Megalencephaly Capillary Malformation Syndrome

Review Article

Megalencephaly Capillary Malformation Syndrome Andrea D. Praticò1,2 Agata Polizzi3 Stefania Salafia4 Elena R. Praticò5 Maria Teresa Garozzo1 Federica Sullo1 Stefano Catanzaro1 Giuseppe Belfiore6 Concetta Pirrone7 Antonio Zanghì8 Agata Fiumara9 Martino Ruggieri1 Nicoletta Resta10

Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy 2 Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, United Kingdom 3 Institute of Neurological Sciences, National Research Council, Catania, Italy 4 Unit of Pediatrics, Lentini Hospital, Lentini, Italy 5 Unit of Pediatrics, Carpi Hospital, Carpi, Italy 6 Unit of Paediatric Radiology, AOU “Policlinico-Vittorio Emanuele,” Catania, Italy 7 Section of Psychology, Department of Educational Sciences University of Catania, Catania, Italy

Address for correspondence Andrea D. Praticò, MD, PhD, Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy (e-mail: [email protected]). 8 Department of Medical and Surgical Sciences and Advanced

Technology “G.F. Ingrassia,” University of Catania, Catania Italy

9 Unit of Clinical Pediatrics, Department of Clinical and Experimental

Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy 10 Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari “Aldo Moro,” Bari, Italy

J Pediatr Neurol

Abstract

Keywords

► megalencephaly ► polymicrogyria ► capillary malformations ► hydrocephalus ► AKT-PI3K-mTOR ► developmental delay

received January 5, 2018 accepted after revision May 5, 2018

Megalencephaly capillary malformation polymicrogyria (MCAP) syndrome is characterized by the sporadic occurrence of congenital and progressive megalencephaly, brain malformations including polymicrogyria, pre- and postnatal overgrowth with body asymmetry, cutaneous vascular malformations (including capillary malformation and cutis marmorata), digital anomalies connective tissue dysplasia (including skin and joint laxity), and developmental delay. In the past 10 years, the specific cause of the disease has been found in gain-of-function mutations of PIK3CA gene, mostly somatic/ postzygotic but in rare cases also de novo germline. Such gene encodes for PI3K, a critical member of the PI3K-AKT-mTOR pathway: genetic changes lead to an overactivation of this signaling system, with increased vascular, limb, and brain cell development, progression, and survival. Interestingly, mutations in the same gene can cause other clinically heterogeneous syndromes, including CLOVE syndrome, macrodactyly, focal adipose overgrowth, epidermal nevi, facial infiltrating lipomatosis: all these syndromes (even if heterogeneous) are now considered a unique spectrum, known as PIK3CA-related overgrowth syndrome. On the contrary, a disease strictly similar to MCAP, characterized by megalencephaly, polymicrogyria, polydactyly, and hydrocephalus has been found to be caused by mutations in two other PI3K-AKT-mTORreleted genes, AKT3 and PIK3R2, and for this reason is not included in the upper mentioned group of syndromes. With the exception of neurosurgery strategies for hydrocephalus and posterior fossa overcrowding, therapeutic options are nowadays limited, even if gene-targeted treatment protocols have been proposed and protocols with such agents (i.e., Arq092) are currently ongoing in small groups of patients with promising results.

Issue Theme Rare Neurocutaneous Disorders: Update and State of Art; Guest Editors: Martino Ruggieri, BA, MD, PhD; Andrea Praticò, MD, PhD; Giuseppe Micali, MD

Copyright © by Georg Thieme Verlag KG, DOI https://doi.org/ Stuttgart · New York 10.1055/s-0038-1667010. ISSN 1304-2580.

Downloaded by: Thieme Publishers Delhi. Copyrighted material.

