Can Boys Get Rett Syndrome? Causes & Genetics

Yes, boys can get Rett syndrome, though it is extremely rare ^[1][2]. While the condition is widely known as a disorder that almost exclusively affects females, certain biological exceptions allow boys to survive infancy and develop the classic features of the syndrome ^[3][4].

Why is Rett Syndrome Usually a “Girls’ Disease”?

In nearly all cases, the primary cause of Rett syndrome is a mutation in the MECP2 gene, which is located on the X chromosome ^[5]. This gene is essential for normal brain development and function ^[6].

Because females have two X chromosomes, a mutation on one X chromosome is partially offset by the healthy gene on the other ^[3]. Through a natural biological process called X-chromosome inactivation, one X chromosome is randomly “turned off” in every cell ^[7]. This means girls with an MECP2 mutation still produce some healthy MECP2 protein, allowing them to survive infancy while developing the neurodevelopmental symptoms associated with Rett syndrome ^[3].

What Happens When Boys Have an MECP2 Mutation?

Boys typically have one X chromosome and one Y chromosome. If a boy inherits an MECP2 mutation on his single X chromosome, he does not have a second, healthy X chromosome to act as a backup ^[8].

Because the body has no way to produce functional MECP2 protein, the impact is severe. Most boys with this typical genetic makeup who have an MECP2 mutation develop severe neonatal encephalopathy (a severe brain condition affecting newborns) ^[8]. Unfortunately, this condition is often life-threatening, and these boys rarely survive past early infancy ^[9].

The Exceptions: How Boys Can Develop Classic Rett Syndrome

Some boys do survive early infancy and present with the classic features of Rett syndrome, such as loss of purposeful hand skills and developmental regression ^[10][11]. This typically happens through one of two rare genetic mechanisms:

• Klinefelter Syndrome (47, XXY): In rare cases, a boy is born with an extra X chromosome. Because he has two X chromosomes (like a female), his cells can undergo X-chromosome inactivation ^[12][3]. The healthy X chromosome produces enough functional MECP2 protein for survival, but the mutated chromosome still causes the classic symptoms of Rett syndrome.
• Somatic Mosaicism: Sometimes, the MECP2 mutation is not present at conception but occurs spontaneously as the embryo develops ^[4][13]. This results in mosaicism, meaning the boy’s body is a “mosaic” or mixture of healthy cells and mutated cells ^[14]. The presence of healthy cells allows the boy to survive infancy, while the mutated cells drive the development of Rett syndrome symptoms ^[11][15]. The severity of symptoms often depends on the proportion and location of the mutated cells in the boy’s brain and body ^[11].

Boys who survive through these genetic exceptions typically follow a symptom trajectory and require similar multidisciplinary care and therapies as girls with the condition.

Diagnosis Challenges in Boys

Because Rett syndrome is historically known as a “girls’ disease,” a major hurdle to diagnosis is that clinicians often do not suspect it in males, leading to delayed testing ^[15]. When testing is performed, standard genetic blood tests can sometimes miss mosaicism if the mutated cells are not heavily present in the blood ^[15]. To confirm a diagnosis in boys with Rett-like symptoms, doctors may recommend advanced high-depth genetic sequencing or testing alternative tissues, such as skin cells (fibroblasts), to locate the hidden MECP2 mutation ^[15][11].