J Pediatr Genet 2017; 06(02): 103-106
DOI: 10.1055/s-0036-1588028
Case Report
Georg Thieme Verlag KG Stuttgart · New York

Multisystem Involvement in a Patient with a PTCH1 Mutation: Clinical and Imaging Findings

Antonio Richieri-Costa
1   Serviço de Genética, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, Sao Paulo, Brazil
,
Siulan Vendramini-Pittoli
1   Serviço de Genética, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, Sao Paulo, Brazil
,
Nancy Mizue Kokitsu-Nakata
1   Serviço de Genética, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, Sao Paulo, Brazil
,
Roseli Maria Zechi-Ceide
1   Serviço de Genética, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, Sao Paulo, Brazil
,
Camila Wenceslau Alvarez
1   Serviço de Genética, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, Sao Paulo, Brazil
,
Lucilene Arilho Ribeiro-Bicudo
2   Departamento de Genética, Instituto de Ciências Biológicas, Universidade Federal de Goias, Goiania, Goiás, Brazil
› Institutsangaben
Weitere Informationen

Publikationsverlauf

29. Januar 2016

21. Juli 2016

Publikationsdatum:
14. September 2016 (online)

Abstract

In this article, we report on a Brazilian female patient born to consanguineous parents and presenting with alobar holoprosencephaly, severe eye involvement, and unusual skin hyperpigmented lesions. She was found to have a mutation (c.2240T > C; p.Val751Gly) in exon 15 of the PTCH1 gene. Mutations in this gene are associated with the nevoid basal cell carcinoma syndrome (NBCCS, OMIM 109400) and, in other instances, with holoprosencephaly (holoprosencephaly-7, OMIM 610828). Severe eye involvement ranging from orbital coloboma to microphthalmia has been seldom reported in patients with NBCCS with PTCH1 mutations. To our knowledge, this is the first report of an individual with central nervous system, skin, and eye manifestations due to a PTCH1 mutation. Mechanisms involved in these multisystem manifestations are discussed.

 
  • References

  • 1 Cohen Jr MM. The hedgehog signaling network. Am J Med Genet A 2003; 123A (1) 5-28
  • 2 Marini M, Cusano R, De Biasio P , et al. Previously undescribed nonsense mutation in SHH caused autosomal dominant holoprosencephaly with wide intrafamilial variability. Am J Med Genet A 2003; 117A (2) 112-115
  • 3 Hahn JS, Plawner LL. Evaluation and management of children with holoprosencephaly. Pediatr Neurol 2004; 31 (2) 79-88
  • 4 Rahimov F, Ribeiro LA, de Miranda E, Richieri-Costa A, Murray JC. GLI2 mutations: phenotypical manifestations in four Brazilian patients. How wide is the phenotype?. Am J Med Genet A 2006; 140: 2571-2576
  • 5 OMIM – Online Mendelian Inheritance in Man. An Online Catalog of Human Genes and Genetic Disorders. Available at http://www.omim.org/entry/109400 . Accessed January 21, 2016
  • 6 Ragge NK, Salt A, Collin JR, Michalski A, Farndon PA. Gorlin syndrome: the PTCH gene links ocular developmental defects and tumour formation. Br J Ophthalmol 2005; 89 (8) 988-991
  • 7 Rodrigues AL, Carvalho A, Cabral R , et al. Multiple nevoid basal cell carcinoma syndrome associated with congenital orbital teratoma, caused by a PTCH1 frameshift mutation. Genet Mol Res 2014; 13 (3) 5654-5663
  • 8 Derwińska K, Smyk M, Cooper ML, Bader P, Cheung SW, Stankiewicz P. PTCH1 duplication in a family with microcephaly and mild developmental delay. Eur J Hum Genet 2009; 17 (2) 267-271
  • 9 Ribeiro LA, Murray JC, Richieri-Costa A. PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI. Am J Med Genet A 2006; 140 (23) 2584-2586
  • 10 Ming JE, Muenke M. Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 2002; 71 (5) 1017-1032
  • 11 Mansilla MA, Cooper ME, Goldstein T , et al. Contributions of PTCH gene variants to isolated cleft lip and palate. Cleft Palate Craniofac J 2006; 43 (1) 21-29
  • 12 Lindström E, Shimokawa T, Toftgård R, Zaphiropoulos PG. PTCH mutations: distribution and analyses. Hum Mutat 2006; 27 (3) 215-219
  • 13 Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgård R, Undén AB. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol 2006; 208 (1) 17-25
  • 14 Larsen AK, Mikkelsen DB, Hertz JM, Bygum A. Manifestations of Gorlin-Goltz syndrome. Dan Med J 2014; 61 (5) A4829
  • 15 Chung JH, Bunz F. A loss-of-function mutation in PTCH1 suggests a role for autocrine hedgehog signaling in colorectal tumorigenesis. Oncotarget 2013; 4 (12) 2208-2211
  • 16 Ponti G, Manfredini M, Ruini C. Wall paintings facies and their possible genetic correlates in the ancient Pompeii: a bio-anthropologic message from the past?. Gene 2016; 589 (2) 151-156
  • 17 Ponti G, Pellacani G, Tomasi A, Sammaria G, Manfredini M. Skeletal stigmata as keys to access to the composite and ancient Gorlin-Goltz syndrome history: the Egypt, Pompeii and Herculaneum lessons. Gene 2016; 589 (2) 104-111
  • 18 Levanat S, Gorlin RJ, Fallet S, Johnson DR, Fantasia JE, Bale AE. A two-hit model for developmental defects in Gorlin syndrome. Nat Genet 1996; 12 (1) 85-87
  • 19 Dubourg C, Lazaro L, Pasquier L , et al. Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: mutation review and genotype-phenotype correlations. Hum Mutat 2004; 24 (1) 43-51
  • 20 Petryk A, Graf D, Marcucio R. Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans. Wiley Interdiscip Rev Dev Biol 2015; 4 (1) 17-32
  • 21 Ming JE, Roessler E, Muenke M. Human developmental disorders and the Sonic hedgehog pathway. Mol Med Today 1998; 4 (8) 343-349
  • 22 Hehr U, Gross C, Diebold U , et al. Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation. Eur J Pediatr 2004; 163 (7) 347-352
  • 23 Lazaro L, Dubourg C, Pasquier L , et al. Phenotypic and molecular variability of the holoprosencephalic spectrum. Am J Med Genet A 2004; 129A (1) 21-24
  • 24 Chassaing N, Davis EE, McKnight KL , et al. Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network. Genome Res 2016; 26 (4) 474-485
  • 25 Ming JE, Kaupas ME, Roessler E , et al. Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 2002; 110 (4) 297-301
  • 26 Roudgari H, Farndon PA, Murray AD, Hardy C, Miedzybrodzka Z. Is PATCHED an important candidate gene for neural tube defects? Cranial and thoracic neural tube defects in a family with Gorlin syndrome: a case report. Clin Genet 2012; 82 (1) 71-76
  • 27 Thomas C, Ingham PW. Hedgehog signaling in the Drosophila eye and head: an analysis of the effects of different patched trans-heterozygotes. Genetics 2003; 165 (4) 1915-1928
  • 28 Moshiri A, Reh TA. Persistent progenitors at the retinal margin of ptc+/- mice. J Neurosci 2004; 24 (1) 229-237