Congenital Patterned Leukodermas Clinical Presentation
- Author: Raymond E Boissy, PhD; Chief Editor: William D James, MD more...
See the list below:
- Persons with type I Waardenburg syndrome present with unpigmented macules of the skin varying markedly in size and number. Associated with the cutaneous amelanosis are heterochromic irides that can be partial and/or unilateral (bichromia), sensorineural deafness with the absence or reduction of melanocytes in the cochlea, and dystopia canthorum, which manifests as a broadening of the base of the nose.
- Persons with type II Waardenburg syndrome present with features similar to those with type I Waardenburg, but they lack dystopia canthorum.
- Persons with type III Waardenburg syndrome present with the same features as those with type I Waardenburg syndrome but with additional musculoskeletal abnormalities of the face and upper torso.
- Persons with type IV Waardenburg syndrome present with variable cutaneous hypopigmentation, cochlear neurosensory deafness, and enteric aganglionosis, similar to persons with Hirschsprung syndrome.[8, 9]
- Persons with Apert syndrome present with craniosynostosis (premature fusion of cranial sutures), craniofacial anomalies, and asymmetric syndactyly of both the hands and the feet.[10, 11] Cutaneous and ocular hypopigmentation is readily apparent in approximately 27% of people with Apert syndrome.
- Persons with Pfeiffer syndrome present with craniosynostosis and broadening of the greater toes and thumbs. Cutaneous hypopigmentation occurs in approximately 10%.
- Persons with Jackson-Weiss syndrome present with craniosynostosis, wide feet, and normal hands.
- Persons with Crouzon syndrome present with cranial defects only. (Apparent cutaneous hypopigmentation has not been described in people with Jackson-Weiss or Crouzon syndromes.)
- Persons with Waardenburg syndrome type IV (Hirschsprung syndrome) primarily present with congenital aganglionic megacolon. This syndrome results from the absence of neural crest cells in the colon with the subsequent failure to form Meissner and Auerbach autonomic plexuses in the intestinal smooth muscle wall. Hirschsprung syndrome, in many people, is associated with hypopigmentation of varying extent, heterochromic irides, and deafness.
- Persons with piebaldism present with cutaneous amelanosis ranging from only a small, white forelock with minimal ventral unpigmented areas to an almost total lack of skin and hair pigmentation. Rarely, the melanocytes in the eye or ear are affected.
See the list below:
- The causes of these congenital patterned leukodermas are mutations in specific genes.
- Type I and type III Waardenburg syndromes result from mutations in the PAX3 gene, which maps to band 2q35-q37.3. The syndrome is inherited as an autosomal dominant trait. The PAX3 gene encodes a transcription factor with a paired box domain, an octapeptide domain, and a homeobox domain essential for survival of melanocytes during development. The genes up-regulated by this transcription factor have not been identified; however, the PAX3 gene product can bind to the promoter of the MITF gene.[6, 13, 14, 15, 16]
- Type II Waardenburg syndrome results from mutations in the microphthalmia transcription factor (MITF) gene, which maps to band 3p12. The syndrome is inherited as an autosomal dominant trait. The MITF gene encodes a transcription factor containing a basic-helix-loop-helix-leucine zipper. The genes up-regulated by this transcription factor during embryogenesis have not been identified.
- Type IV Waardenburg syndrome (Hirschsprung syndrome) results from mutations in either (1) the SOX10 gene, which maps to band 22q13, or (2) the EDN3 gene, which maps to band 20q13.2-q13.3. The SOX10 gene encodes a member of the high-mobility group-domain Sox family of transcription factors that regulate neural crest development. The genes up-regulated by this transcription factor during embryogenesis have not been identified; however, the SOX10 gene product can bind to the promoter of the MITF gene. The EDN3 gene encodes a ligand called endothelin-3 for the endothelin-B receptor.[13, 14, 18, 19]
- Apert, Pfeiffer, Jackson-Weiss, and Crouzon syndromes result from mutations in the fibroblast growth factor receptor-2 (FGFR2) gene, which maps to band 10q25-q26. These syndromes are inherited as autosomal dominant traits. The FGFR2 gene encodes a tyrosine kinase receptor with 3 immunoglobulin domains, a signal sequence, an acidic region in the extracellular ligand binding site, and 2 tyrosine kinase domains localized intracellularly. Some patients with Pfeiffer syndrome have demonstrated mutations in the fibroblast growth factor receptor-1 (FGFR1) gene, which maps to band 8p11.2-12.[20, 21]
- Hirschsprung syndrome type 2 results from mutations in the endothelin-B receptor (EDNRB) gene, which maps to band 13q22. This syndrome is inherited as an autosomal recessive trait. The EDNRB gene encodes a G protein–coupled plasma membrane receptor with 7 transmembrane domains and 2 autophosphorylation sites.
