Neuroimaging features of genetic syndromes associated with CNS overgrowth

CLOVES is an acronym referring to congenital lipomatous overgrowth (CLO), vascular anomalies (V), epidermal nevi (E) and skeletal/spinal deformities (S). The syndrome falls under the umbrella PROS. Historically, many patients with CLOVES were previously diagnosed as having Proteus or Klippel-Trenaunay syndrome, but with better understanding of the syndromes, correct classification can now be made [4].

Thoracic lipomatous overgrowth is one of the most distinctive physical exam features in patients with CLOVES syndrome (Fig. 3). The overgrowth is typically asymmetrical and is usually quite noticeable in many patients. In addition, the overgrowth is congenital in CLOVES syndrome, whereas patients with Proteus syndrome are normal at birth then the overgrowth changes dramatically with age [4]. The head size is usually normal in CLOVES syndrome, while it is large in MCAP [7].

Both high and low flow vascular malformations have been reported in CLOVES syndrome. While high flow malformations are less common, spinal or paraspinal arteriovenous malformations (AVMs) are a characteristic feature [8]. Low flow malformations include lymphatic, venous and capillary malformations (Fig. 3).

Epidermal nevi may be seen and are hamartomatous lesions derived from the epidermis and manifest as hyperpigmented verrucous plaques (Fig. 1). The nevi are usually linear in morphology.

Multiple musculoskeletal abnormalities have been described and include scoliosis, spinal dysraphism, pectus deformities, sandal gap toes (Fig. 2), macro-, poly- and syndactyly, chondromalacia patellae and dislocated knees [5, 8, 9].

Neuroimaging features include hemimegalencephaly and agenesis or dysgenesis of the corpus callosum (Figs. 1 and 2). Spinal abnormalities consist of scoliosis, neural tube defects and spinal or paraspinal AVMs with possible ischemic myelopathy. Contrast-enhanced magnetic resonance (MR) angiography can be performed along with traditional spine MR imaging in the setting of an AVM for lesion characterization and potential treatment planning.

Thoracic lipomatous overgrowth can be seen on spine MRI or computed tomography (CT) and is usually over the back or side. Muscular overgrowth can be an accompanying feature as well as cutaneous or deep low flow vascular malformations.

Other than the neuroimaging features, renal agenesis and splenic vascular malformations have been reported (Fig. 3) [5, 9]. Wilms tumor has been reported in a minority of patients with CLOVES syndrome, and some authors recommend abdominal ultrasound screening every three months until the age of 7 [10].

Megalencephaly-capillary malformation (MCAP) syndrome is characterized by megalencephaly, capillary malformation and somatic overgrowth. The syndrome has been previously referred to as megalencephaly-capillary formation and macrocephaly-cutis marmorata telangiectatica congenita, although MCAP is the name commonly used [11].

The majority of MCAP cases are reported to arise from somatic mosaic mutations in PIK3CA, suggesting that the mutation occurred post-fertilization in one cell of the multicellular embryo. For these reasons, genetic analysis from affected tissue is suggested for diagnosis. Germline PIK3CA mutations have also been reported from blood sampling but are less common [5, 9].

The clinical profile in patients with MCAP varies greatly from very mild symptoms to severe. Most patients have enlarged heads due to megalencephaly (occipitofrontal circumference ≥3 standard deviations above the mean) that may either be congenital or present in the early postnatal period and tends to be progressive as the child grows. Because of the abnormal brain growth, developmental delay, seizures and hypotonia are common. Somatic overgrowth may also be present and ranges from facial overgrowth to frank hemihypertrophy. While the aforementioned brain overgrowth is typically progressive, the somatic overgrowth can stabilize over time and even regress. In general, the somatic overgrowth is diffuse with mild asymmetry, whereas the somatic overgrowth in CLOVES patients is typically segmental and severe [7, 11].

Capillary malformations are the main vascular anomaly seen in patients with MCAP and can occur in the trunk, limbs and midline face (nevus flammeus). The capillary malformations can be extensive and resemble cutis marmorata (Fig. 4). Infantile hemangiomas and venous malformations have also been reported but are less common [5, 9].

Other physical exam findings include frontal bossing, syndactyly of the 2nd-4th toes or fingers, sandal gap toe deformity, polydactyly, hyperelastic skin and joint laxity. Rarely, cardiac anomalies (atrial and ventricular septal defects and/or abnormalities of the great vessels) and genitourinary abnormalities (cryptorchidism, micropenis, hypospadias, duplicated urinary collection system) may occur [11].

Ventriculomegaly or hydrocephalus with or without hemimegalencephaly is the most common neuroimaging finding in patients with MCAP. The etiology is potentially obstructive in some patients with cerebellar overgrowth, but it is unclear if this is the case in all patients [5, 12]. The hydrocephalus can lead to neurosurgical treatment necessitating a ventriculoperitoneal shunt or endoscopic third ventriculostomy [13].

