KIT Gene Mutation Causing Piebaldism Associated with Multiple Café Au-Lait Like Macules and Freckling: Delineating a Cause of this Coexistence

Abstract

Piebaldism is a rare genetic disorder of congenital leukoderma caused by mutation in KIT proto-oncogene receptor tyrosine kinase. We present a 10-year-old boy with congenital depigmented macules suggestive of piebaldism associated with café au lait macules and skin fold freckling complicating the diagnosis. A diagnosis of piebaldism was made via exome sequencing that showed a pathogenic variant of KIT gene with no pathogenic variants of NF1 or SPRED1 gene. Our current understanding of the KIT tyrosine kinase function may provide a better explanation into this phenotypic coexistence and does not necessarily represent an overlap with Neurofibromatosis type 1.

Introduction

Piebaldism is a rare disorder of melanoblast migration characterised by congenital stable leukoderma patches and white forelock.^[1] During embryonic life, KIT gene located on chromosome 4 affects the differentiation and migration of melanoblasts from neural crest, thus explaining characteristic absence of melanocytes from leucoderma patches.^[2] Another gene encoding snail family zinc finger 2 (SNAI2/SLUG) has also been implicated. Hyperpigmentation is usually noted as islands within the depigmented patches or at its periphery. Coexistence of café au lait like macules (CALM) and freckling leads to diagnostic dilemma.^[3] Without genetic testing, these overlapping presentations make it difficult to assess prognosis in such patients.

Case Report

A 10-year-old boy born of a second-degree consanguineous marriage presented with stable depigmented patches on the forehead, chest, abdomen and mid extremities since birth. Over time, multiple hyperpigmented lesions of varying sizes were noted on the trunk. He was developmentally normal with no visual or hearing difficulties. A similar pattern of depigmentation was noted in the father. However, due to a fatal road traffic accident, we were unable to examine him but the family provided old photographs that cemented similar clinical findings in the deceased father.

Cutaneous examination showed white forelock and diamond shaped depigmented patch on the central forehead with poliosis of medial eyebrows [Figure 1] and a large depigmented patch on his lower chest and abdomen. Similar patches were seen on the mid upper and lower extremities [Figure 2]. Islands of hyperpigmentation were noted within these depigmented macules. Distinct macules akin to CALM (6 in number ranging from 5 mm to 5 cm) were present on the chest and back. Discrete freckle-like pigmentation was present over normal skin with clustering over bilateral axillary and inguinal folds [Figures 3a, 3b and 4]. There were no neurofibromas. Ophthalmological and audiometry studies were normal.

Figure 1: Diamond shaped depigmentation over forehead with anterior white forelock and poliosis of medial eyebrows

Figure 2: Depigmentation with islands of hyperpigmentation over lower chest and abdomen. Multiple CALM and freckles over neck and upper chest

Figure 3: (a) Multiple freckles over the right axilla. (b) Multiple freckles over the left axilla

Figure 4: Multiple CALM and freckles over back

After obtaining a written informed consent, clinical exome sequencing was performed on proband using next generation sequencing.

A heterozygous missense mutation in exon 12 of KIT gene (ch4:g.54727909G>A) that resulted in amino acid substitution of threonine for alanine at codon 621 (c. 1861G>A, p.Ala621Thr) that lies in the protein kinase domain of KIT protein, reported to be ‘likely pathogenic’ was present [Figure 5]. This variant was previously reported.^[4] No pathogenic variant was observed for NF1 or SPRED1 gene. This variation could not be confirmed with sanger sequencing in the father due to his demise.

Figure 5: Integrative genomics viewer: Exon 12 of KIT gene showing amino acid substitution of threonine for alanine at codon 621

Discussion

Piebaldism is a rare genetic pigmentary disorder with an incidence of less than 1:20000.^[2]

Microphthalmia transcription factor (MITF), also termed master transcription regulator, holds a strong role in melanocyte survival, migration and differentiation. Transcription factors and extracellular signalling pathways regulate the expression of MITF. Mutations in MITF or any of the regulatory genes can cause a striking pattern of depigmentation.^[5]

CALM and freckling have been occasionally reported in patients with piebaldism where diagnostic criteria for Neurofibromatosis 1 (NF1) were met. Hence, the coexistence of NF1 and piebaldism was theorised. The reported cases were documented to not develop neurofibromas. The proposed theories in such cases were KIT preventing neurofibroma formation and haploinsufficiency of neurofibromin rescuing pigmentary defect by restoring KIT signalling pathway.^[6] Both theories reinforced the speculating overlap of these two genetic disorders.

However, better understanding of KIT tyrosine kinase function gives us an alternative pathway that not only explains the coexistence of CALM and freckling in piebaldism but also debunks the older theories. Chiu et al.^[6] first proposed that mutations in KIT binding domain of Sprouty-related, ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1) gene could explain its insufficient activation leading to insufficient suppression of Ras/mitogen-activated protein kinase (MAPK) pathway that then results in hyperpigmentation akin to CALM and freckling. KIT cell surface receptor tyrosine kinase, activated by its ligand stem cell factor (SCF) phosphorylates several signal transduction pathways, including SPRED1 via its KIT binding domain. SPRED1 normally negatively regulates Ras/MAPK pathway.^[7] Inadequate phosphorylation of SPRED1 protein’s KIT ligand will lead to hyperactivity of Ras/MAPK pathway which is implicated in the pathogenesis of CALM [Figure 6]. Resultant phenotype would have both depigmentation of piebaldism and hyperpigmentation of Legius-like syndrome. Similar clinical phenotypes with some reporting a genetic backup have been reported before [Table 1].

Figure 6: Normal KIT and SPRED1 functioning (a) with RAS/MAPK pathway (inset) and effect of mutation in KIT gene causing inadequate SPRED 1 functioning (b). MAPK- mitogen-activated protein kinase, ERK- extracellular signal-regulated kinases, MEK-MAPK/ERK Kinase, SPRED 1- Sprouty-related, ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1. Adapted from Saleem MD,^{[ 5 ]} Larribère L et al.^{[ 7 ]} and Wakioka T et al ^{[ 14 ]}

Table 1: Phenotype and genotype of all reported patients and families of Piebaldism with café au lait macules and freckling

Our case report shows a tyrosine kinase domain mutation in the KIT gene without any NF1 or SPRED1 mutation showing no true overlap of these genetic disorders. Similar molecular confirmation of KIT mutation without NF1 and SPRED1 mutation has been made earlier by Nagaputra JC et al. (2018)^[3] and Stevens CA et al. (2012)^[12] supporting the hypothesis of Chiu et al.^[6] Risk of co-segregation of the above-mentioned genes is highly unlikely because of their locations on different chromosomes.

Conclusion

We provide a genetic backup to the theory that the tyrosine kinase KIT binding domain on SPRED1 would explain this phenotypic variation of CALM and freckling in piebaldism and rebutting the coexistence of these genodermatoses. This form of hyperpigmentation is just an extension of the piebaldism phenotypic spectrum, and these patients need not be subjected to unnecessary and rigorous follow ups as they are not associated with development of tumours. This case also highlights the significance of molecular confirmation for appropriate genetic counselling in such cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.