1 Unit of Rare Diseases of the Nervous System in Childhood, Department of

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Introduction

Historical Background and Eponyms Differently from other neurocutaneous disorders, known and recognized since centuries,10–14 a possible nosological entity disease presenting with the association of macrocephaly, limb asymmetry, and capillary malformations was first documented around 40 years ago;15 only in 1997 Moore and coll.4 and Clayton-Smith and coll.2 independently reported on 22 patients with common clinical findings and a similar face phenotype, proposing it as a distinct disorder. The main clinical features of these patients were overgrowth, macrocephaly, and cutis marmorata telangiectatica congenita along with other associated anomalies. In the past 20 years, the name of the syndrome has been changed after the reports on new findings and observations in patients affected by the syndrome: initially it was designated as M-CMTC syndrome, then the name was shortened to “macrocephaly cutis marmorata” (M-CM). After dermatology studies on the nature of the vascular anomalies (included in the “capillary malformations” type), the name has been changed into “macrocephaly capillary malformation” (MCAP). Lastly, after the genetic discoveries on the involvement of PI3K-AKT-mTOR pathway and on the nature of the primitive brain enlargement (i.e., megalencephaly) not secondary to hydrocephalus (i.e., macrocephaly), the term “macrocephaly” has been substituted with “megalencephaly.”16 Furthermore, in recent years, the “P” of the acronym has been considered as “polymicrogyria,” another common finding of the brain of such patients.15–17

Fig. 1 Combination of cutis marmorata, nevus flammeus, and flat hemangioma in the right upper limb.

gender), pre- and postnatal overgrowth, body asymmetry, cutaneous vascular malformations, including capillary malformation and/or cutis marmorata, digital anomalies (i.e., syndactyly, polydactyly), connective tissue dysplasia, including skin and joint laxity, and developmental delay.

Skin and Connective Tissue The skin is affected in almost all patients with MCAP. Most of them have a combination of capillary malformations, nevus flammeus, and flat or cavernous hemangiomas, usually most conspicuous in the limbs (►Fig. 1), but they may be present in all body districts, including parotids.39 The capillary malformation on the philtrum and/or the upper lip is perhaps the most characteristic (►Fig. 2) but some children have had a capillary malformation also of the back or buttocks. The generalized cutis marmorata tends to fade with time. One patient developed a mastocytoma-like nodule in the face.39 Deep vein thrombosis was observed in two cases.42 The majority of patients have demonstrable increased skin laxity with or without thickening of the subcutaneous tissue.

Incidence and Prevalence Differently from other neurocutaneous disorders,18–35 MCAP is a rare syndrome, with no more than 200 patients so far reported.1–9,36–41 There is a slight preponderance of males but this has not been proven to be statistically significant.

Clinical Manifestations The main characteristics of MCAP are congenital and progressive megalencephaly (occipitofrontal circumference [OFC] of 2 or more standard deviation [SD] above the mean for age and Journal of Pediatric Neurology

Fig. 2 Capillary malformation in the posterior region of the neck of a 5-year-old girl affected by a mutation of PI3KCA gene.


The association of megalencephaly, capillary malformation, cavernous hemangioma, asymmetric growth pattern, central nervous system malformations, in particular polymicrogyria, and developmental delay has been recently referred as “Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome” (MCAP).1 In the past, the syndrome has been known as “macrocephaly-cutis marmorata telangiectatica (M-CMTC)2–5 and then as “macrocephaly-capillary malformation syndrome.”6,7 No specific causes for the condition were identified until the discovery of PI3K-AKT pathway anomalies in the affected patients: in particular, de novo germline or postzygotic mutations in the PIK3CA genes have been found as causative of MCAP, thus suggesting a critical role of PI3K-AKT-mTOR signaling in vascular, limb, and brain development.8,9