- Piebaldism results from mutations in the c-KIT gene, which maps to band 4q12. This syndrome is inherited as an autosomal dominant trait. The KIT gene encodes a plasma membrane receptor with a ligand-binding domain containing 5 immunoglobulinlike regions and 2 tyrosine kinase domains in the cytoplasm. Specific mutations of c-KIT correlate with the severity (ie, extent) of the cutaneous hypopigmentation.[13, 22, 23] According to Yang et al, deletion of the SNAI2 gene causes human piebaldism.
Boissy RE. Melanosome transfer to and translocation in the keratinocyte. Exp Dermatol. 2003. 12 Suppl 2:5-12. [Medline].
Boissy RE, Nordlund JJ. Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res. 1997 Feb-Apr. 10(1-2):12-24. [Medline].
Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. 2010 Apr. 31(4):391-406. [Medline].
Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet. 2004 Nov 15. 131C(1):75-81. [Medline].
Yang YJ, Zhao R, He XY, Li LP, Chen W, Wang KW, et al. SNAI2 mutation causes human piebaldism. Am J Med Genet A. 2014 Mar. 164A(3):855-7. [Medline].
Shields CL, Nickerson SJ, Al-Dahmash S, Shields JA. Waardenburg syndrome: iris and choroidal hypopigmentation: findings on anterior and posterior segment imaging. JAMA Ophthalmol. 2013 Sep. 131(9):1167-73. [Medline].
Kontorinis G, Goetz F, Lanfermann H, Luytenski S, Giesemann AM. Inner ear anatomy in Waardenburg syndrome: Radiological assessment and comparison with normative data. Int J Pediatr Otorhinolaryngol. 2014 Aug. 78(8):1320-6. [Medline].
Harvey I, Brown S, Ayres O, Proudman T. The apert hand-angiographic planning of a single-stage, 5-digit release for all classes of deformity. J Hand Surg Am. 2012 Jan. 37(1):152-8. [Medline].
Soanca A, Dudea D, Gocan H, Roman A, Culic B. Oral manifestations in Apert syndrome: case presentation and a brief review of the literature. Rom J Morphol Embryol. 2010. 51(3):581-4. [Medline].
Ettinger N, Williams M, Phillips JA 3rd. Variable expressivity and clinical heterogeneity can complicate the diagnosis and management of Pfeiffer syndrome. J Craniofac Surg. 2013 Sep. 24(5):1829-32. [Medline].
Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol. 2009 Sep. 18(9):741-9. [Medline].
Hornyak TJ. The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation. Adv Dermatol. 2006. 22:201-18. [Medline].
Tachibana M. A cascade of genes related to Waardenburg syndrome. J Investig Dermatol Symp Proc. 1999 Sep. 4(2):126-9. [Medline].
Tassabehji M, Read AP, Newton VE, et al. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature. 1992 Feb 13. 355(6361):635-6. [Medline].
Tassabehji M, Newton VE, Read AP. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet. 1994 Nov. 8(3):251-5. [Medline].
Mollaaghababa R, Pavan WJ. The importance of having your SOX on: role of SOX10 in the development of neural crest-derived melanocytes and glia. Oncogene. 2003 May 19. 22(20):3024-34. [Medline].
Moore SW. The contribution of associated congenital anomalies in understanding Hirschsprung's disease. Pediatr Surg Int. 2006 Apr. 22(4):305-15. [Medline].
Park WJ, Meyers GA, Li X, et al. Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet. 1995 Jul. 4(7):1229-33. [Medline].
Park WJ, Theda C, Maestri NE, et al. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet. 1995 Aug. 57(2):321-8. [Medline].
Thomas I, Kihiczak GG, Fox MD, Janniger CK, Schwartz RA. Piebaldism: an update. Int J Dermatol. 2004 Oct. 43(10):716-9. [Medline].
Mollet I, Ongenae K, Naeyaert JM. Origin, clinical presentation, and diagnosis of hypomelanotic skin disorders. Dermatol Clin. 2007 Jul. 25(3):363-71, ix. [Medline].