Megaencephaly-Capillary Malformation Syndrome (MCAP)

SUMMARY PIK3CA-Related Overgrowth Spectrum (PROS) represents a group of rare disorders characterized by exaggerated growth that results in abnormal development of parts of the body, caused by pathogenic mutations in the PIK3CA gene (Phosphatidylinositol 3-kinase, Catalytic, Alpha, OMIM # 171834), with cytogenetic location 3q26.32 [3, 4]. Disorders specific to this spectrum include: fibroadipose hyperplasia, CLOVES syndrome, Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP syndrome), Hemihyperplasia‐multiple lipomatosis syndrome (HHML syndrome). We present the case of an 8-month-old male patient, born at 39 weeks by caesarean section with a birth weight of 4,540 g and macrocephaly. At the age of 2 months, he presented 2 convulsive episodes, being evaluated neurologically and genetically. A multigenic panel including 30 genes associated with different genetic forms of macrocephaly / macrosomia was used for testing. The genetic testing results revealed the presence of 2 mutations in 2 distinct genes, each possibly associated with the pathology described in the patient Genetic testing thus becomes essential not only for the specific diagnosis of this spectrum of disorders but also for the personalized therapy of the patients with this range of symptomatology. We emphasize the importance of genetic testing through new generation sequencing and of genotype-phenotype correlations in the algorithm of diagnosing and differentiating overgrowth syndromes. Keywords: megalencephaly-capillary malformation, mutation, genetic
BACKGROUND PIK3CA-Related Overgrowth Spectrum (PROS) represents a group of rare disorders characterized by exaggerated growth that results in abnormal development of parts of the body [1, 2], caused by pathogenic mutations in the PIK3CA gene (Phosphatidylinositol 3-kinase, Catalytic, Alpha, OMIM # 171834), with cytogenetic location 3q26.32 [3, 4].
Disorders specific to this spectrum include: fibroadipose hyperplasia, CLOVES syndrome, Megalencephaly-capillary malformation-poly micro gyria syndrome (MCAP syndrome), Hemihyperplasia‐multiple lipomatosis syndrome (HHML syndrome) [1-4]. The specific signs and symptoms of this malformation spectrum depend on the underlying genetic modification [1-5].
Depending on the pathogenic genetic variant, these symptoms may include megalencephaly, hypotonia, seizures, intellectual disability, blood vessels malformations (vascular system) and hypertrophy of an area of the body (focal hypertrophy) or several areas of the body (segmental hypertrophy), with normal development of the rest of the body [1, 2, 5, 6]. PROS usually develops as a result of somatic mutations in the PIK3CA gene [7-9]. These changes are usually present only in some cells or in certain areas of the body (cellular mosaicism). In rare cases, a de novo germline PIK3CA mutation level (present in all cells of the affected individual’s body) may cause PROS [10]. Most patients with PIK3CA mutations have classic features of MCAP: megalencephaly, cutaneous vascular malformations, connective tissue laxity and limb abnormalities (polydactyly and syndactyly), cardiac defects or complex structural arrhythmias, lymphatic malformations, lymph node dysfunction and prognosis endocrine, including hypothyroidism, growth hormone deficiency and rhizomelic shortening of the extremities [1, 2, 4, 6]. CLINICAL PRESENTATION We present the case of an 8-month-old male patient, born at 39 weeks by caesarean section with a birth weight of 4,540 g and macrocephaly. At the age of 2 months, he presented 2 convulsive episodes, being evaluated neurologically and genetically. Clinical symptomatology includes macrocephaly, abnormalities of the distal limbs (sandal sign, brachydactyly), asymmetric growth (including hemihypertrophy and discrepancy in the length of the legs), cutaneous hyperelasticity and joint hypermobility, cranial dysfunction, craniofacial dysfunction, delayed developmental and characteristic flattened nose, hyperthermia). GENETIC TESTING Genetic testing was performed using Next Generation Sequencing (NGS) for all exonic and splicing regions, using the Illumina TruSight One kit for targeted amplification. The resulting sequences were analyzed and interpreted using the VariantStudio computer software. A multigenic panel including 30 genes associated with different genetic forms of macrocephaly / macrosomia was used for testing. The analysed genes are: AKT3, ASPA, DHCR24, EZH2,
