• Asymmetric growth disorder.
  • Combined with patchy pigmentary skin lesions (such as café-au-lait spots, nevi, etc.), particularly if distributed along the lines of Blaschko.
  • Combined with vascular malformations.

• The presence of pigmentary cutaneous mosaicism is a risk factor for neurodevelopmental disorders (up to 56% present extracutaneous manifestations, which may be neurological, skeletal, endocrinological, etc.).
• Mosaic presentation diseases can have several underlying genetic causes, from point mutations to chromosomal rearrangements.
• Differential diagnosis of the distinct types of mosaic diseases is difficult. They are characterized by a very wide phenotypic spectrum with a degree of clinical variability, as the essence of mosaicism is the combination of several cell populations with different genetic codes, and their distribution and proportion are random.

• There are some brain malformations that are caused by a mosaic mutation.
• The anatomical distribution of the malformation can help infer that it is a mosaic disease, so neuroimaging is useful for planning the genetic study.

Genetic mosaicism is frequently not detectable in peripheral blood, and it is necessary to study the affected tissue.

• Mosaic diseases occur due to a de novo, postzygotic mutation that occurred in the individual themselves, and are not inherited (by definition).
• They can only be transmitted if the affected individual carries the mutation in the germline (germline mosaicism).
• In the event of transmitting the disease, the clinical presentation in the offspring will not be mosaic, but in the form of a constitutional mutation.

• Specific treatment alternatives exist for some mosaic diseases, particularly those affecting genes in the PI3K/AKT pathway and the RAS/RAF pathway.

🧠🧬 Clinical algorithm: Pigmentary skin mosaicism → neurodevelopmental risk

1️⃣ Confirm that the skin pattern is really blaschkoid

Clinical keys:

• “S” lines on the trunk, “V” on the back, curves on the extremities
• Respects midlines (non-dermatomeric, non-vascular)
• Segmental hyper- or hypopigmentation

👉 Yes No Blaschko continues → lower probability of relevant genetic mosaicism.

2️⃣ Initial stratification of neurological risk

🔴 High risk (≥1 criterion):

• Extensive or bilateral lesions
• Facial or scalp involvement
• Associated with:
  • Development delay
  • Epilepsy
  • Hypotonia/spasticity
  • Macro/microcephaly
  • Dysmorphic traits
  • body asymmetry

➡️ Go directly to expanded neurological and genetic study.

🟡 Intermediate risk:

• Limited injuries
• Asymptomatic child or child with mild developmental doubts
• Normal neurological examination

➡️ Structured follow-up + neuropsychological screening.

🟢 Low risk:

• Small, localized lesion
• No other findings
• Clearly normal development

➡️ Clinical follow-up, without initial invasive tests.

3️⃣ Recommended neurological evaluation

🔹 Always

• Detailed development history
• Targeted neurological examination
• Language screening and executive functions

🔹 If there is clinical suspicion

• EEG:
  • Crisis, regression, TDL with fluctuation
• Brain MRI (3T if possible):
  • Epilepsy
  • Overall delay
  • neurological asymmetry
  • Suspected cortical malformation

📌 MRI can be normal even with cerebral mosaicism → normality ≠ exclusion.

4️⃣ Genetic studies: what to order and in what tissue

❌ What is NOT enough

• Array or exome only in blood (frequent false negative)

✔️ Recommended strategy (staggered)

Level 1

• Array-CGH or SNP-array in blood
  • Detects aneuploidies or high percentage CNV
  • Useful if there are dysmorphia or global delay

Level 2 (if suspicion persists)

• Genetic study in affected skin
  • Punch biopsy
  • Ideally:
    • Targeted NGS
    • Clinical exome with high depth
    • Comparison of affected skin vs blood

Level 3 (specific phenotype)

• Panels directed according to clinic:
  • Epilepsy (PI3K-AKT-mTOR, MTOR, PIK3CA)
  • Pigmentary/neurocutaneous disorders
  • ASD + macrocephaly

📌 Mosaicisms <10% require depth >300×.

5️⃣ Skin patterns with greater neurological correlation

6️⃣ Neurodevelopment monitoring

Even if asymptomatic:

• Developmental evaluation every 6–12 months
• Language, attention, coordination
• Low threshold for early intervention

👉 Many phenotypes are evolutionary, not complete congenital.

7️⃣ Key messages for the family (very important)

• ❌ Does not imply fault or causal relationship with IVF
• ✔️ It is an early biological discovery
• ✔️ Most children do not develop serious disability
• ✔️ Early detection improves functional prognosis