Piebaldism

Introduction

Piebaldism is a rare, autosomal dominant genetic disorder characterized by the absence of melanocytes in patches of skin and hair. Melanocytes are responsible for pigmentation, so their absence results in unpigmented areas of the scalp, forehead, chest, abdomen, and extremities that are present at birth and stable throughout life (Spritz, 1992). The most common symptoms of piebaldism is localized poliosis, depigmentation of the hair, and congenital leukoderma, white patches on the skin due to lack of pigmentation (Yang et al., 2013). A white forelock, a section of white hair above the forehead, is a common manifestation of piebaldism, however, the expressivity of any pigmentation symptoms varies between individuals. In some cases, development problems occur. Developmental anomalies can lead to anemia, sterility, deafness, and the absence of nerves controlling peristalsis in the gastrointestinal tract (Gilbert, 2010). The genetic basis of piebaldism stems from a mutation in the KIT proto-oncogene or the SNAI2 (Slug) gene (Lopez et al., 2011). Mutations of the KIT gene results in 75% of piebaldism cases and the remainder is usually attributed to mutations of SNAI2 (“Piebaldism”). Genetic screens are conducted to verify a clinical diagnosis because similar physical symptoms are present in other genetic, skin pigmentations disorders, such as vitiligo and Waardenburg Syndrome.

Figure 1. A white forelock expressed in a 2 year old girl

Figure 2. Pigmentation Phenotype

Genetic Basis

KIT Proto-oncogene

The KIT gene is located on the long arm of chromosome 4 and encodes a protein expressed in neural crest cells that controls precursor blood and stem cell proliferation and migration during development (Gilbert, 2010). If there is a mutation in this gene, the pigment, ear, gut, blood, and germ cells will not divide and proliferate properly, resulting in depigmented skin and hair, deafness, decreased peristalsis, anemia, and sterility (Gilbert, 2010). 28 different mutations have been documented in the KIT gene and the particular location and extent of the mutation correlates with the severity of piebaldism symptoms (Lopez et al., 2011). Binding of the KIT ligand to the KIT receptor leads to tyrosine kinase activation, which regulates cell proliferation and migration (Yang et al., 2013). A mutation in one of the seven domains in the KIT receptor leads to varying symptoms. A mutation in the extracellular domain results in mild piebaldism symptoms, while a mutation in an intracellular or cytoplasmic domain has been correlated with severe cases of piebaldism (Yang et al., 2013). Intracellular domain mutations severely impair the tyrosine kinase activation leading to more systemic developmental problems. The mouse Kit gene is homologous to the human KIT gene and an animal model can be used to study the mutations and phenotypes of the disease (Gilbert, 2010).

SNAI2 (Slug) Gene

The SNAI2 gene is located on the long arm of chromosome 8 and encodes a protein called snail 2, which is a zinc finger neural crest transcription factor (Lopez et al., 2010). Snail 2 binds to DNA and regulates expression of other genes. During embryonic development, snail 2 is required for the development of neural crest cells, which will eventually differentiate into many cell types, including melanocytes, hematopoietic stem cells, and germ cells (“Piebaldism”). Piebaldism results from a deletion of the SNAI2 gene. Without the SNAI2 gene and snail 2, the neural crest cells cannot develop, migrate, and differentiate correctly into specific cell types resulting in the symptoms of piebaldism.

Implications and Relevance

Overall, this experiment shows that KIT mutations result in the auburn hair typical of Piebaldism. The Tyrosine Kinase Activation executed in the final step of the KIT banding process triggers the regulation of the “migration of melanocytes, cell proliferation, differentiation, survival, melanogenesis, and melanosome transfer” (Yang et al., 2013). Loss of KIT signaling disrupts the proliferation and migration of melanocytes during development, resulting in lack of pigmentation (2013).

Previous studies suggested homogeneous MC1R, a gene associated with mammalian pigment production, in coordination with KIT mutation results in auburn hair. However, this experiment found that MC1R was not cosegregated with piebaldism, but rather a splicing mutation of the KIT gene (Yang et al., 2013). The splicing mutation identified in the study resulted in a deletion of exon 17 within the TK2 domain of KIT. This is in a highly conserved catalytic site of KIT (2013). Mutations of the TK domains have been shown to result in the most severe forms of piebaldism (GHR, 2013).

