Subscribe to RSS
DOI: 10.1055/s-0039-3402047
Microphthalmia, Linear Skin Defects, Callosal Agenesis, and Cleft Palate in a Patient with Deletion at Xp22.3p22.2
Funding This work was supported by CNPq (301926/2007-7 to A.R.-C.).Publication History
17 June 2019
07 November 2019
Publication Date:
03 January 2020 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00029027/202004/lookinside/thumbnails/10-1055-s-0039-3402047_1900047-1.jpg)
Abstract
The authors describe the clinical findings observed in a Brazilian girl that are suggestive of microphthalmia and linear skin defects (MLS) also known as MIDAS syndrome (OMIM #309801). She also presented with short stature, agenesis of corpus callosum, cleft palate, enamel defects, and genitourinary anomalies, which are rarely reported within the clinical spectrum of MLS. The 11,5 Mb deletion in Xp22.3p22.2 observed in the patient includes the entire HCCS gene (responsible for the MLS phenotype) and also encompasses several other genes involved with behavioral phenotypes, craniofacial and central nervous system development such as MID1, NLGN4X, AMELX, ARHGAP6, and TBL1X. The whole clinical features of our proband possibly represents an unusual MLS syndromic phenotype caused by an Xp22.3p22.2 continuous gene deletion.
-
References
- 1 OMIM#309801. [Online Mendelian Inheritance in Man. An Online Catalog of Human Genes and Genetic Disorders]. Available at: http://www.omim.org/entry/309801 . Accessed April, 2019
- 2 Happle R, Daniëls O, Koopman RJ. MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome. Am J Med Genet 1993; 47 (05) 710-713
- 3 Schaefer L, Ballabio A, Zoghbi HY. Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS). Genomics 1996; 34 (02) 166-172
- 4 Quaderi NA, Schweiger S, Gaudenz K. , et al. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet 1997; 17 (03) 285-291
- 5 Couser NL, Masood MM, Aylsworth AS, Stevenson RE. Ocular manifestations in the X-linked intellectual disability syndromes. Ophthalmic Genet 2017; 38 (05) 401-412
- 6 Kumar P, Rajab A. Microphthalmia with linear skin defects (MLS) syndrome: familial presentation. Clin Exp Dermatol 2018; 43 (02) 196-197
- 7 Morleo M, Pramparo T, Perone L. , et al. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases. Am J Med Genet A 2005; 137 (02) 190-198
- 8 Morleo M, Franco B. Microphthalmia with linear skin defects syndrome. In: Adam MP, Ardinger HH, Pagon RA. , et al., eds. SourceGeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2009: 1993 2019
- 9 Wimplinger I, Shaw GM, Kutsche K. HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations?. Mol Vis 2007; 13: 1475-1482
- 10 García-Rabasco A, De-Unamuno B, Martínez F, Febrer-Bosch I, Alegre-de-Miquel V. Microphthalmia with linear skin defects syndrome. Pediatr Dermatol 2013; 30 (06) e230-e231
- 11 Sharma VM, Ruiz de Luzuriaga AM, Waggoner D, Greenwald M, Stein SL. Microphthalmia with linear skin defects: a case report and review. Pediatr Dermatol 2008; 25 (05) 548-552
- 12 Margari L, Colonna A, Craig F. , et al. Microphthalmia with linear skin defects (MLS) associated with autism spectrum disorder (ASD) in a patient with familial 12.9Mb terminal Xp deletion. BMC Pediatr 2014; 14: 220
- 13 Hobson GM, Gibson CW, Aragon M. , et al. A large X-chromosomal deletion is associated with microphthalmia with linear skin defects (MLS) and amelogenesis imperfecta (XAI). Am J Med Genet A 2009; 149A (08) 1698-1705
- 14 Schaefer L, Prakash S, Zoghbi HY. Cloning and characterization of a novel rho-type GTPase-activating protein gene (ARHGAP6) from the critical region for microphthalmia with linear skin defects. Genomics 1997; 46 (02) 268-277
- 15 Jamain S, Quach H, Betancur C. , et al; Paris Autism Research International Sibpair Study. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003; 34 (01) 27-29
- 16 Wimplinger I, Morleo M, Rosenberger G. , et al. Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome. Am J Hum Genet 2006; 79 (05) 878-889
- 17 Hu JC, Chan HC, Simmer SG. , et al. Amelogenesis imperfecta in two families with defined AMELX deletions in ARHGAP6. PLoS One 2012; 7 (12) e52052
- 18 Vergult S, Leroy B, Claerhout I, Menten B. Familial cases of a submicroscopic Xp22.2 deletion: genotype-phenotype correlation in microphthalmia with linear skin defects syndrome. Mol Vis 2013; 19: 311-318
- 19 Wimplinger I, Rauch A, Orth U, Schwarzer U, Trautmann U, Kutsche K. Mother and daughter with a terminal Xp deletion: implication of chromosomal mosaicism and X-inactivation in the high clinical variability of the microphthalmia with linear skin defects (MLS) syndrome. Eur J Med Genet 2007; 50 (06) 421-431
