Yes. Although Rett syndrome predominantly affects females, boys can also develop conditions associated with pathogenic variants in the MECP2 gene. The clinical presentation in males can differ considerably from that in females.
Classic Rett syndrome is much more commonly recognized in girls. In boys, an MECP2 variant may cause a severe neurological condition beginning in the neonatal period, intellectual disability, or another MECP2-related disorder. Rare males have also been reported with a clinical presentation resembling classic Rett syndrome. MedlinePlus

Why is Rett syndrome usually more severe in boys?
The explanation involves the sex chromosomes and the function of the MECP2 gene.
Most females have two X chromosomes, while most males have one X chromosome and one Y chromosome.
In females with Rett syndrome, one copy of the MECP2 gene may contain a pathogenic variant, while the other copy may function normally. X-chromosome inactivation determines which X chromosome is predominantly active in individual cells.
This creates a mixture of cells expressing the altered or unaffected copy of the gene. The distribution of these cells contributes to the variability in clinical severity.
In males with a typical 46,XY chromosome pattern, there is only one copy of the MECP2 gene. A severe pathogenic variant can therefore affect gene function across many cells without a second copy on another X chromosome.
This may lead to severe neurological dysfunction, sometimes beginning shortly after birth.

What conditions can occur in boys with MECP2 variants?

1. MECP2-related severe neonatal encephalopathy
This is a severe neurological condition that can occur in males with certain pathogenic MECP2 variants.
Clinical features may include:
– Severe developmental impairment beginning early in life.
– Abnormal muscle tone.
– Seizures.
– Involuntary movements.
– Breathing abnormalities.
– Difficulties with feeding and other neurological functions.
The condition can be life-threatening, and many severely affected boys die in infancy or early childhood.

2. Rett-like clinical presentations
Rare males may develop features resembling Rett syndrome, including intellectual disability, loss of skills, seizures, and movement difficulties.
These presentations may occur in individuals with an additional X chromosome, such as those with a 47,XXY karyotype, or in individuals with mosaicism.

3. Other MECP2-related disorders
Not every male with an MECP2 variant has Rett syndrome or severe neonatal encephalopathy. Other associated conditions include intellectual disability and PPM-X syndrome, which is characterized by pyramidal signs, parkinsonism, and macroorchidism.
It is also important to distinguish MECP2-related disorders from MECP2 duplication syndrome. Duplication syndrome results from an extra copy of the gene and is a separate condition, not the same as Rett syndrome.

What is mosaicism?
Mosaicism occurs when an individual has two or more genetically different cell populations that originated from the same fertilized egg.
For example, an MECP2 variant may arise after fertilization, meaning that only a proportion of the body’s cells carry the variant. This can influence the clinical presentation.
The severity depends on several factors, including the specific variant, the proportion of affected cells, and their distribution in different tissues.

How is the diagnosis confirmed in boys?
Clinical assessment and genetic testing are important. Depending on the presentation, testing may include MECP2 sequencing and deletion/duplication analysis. Chromosome analysis may also be considered when a sex-chromosome abnormality is suspected.
A genetic counsellor can explain the findings, inheritance implications, and testing options for family members.