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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Question 1DermatologyMedium
A 7-year-old boy is brought in for evaluation of multiple light-brown skin patches that his mother first noticed in infancy and that have increased in number over time. He has had difficulty in school and is in a reading-support program. On examination, there are eight uniformly tan, sharply demarcated macules measuring 6 to 12 mm on the trunk and limbs, along with freckling in both axillae and the groin. Slit-lamp examination shows two small pigmented nodules on each iris. His father has similar skin patches and a few soft cutaneous nodules on his back. Which of the following is the most likely diagnosis?
ANeurofibromatosis type 1
BLEOPARD syndrome
CMcCune-Albright syndrome
DLegius syndrome
Reveal answer & full explanation
Correct answer: A — Neurofibromatosis type 1
ANeurofibromatosis type 1✓
BLEOPARD syndrome
CMcCune-Albright syndrome
DLegius syndrome
Why Neurofibromatosis type 1 is correct
This child meets the revised NIH/NF1 diagnostic criteria (Legius et al., 2021): he has 6 or more cafe-au-lait macules >5 mm (prepubertal threshold), axillary AND inguinal freckling (Crowe sign), and 2 or more Lisch nodules (iris hamartomas). Any two features establish the diagnosis, and he has three.
Autosomal dominant inheritance is supported by an affected first-degree relative (father with cafe-au-lait macules and cutaneous neurofibromas); NF1 has full penetrance with variable expressivity.
Learning disability/ADHD (30-50% of patients) fits the school difficulties, and the combination of Lisch nodules plus freckling reliably distinguishes NF1 from isolated cafe-au-lait macules.
Why the others are wrong
Legius syndrome mimics mild NF1 with multiple cafe-au-lait macules and axillary freckling, but it lacks Lisch nodules and neurofibromas; the iris nodules here and the father's cutaneous neurofibromas argue against it, and it is caused by a SPRED1 rather than NF1 mutation.
McCune-Albright syndrome features a few large cafe-au-lait macules with irregular coast-of-Maine borders, polyostotic fibrous dysplasia, and precocious puberty from a mosaic GNAS mutation; it does not cause Lisch nodules, freckling, or autosomal dominant inheritance.
LEOPARD syndrome, caused by a PTPN11 mutation, produces many small dark lentigines plus cardiac/ECG, growth, and genital abnormalities, not large uniform cafe-au-lait macules with Lisch nodules and freckling.
Question 2DermatologyMedium
An 8-year-old boy is brought in for evaluation of multiple skin findings. Examination reveals seven well-demarcated, uniformly tan-brown macules measuring 6-12 mm scattered over the trunk, along with freckling in both axillae and two small pigmented iris hamartomas. His mother has similar skin findings and a history of a benign nerve sheath tumor. Genetic testing confirms a pathogenic variant on chromosome 17q11.2. Which of the following best explains the findings?
ABiallelic mismatch repair loss causing genome-wide microsatellite instability
Why Loss-of-function neurofibromin causing unchecked Ras-MAPK pathway signaling is correct
The boy meets revised NIH/NF1 criteria (>=6 cafe-au-lait macules >5 mm prepubertal, axillary freckling, >=2 Lisch nodules, affected first-degree relative) with a confirmed variant at 17q11.2, the NF1 locus.
NF1 is a loss-of-function mutation in the NF1 tumor-suppressor gene encoding neurofibromin, a Ras-GAP (GTPase-activating protein). Loss of neurofibromin removes the brake on Ras, accelerating Ras-MAPK signaling and predisposing to neurofibromas, optic gliomas, and malignant peripheral nerve sheath tumors.
This pathway biology underpins selumetinib, a MEK inhibitor and the first FDA-approved targeted therapy for symptomatic inoperable plexiform neurofibromas in pediatric NF1.
Why the others are wrong
Activating GNAS mutation causing constitutive Gs-protein cyclic AMP signaling is the mosaic mechanism of McCune-Albright syndrome, which produces a few large cafe-au-lait macules with irregular (coast of Maine) borders, polyostotic fibrous dysplasia, and precocious puberty rather than freckling, Lisch nodules, or an autosomal dominant family history.
Gain-of-function PTPN11 mutation causing enhanced RAS-ERK phosphatase activity underlies Noonan/LEOPARD-spectrum disorders, which feature multiple small lentigines plus cardiac, ECG, growth, and genital findings rather than the CALM-plus-Lisch-nodule picture localizing to 17q11.2.
Biallelic mismatch repair loss causing genome-wide microsatellite instability is constitutional mismatch repair deficiency (CMMRD), which can mimic NF1 with multiple CALMs but is defined by childhood-onset hematologic, brain, or GI cancers from biallelic MMR mutations rather than a heterozygous NF1 variant.
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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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