Se debe sospechar mosaicismo genético cuando el paciente presente:
  • Trouble de croissance asymétrique.
    • Associées à des lésions pigmentaires de la peau à répartition inégale (telles que taches café au lait, naevus, etc.), notamment si elles présentent une répartition suivant les lignes de Blaschko.
    • Combiné avec des malformations vasculaires.
Principaux types de mosaïcisme : Selon la lignée cellulaire atteinte : somatique (a), gonosomale (b), germinale (c). Modèles reconnaissables de mutations en mosaïque dans la peau : lignes de Blaschko étroites (d), lignes de Blaschko larges (e), motif en damier (f), motif phylloïde (g), motif inégal sans séparation sur la ligne médiane (h). 
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1.
Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nat Rev Genet [Internet]. 2013 May [cited 2015 Oct 2];14(5):307–20. Available from: http://www.nature.com/nrg/journal/v14/n5/abs/nrg3424.html
Mosaïcisme cutané et troubles neurocutanés en mosaïque.
  • La présence d'un mosaïcisme pigmentaire cutané est un facteur de risque de troubles neurodéveloppementaux (jusqu'à 56 % présentent des manifestations extracutanées, qui peuvent être neurologiques, squelettiques, endocrinologiques, etc.).
  • Les maladies mosaïques peuvent avoir plusieurs causes génétiques sous-jacentes, allant des mutations ponctuelles aux réarrangements chromosomiques.
  • Le diagnostic différentiel des différents types de maladies mosaïques est difficile. Ils se caractérisent par la présentation d'un spectre phénotypique très large avec un degré élevé de variabilité clinique, puisque l'essence du mosacisme est la combinaison de plusieurs populations cellulaires avec des codes génétiques différents, et leur distribution et proportion sont aléatoires.
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1.
Kromann AB, Ousager LB, Ali IKM, Aydemir N, Bygum A. Pigmentary mosaicism: a review of original literature and recommendations for future handling. Orphanet Journal of Rare Diseases [Internet]. 2018 Mar 5 [cited 2019 July 20];13(1):39. Available from: https://doi.org/10.1186/s13023-018-0778-6
Réarrangements chromosomiques en mosaïque (CNV).
  • Le Hypomélanose Ito Il s'agit d'une maladie neurocutanée classique dans laquelle il existe un réarrangement chromosomique identifiable par biopsie (qui peut affecter plusieurs régions chromosomiques différentes), et qui provoque des modifications pigmentaires en affectant le développement de la crête neurale (neurocristopathie).
Maladies de la mosaïque monogénétique.
  • Ce sont des maladies de transmission autosomique dominante.
  • Certains d'entre eux ne sont pas compatibles avec la vie dans leur présentation constitutionnelle (ils conduisent à l'avortement ou à la mort fœtale, comme le syndrome de l'ENFANT), car le gène affecté a une grande importance évolutive, de sorte que seules les mosaïques avec un phénotype atténué survivent.
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1.
Ruggieri M, Praticò PD, Happle R. Mosaic Neurocutaneous Disorders and Their Causes. Seminars in Pediatric Neurology [Internet]. 2015 Nov 13 [cited 2015 Nov 13]; Available from: http://www.sciencedirect.com/science/article/pii/S1071909115000765
Mosaïcisme cérébral et malformations cérébrales :
  • Certaines malformations cérébrales sont dues à une mutation en mosaïque.
  • La distribution anatomique de la malformation peut aider à déduire qu'il s'agit d'une maladie mosaïque, la neuroimagerie est donc utile pour planifier l'étude génétique.
Lissencéphalie, hémimégalencéphalie, syndrome du double cortex.
Dysplasie corticale focale.
Le type de malformation cérébrale dépendra du moment de l'apparition de la mutation somatique au cours de l'organogenèse cérébrale.
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1.
Rodin RE, Walsh CA. Somatic Mutation in Pediatric Neurological Diseases. Pediatric Neurology [Internet]. 2018 [cited 2018 Dec 4];87:20–2. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0887899418308580
Techniques de diagnostic du mosaïcisme cérébral.

Le mosaïcisme génétique n'est souvent pas détectable dans le sang périphérique et il est nécessaire de réaliser une étude dans le tissu affecté.