MCAP Syndrome

Craniofacial Anomalies The facial features and craniofacial anomalies seen in these patients are striking and give rise to a distinctive facial “gestalt” (►Fig. 2). Megalencephaly, present at birth and progressive in nature, is the key symptom of the syndrome and is present in virtually all children.5 The increased OFC is independent of the presence of hydrocephalus and the head size may continue to increase in size disproportionately even after shunting: for this reason the correct term “megalencephaly” (i.e., pure cerebral overgrowth) has been used instead of macrocephaly (i.e., cranial overgrowth due to other causes, as hydrocephalus).59–61 The largest so far reported OFC in patients with MCAP was þ9–10 SD.16 Frontal bossing, large forehead, short nose, small chin, full lips, and thick gums are usually present. A characteristic finding is a midfacial capillary malformation, found mostly on the philtrum and/or upper lip. This finding is a useful diagnostic feature. The cheeks may be full and fleshy and sometimes with patchy reddish areas of skin. Most patients have deep-set eyes with prominent supraorbital ridges. A “sun-setting” appearance of the eyes may be present along with ptosis of the eyelids and facial asymmetry (►Fig. 2). Along with the latter, there may also be asymmetric gingival hyperplasia. Macroglossia and craniosynostosis are infrequent findings.4,62,63

Growth More than 95% of the patients have had prenatal overgrowth with a high birth weight and increased OFC. Length was

normal or just slightly increased in the majority of children. In view of the neonatal macrosomia, this syndrome is included in the nosology of the overgrowth syndromes,64 as well as a possible cause of fetal hydrops.65 Postnatal overgrowth may occur but is less common and with age the weight and height tend to normalize or even fall below the normal centiles for age and sex.4 Postnatal failure to thrive was reported in a small number of cases.66 Asymmetric growth in the form of hemihyperplasia/ hemihypertrophy or unilateral overgrowth of the face, thorax, and/or limbs is commonly observed. A statistically significant association of somatic overgrowth and vascular anomalies has been found.4,42

Central Nervous System and Performance Brain imaging by magnetic resonance imaging or computed tomography scans demonstrated that megalencephaly with or without hydrocephalus is the clinical hallmark of MCAP (►Fig. 3). It has been showed that the progressive overgrowth of the cerebellum can lead to communicating type hydrocephalus (CTH), while cerebral overgrowth is the cause of megalencephaly. In such context, hydrocephalus could be a secondary event resulting from the reduced drainage of cerebrospinal fluid following the development of CTH or megalencephaly. Conway et al suggested that the enlarged cerebellum obstructs the venous outflow, causing reduced cerebrospinal fluid absorption, but that the cause of such finding could be the compression of the cerebral aqueduct due to the increased crowding of the posterior fossa content.7,63 Cortical dysgenesis, a thickened, hypoplastic or agenetic corpus callosum, enlarged cerebellum with posterior fossa crowding and a resulting Chiari type I malformation, loss of normal sulcation, pachygyria, polymicrogyria, and abnormal myelinization have all been observed.7,16,37,64–72 Other common findings are ventriculomegaly (that may progress to hydrocephalus), asymmetry of the lateral ventricles, bifrontal extra-axial fluid collections, and cavum septi pellucidum

Fig. 3 (A) axial and (B) sagittal, T1-weighted magnetic resonance of a patient affected by MCAP. An area of polymicrogyria is present in the right parietal lobe (white arrows). Journal of Pediatric Neurology


Pigmentary abnormalities (hyper- or hypopigmentation, following the Blaschko lines) epidermal nevus, and deep plantar and palmar creases have been observed in some patients,43 but with a lower incidence in comparison to other neurocutaneous disorders.44–58 Hyperextensible joints, diastasis recti, umbilical hernia, and inguinal hernia are additional findings suggesting a connective tissue component to the condition.

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and vergae. White matter anomalies have also been recorded. Focal central nervous system infarcts and ischemic changes have occasionally been reported.40 All degrees of developmental delay have been observed in MCAP, with a predominance of moderate-to-severe retardation.73 This retardation seems to be related not only to brain anatomic anomalies (increased size of cerebral ventricles, hemimegalencephaly, white matter abnormalities) but also to cortical dysplasia.74,75 Ventriculoperitoneal shunts (VPS) were inserted in about half of the patients but these had little influence on the macrocephaly, suggesting a true megalencephaly.4,63 Hypotonia, anisocoria, esotropia, facial nerve palsy, optic atrophy, and brain arteriovenous malformation were observed in several patients. In the recent years, an increase in the occurrence of seizures has been documented, from being an uncommon finding,5 to more than 50% of patients with MCAP,16 similarly to other neurocutaneous and neurological syndromes.76–82 They have been associated with polymicrogyria and cortical dysplasia in many cases, have an onset from childhood to 4.5 years of age and, in rare cases, are drug resistant.

