Se debe sospechar mosaicismo genético cuando el paciente presente:
  • Trastorno del crecimiento asimétrico.
    • Combinado con lesiones pigmentarias de la piel de distribución parcheada (como por ejemplo manchas café con leche, nevus, etc.), particularmente si tienen una distribución siguiendo las líneas de Blaschko.
    • Combinado con malformaciones vasculares.
Principales tipos de mosaicismo: En función de la línea celular afectada: somático (a), gonosomal (b), germinal (c). Patrones reconocibles de mutaciones en mosaico en la piel: Lineas de Blaschko estrechas (d), lineas de Blaschko anchas (e), patrón en tablero de ajedrez (f), patrón filoide (g), patrón parcheado sin separación en la línea media (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
Mosaicismo cutáneo y trastornos neurocutáneos en mosaico.
  • La presencia de mosaicismo cutáneo pigmentario es un factor de riesgo de trastornos del neurodesarrollo (hasta el 56% presentan manifestaciones extracutáneas, que pueden ser neurológicas, esqueléticas, endocrinológicas, etc.).
  • Las enfermedades de presentación en mosaico pueden tener varias causas genéticas subyacentes, desde mutaciones puntuales hasta reordenamientos cromosómicos.
  • El diagnóstico diferencial de los distintos tipos de enfermedades en mosaico es dificil. Se caracterizan por presentar un espectro fenotípico muy amplio con un grado elevado de variabilidad clínica, ya que la esencia del mosacismo es la combinación de varias poblaciones celulares con distinto código genético, y su distribución y proporción es aleatoria.
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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
Reordenamientos cromosómicos en mosáico (CNV).
  • La hipomelanosis de Ito es un trastorno neurocutáneo clásico en el que existe un reordenamiento cromosómico identificable por biopsia (que puede afectar a múltiples regiones cromosómicas distintas), y condiciona cambios pigmentarios por afectación del desarrollo de la cresta neural (neurocristopatía).
Enfermedades monogenéticas en mosaico.
  • Se trata de enfermedades de herencia autosómico dominante.
  • Algunas de ellas no son compatibles con la vida en su presentación constitucional (conducen a aborto o muerte fetal, como el síndrome CHILD), debido a que el gen afecto es de elevada importancia evolutiva, por lo que sólo sobreviven los mosaicos con fenotipo atenuado.
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1.
Ruggieri M, Praticò PD, Happle R. Mosaic Neurocutaneous Disorders and Their Causes. Seminars in Pediatric Neurology [Internet]. [cited 2015 Nov 13]; Available from: http://www.sciencedirect.com/science/article/pii/S1071909115000765
Mosaicismo cerebral y malformaciones cerebrales:
  • Existen algunas malformaciones cerebrales que se producen por una mutación en mosaico.
  • La distribución anatómica de la malformación puede ayudar a inferir que se trata de una enfermedad en mosaico, por lo que la neuroimagen es de utilidad para planificar el estudio genético.
Lisencefalia, hemimegalencefalia, double cortex syndrome.
Displasia cortical focal.
El tipo de malformación cerebral dependerá del momento de aparición de la mutación somática durante la organogénesis cerebral.
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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
Técnicas diagnósticas de mosaicismo cerebral.

El mosaicismo genético frecuentemente no es detectable en sangre periférica y es necesario realizar un estudio en el tejido afecto.

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1.
Ye Z, McQuillan L, Poduri A, Green TE, Matsumoto N, Mefford HC, et al. Somatic mutation: The hidden genetics of brain malformations and focal epilepsies. Epilepsy Research [Internet]. 2019 [cited 2019 Aug 20];155:106161. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0920121119301810
Herencia y consejo genético en el mosaicismo.
Tipos de mosaicismo en función de la genética.
  • Las enfermedades en mosaico ocurren por una mutación de novo, postcigótica, que aconteció en el propio indivíduo, y no son heredadas (por definición).
  • Sólo pueden ser transmitidas en caso de que el individuo afecto sea portador de la mutación en la línea germinal (mosaicismo germinal).
  • En caso de trasmitir la enfermedad, la presentación clínica en la descendencia no será en mosaico, sino en forma de mutación constitucional.
Tratamiento específico
  • Existen alternativas de tratamiento específico para algunas enfermedades en mosaico, en particular aquellas que afectan a los genes de la vía PI3K/AKT y la via 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
    • Epilepsia
    • 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):
    • Epilepsia
    • 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