Ash-leaf stain Q85.1

Already present at birth, clinically usually less conspicuous, disc-shaped, a few centimeters in size, but also larger, usually randomly distributed hypomelanotic, bright spots. The spots can be detected particularly well as negatives in Wood light. A number of spots > 5 is characteristic for the diagnosis of M. Pringle.

The hypopigmentations (ash leaf spots) observed in patients with tuberous sclerosis (TSC) are characterized by functional disturbance of the epidermal and follicular melanocytes. The density of active melanocytes is normal. The dendrites of the melanocytes are poorly developed, the melanosomes are smaller and less melanized than in melanocytes of uninvolved skin and hair. The number of melanosomes within the melanocytes is reduced, but without abnormal autophagic aggregation. These dysfunctional melanocytes release fewer melanosomes to the surrounding keratinocytes, so that the overall melanin content in the affected skin and hair is reduced (Jimbow K 1997).

This is caused by mutations in the TSC1/TSC2gene. The gene products of TSC1/2 form a complex that downregulates the activity of the mammalian target of rapamycin complex1(mTORC1) in energy-limiting states. mTORC1 is a regulator of protein synthesis. It can be assumed that the development of hypomelanotic spots is associated with constitutive activation of mTORC1, while slight deregulation of mTORC1 enables the maintenance of normal skin (Møller LB et al. 2017). mTORC1 activation leads to hyperactivation of glycogen synthase kinase 3β (GSK3β), followed by phosphorylation and loss of beta-catenin from the nucleus, resulting in decreased expression of microphthalmia-associated transcription factor(MITF). This leads to a consecutive reduction in tyrosinase activity. In addition, other genes that are required for melanogenesis are downregulated (Cao J et al. 2017).

Importantly, primary melanocytes isolated from hypomelanotic patches of TSC patients showed reduced TSC2 protein expression. One biallelic TSC2 mutation was germline-related and a second was acquired in the melanocytes of the hypopigmented patches (somatic mutation). These results suggest that the TSC/mTORC1/AKT/GSK3β/β-catenin/MITF axis plays a central role in the regulation of melanogenesis (Cao J et al. 2017).

1. Cao J et al. (2017) Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation. J Clin Invest 127:349-364.
2. Jimbow K (1997) Tuberous sclerosis and guttate leukodermas. Semin Cutan Med Surg 16:30-35.
3. Møller LB et al. (2017) Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex. Mol Genet Metab 120:384-391.