Don't Be Rash: When a Birthmark Is a Warning Sign

Café-au-lait macules (CALMs) are common pigmented findings in children, yet their link to neurofibromatosis type 1 (NF1) drives parental anxiety. Most isolated spots carry no systemic significance, but their number, size, and timing can signal an underlying RASopathy.

In this episode of Don't Be Rash, the Society for Pediatric Dermatology's official podcast, host Andrew Krakowski, MD, spoke with Joseph Lam, MD, FRCPC, of BC Children's Hospital in Vancouver. Their conversation centered on separating benign CALMs from early NF1 and its mimics.

Unlike melanocytic nevi, CALMs reflect increased pigment rather than more melanocytes. Revised 2021 consensus criteria require 2 or more of 7 features for NF1, and CALMs qualify only at 6 or more, each over 5 mm before puberty or 15 mm after.¹ Other criteria include intertriginous freckling, neurofibromas, Lisch nodules, optic pathway glioma, distinctive bone lesions, and a pathogenic NF1 variant or affected parent.¹

Age shapes interpretation. In an Israeli cohort with molecular testing in Alabama, children younger than 29 months with 6 or more CALMs had an 80.4% risk of constitutional NF1.² Children older than 29 months with fewer than 6 or atypical CALMs carried a 0.9% risk.²

A separate St Louis cohort found most children with 6 or more typical CALMs met NF1 criteria by age 6 years.³ Children below the threshold still warrant periodic full-skin examinations as new spots and freckling emerge. Lisch nodules also become more likely with age, so their absence in an adolescent is reassuring.

Among NF1 mimics, Legius syndrome, caused by SPRED1 variants in the same RAS pathway, produces CALMs and intertriginous freckling without the full NF1 phenotype.¹ Maculopapular cutaneous mastocytosis presents with raised, less sharply demarcated brown lesions, and a positive Darier sign confirms the diagnosis.

Postzygotic McCune-Albright syndrome pairs segmental CALMs with polyostotic fibrous dysplasia and endocrine hyperfunction, including precocious puberty and neonatal Cushing syndrome. Segmental pigmentary mosaicism is far more common, and mosaic NF1 can mimic a speckled lentiginous nevus.

Genetic testing, now accepted in place of family history, is most useful when results change management.¹ A RASopathy panel including SPRED1 can separate NF1 from Legius syndrome, and affected siblings with unaffected parents should raise concern for constitutional mismatch repair deficiency. For confirmed NF1, health supervision guidance centers on regular surveillance, including routine blood pressure checks.⁴

Careful counting, age-adjusted risk estimates, and targeted referral allow clinicians to reassure most families while identifying children who need structured NF1 surveillance.

References

1. Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506-1513. doi:10.1038/s41436-021-01170-5

2. Ben-Shachar S, Dubov T, Toledano-Alhadef H, et al. Predicting neurofibromatosis type 1 risk among children with isolated café-au-lait macules. J Am Acad Dermatol. 2017;76(6):1077-1083.e3. doi:10.1016/j.jaad.2017.02.027

3. Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol. 2009;145(8):883-887. doi:10.1001/archdermatol.2009.169

4. Miller DT, Freedenberg D, Schorry E, et al. Health supervision for children with neurofibromatosis type 1. Pediatrics. 2019;143(5):e20190660. doi:10.1542/peds.2019-0660