The brain overgrowth in one study of 11 patients with brain MRIs showed 8 with megalencephaly and 3 with hemimegalencephaly [14]. The progressive nature of megalencephaly, particularly if it involves the cerebellum, tends to result in cerebellar tonsillar ectopia because of a crowded posterior fossa [12]. Some studies have reported Chiari I as a feature in MCAP, although it has been suggested that cerebellar tonsillar ectopia is the preferred term given that Chiari I deformities have congenitally small posterior fossas, and in MCAP, the posterior fossa typically becomes crowded due to brain overgrowth [13]. Regardless of the terminology, resultant syringomyelia and suboccipital decompression may be necessary in symptomatic patients.

Polymicrogyria is an increasingly recognized feature with MCAP that is commonly bilateral and perisylvian but may also occur in the bifrontal location or be focal [13]. A thick corpus callosum, abnormal T2 signal in the deep and periventricular white matter (Fig. 4), cavum septum pellucidum or vergae, enlarged dural venous sinuses and prominent perivascular spaces are additional imaging features reported in MCAP [13]. Meningioma and retinoblastoma are rarely reported tumors on neuroimaging [12].

Certain publications recommend surveillance imaging of brain MRIs every 6 months for the first 2 years of life, followed by annually until the age of 8 to monitor for hydrocephalus and cerebellar tonsillar ectopia [5, 9].

MPPH is another overgrowth syndrome that can sometimes mimic MCAP, as there are overlapping imaging features (hemimegalencephaly, polymicrogyria, ventriculomegaly), but intracranial heterotopia, vascular malformations and syndactyly are absent [11].

Like PIK3CA and the PROS family of syndromes, PTEN hamartoma tumor syndrome (PHTS) represents a spectrum of disorders secondary to a mutation in the PTEN gene. PTEN is a tumor suppressor gene and germline mutations result in a loss of function.

The main two syndromes within the PHTS family are Cowden and Bannayan-Riley-Ruvalcaba syndromes, which were initially described as separate disorders but would later be characterized as having a common germline PTEN mutation. One of the challenging features in diagnosing patients with PHTS syndrome is the broad phenotypic variability between patients with the same mutation and even with patients in the same family. Major and minor criteria exist for the diagnosis of PHTS but are beyond the scope of this article [15].

While there are unique imaging features within the respective PHTS syndromes, there are common neuroimaging features that can be observed. Increased white matter volume, including an enlarged corpus callosum, is a feature of PHTS and can be assessed qualitatively or with volume segmentation [16]. These findings are one of the principal reasons for macrocephaly in these patients, and hypermyelination is one of the postulated reasons for the increased white matter. PTEN conditional knockout mice have been studied, and brain analysis has revealed enlarged neuronal projections, increased dendritic spine density and increased glial cells, leading to the hypermyelination [16]. Enlargement of the cerebellum and lateral ventricles can be another cause of macrocephaly but is less severe compared to the white matter overgrowth [17]. Lhermitte-Duclos disease can be observed and is a benign lesion representing a dysplastic gangliocytoma or hamartoma. This entity always occurs in the cerebellum and shows T2 hyperintense white matter signal with a normal cortex in a striated or tigroid pattern. Facilitated diffusion and no or mild enhancement are observed after contrast administration [18]. Additional imaging features in PHTS patients include multiple dilated perivascular spaces, white matter signal abnormalities, decreased cortical thickness, vascular malformations such as cavernous malformations, developmental venous anomalies or dural arteriovenous fistulas, cortical malformations and hemimegalencephaly, and cerebellar ectopia (Figs. 5, 6 and 7) [17, 19, 20].

In addition to routine vascular malformations that can occur throughout the body, patients with PHTS can exhibit a unique vascular malformation called PTEN hamartoma of soft tissue (PHOST) (Fig. 6). These lesions are usually complex-appearing and can demonstrate slow and high flow components. Fibrofatty infiltration of muscle, fascia and even bone may be seen. Because of the diverse features within PHOST lesions, these masses are often misdiagnosed in the absence of a known PTEN mutation. Differential diagnoses can include venous malformation, arteriovenous malformation and fibroadipose vascular anomaly [21].

Cowden syndrome is a rare multisystemic disease characterized by overgrowth of various tissues and increased risk for several malignancies throughout the body. Most patients present in early adulthood with macrocephaly, characteristic skin lesions, hamartomas and malignancies.

More than 90% of patients with Cowden syndrome have clinical manifestations in their late 2nd decade, and by the fourth decade, 99% have some clinical features [22]. On physical exam, patients usually have macrocephaly and dolichocephaly. A skin exam can show trichilemmomas (benign follicular epithelial neoplasms), papillomatous papules (skin-colored raised bumps), acral and plantar keratoses (dark flat spots on hands and feet) and vascular malformations. Autism spectrum disorder and developmental delay may be observed [22].

