1 Department of Dermatology-Division of Pediatric Dermatology, Medical College of Wisconsin and Children’s Hospital of Wisconsin
2 Department of Pediatrics-Section of Genetics, Medical College of Wisconsin and Children’s Hospital of Wisconsin
A 5 year old boy presented with a congenital depigmented patch of the forehead, as well as acquired white forelock, depigmentation of the medial eyebrows, and depigmented patches of the body. Additionally, he had started to develop multiple café-au-lait macules (CALMs) and freckling of the axillae and inguinal folds. His past history was significant for mild asthma, chronic sinusitis, surgical excision of a thyroglossal duct cyst, and umbilical hernia repair. There was no developmental delay or hearing loss. Given concerns by other providers for tuberous sclerosis, neurofibromatosis type 1 (NF1), and Waardenburg syndrome, the patient had a prior work-up consisting of a normal brain MRI, echocardiogram, audiogram, and ophthalmology exam. His family history was significant for similar skin findings in his father, paternal half-brother, paternal grandmother, and paternal great-grandfather.
On examination, there was a diamond-shaped, depigmented patch on the midline forehead with adjacent white forelock and poliosis of the medial eyebrows. On the midline chest and bilateral calves were depigmented patches. Scattered on the entire body were numerous CALMs, twelve of which were >1 cm in size. There were subtle freckles present in the bilateral axillae and inguinal folds. There were no neurofibromas, iris heterochromia, or dystopia canthorum. There was relative macrocephaly; head circumference was 50th percentile, while height and weight were 25th percentile. KIT gene testing was performed, and a novel missense mutation was detected in the intracellular tyrosine kinase domain.
Piebaldism is a disorder of melanocyte development resulting in leukoderma (white skin) and poliosis (white hair), characteristically a white forelock.1 It is caused by an autosomal dominant mutation in the KIT proto-oncogene.2 The KIT protein product is a receptor tyrosine kinase that activates several intracellular signaling pathways. Legius syndrome is characterized by multiple CALMs and axillary or inguinal freckling, without other features of NF1 such as neurofibromas, Lisch nodules, and central nervous system tumors.3 Autosomal dominant loss-of-function mutations in SPRED1, resulting in induction of the Ras/MAP kinase pathway, is the cause of Legius syndrome.4 Phosphorylation of SPRED1 by kinases such as KIT is required for activation and efficient suppression of the Ras/MAP kinase pathway.4,5
There have been five patients reported to have congenital depigmentation consistent with piebaldism, as well as multiple CALMs and intertriginous freckling.6-9 The prior published reports attribute the cutaneous findings to the co-existence of piebaldism with NF1. We believe that these cases are better classified as a variant of piebaldism, where loss of SPRED1 function due to inadequate phosphorylation by KIT is the cause for the CALMs and freckling seen in some patients. To date, SPRED1 mutations and Legius syndrome have not been associated with neurofibromas and other tumors, suggesting that piebaldism patients with multiple CALMs and axillary or inguinal freckling may not need the rigorous monitoring that NF1 patients require.
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