The PI3K/AKT/mTOR pathway is among the most important signalling pathways in the cell [6, 7]. Mutations in this large cell-signalling axis, first known in cancer, have been linked to megalencephaly and overgrowth syndromes (MCAP, CLOVES, Klippel-Trenaunay or Proteus syndromes) or localized body overgrowth (macrodactyly) [3, 8,9,10]. These disorders are variably accompanied with other malformations, including musculoskeletal abnormalities (scoliosis, bone overgrowth) and vascular and lymphatic malformations, and single tissue dysplasia (epidermal and other types of skin nevi, lipomatosis) [10, 11]. Because of the phenotypic variability of these disorders caused by somatic PIK3CA mutations, the umbrella-term PROS was proposed to encompass all these clinical entities and highlights the spectrum of findings . In fact, the clinical presentation of the patients is variable, and exists considerable overlap between PROS entities . The finding of a mosaic mutation can be very useful to establish a diagnosis of a PROS disorder. Nevertheless, some mutations appear to have tissue-specific distribution, while others are more pleiotropic; thus the correlation of the mutation to manifestations and disease severity is poor [2, 3, 5, 12]. Based on clinical and instrumental findings, we diagnosed our case of PROS as MCAP, according to the diagnostic criteria proposed by Mirzaa et al. [9, 10] We were also supported by the association, already reported in literature between the phenotype and the pathogenic mutation p.Arg115Pro in PIK3CA gene . In particular, the heterozygous variant R115P in PIK3CA gene found in our patient was originally reported in an 8-year-old girl who presented isolated macrodactyly, with enlarged index and middle fingers on one hand, with other digits being normal and no other vascular abnormalities were noted. The novel mutation was detected in mosaic, present only in the affected nerve tissue in a percentage of about 28%, but not in blood DNA . Subsequently, the same variant was reported in 2 patients affected by CLAPO syndrome in which the mutation was detected on skin biopsy of affected tissue with percentage of mosaicism ranging from 7.5 to 16%. In one of the two patients, the mutation was also found in mosaic at a level of 1.26% in a blood sample . The PIK3CA (R115P) was so far, not reported in patients with a clinical phenotype closer to MCAP. This syndrome is characterized by congenital or early postnatal megalencephaly, with a progressive ventriculomegaly leading to hydrocephalus and cerebellar tonsillar ectopia leading to Chiari malformation, and cortical brain abnormalities, specifically polymicrogyria [9, 10]. MCAP is associated also with other features, such as cutaneous vascular malformations, mainly capillary malformations of the face and reticulated capillary malformation on the trunk; digital anomalies consisting of syndactyly, polydactyly or both; connective tissue dysplasia as joint hypermobility; focal or segmental body overgrowth; hypotonia, and mild to severe intellectual disability [9, 10]. Our patient however presented an uncommon phenotype. In fact, in addition to the most typical features of MCAP, we observed a bilateral hypopigmented, linear skin lesions on her lower limbs. This feature has been described only by Choi et al. in a Korean female diagnosed with MCAP on the basis of clinical and neuroradiological findings, but without confirmation with genetic investigation . Mathew et al. described a case of FAO with blaschkoid hypopigmentation on the neck which was found to be unrelated to the overgrowth .
In literature, several clinical reports of hemimegalencephaly and skin pigmentary mosaicism are described, initially so-called hypomelanosis of Ito. Then, Dobyns and Mirzaa designated this condition as the megalencephaly-polymicrogyria-pigmentary mosaicism syndrome (MPPM) [9, 16]. Among these cases, none is caused by PIK3CA mutation, but mosaic mutations of MTOR gene, within the same PI3K/AKT/mTOR pathway, are associated with this syndrome [9, 15]. The skin phenotype related with mutations of MTOR gene corresponds to cutis tricolor of the Blaschko-linear type, a form of pigmentary mosaicism, previously defined “hypomelanosis of Ito” and reflecting the association with hypopigmented and hyperpigmented streaks [12, 16]. The diagnostic criteria for MCAP syndrome have been changed and reported by many clinical groups, therefore describing new cases with different features is important to enrich these criteria [9, 10]. Causative germline or postzygotic mutations in the PIK3CA, PIK3R2 and AKT3 genes have been identified in patients with megalencephaly and polymicrogyria . We detected in our patient PIK3CA mosaic mutation in blood and affected tissue samples with a frequency of the allele mutated to about 12 and 15%, respectively. Literature data showed that blood and buccal samples lead to lower diagnostic rates and mutant allele levels than skin and other affected tissues . We therefore recommend affected skin and overgrown tissues as primary samples for molecular diagnosis of PROS, and blood sample as control. As in our case, NGS is the preferred method for molecular diagnosis of PROS because it offers a much deeper sequencing coverage and allows the detection of low-level mosaicism . The wide phenotypic variability observed, not only in MCAP, but in all the PROS is not surprising, given the mosaic nature and the genetic heterogeneity of these syndromes. Indeed, we expect that the phenotype may differ based on distribution of mosaicism. Moreover, our patient provides additional evidence that a rigid nosological distinction between the different PIK3CA-associated segmental overgrowth entities cannot longer be applied. The same mutation can be found in extreme phenotypes of the PIK3CA related disorders, ranging from isolated macrodactyly, to CLOVE syndrome, to MCAP (as in our patient) with a variable percentage in tissue lesions and, in some cases, in blood. Our findings provide evidence for a wide phenotypic diversity associated with the same mutation affecting PIK3CA, and occurrence of a clinical continuum associated with PIK3CA molecular defects. Continuous understanding of the clinical spectrum and of molecular basis of PROS and their overlap will lead to improve diagnosis. In particular, we need to further define the phenotypic spectrum of germline and somatic mutations in PIK3CA, with the aim of paving the way to improved management and new treatment strategies.
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