001).
33.
Rogers DG, Aswini RS: Response to growth hormone treatment in a patient with 18p-syndrome. J Pediatr Endocrinol Metab 25:1023-1025 (2012).
34.
Sebold C, Soileau B, Heard P, Carter E, O'Donnell L, et al: Whole arm deletions of 18p: medical and developmental effects. Am J Med Genet A 167A:313-323 (2015).
35.
Shaffer JR, Feingold E, Wang X, Lee M, Tcuenco K, et al: GWAS of dental caries patterns in the permanent dentition. J Dent Res 92:38-44 (2013).
36.
Taniguchi K, Anderson AE, Sutherland AE, Wotton D: Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. PLoS Genet 8:e1002524 (2012).
37.
Tatsi C, Sertedaki A, Voutetakis A, Valavani E, Magiakou MA, et al: Pituitary stalk interruption syndrome and isolated pituitary hypoplasia may be caused by mutations in holoprosencephaly-related genes. J Clin Endocrinol Metab 98:E779-784 (2013).
38.
Tezzon F, Zanoni T, Passarin MG, Ferrari G: Dystonia in a patient with deletion of 18p. Ital J Neurol Sci 19:90-93 (1998).
39.
Turleau C: Monosomy 18p. Orphanet J Rare Dis 3:4 (2008).
40.
Vilboux T, Malicdan MC, Chang YM, Guo J, Zerfas PM, et al: Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects. J Med Genet 53:318-329 (2016).
41.
Vuoristo JT, Berrettini WH, Overhauser J, Prockop DJ, Ferraro TN, Ala-Kokko L: Sequence and genomic organization of the human G-protein Golfalpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia. Mol Psychiatry 5:495-501 (2000).
42.
Willoughby BL, Favero M, Mochida GH, Braaten EB: Neuropsychological function in a child with 18p deletion syndrome: a case report. Cogn Behav Neurol 27:160-165 (2014).
43.
Xu LJ, Wu LX, Yuan Q, Lv ZG, Jiang XY: A case of 18p deletion syndrome after blepharoplasty. Int Med Case Rep J 10:15-18 (2017).
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2018
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