Limbs The hands are usually large and broad with a “fleshy” appearance. The most distinctive anomaly found in these patients is finger syndactyly or polysyndactyly; cutaneous syndactyly of the second and third toes, usually up to the distal phalanx is very frequent. some patients may present postaxial polydactyly (►Fig. 4).2,4,68 Macrodactyly, sandalgap toe, broad thumbs and toes, and overlapping toes have been observed more rarely. There is often a wide space between the first and second toes. One patient had bilateral oligodactyly with absent fifth toes.41 Hypoplastic toenails were observed sporadically. In some patients, the nails are flattened and have an appearance similar to that seen when there has been edema in utero. A degree of body disproportion and asymmetry has been observed in a high percentage of cases, with or without vascular compromise of the involved region. The asymmetry may be present in the face, the trunk and in the legs, with length

discrepancy and differences in diameter sometime present in these patients, mainly congenitally, like in other syndromes.83 Joints may be hyperelastic with a tendency to subluxation in some occasions. Hip dysplasia was reported in a small number of cases. Connective tissue dysplasia may be underreported, as skin hyperelasticity and thick subcutaneous tissues have been assessed only in recent years.16

Thorax and Abdomen Complex cardiac malformations were described in several cases,2,41,42,84 a ventricular septal defect in another and a dilated aortic root in further children.4,39 Akcar et al37 reported a child with an atrial septal defect and a giant atrial septal aneurysm, and Giuliano et al reported a further patient with an autism spectrum disorder.40 Cardiac arrhythmias such as atrial flutter or supraventricular tachycardia have been observed and are often life-threatening situations requiring intervention.2,41,85 In one patient, supraventricular tachycardia has been documented, and in another case fetal arrhythmia was reported.86 Heart abnormalities may range from single atrial or ventricular septal defects to complex cardiovascular anomalies. Mesenteric angina was reported by Howells et al,87 and intestinal lymphangiectasia and atrophic abdominal aorta by others.88,89 Unlike other overgrowth syndromes, enlargement of the liver, spleen, or kidneys is not often seen.

Other Medical Problems Some patients with MCAP have developed tumors (acute leukemia, meningioma, Wilms tumor, and retinoblastoma).4,5,90–92 The boy with retinoblastoma reported by Schwartz et al92 did not have the typical characteristics of MCAP however and might be an atypical case. Although the number of patients with MCAP currently reported is low and the types of neoplasia seen so far are heterogeneous, the putative 5 to 6% tumor risk appears to be similar to other overgrowth syndromes.5,93 Thus, it has been recommended that patients with this syndrome should have regular screening for tumors.5,84 Genital abnormalities have been also documented, with cryptorchidism, micropenis, hypospadias, as well as renal problems (cystic kidney, uteropelvic junction obstruction).40

Pathogenesis and Molecular Genetics

Fig. 4 Syndactyly of the second and third toes. Journal of Pediatric Neurology

Since the last decade, investigations on an inheritable cause had failed to find a genetic mutation linked to the disease. The report of two monozygotic female twins showing a discordant phenotype (one affected by MCAP, one unaffected) suggested that the disease could be caused by an early postzygotic mutation or a random X-inactivation of unknown genes or by a nongenetic factor (in utero infection, drug consumption).94 However, in the last decade, the cause of MCAP (and the closely related MPPH) has been found in de novo germline or postzygotic mutations of three genes encoding key factors of the PI3K-AKT-mTOR pathway: AKT3, PIK3R2, and PIK3CA. In the first report by Rivière et al,8 the authors performed a whole exome and targeted


