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Patchy hypopigmentation

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Skin Presentations/Pigmentation

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A child or adult with one or more areas of skin lighter than the surrounding background. The lesion may be a single discrete macule, a constellation of small patches, a streaked or whorled pattern along developmental lines, or near-total skin and hair hypopigmentation. The reasoning frame is whether the pigment loss is localized (a few discrete macules or patches, often with sharp borders) versus generalized (skin, hair, iris all involved), and whether there are systemic features that move the patient out of an isolated-skin differential and into a syndromic one.

Three features sort the differential:

  1. Distribution: isolated discrete macule(s) versus segmental whorls/streaks along Blaschko lines versus generalized (skin + hair + iris).
  2. Pattern stability: congenital and stable (piebaldism, Waardenburg, albinism) versus acquired and progressive (vitiligo).
  3. Systemic features: seizures, intellectual disability, sensorineural hearing loss, immunodeficiency, bleeding diathesis, ocular abnormalities. A hypopigmented macule with any of these moves the work-up to a syndromic differential.

Localized hypopigmented macules with systemic features

  • Tuberous sclerosis complex (TSC1, TSC2, AD): ash-leaf macules (oval, lance-shaped hypopigmented patches) are often the earliest visible sign, present at birth or in early infancy. Wood's lamp enhances visibility against unaffected skin. The diagnosis is locked in by additional findings that appear over time: shagreen patch (lumbosacral connective-tissue nevus), facial angiofibromas (mid-face, after age 2-3), cardiac rhabdomyoma (often the prenatal clue), cortical tubers + subependymal nodules + SEGAs on brain MRI, renal angiomyolipomas + cysts, lymphangioleiomyomatosis in adult women. Surveillance is multisystem; everolimus (mTOR inhibitor) is approved for SEGAs, renal AMLs, and refractory seizures.
  • Hypomelanosis of Ito (mosaic chromosomal anomalies): whorls, streaks, and patches of hypopigmentation along the lines of Blaschko; often unilateral or asymmetric. Variable neurodevelopmental features (seizures, ID), ocular, dental, and skeletal anomalies. Karyotype on skin fibroblasts (not just blood) is often needed to detect the mosaic abnormality.
  • Incontinentia pigmenti (IKBKG, X-linked dominant, lethal in males): the classic progression is vesicular → verrucous → hyperpigmented swirls → hypopigmented streaks along Blaschko lines (the chronic, "burned-out" phase). Dental, ocular, and CNS features support the diagnosis.

Congenital and stable, localized

  • Piebaldism (KIT, AD): congenital, non-progressive white forelock + sharply demarcated ventral midline depigmented patches (forehead, chin, anterior trunk, mid-extremities). Hyperpigmented islands within the depigmented patches are characteristic. Systemic features absent.
  • Waardenburg syndrome (PAX3, MITF, SOX10, EDN3, EDNRB, AD or AR): white forelock + dystopia canthorum + sensorineural hearing loss + heterochromia iridum + patchy depigmentation. The auditory-pigmentary overlap is the recognition pattern; type 4 includes Hirschsprung disease.

Generalized hypopigmentation (skin + hair + iris)

  • Oculocutaneous albinism (TYR most common, also OCA2, TYRP1, SLC45A2, AR): generalized hypopigmentation of skin and hair from birth + iris transillumination + foveal hypoplasia + nystagmus + reduced visual acuity + photophobia. Skin-cancer surveillance is lifelong.
  • Chédiak-Higashi syndrome (LYST, AR): partial (silvery) albinism + immunodeficiency + bleeding tendency + progressive neurodegeneration. Giant cytoplasmic granules in leukocytes on peripheral smear are pathognomonic. Hematopoietic stem cell transplant addresses the immune/hematologic phenotype but not the neurologic course.
  • Hermansky-Pudlak syndrome (multiple HPS genes, AR): oculocutaneous albinism + platelet storage-pool deficiency (bleeding). Specific subtypes add pulmonary fibrosis (HPS-1, HPS-4), granulomatous colitis, or neutropenia.

Acquired

  • Vitiligo: acquired autoimmune depigmentation; symmetric well-demarcated white patches often over acral surfaces, periorificial regions, and sites of friction. Familial clustering is common; associated with thyroid autoimmunity, type 1 diabetes, pernicious anemia. Not "genetic" in the Mendelian sense but counts in the differential.
  • Ash-leaf macule on a baby (sometimes only visible under Wood's lamp) → check for tuberous sclerosis complex. Prenatal cardiac rhabdomyoma + ash-leaf macules at birth is the textbook setup.
  • Whorls and streaks along Blaschko lines → hypomelanosis of Ito; karyotype the skin fibroblasts, not just the blood.
  • White forelock + sensorineural hearing loss + heterochromia → Waardenburg. Without hearing loss, with ventral midline patches → piebaldism.
  • Generalized hypopigmentation + nystagmus + iris transillumination → oculocutaneous albinism. Add easy bruising → Hermansky-Pudlak. Add recurrent infections + giant granules on smear → Chédiak-Higashi.
  1. Wood's lamp exam to enhance hypopigmented lesion borders (essential for ash-leaf macules and fair-skinned patients).
  2. Detailed family and developmental history: seizures, ID, hearing loss, bleeding, recurrent infections, cancer.
  3. Targeted imaging based on suspected diagnosis: brain MRI + renal US + echo for TSC; audiogram for Waardenburg.
  4. Slit-lamp / ophthalmology exam: iris transillumination (albinism), foveal hypoplasia (albinism), Lisch nodules (NF1 mimics).
  5. Peripheral blood smear if Chédiak-Higashi is on the differential (giant granules).
  6. Platelet aggregation studies if Hermansky-Pudlak is suspected.
  7. Targeted gene panel or exome based on the syndromic differential; TSC has a dedicated panel (TSC1/TSC2), albinism panels cover the OCA genes, Waardenburg panels cover PAX3/MITF/SOX10/EDN3/EDNRB.
  8. Karyotype + microarray on skin fibroblasts if hypomelanosis of Ito is suspected (mosaic abnormality may be undetectable in blood).
  • Ash-leaf macule on a baby is tuberous sclerosis until proven otherwise. It is often the only sign before angiofibromas appear at age 2-3; the cardiac rhabdomyoma may have already been seen on prenatal imaging.
  • Wood's lamp belongs at the bedside for any patient where a hypopigmented macule is part of the question. Subtle ash-leaf macules disappear in normal room light.
  • Whorls and streaks following Blaschko lines = mosaicism. The diagnostic yield from blood karyotype is poor; fibroblasts from a skin biopsy of an involved area are the right specimen.
  • Hypopigmentation + bleeding tendency is never one diagnosis. Sort by smear (giant granules → Chédiak-Higashi) versus platelet function (storage-pool deficiency → Hermansky-Pudlak).
  • A patient with oculocutaneous albinism needs lifelong dermatology surveillance. Cumulative UV exposure plus deficient melanin protection is the cancer-risk substrate.