GFAP, HEPACAM, MAPK10, MED12, MLC1, NSD1, PIGA, PIGN, PIK3CA, PIK3R2 , PTEN, AKT2, CDKN1C, CUL4B, DIS3L2, DNMT3A, GLI3, GPC3, KPTN, MTOR, NF1, NFIX, NPR2, PHF6, SETD2 and SPRED1. Identified variants were compared with the reference sequences for the sequenced genes (Human Gene Mutation Database Professional hg19). Mutations are reported according to HGVS guidelines [11]. RESULTS The genetic testing results revealed the presence of 2 mutations in 2 distinct genes, each possibly associated with the pathology described in the patient: – the c.2740G> A / p.Gly914Arg / G914R missense heterozygous variant of pathogenic clinical significance (class 5, P – Pathogenic) in exon 19 of the PIK3CA gene [12]. – the c.6253C> T / p.Pro2085Ser missense heterozygous variant of unknown clinical significance (class 3, SUV – Variant of Unknown Significance) in exon 21 of the NSD1 gene (Nuclear Receptor-Binding Set Domain Protein 1, OMIM # 606681, cytogenetic location 5q35.3) [13]. DISCUSSIONS MCAP (Megaencephaly-Capillary Malformation-Polymicrogyria syndrome, OMIM # 602501 / MedGen # 355421) is characterized by a spectrum of abnormalities including primary megalencephaly with prenatal onset, cerebral and body asymmetry, cutaneous vascular malformations, finger abnormalities, connective tissue anomalies involving the skin, tissue and subcutaneous joints and malformations of the brain – polymicrogiria [1, 2, 5, 6, 14]. It is a rare genetic disorder, firstly described in 1997 by Clayton-Smith et al. [15] and Moore et al. [16], and only 130 cases have been reported in literature so far [17]. PI3Ks kinase is an important signalling molecule belonging to the PI3K-AKT pathway. It regulates cell growth, proliferation, survival, migration, metabolism, angiogenesis, apoptosis, tumorigenesis and, in particular, plays an important role in brain development, synaptic plasticity and neurodevelopment [3, 4]. Pathogenic variants in the NSD1 gene are associated with Sotos syndrome type 1 (OMIM # 117550), an autosomal dominant disorder characterized by exacerbated growth [13, 1
The variant identified in the NSD1 gene, however, is of unknown clinical significance, not being reported in the literature to date. However, given the low frequency in the general population, the classifications according to the SIFT and PolyPhen portals, the high degree of conservation and the fact that the aminoacid modified as a result of the c.6253C> T mutation is situated in the close vicinity of the highly conserved SET domain of the NSD1 protein [19], the possibility that this variant might have a pathogenic clinical significance cannot be excluded. The association of this variant with the pathology of the patient cannot nevertheless be estimated with certainty in this situation. The c.2740G>A identified mutation from the PIK3CA gene level has been described in multiple studies in patients with autosomal dominant MCAP, being reported in literature in association with macrocephaly, hemihypertrophy and macrosomia, and in conclusion representing the genetic cause of the pathology observed in the patient [12, 14]. There is currently no specific therapy for PROS, the treatment being symptomatic [20]. In this particular case, the patient’s seizures were treated with phenobarbital but continued to progress,
alongside moderate language and significant motor delays. Facial asymmetry and generalized right hemipertrophy became more evident with age and developed a discrepancy in the length of the lower limbs. Studies are currently being conducted in the respect of targeted molecular therapies for PROS, BYL719 therapy, a potent PIK3CA inhibitor, showing promising results in improving PROS-specific symptomatology, apparently lacking important side effects [21]. Genetic testing thus becomes essential not only for the specific diagnosis of this spectrum of disorders but also for the personalized therapy of the patients with this range of symptomatology [21, 22]. CONCLUSIONS The patient presented in this paper is the first case diagnosed with MCAP syndrome produced by a PIK3A gene mutation reported in the Romanian population. We emphasize the importance of genetic testing through new generation sequencing and of genotypephenotype correlations in the algorithm of diagnosing and differentiating overgrowth syndromes.

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