MCAP Syndrome

Sanger sequencing in affected tissues of three families with MCAP and MPPH, and then extended this analysis also to other seven individuals affected by MCAP. De novo germline or postzygotic mutations were found in these three core components of PI3K-AKT pathway: AKT3, PIK2R2 in MHHP patients, and PIK3CA in MCAP. All the mutations lead to a gain-of-function of the pathway, with an increased growth rate in the vascular system, limbs and brain cells, as PI3K-AKT pathway plays a critical role in cell growth, proliferation, survival, apoptosis, angiogenesis, and tumorigenesis.40 These effects are closely related to the function of PI3K proteins which is due to their ability to phosphorylate the 3′-hydroxyl group of phosphatidylinositol and phosphoinositides, leading to a cascade of reaction (and activation) of AKT-mTOR network. In particular, PIK3CA encodes for the p110α catalytic subunit of class IA PI3K proteins, activated by specific growth factor receptor tyrosine kinase and widely expressed in all the body.95 Somatic mutations of this gene are found in different tumors (up to 15–20% of colorectal cancer), with the most frequent mutations found in specific “cancer hotspots” in exons 9 (E542K, E545K) and 20 (H1047R). After the initial report by Rivière et al,8 postzygotic mutations of PIK3CA have been found in up to 30 individuals with MCAP syndrome,40,96 with mutant allele frequencies ranging from 1 to 48% of analyzed cells. Interestingly, also de novo germline mutations have been found in two patients: one presenting a mild phenotype and the other showing a severe asymmetric phenotype (with hemimegalencephaly and focal somatic overgrowth).40 Given the fact that in most of the cases, mosaic postzygotic mutations are the cause of the disease, a sample of involved tissue is usually taken from patients and therefore analyzed. The best tissue for genetic analysis is the skin surrounding the capillary malformation,97,98 but mutations have been also found in other tissues (e.g., dental DNA).99 In the recent years, postzygotic mutations in PIK3CA have been found also in other mosaic overgrowth syndromes, including CLOVE syndrome and its variants,100 Klippel-Trenaunay disease,100 fibroadipose hyperplasia,101 and type 1 macrodactyly.102 Other conditions associated with somatic activating mutations of this gene are muscle hemihyperplasia, facial infiltrating lipomatosis, epidermal nevi, seborrheic keratosis, and benign lichenoid keratosis.9 Germline mutations have been found in individuals affected by Cowden syndrome.103 All the affected patients harboring mutations in this gene presented with phenotypes and symptoms sometime overlapping MCAP (i.e., megalencephaly, hemimegalencephaly, and vascular malformations) and for this reason, the term “PIK3CA-Related Overgrowth Spectrum” has been recently used to designate this broad spectrum of disorders.9,96 However, despite some common symptoms, these syndromes are phenotypically different, and the mechanism underlying these wide phenotypic differences remains partly unclear. Hypotheses are concentrated on the timing of the mutation events in the phases of in utero development (earlier mutations are linked to a more severe phenotype, as CLOVES, while later mutations usually lead “only” to milder

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syndromes, such as the isolated macrodactyly). Nevertheless, even the type of mutation may have its importance: patients with MCAP can present mutations in all PI3KCA gene (not only in the upper mentioned “cancer-related hotspots”), while patients presenting CLOVES usually show only that mutations, and present more severe brain involvement and malformations. Regarding these “cancer-related hotspots,” mutations E542K and E545K have been found in all the PIK3CA-related overgrowth spectrum (including fibroadipose overgrowth, macrodactyly, hemimegalencephaly), while the mutation H1047R has never been associated with hemimegalencephaly, epidermal nevi, and benign lichenoid keratosis. Given the same genetic mutations, the clinical heterogeneity of these different phenotypes in this case can be due only to the different time of onset of the mutation, with earlier mutations in embryonic life associated with the more severe, pleiotropic, or tissue-specific, clinical pictures (MCAP, facial infiltrating lipomatosis, dysplastic megalencephaly).9 However, it cannot be excluded that other genes or extragenetic factors can improve or worsen the clinical phenotype. In patients harboring a germline mutation, the phenotype is usually milder (i.e., Cowden syndrome), thus confirming that patients carrying severe mutations can survive only if these are present as postzygotic mutations. Mutations in the two other PI3K-AKT-mTOR genes (i.e., AKT3, PIK3R2) have been found in at least 20 patients affected by MHHP.8,40 PIK3R2 encodes a regulatory subunit of class IA PI3K enzymatic complex, while AKT3 encodes for Akt (Protein kinase B, PKB), a serine/threonine kinase that plays a key role in regulating cell survival, insulin signaling, angiogenesis, and tumor formation, which is a downstream mediator of the PI3K pathway. Differently from MCAP, in MHHP mutations usually arise as de novo germline.40