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1.
Ye Z, McQuillan L, Poduri A, Green TE, Matsumoto N, Mefford HC et al. Mutation somatique : La génétique cachée des malformations cérébrales et des épilepsies focales. Recherche sur l'épilepsie [Internet]. 2019 [cité le 20 août 2019];155:106161. Disponible à partir de : https://linkinghub.elsevier.com/retrieve/pii/S0920121119301810
Héritage et conseil génétique en mosaïcisme.
Types de mosaïcisme basés sur la génétique.
  • Les maladies mosaïques surviennent en raison d’une mutation postzygotique de novo survenue chez l’individu lui-même et ne sont pas héréditaires (par définition).
  • Ils ne peuvent être transmis que si la personne affectée est porteuse de la mutation germinale (mosaïcisme germinal).
  • Si la maladie est transmise, la présentation clinique chez la progéniture ne sera pas en mosaïque, mais sous la forme d'une mutation constitutionnelle.
Traitement spécifique
  • Il existe des alternatives thérapeutiques spécifiques pour certaines maladies mosaïques, notamment celles qui affectent les gènes de la voie PI3K/AKT et de la voie RAS/RAF.
Protocolo diagnóstico

🧠🧬 Algoritmo clínico: Mosaicismo cutáneo pigmentario → riesgo neurodesarrollo

1️⃣ Confirmar que el patrón cutáneo es realmente blaschkoide

Claves clínicas:

  • Líneas en “S” en tronco, “V” en espalda, curvas en extremidades
  • Respeta líneas medias (no dermatomérico, no vascular)
  • Hiper- o hipopigmentación segmentaria

👉 Si no sigue Blaschko → menor probabilidad de mosaicismo genético relevante.

2️⃣ Estratificación inicial de riesgo neurológico

🔴 Alto riesgo (≥1 criterio):

  • Lesiones extensas o bilaterales
  • Afectación facial o cuero cabelludo
  • Asociadas a:
    • Retraso del desarrollo
    • Épilepsie
    • Hipotonía / espasticidad
    • Macro/microcefalia
    • Rasgos dismórficos
    • Asimetría corporal

➡️ Pasar directamente a estudio neurológico y genético ampliado.

🟡 Riesgo intermedio:

  • Lesiones limitadas
  • Niño asintomático o con dudas leves del desarrollo
  • Exploración neurológica normal

➡️ Seguimiento estructurado + cribado neuropsicológico.

🟢 Bajo riesgo:

  • Lesión pequeña, localizada
  • Sin otros hallazgos
  • Desarrollo claramente normal

➡️ Seguimiento clínico, sin pruebas invasivas iniciales.

3️⃣ Evaluación neurológica recomendada

🔹 Siempre

  • Historia del desarrollo detallada
  • Exploración neurológica dirigida
  • Cribado del lenguaje y funciones ejecutivas

🔹 Si hay sospecha clínica

  • EEG:
    • Crisis, regresión, TDL con fluctuación
  • RM cerebral (3T si posible):
    • Épilepsie
    • Retraso global
    • Asimetría neurológica
    • Sospecha de malformación cortical

📌 La RM puede ser normal incluso con mosaicismo cerebral → normalidad ≠ exclusión.

4️⃣ Estudios genéticos: qué pedir y en qué tejido

❌ Lo que NO es suficiente

  • Array o exoma solo en sangre (falso negativo frecuente)

✔️ Estrategia recomendada (escalonada)

Nivel 1

  • Array-CGH o SNP-array en sangre
    • Detecta aneuploidías o CNV de alto porcentaje
    • Útil si hay dismorfias o retraso global

Nivel 2 (si sospecha persiste)

  • Estudio genético en piel afectada
    • Biopsia punch
    • Idealmente:
      • NGS dirigido
      • Exoma clínico con alta profundidad
      • Comparación piel afectada vs sangre

Nivel 3 (fenotipo específico)

  • Paneles dirigidos según clínica:
    • Epilepsia (PI3K-AKT-mTOR, MTOR, PIK3CA)
    • Trastornos pigmentarios / neurocutáneos
    • ASD + macrocefalia

📌 Mosaicismos <10% requieren profundidad >300×.

5️⃣ Patrones cutáneos con mayor correlación neurológica

Patrón cutáneoRiesgo neurológico
Hipomelanosis de Ito extensa🔴 Alto
Blaschko bilateral🔴 Alto
Lesiones con asimetría corporal🔴 Alto
Segmentaria localizada🟡 Variable
Mancha aislada pequeña🟢 Bajo

6️⃣ Seguimiento del neurodesarrollo

Incluso si asintomático:

  • Evaluación del desarrollo cada 6–12 meses
  • Lenguaje, atención, coordinación
  • Umbral bajo para intervención precoz

👉 Muchos fenotipos son evolutivos, no congénitos completos.

7️⃣ Mensajes clave para la familia (muy importantes)

  • ❌ No implica culpa ni relación causal con FIV
  • ✔️ Es un hallazgo biológico temprano
  • ✔️ La mayoría de niños no desarrollan discapacidad grave
  • ✔️ La detección precoz mejora pronóstico funcional
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1.
Kinsler VA. Mosaic disorders affecting pigmentation – part 2: how to make a genetic diagnosis. Br J Dermatol [Internet]. 2025 Dec 1 [cited 2025 Dec 20];193(6):1047–55. Available from: https://doi.org/10.1093/bjd/ljaf224