Congenital Patterned Leukodermas Clinical Presentation

  • Author: Raymond E Boissy, PhD; Chief Editor: William D James, MD   more...
 
Updated: Jan 13, 2012
 

Physical

  • 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.
  • Persons with Apert syndrome present with craniosynostosis (premature fusion of cranial sutures), craniofacial anomalies, and asymmetric syndactyly of both the hands and the feet.[5, 6] 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.
Next

Causes

  • 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.[7, 8, 9, 10]
  • 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.[11]
  • 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.[7, 8, 12, 13]
  • 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.[14, 15]
  • 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.[7, 16, 17]
Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Raymond E Boissy, PhD  Director of Basic Science Research, Professor, Departments of Dermatology and Cell Biology, University of Cincinnati College of Medicine

Raymond E Boissy, PhD is a member of the following medical societies: Sigma Xi

Disclosure: University of Cincinnati None None

Coauthor(s)

Steven Hoath, MD  Director of Skin Sciences Institute, Professor of Pediatrics, Department of Pediatrics, University of Cincinnati College of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Kathryn Schwarzenberger, MD  Associate Professor of Medicine, Division of Dermatology, University of Vermont College of Medicine; Consulting Staff, Division of Dermatology, Fletcher Allen Health Care

Kathryn Schwarzenberger, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Contact Dermatitis Society, American Dermatological Association, Dermatology Foundation, Medical Dermatology Society, and Women's Dermatologic Society

Disclosure: Nothing to disclose.

Michael J Wells, MD  Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Van Perry, MD  Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery

Disclosure: Nothing to disclose.

Joel M Gelfand, MD, MSCE  Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

William D James, MD  Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Elsevier Royalty Other

References

  1. Boissy RE. Melanosome transfer to and translocation in the keratinocyte. Exp Dermatol. 2003;12 Suppl 2:5-12. [Medline].

  2. Boissy RE, Nordlund JJ. Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res. Feb-Apr 1997;10(1-2):12-24. [Medline].

  3. Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat. Apr 2010;31(4):391-406. [Medline].

  4. Samatha Y, Vardhan TH, Kiran AR, Sankar AJ, Ramakrishna B. Familial Crouzon syndrome. Contemp Clin Dent. Oct 2010;1(4):277-80. [Medline]. [Full Text].

  5. 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. Jan 2012;37(1):152-8. [Medline].

  6. 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].

  7. Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol. Sep 2009;18(9):741-9. [Medline].

  8. Hornyak TJ. The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation. Adv Dermatol. 2006;22:201-18. [Medline].

  9. Tachibana M. A cascade of genes related to Waardenburg syndrome. J Investig Dermatol Symp Proc. Sep 1999;4(2):126-9. [Medline].

  10. 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. Feb 13 1992;355(6361):635-6. [Medline].

  11. Tassabehji M, Newton VE, Read AP. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet. Nov 1994;8(3):251-5. [Medline].

  12. 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. May 19 2003;22(20):3024-34. [Medline].

  13. Moore SW. The contribution of associated congenital anomalies in understanding Hirschsprung's disease. Pediatr Surg Int. Apr 2006;22(4):305-15. [Medline].

  14. 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. Jul 1995;4(7):1229-33. [Medline].

  15. Park WJ, Theda C, Maestri NE, et al. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet. Aug 1995;57(2):321-8. [Medline].

  16. Giebel LB, Spritz RA. Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. Proc Natl Acad Sci U S A. Oct 1 1991;88(19):8696-9. [Medline].

  17. Thomas I, Kihiczak GG, Fox MD, Janniger CK, Schwartz RA. Piebaldism: an update. Int J Dermatol. Oct 2004;43(10):716-9. [Medline].

  18. Mollet I, Ongenae K, Naeyaert JM. Origin, clinical presentation, and diagnosis of hypomelanotic skin disorders. Dermatol Clin. Jul 2007;25(3):363-71, ix. [Medline].

  19. Puffenberger EG, Kauffman ER, Bolk S, et al. Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet. Aug 1994;3(8):1217-25. [Medline].

  20. Read AP, Newton VE. Waardenburg syndrome. J Med Genet. Aug 1997;34(8):656-65. [Medline].

  21. Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet. Nov 15 2004;131C(1):75-81. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.