Diagnosis and Diagnostic Criteria Diagnosis must be based on clinical and genetic findings. Major and minor criteria of MCAP were described by Franceschini et al68 who suggested that the diagnosis could be made in the presence of (1) macrocephaly and at least two other findings such as (2) cutis marmorata, overgrowth, capillary malformation, syndactyly, or asymmetry. Other groups have proposed similar criteria,43,85 suggesting that the diagnosis should be sustained on the presence of macrocephaly and at least two of the following findings: overgrowth, cutis marmorata, capillary malformation, polydactyly/syndactyly, and asymmetry. Robertson et al83 have laid down more stringent criteria. They suggested as major criteria the presence of congenital macrocephaly and CMTC and in addition at least four of the following findings: neonatal hypotonia, developmental delay, connective tissue defect, frontal bossing, midline facial nevus flammeus, cutaneous toe syndactyly, segmental overgrowth, and hydrocephalus. With a condition such as M-CMTC where the spectrum of problems is broad, more stringent criteria might exclude milder cases which could provide useful clues to the etiology of the condition. On the other hand, the less Journal of Pediatric Neurology


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stringent criteria may not be restrictive enough. Only when the underlying genetic basis is identified will it be possible to validate the different sets of diagnostic criteria suggested. In 2009, Wright et al proposed a combination of the upper mentioned diagnostic criteria, including macrocephaly and capillary malformation as major criteria, and asymmetry/ overgrowth, developmental delay, midline facial capillary malformation, neonatal hypotonia, syndactyly or polydactyly, frontal bossing, connective tissue abnormality, and hydrocephalus as minor criteria.104,105 Abnormalities have been identified prenatally in several patients when macrocephaly, macrosomia, limb asymmetry, hemimegalencephaly, polyhydramnios, ascitis and/or pleural effusions were observed.4,39,63,73 Elevated maternal serum alpha fetoprotein was observed in one occasion.73 It is difficult to make a firm diagnosis if M-CAP prenatally, however, as the characteristic skin signs, one of the diagnostic hallmarks of the condition, cannot be visualized. The last classification of features (and diagnostic criteria) of the syndrome was proposed by Mirzaa et al16 Core features are (1) early overgrowth (brain more than other somatic features and progressive megalencephaly, (2) developmental vascular disorders including capillary malformations (midline, face, and body), (3) distal limb anomalies (in particular syndactyly 2–3, 3–4, 2–3-4 of toes or fingers), (4) cortical brain malformation (including polymicrogyria), (5) connective tissue dysplasia (skin hyperelasticity, joint hypermobility, thick subcutaneous tissue). Supportive features may be ventriculomegaly or hydrocephalus, cerebellar tonsillar ectopia, mega-corpus callosum, congenital somatic overgrowth, somatic asymmetry, as well as infantile hemangiomas, venous aneurysm, vascular rings, polydactyly, and sandal gap toes. In this setting of malformations, hypotonia, developmental delay, distinctive facial features, and seizures may be considered as prominent symptoms of patients affected by the syndrome.

Other Syndrome with Megalencephaly/ Macrocephaly Differential diagnosis includes other disorders with overgrowth/macrocephaly16,22,114–118 such as Beckwith–Wiedemann syndrome, Simpson–Golabi–Behmel syndrome, Sotos syndrome, Perlman syndrome, Proteus syndrome, Costello syndrome, and Bannayan-Zonana syndrome. Disorders with skin vascular malformations and asymmetry such as Klippel– Trenaunay syndrome and Parkes–Weber syndrome must also be considered. MCAP may be easily diagnosed when the full phenotype, characteristic features, and typical appearance are present.