Mutations of KIT have been identified in other diseases, such as Gastrointestinal Stromal Tumors (Antonescu et al., 2003). The impact of KIT mutations has not been well defined. The mutation described in this paper has since been described to be the cause of café-au-lait macules and freckling seen in piebaldism, and not necessarily the previously assumed neurofibromatosis type 1, caused by a mutation in NF1 and resulting in skin depigmentation and benign tumor growth (Jia et al., 2015). Identification of a splicing mutation in KIT may help further studies in defining the implications of KIT mutations and their effect on human health.

Genetic Testing Methods

A Chinese family was chosen for this study because five members were affected by piebaldism and auburn hair color. The family was compared to a group of 60 healthy individuals who acted as controls.

To test for mutations in the KIT gene, genomic DNA was sequenced. DNA was extracted and purified from the patients' blood. The KIT gene was then amplified by PCR using synthetic primers. The PCR products were purified and ran through a sequencing reaction. The patients' KIT sequence was compared to a reference sequence to find discrepancies.

To test for splicing mutations in the KIT gene, RNA was sequenced. RNA was extracted from peripheral blood and used as a template to make a cDNA strand. PCR was performed using primers that flanked the patients' cDNA sequence of the KIT gene. The PCR products were separated on a polyacrylamide gel using electrophoresis and sequenced (Yang et al., 2013).

Treatment and Management

Pigment of the leukoderma has been shown to be rescued utilizing dermabrasion and split-skin grafting followed by minigrafting (Medscape 2015). Autologous punch grafting may also be used for repigmentation (2015). Unpigmented skin has an increased risk of sunburn and skin cancer when exposed to excessive sun, so special care should be taken to limit sun exposure. Piebaldism may be a symptom of Waardenburg syndrome, which can also be caused by mutations in SLUG (Waardenburg Syndrome, 2005). Therefore treatment for conditions such as deafness maybe also be required.

References

1. Antonescu, C. R., Sommer, G., Sarran, L., Tschernyavsky, S. J., Riedel, E., Woodruff, J. M., ... & DeMatteo, R. P. (2003). Association of KIT Exon 9 Mutations with Nongastric Primary Site and Aggressive Behavior KIT Mutation Analysis and Clinical Correlates of 120 Gastrointestinal Stromal Tumors. Clinical Cancer Research, 9(9), 3329-3337.

2. Bocchini, Carol A. "Piebaldism Trait." N.p., 16 July 2012. Web. 11 Feb. 2016.

3. Gilbert, Scott F. "Developmental Anatomy." Developmental Biology. 9th ed. Sunderland, MA: Sinauer Assoc., 2010. 27. Print.

4. Jia, W. X., Xiao, X. M., Wu, J. B., Ma, Y. P., Ge, Y. P., Li, Q., ... & Li, C. R. (2015). a novel missense KIT mutation causing piebaldism in one Chinese family associated with café-au-lait macules and intertriginous freckling.Therapeutics and clinical risk management, 11, 635.

5. Lopez, Veronica, MD, and Esperanza Jorda, MD PhD. “Piebaldism in a 2-year-old Girl.” Dermatology Online Journal, 2011. Web. 11 Feb. 2016.

6. "Piebaldism." Genetics Home Reference. U.S. National Library of Medicine, 2013. Web. 11 Feb. 2016.

7. Piebaldism Treatment & Management [Internet]. Medscape; 2015 [cited 2016 February 26] Available from: http://emedicine.medscape.com/article/1113248-treatment

8. Spritz, Richard A. "The Molecular Basis of Human Piebaldism." N.p., 1 July 1992. Web. 11 Feb. 2016.

9. Waardenburg Syndrome (WS) [Internet]. Atlas of Genetics and Cytogenetics in Oncology and Haematology; 2005. [cited 2016 February 26] Available from: http://atlasgeneticsoncology.org/Kprones/WaardenburgID10089.html

10. Yang, Yong-jia, Rui Zhao, Xin-yu He, Lioping Li, Kewei Wang, Liu Zhaou, Ming Tu, Jin-song Tang, Zhiguo Xie, and Yi-min Zhu. "A Novel Splicing Mutation of KIT Results in Piebaldism and Auburn Hair Color in a Chinese Family." BioMed Research International, 2013. Web. 11 Feb. 2016.

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