Patients with Cowden syndrome have a very high risk of developing malignancies throughout the body, including breast, thyroid, endometrial, gastrointestinal, renal and cutaneous melanoma. Cancer screening guidelines exist for each of these malignancies to ensure early detection.

Neuroimaging in patients with Cowden syndrome classically shows Lhermitte-Duclos disease. In addition, meningiomas have been reported with Cowden syndrome, but it is unclear if there is a true higher incidence, as meningiomas are common in the general population.

This syndrome classically exhibits the cardinal features of macrocephaly, hamartomatous intestinal polyposis, lipomas, vascular malformations and pigmented macules of the glans penis.

In addition to the classic triad of macrocephaly, lipomatosis and pigmented macules of the glans penis, these patients can have high birth weight, myopathies in proximal muscles, joint hyperextensibility, pectus excavatum, scoliosis and abnormal facial features [22]. Developmental and motor delays are observed, and most patients are diagnosed in childhood. Formal diagnostic criteria have not been agreed upon, but diagnosis is established based on the combination of genetic analysis, clinical and radiologic features. Cancer risk and screening of breast, thyroid, endometrial, gastrointestinal, renal and cutaneous melanoma are similar to Cowden syndrome, although no formal studies have studied malignancy risk in this patient population [22].

Macrocephaly and dilated perivascular spaces have been reported on patients with Bannayan-Riley-Ruvalcaba syndrome [23]. Spinal anomalies have also been reported in these patients, and the main feature is excess fat. On imaging, patients can exhibit lipomatous overgrowth in the subcutaneous tissues, epidural lipomatosis, fat within the muscles and neural foramina, and even fatty conversion of bone marrow (Fig. 8) [23]. The lipomatosis can be progressive.

Proteus syndrome is an overgrowth syndrome that results in severe overgrowth and disfigurement. The disease is exceptionally rare, with a very rough prevalence estimate of 1 out of 1–10 million people [24]. Furthermore, some of the previous reports in the literature were published before modern genomic testing, and some of these reports may have represented PIK3CA or other mutations rather than represent Proteus syndrome [25].

Proteus syndrome is caused by a somatic activation mutation in AKT1, which is responsible for cell growth and proliferation [26]. Tissue sampling from affected tissue can detect AKT1.

The growth pattern of Proteus syndrome is unique and helpful in making the diagnosis. Patients have little or no manifestations at birth but rapidly develop disfiguring asymmetrical and disproportionate skeletal overgrowth in childhood. This pattern separates it from other overgrowth syndromes, especially PIK3CA. While the somatic overgrowth is usually progressive, macrocephaly secondary to hemimegalencephaly can be congenital. To date, no AKT1 mutations have been identified in affected brain tissue, and this is likely due to its inherent low levels of brain expression. AKT3 mutations, on the other hand, have higher levels of brain expression and readily result in malformations of cortical development (Fig. 9), although this gene does not result in Proteus syndrome [27, 28].

Cerebriform connective tissue nevi is essentially pathognomonic for Proteus syndrome and are nevi that resemble the brain gyration pattern. They commonly occur on the hands and feet, but other locations have been reported. Linear verrucous epidermal nevi are another dermatologic finding. Patients often have dysmorphic facial features that develop in childhood [26].

Patients often develop alterations in fat and can both develop lipomatous overgrowth and atrophy. Vascular malformations have been reported, including capillary, lymphatic and venous subtypes, while arteriovenous malformations are rare. Thromboembolism in the deep veins and pulmonary arteries is a potential risk. There is an increased predisposition of certain tumors, including meningioma, ovarian cystadenoma and parotid adenoma. Psychosocial issues and developmental delay may be witnessed, although the majority of patients have normal intelligence [29].

Hemimegalancephaly and other malformations of cortical development can be observed in patients with Proteus syndrome. Meningiomas, dolichocephaly and hyperostosis of the skull and external auditory canal have been reported. Within the spine, the vertebral bodies can abnormally enlarge and result in scoliosis [24].

Weaver syndrome is secondary to an EZH2 mutation, which is responsible for normal embryonal development. The syndrome shares some clinical features similar to Sotos syndrome but with a “stuck on” protruding chin that may be one of the differentiating features on physical exam. Neuroimaging has only been reported in a few patients, but ventriculomegaly, periventricular leukomalacia and malformations of cortical development have been reported [34].

Beckwith-Wiedemann syndrome is an overgrowth disorder secondary to epigenetic alterations in growth regulatory genes at 11p15.5, primarily due to genetic imprinting. Cardinal features of this common overgrowth syndrome consist of macroglossia, persistent hypoglycemia, visceromegaly and Wilms tumor. Intracranial anomalies have been reported in a minority of patients and consist of malformations within the Dandy-Walker continuum as well as callosal dysgenesis [35].