Pubertal Development in Rett Syndrome Deviates From Typical Females

Abstract

Background Rett syndrome is a unique neurodevelopmental disorder, affecting approximately 1 in 10,000 live female births, most experiencing reduced growth. We characterized pubertal trajectories in females with Rett syndrome. We hypothesized that pubertal trajectory deviates from the general female population with early pubertal onset and delayed menarche. Methods Participants were individuals enrolled in the Rett Syndrome Natural History Study with clinical diagnosis of Rett syndrome or mutations in MECP2. Intervals to thelarche, adrenarche, and menarche were assessed by survival analysis; BMI, mutation type, clinical severity, and pubertal milestone relationships were assessed by log-likelihood test; pathway synchrony (relationship between thelarche, adrenarche, and menarche) was assessed by Chi-squared analysis. Results Compared to the general female population, over 25% initiated puberty early, yet entered menarche later (median age 13.0 years). 19% experienced delayed menarche. Median length of puberty, from thelarche to menarche, was 3.9 years. Higher BMI correlated with earlier thelarche and adrenarche but not menarche; milder mutations correlated with earlier menarche; and milder clinical presentation correlated with earlier thelarche and menarche. Fifty-two percent entered puberty in synchrony, but differing from general population, 15% led with thelarche, and 32% with adrenarche. Conclusions Pubertal trajectories in Rett syndrome differ from general population, entering puberty early and reaching menarche later. BMI affects pubertal timing, but the relationship between specific mutations, clinical presentation, and underlying neuroendocrine pathology is less clear.

Consensus guidelines on managing Rett syndrome across the lifespan

“… 65 Longitudinal assessment of pubertal development indicates an increased prevalence of early thelarche and adrenarche but delayed menarche. 66 Difficulties with abnormal tone in this age range typically are characterised by hypotonia evolving to rigidity. 67 68 …”

Scoliosis in Rett Syndrome: Progression, Comorbidities, and Predictors

“…We have recently shown that pubertal development in RTT differs from typically developing females 20 . More than 25% may demonstrate premature onset of puberty, the time between the onset of puberty and the onset of menarche is significantly longer than normal (3.9 years in RTT versus 3.0 years in typical females), and the age of menarche is later in RTT (13.0 years) than in typical females (12.5 years).…”

Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

“…This patient was in stage 3 of Tanner at 6 years of age, had low gonadotrophins levels and showed an exaggerated response of LH and FSH to stimulation with GnRH (gonadotrophin-releasing hormone). A larger study carried out in 802 women with classic RTT [40], indicated that a significant percentage of patients had premature breast development (Tanner stage 2) and premature appearance of pubic hair (Tanner stage 2). In normal girls, there is usually a synchronic transition between thelarche and pubarche, while the data from that RTT study indicate that in RTT girls there is an inversion of the normal pattern, so that pubarche precedes thelarche by a ratio of 3:1, as happened in our patient.…”

“…Another possibility, which does not exclude an abnormal functioning of HPG in RTT girls, could be an increase in the secretion of adrenal androgenic hormones, due to excessive production of corticotropin-releasing hormone (CRH) and ACTH [40], as described in an RTT mouse model [100]. However, plasma adrenal steroids were normal in our patient, while it would be expected that the adrenal precursors of testosterone were in high values, and cortisol in low values, but this did not occur.…”

“…There was also a discrete clitoromegaly. Although it has been postulated that girls with RTT have an abnormal pubertal development [40], given the observed findings, in addition to the routine blood tests that we requested before starting any medical treatment, plasma levels of gonadotrophins and sex hormones were also evaluated in this case.…”