Congenital variant of Rett syndrome, also known as Rolando variant, presents with congenital hypotonia, poor responsiveness and eye contact. Developmental delay becomes evident already during the first few months of life with social impairment and autistic behaviours, and no language development. Head circumference is normal at birth but head growth is reduced with progressive microcephaly. Gross and fine motricity is impaired early, epilepsy develops after the first year of life but EEG is usually poorly organized since early stages [
3‐
6]. The association of such variant of Rett syndrome and the mutation of FOXG1 is becoming recognised as a specific entity called FOXG1 syndrome and we endorse this to avoid terminological overlaps [
3]. As our patient presents all the clinical presentation of Rolando variant, we consider she has a congenital variant-like Rett syndrome. Moreover, it is becoming clear that various mutations of FOXG1 gene lead to a wide range of clinical manifestations that can completely differ from the congenital variant of Rett syndrome [
7]. At the other side, some patients with congenital Rett syndrome-like features do not present FOXG1 mutations as in our case [
8]. our patient, in particular, shows a mutation encoding for a stop codon with a likely deep impairment in the protein function. Such type of mutation fits with the particularly severe clinical picture of the patient and the neonatal onset in contrast with what was previously reported [
9]. Rett syndrome-related breathing features, like hyperpnoea followed by breath-holding, Valsalva efforts, and periodic breathing, are easily identifiable during wakefulness. Such symptoms usually reduce or even abruptly disappear at sleep onset [
1,
10]. Among the patients with Rett syndrome with pathological polygraph, nearly all manifest obstructive events during sleep, with a minority of central events associated with severe obstructive ones [
11]. Literature reports several cases of patients with RS presenting hypoventilation, often alternated to hyperventilation during wakefulness [
12,
13]. On the contrary, few data are reported about hypercapnia during sleep time in RS mentioning congenital variant or congenital variant-like [
13,
14]. Our patient presents congenital variant-like Rett syndrome caused by a novel de novo mutation in
MECP2.
MECP2 gene plays an important role in autonomic system regulation and its mutations are causative of Rett syndrome [
15]. Animal models showed the importance of MECP2 for a correct sensitivity to CO2 of breathing centres, and its mutations may lead to the typical respiratory instability of RS [
16], and possibly to hypoventilation as proved by animal models [
17]. To the best of our knowledge, this is the first case reporting hypoxemia and persistent hypercapnia during sleep-time in a patient affected by a congenital form of RS. Patients with CRS are a peculiar cohort; they never walk autonomously and may acquire the ability to articulate a few simple words at best, usually showing severe mental retardation since the very first months of life. Only a few cases present epilepsy (the landmark of the classic form) at the diagnosis, but electrical activity alterations are nearly always identified at the EEG [
8,
9,
18].
As previously stressed, the congenital variant is mainly characterized by hypotonia, that is severe enough to cause scoliosis within the very first years of life [
5]. Therefore, in CRS, hypotonia may cause, per se, desaturation and hypercapbnia, as occur in other neuromuscular diseases of childhood, suggesting a different pathogenesis than classic RS [
19]. The normal PtcCO2 values during waketime (when muscle strength is relatively increased) supports this suggestion [
20,
21]. Of particular interest is the persistent periodic breathing of this patient. Breathing centres homeostasis is very fragile in RS due to
MECP2 mutation [
16], with a consequent high gain loop causing periodic breathing. Such events may be boosted by repeated desaturations caused by CRS-related hypotonia [
12,
13]. Therefore, although an ST mode of ventilation is usually preferred to maximize patient comfort, an assisted pressure-controlled mode could be necessary to overcome the lack of appropriate respiratory centres control. Providing adequate ventilation in such patients could contribute to the daytime quality of life and hypotonia improvement, as already reported for other diseases with hypotonia [
22].
The diagnosis of neonatal hypotonia requires an integrated clinical and instrumental approach initially focused at excluding etiologically treatable conditions such as spinal motoneuron atrophy (SMA). NGS technique can have a key in the diagnosis of unsolved hypotonic conditions in early infancy.
This single case suggests the need for a very early polygraph or at least pulse oximetry plus capnography in each patient affected by the congenital variant of Rett syndrome. Broadly speaking, we suggest considering NGS techniques to reach tricky diagnosis such as Rett syndrome with congenital features in hypotonic patients.