Café-au-Lait Macules and Neurofibromatosis Associations
Tan-brown macules that, when numerous or large, prompt evaluation for NF1 and related disorders.
Also known as: CALM, café-au-lait spot, NF1, neurofibromatosis type 1, von Recklinghausen disease
Overview
Café-au-lait macules (CALMs) are well-circumscribed, uniformly pigmented light- to dark-brown macules and patches present from birth or acquired in early childhood. Single small CALMs are common and benign, but multiple or large CALMs may herald neurofibromatosis type 1 (NF1), Legius syndrome, McCune-Albright syndrome, or other genodermatoses.
Epidemiology
Approximately 10-30% of healthy individuals have at least one CALM. NF1 occurs in about 1 in 3,000 births (autosomal dominant, full penetrance, variable expressivity, 50% de novo mutations of the NF1 gene on 17q11.2). Legius syndrome — clinically similar to mild NF1 — is rarer and due to SPRED1 mutations.
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Race-independent prevalence; CALMs may appear more prominent on lighter skin
Genetic mosaicism (segmental NF1) — CALMs and neurofibromas restricted to a body segment
Pathophysiology
CALMs result from increased melanin production by basal melanocytes with normal melanocyte density; on biopsy, giant melanosomes ('macromelanosomes') may be seen. NF1 is caused by loss-of-function mutations in the NF1 tumor-suppressor gene encoding neurofibromin, a Ras-GAP; loss accelerates Ras-MAPK signaling, predisposing to a wide range of neural and other tumors (neurofibromas, optic gliomas, malignant peripheral nerve sheath tumors).
Clinical presentation
Symptoms
CALMs alone are asymptomatic
NF1: progressive cutaneous and subcutaneous neurofibromas in adolescence and adulthood, learning disabilities, scoliosis, short stature, headaches, vision changes (optic glioma), hypertension (renal artery stenosis or pheochromocytoma)
Family members may have similar features (autosomal dominant inheritance)
Signs / physical exam
CALMs: 0.5-20 cm uniformly tan-brown, sharply demarcated macules/patches
Hypertension or thyroid mass (medullary thyroid carcinoma in MEN2 — distinct)
Classic findings
Six or more CALMs ≥5 mm prepubertal (or ≥15 mm postpubertal), axillary/inguinal freckling, Lisch nodules, neurofibromas in NF1.
Differential diagnosis
Legius syndrome — Multiple CALMs and axillary freckling without neurofibromas, Lisch nodules, or tumor predisposition; SPRED1 mutation; gene testing distinguishes
McCune-Albright syndrome — Few large CALMs with 'coast of Maine' (irregular) borders, polyostotic fibrous dysplasia, precocious puberty; GNAS mosaic mutation
Neurofibromatosis type 2 (NF2) — Bilateral vestibular schwannomas, meningiomas, ependymomas; CALMs less prominent
Constitutional mismatch repair deficiency (CMMRD) — Multiple CALMs + childhood-onset hematologic, brain, or GI cancers; biallelic MMR gene mutations
Becker nevus — Unilateral, large, hairy, irregular tan patch on shoulder/back; appears in adolescence
Lentigines (LEOPARD syndrome) — Many small dark macules; cardiac, ECG, growth, and genital findings; PTPN11 mutation
Pigmentary mosaicism (segmental pigmentation disorders) — Hyper- or hypopigmented patches following Blaschko lines or broad-band patterns; mosaic genetic change
Diagnostic workup
Diagnostic criteria
Revised NIH/NF1 criteria (Legius et al., 2021) — at least two of the following: ≥6 CALMs >5 mm prepubertal (>15 mm postpubertal); ≥2 cutaneous/subcutaneous neurofibromas or one plexiform neurofibroma; axillary or inguinal freckling; optic pathway glioma; ≥2 Lisch nodules or ≥2 choroidal abnormalities on OCT; distinctive bony lesion (sphenoid dysplasia, tibial pseudarthrosis, long-bone bowing); heterozygous pathogenic NF1 variant in normal tissue; or first-degree relative meeting NF1 criteria.
Labs
Genetic testing (NF1 gene sequencing and deletion/duplication analysis; SPRED1 testing for suspected Legius syndrome) when criteria are met or uncertain
Family genetic counseling
Endocrine evaluation if precocious puberty or growth abnormalities
Imaging
Brain and orbital MRI when neurologic or visual symptoms or for surveillance per current NF1 guidelines
Spine MRI for scoliosis or neurologic signs
Skeletal survey if McCune-Albright suspected (polyostotic fibrous dysplasia)
Imaging-directed evaluation of plexiform neurofibromas (whole-body MRI in select cases)
No specific therapy for isolated CALMs; reassurance and observation
NF1: multidisciplinary surveillance — annual physical exam, ophthalmology (yearly until age 8, then less frequent), neurodevelopmental assessment in childhood, blood pressure monitoring, dermatology surveillance for new neurofibromas and MPNST signs
Symptomatic neurofibromas: surgical excision when painful, cosmetically distressing, or functionally limiting
Selumetinib (MEK inhibitor) — FDA-approved 2020 for symptomatic inoperable plexiform neurofibromas in pediatric NF1 (SPRINT trial, Gross et al., NEJM 2020)
Pain control, physical therapy, and psychosocial support
Second-line / adjunct
Q-switched and pico-second lasers for cosmetic treatment of selected CALMs (variable response, frequent recurrence)
MEK inhibitors (selumetinib, trametinib) for plexiform neurofibromas; trials ongoing for cutaneous neurofibromas
Surveillance for malignant peripheral nerve sheath tumor (MPNST) — sudden growth, new pain, or neurologic deficit in a known neurofibroma warrants prompt MRI/PET and biopsy
Bisphosphonates and orthopedic management for fibrous dysplasia in McCune-Albright; treat precocious puberty per pediatric endocrinology
Complications
NF1: optic glioma (15-20% of children, often indolent), learning disabilities and ADHD (30-50%), scoliosis, hypertension (renal artery stenosis, pheochromocytoma), MPNST (lifetime risk ~8-13%), cardiovascular malformations, breast cancer (earlier onset in women with NF1)
Legius syndrome: generally benign course; no tumor predisposition like NF1
Psychosocial: stigma from visible neurofibromas; depression and anxiety
PANCE pearls
Six or more CALMs ≥5 mm in a child should prompt evaluation for NF1; remember the postpubertal threshold rises to ≥15 mm.
Axillary or inguinal freckling (Crowe sign) is a high-yield clinical clue distinguishing NF1 from isolated CALMs.
Legius syndrome mimics mild NF1 (CALMs + freckling) but lacks neurofibromas, Lisch nodules, and tumor predisposition — genetic testing differentiates.
Sudden growth, new pain, or neurologic deficit in a known neurofibroma is concerning for MPNST and warrants urgent imaging and biopsy.
Selumetinib is the first FDA-approved targeted therapy for symptomatic, inoperable plexiform neurofibromas in pediatric NF1 (SPRINT trial).
Always evaluate first-degree relatives — NF1 is autosomal dominant with full penetrance and variable expressivity.
References
Revised NF1 Criteria — Legius E et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation (Genet Med 2021)
SPRINT Trial — Gross AM et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas (NEJM 2020)
AAP/Children's Tumor Foundation — Miller DT et al. Health supervision for children with neurofibromatosis type 1 (Pediatrics 2019)
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