- 20 Franco B, Ballabio A. X-inactivation and human disease: X-linked dominant male-lethal disorders. Curr Opin Genet Dev 2006; 16 (03) 254-259
- 21 van Rahden VA, Rau I, Fuchs S. , et al. Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome. Orphanet J Rare Dis 2014; 9: 53
- 22 Indrieri A, van Rahden VA, Tiranti V. , et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am J Hum Genet 2012; 91 (05) 942-949
- 23 van Rahden VA, Fernandez-Vizarra E, Alawi M. , et al. Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome. Am J Hum Genet 2015; 96 (04) 640-650
- 24 Hoebel AK, Drichel D, van de Vorst M. , et al. Candidate genes for nonsyndromic cleft palate detected by exome sequencing. J Dent Res 2017; 96 (11) 1314-1321
- 25 Tettamanti L, Avantaggiato A, Nardone M, Palmieri A, Tagliabue A. New insights in orofacial cleft: epidemiological and genetic studies on italian samples. Oral Implantol (Rome) 2017; 10 (01) 11-19
- 26 OMIM#308700. [Online Mendelian Inheritance in Man. An Online Catalog of Human Genes and Genetic Disorders]. Available at: https://www.omim.org/entry/308700?search=308700&highlight=308700 . Accessed April, 2019
- 27 Gonçalves CI, Fonseca F, Borges T, Cunha F, Lemos MC. Expanding the genetic spectrum of ANOS1 mutations in patients with congenital hypogonadotropic hypogonadism. Hum Reprod 2017; 32 (03) 704-711
- 28 Nie M, Xu H, Chen R. , et al. Analysis of genetic and clinical characteristics of a Chinese Kallmann syndrome cohort with ANOS1 mutations. Eur J Endocrinol 2017; 177 (04) 389-398
- 29 Lopategui DM, Griswold AJ, Arora H, Clavijo RI, Tekin M, Ramasamy R. A rare ANOS1 variant in siblings with Kallmann syndrome identified by whole exome sequencing. Andrology 2018; 6 (01) 53-57
- 30 Meczekalski B, Podfigurna-Stopa A, Smolarczyk R, Katulski K, Genazzani AR. Kallmann syndrome in women: from genes to diagnosis and treatment. Gynecol Endocrinol 2013; 29 (04) 296-300
- 31 Sonne J, Lopez-Ojeda W. Kallmann Syndrome. Source Stat Pearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2019
- 32 Sato N, Katsumata N, Kagami M. , et al. Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients. J Clin Endocrinol Metab 2004; 89 (03) 1079-1088
- 33 OMIM#300000. [Online Mendelian Inheritance in Man. An Online Catalog of Human Genes and Genetic Disorders]. Available at: https://www.omim.org/entry/300000?search=%23%20300000&highlight=300000 . Accessed May, 2019
- 34 Robin NH, Opitz JM, Muenke M. Opitz G/BBB syndrome: clinical comparisons of families linked to Xp22 and 22q, and a review of the literature. Am J Med Genet 1996; 62 (03) 305-317
- 35 De Falco F, Cainarca S, Andolfi G. , et al. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet A 2003; 120A (02) 222-228
- 36 Fontanella B, Russolillo G, Meroni G. MID1 mutations in patients with X-linked Opitz G/BBB syndrome. Hum Mutat 2008; 29 (05) 584-594
- 37 Hsieh EW, Vargervik K, Slavotinek AM. Clinical and molecular studies of patients with characteristics of Opitz G/BBB syndrome shows a novel MID1 mutation. Am J Med Genet A 2008; 146A (18) 2337-2345
- 38 Meroni G. X-linked Opitz G/BBB syndrome. In: Pagon RA, Adam MP, Ardinger HH. , eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2004: 1993 2016
- 39 Xu X, Xiong Z, Zhang L. , et al. Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients. Mol Biol Rep 2014; 41 (06) 4133-4140
- 40 Ross JL, Tartaglia N, Merry DE, Dalva M, Zinn AR. Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features. Genes Brain Behav 2015; 14 (02) 137-144
- 41 Nakanishi M, Nomura J, Ji X. , et al. Functional significance of rare neuroligin 1 variants found in autism. PLoS Genet 2017; 13 (08) e1006940
- 42 Unichenko P, Yang JW, Kirischuk S. , et al. Autism related neuroligin-4 knockout impairs intracortical processing but not sensory inputs in mouse barrel cortex. Cereb Cortex 2018; 28 (08) 2873-2886
- 43 Fukami M, Seki A, Ogata T. SHOX haploinsufficiency as a cause of syndromic and nonsyndromic short stature. Mol Syndromol 2016; 7 (01) 3-11
- 44 Monzani A, Babu D, Mellone S. , et al. Co-occurrence of genomic imbalances on Xp22.1 in the SHOX region and 15q25.2 in a girl with short stature, precocious puberty, urogenital malformations and bone anomalies. BMC Med Genomics 2019; 12 (01) 5
- 45 Stamou MI, Georgopoulos NA. Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism. Metabolism 2018; 86: 124-134
- 46 OMIM*312865. [Online Mendelian Inheritance in Man. An Online Catalog of Human Genes and Genetic Disorders]. Available at: https://www.omim.org/entry/312865?search=SHOX&highlight=shox . Accessed May, 2019