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Skin Presentations/Pigmentation

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Sharply demarcated flat hyperpigmented macules ("coffee with milk" color) present at birth or appearing in early childhood. One or two isolated CAL macules are common in the general population (up to 25% of healthy children have at least one) and rarely signal a syndrome. The clinical decision is whether number, size, shape, or accompanying features push the patient into the multiple-CAL syndromic differential. The neurofibromatosis type 1 diagnostic criterion (six or more CALs over 5 mm before puberty or over 15 mm after puberty) is the operational threshold most clinicians anchor on.

Three features narrow the differential:

  1. Number and size: isolated and small versus multiple and large.
  2. Border shape: smooth "coast of California" border versus irregular jagged "coast of Maine" border. Coast-of-Maine is a McCune-Albright signature.
  3. Accompanying features: axillary or inguinal freckling, Lisch nodules, neurofibromas, lentigines, fibrous dysplasia, early endocrinopathy, hematologic or solid tumors in childhood, intellectual disability, pigmentary dysmorphism.

The CMMRD pattern (very large CALs in a child with personal or family history of childhood malignancy) is the discriminating must-not-miss diagnosis hidden in the NF1-mimic differential.

Most common multiple-CAL syndromes

  • Neurofibromatosis type 1 (NF1, AD; ~50% de novo): six or more CALs, axillary or inguinal freckling (Crowe sign), Lisch nodules on slit lamp, cutaneous and plexiform neurofibromas, optic pathway glioma, bony lesions (tibial dysplasia, sphenoid wing dysplasia), learning disability. CALs are the earliest visible feature; freckling appears in school years; neurofibromas in adolescence.
  • Legius syndrome (SPRED1, AD): an NF1 mimic. Multiple CALs + axillary freckling + macrocephaly + learning difficulties without neurofibromas, Lisch nodules, or tumor predisposition. About 2% of patients meeting NF1 CAL/freckling criteria have Legius instead. Test concurrently on NF1 panels.

Other syndromic differentials

  • McCune-Albright syndrome (postzygotic mosaic GNAS activating mutation): the triad is CALs + polyostotic fibrous dysplasia + endocrine hyperfunction (precocious puberty most classic, also hyperthyroidism, growth hormone excess, Cushing). CALs are characteristically large, segmental, midline-respecting, with the irregular "coast of Maine" border that distinguishes them from neurofibromatosis type 1.
  • Noonan syndrome with multiple lentigines (NSML / formerly LEOPARD) (PTPN11, RAF1, BRAF): multiple lentigines (small, dark, scattered) over the trunk, sometimes with a few CALs. _L_entigines, _E_CG conduction abnormalities, _O_cular hypertelorism, _P_ulmonic stenosis, _A_bnormal genitalia, _R_etarded growth, _D_eafness. The lentigines, not the CALs, are the visual hallmark.
  • Constitutional mismatch repair deficiency (CMMRD) (biallelic MLH1, MSH2, MSH6, or PMS2): autosomal recessive; both parents are Lynch syndrome carriers. Very large CALs, often with irregular borders, plus childhood malignancy (T-cell lymphoma, leukemia, brain tumors especially glioblastoma, GI cancers in adolescence). Misdiagnosed as neurofibromatosis type 1 historically because the skin overlaps. The discriminating clue is the childhood cancer history in the patient or siblings.
  • Neurofibromatosis type 2 (NF2): a few CALs are described but the dominant features are bilateral vestibular schwannomas, meningiomas, juvenile cataracts. CALs are not the entry point.
  • Tuberous sclerosis complex (TSC1, TSC2): a small number of CALs may occur, but hypopigmented ash-leaf macules, shagreen patches, facial angiofibromas, and the systemic features dominate.
  • Russell-Silver syndrome (11p15 / 7 imprinting): a few CALs may occur; the diagnosis is driven by IUGR, postnatal short stature, body asymmetry, and triangular face.
  • Bloom syndrome (BLM): photosensitive facial rash + short stature + cancer predisposition + CALs in some patients.
  • Six or more CALs over 5 mm in a prepubertal child → start the neurofibromatosis type 1 work-up. If exam stays negative for Lisch nodules and neurofibromas into late childhood, consider Legius.
  • Multiple CALs + axillary freckling + macrocephaly + no neurofibromas at age 10 → Legius syndrome. Confirm with SPRED1 testing or an NF1/SPRED1 dual panel.
  • Large segmental CAL with irregular "coast of Maine" border + precocious puberty → McCune-Albright.
  • Very large CALs + childhood lymphoma, leukemia, brain tumor, or GI cancer → CMMRD until proven otherwise. Test both parents (Lynch carriers).
  • Scattered small dark lentigines covering the trunk + hypertelorism + pulmonic stenosis → Noonan with multiple lentigines.
  • Children of two Lynch syndrome parents carry a CMMRD risk; family history is the screen.
  1. Careful skin exam under good light (and Wood's lamp): count and measure each CAL; document freckling (axillary, inguinal, periorbital); look for hypopigmented macules (TSC), lentigines (NSML), shagreen patch, neurofibromas.
  2. Slit-lamp exam for Lisch nodules: distinguishes neurofibromatosis type 1 from Legius after age 6 or so.
  3. Detailed three-generation family history: neurofibromatosis type 1 (autosomal dominant, half de novo); Lynch syndromes in the parents (CMMRD risk); fibrous dysplasia or precocious puberty in relatives.
  4. Imaging targeted to suspicion:
    • Brain MRI if neurofibromatosis type 1 suspected (optic pathway glioma, T2 hyperintensities) or CMMRD (glioblastoma surveillance).
    • Skeletal survey or targeted X-rays if McCune-Albright suspected.
    • Whole-body MRI surveillance in CMMRD per consensus protocols.
  5. Genetic testing:
    • First-line for neurofibromatosis type 1 phenotype: combined NF1/SPRED1 panel.
    • McCune-Albright: somatic GNAS testing on affected tissue (skin biopsy, bone), not blood (mosaic; blood often negative).
    • CMMRD: germline MLH1, MSH2, MSH6, PMS2, plus tumor immunohistochemistry for MMR proteins if a tumor is present.
  6. Pediatric oncology referral the same week if CMMRD is on the differential. Surveillance protocols start in infancy.
  • Multiple CALs without freckling, Lisch nodules, or neurofibromas by late childhood is Legius until proven otherwise. A confident Legius diagnosis removes the tumor predisposition counseling that neurofibromatosis type 1 requires.
  • "Coast of Maine" border is the McCune-Albright signature. Smooth borders are neurofibromatosis type 1.
  • A child with very large CALs and a childhood cancer is CMMRD until proven otherwise. This is the single highest-yield "do not miss" in the CAL differential because surveillance changes outcomes.
  • Test SPRED1 when you test NF1. Reflexive concurrent testing avoids the diagnostic odyssey of an NF1-negative result followed by a "now what" pause.
  • Lentigines and CALs look similar at a glance; they are different lesions. Lentigines are smaller, darker, and scattered; CALs are larger, lighter, and few. The distinction maps to different syndromes.