Prognosis and Follow-up Long-term prognosis is usually determined by the neurological and cardiac manifestations,40,41 even if cases of sudden death have been reported in early life.119 Some degree of mental impairment, ranging from mild to severe, is often present and about half of the patients need a ventricular shunt for the treatment of hydrocephalus. Some children can attend normal school, but in general almost all of them will need support and a special educational program. An electrocardiography, together with neurological and cardiac evaluations, is recommended for all patients with MCAP due to the fact that some patients have had life-threatening arrhythmias. It is not clear whether or not these children need to enter a tumor surveillance program. It has been suggested recently that regular physical examination, abdominal and renal ultrasound, and AFP analysis should be performed.120 This recommendation is empirical and more patients need to be followed up for a longer period of time before it can be validated. However, patients affected by the syndrome show a great phenotypic variability, and this issue should be considered when parents ask for the long-term prognosis of their children.

Differential Diagnosis Megalencephaly-Polydactyly-PolymicrogyriaHydrocephalus Syndrome As observed above, recent genetic discoveries have cleared the fact that MCAP and MPPH are caused by mutations in different genes (PI3KCA versus AKT3, PIK3R2) of the same biological pathway (PIK3A-AKT-mTOR). MPPH was first recognized in 2004 in five patients and reported in others in the following years.106–112 Differently from MCAP, the syndrome does not involve the skin, syndactyly has been never observed, and brain anomalies are usually more severe. Connective tissue dysplasia (including skin and joint hyperelasticity) has been never described in these patients, while in a recent report, Nellist et al113 described a patient affected by megalencephaly, polymicrogyria, epilepsy, and hypoglycemia caused by a germline-activating AKT3 mutation: in particular, dysregulations in glycemic metabolism have been never reported in MCAP patients. Conversely, patients with overlaps of the two syndromes have been reported in the past, but it is now accepted that they represent two distinct nosological entities.16,109 Journal of Pediatric Neurology

Treatment An estimated 50% of MCAP patients, in particular those presenting severe hydrocephalus or posterior fossa overcrowding, may benefit from neurosurgical procedures, including VPS or posterior fossa decompression.9,36 However, MCAP cases are rarely reported in the neurosurgical literature, and a defined surgical strategy for this syndrome has not yet been established. Of the few reported cases, Mitha et al successfully treated two patients with ventriculomegaly, regarded as obstructive hydrocephalus, with an endoscopic third ventriculostomy.121 More recently, Martinez-Lage et al reported that use of VPS to treat the hydrocephalus in MCAP patients might prevent CTH development or stop its progression.122 Although the most beneficial treatment for hydrocephalus or CTH is still under discussion, surgical intervention can help relieve symptoms and may be life-saving, because hydrocephalus and CTH have been related to the occurrence of sudden death in this syndrome. The progressive nature of this disorder makes it a good target for pharmaceutical therapy because downregulation of


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the pathway may prevent the disease progression.123 After promising in vitro evidences on the PI3K pharmacological inhibition resulting in reduction in the proliferation rate in cultures,95 phase 1 to 2 studies on selective anti-AKT agents (i.e., ArQ092) are currently ongoing in small groups of patients, with appreciable results in terms of inhibition of tissue overgrowth. Future studies involving larger cohorts of patients are needed to establish if this treatment may have some benefits and if an earlier therapy may prevent the progression of the disease and its complications, especially at younger ages.

15 Stephan MJ, Hall BD, Smith DW, Cohen MM Jr. Macrocephaly in

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ventriculostomy to treat hydrocephalus associated with macrocephaly-cutis marmorata telangiectatica congenita. J Neurosurg Pediatr 2009;4(04):397–401 122 Martínez-Lage JF, Guillén-Navarro E, Almagro MJ, Felipe-Murcia M, López López-Guerrero A, Galarza M. Hydrocephalus and Chiari type 1 malformation in macrocephaly-cutis marmorata telangiectatica congenita: a case-based update. Childs Nerv Syst 2010;26(01):13–18 123 Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A 2014;164A(07):1713–1733


117 Moffitt DL, Kennedy CT, Newbury-Ecob R. What syndrome
