Posterior quadrantic dysplasia with localized hemimegalencephaly in a patient with giant congenital melanocytic nevus: First case report

Abstract

Giant congenital melanocytic nevus (GCMN) is associated with neurocutaneous melanocytosis and various other neurological complications. Its association with migrational anomalies of the brain is extremely rare. Herein, we document the first case of GCMN in a one-day-old baby associated with localized hemimegalencephaly (HME) of the brain with extensive malformation of cortical development including polymicrogyria, pachygyria and sublobar dysplasia, limited to an enlarged quadrant of the brain. HME and GCMN are considered embryological anomalies of cell migration and proliferation. We discuss the unusual magnetic resonance imaging findings along with a brief review of the literature. To the best of our knowledge, our case is the first to report the association of GCMN with localized HME.

Introduction

Congenital melanocytic nevus (CMN) is defined as the abnormal proliferation of melanocytic cells in dermis, epidermis or other tissues, present at birth, generally presenting as brown lesions with a flat or mammillated surface, well-demarcated borders and hypertrichosis. The lesions, if expected to reach more than 20 cm in adult life, are designated as giant congenital melanocytic nevi (GCMN).¹

Apart from the distinctive appearance and social challenges they can confer, GCMN are clinically important for their association with increased risk for pediatric melanoma and other neurological complications. Neurocutaneous melanocytosis (NCM) is abnormal melanocytic proliferations in the brain and spinal cord, often involving leptomeninges, associated with the occurrence of CMN. Other structural brain abnormalities are also associated with CMN such as spinal dysraphism, Dandy-Walker malformation, encephalocoele, inferior vermian hypoplasia, meningiomas, arachnoid cyst, and Chiari type I malformation.^1,2 The recent literature also describes a few rare associations of CMN and central nervous system (CNS) migrational anomalies such as focal cortical dysplasias, lissencephaly and hemimegalencephaly (HME).^2–4 We present a rare case of a neonate presenting with GCMN with the localized form of HME and associated posterior quadrantic dysplasia. To the best of our knowledge, this association has never been reported.

Case report

A one-day-old female child born to a primipara mother presented with extensive brown-black cutaneous plaques involving the face, chest, trunk, groin, arms and legs bilaterally with relative sparing of the forehead, popliteal fossa, palms and soles (Figure 1). Terminal hair follicles were seen almost all over the lesions. In a few places, nodularity was seen over the lower back. The patient was active, accepted breastfeeding, and systemic examination revealed no abnormality. Neurological examination was within normal limits. A clinical possibility of GCMN was noted and a skin biopsy was taken from the left leg. The biopsy showed an asymmetrical, wedge-shaped melanocytic neoplasm made up of melanocytes arranged in nests with preference for appendages and features of maturation with increasing depth, as well as maximum pigmentation in the uppermost dermis (Figure 2). The biopsy findings were conclusive for CMN.

Figure 1.

Extensive brown-black plaques with hypertrichosis involving the face, chest, trunk, groin, arms and legs bilaterally with relative sparing of the forehead, popliteal fossa and palms and soles.

Figure 2.

Biopsy taken from left leg lesions showing an asymmetrical, wedge-shaped melanocytic neoplasm made up of melanocytes arranged in nests (white arrows) with preference for appendages and features of maturation with increasing depth, as well as maximum pigmentation in the uppermost dermis.

Magnetic resonance imaging (MRI) of the brain and spine was performed on a 1.5 Tesla (Siemens Avanto, Erlangen, Germany) superconducting system to rule out any associated CNS lesion. MRI of the brain was conducted using T1, T2, and fluid-attenuated inversion recovery axial sections as well as T2 coronal and sagittal sequences. MRI (Figure 3(a–d)) revealed asymmetrical enlargement of the posterior aspect of the right parietal, temporal and occipital lobe associated with enlarged occipital horn of the right lateral ventricle. Adjacent right peritrigonal cortical hypertrophy was seen. Pachygyria and polymicrogyria were observed in the right temporal lobe. An abnormally deep and dysplastic sulcus was seen causing complete separation of the right temporal and occipital lobe. Another large fissure was seen extending from the anterior surface to the medial temporal lobe bifurcating the temporal lobe. These two abnormal infoldings of the cortex suggested sublobar dysplasia (SLD). The right hippocampus was enlarged and deformed with a few small, nonspecific cystic lesions. Thinning of the corpus callosum was observed along with bilateral inferior vermian hypoplasia. Overall features suggested a localized form of HME and posterior quadrantic dysplasia associated with extensive malformations of cortical development (MCDs). MRI of the spine revealed no significant abnormality.

Figure 3.

(a) Axial T2-weighted images show asymmetrical enlargement of the right cerebral hemisphere confined to the posterior quadrant along with enlargement of the occipital horn of the right lateral ventricle (solid white arrow). Note the abnormal gyral pattern in the right temporal lobe and deep right sylvian fissure (curved white arrow). (b) Grossly distorted right temporal lobe with a large fissure extending from the anterior surface to the medial temporal lobe bifurcating the temporal lobe (black arrow), suggestive of sublobar dysplasia. (c) Another abnormally deep and dysplastic sulcus (causing complete separation of the right temporal and occipital lobe (white arrow). Pachygyria is seen in the anterior aspect of the right temporal lobe (black star). (d) Coronal T2-weighted image shows polymicrogyria in the right temporal lobe (solid black arrow).

The patient's relatives were counseled for surgical resection of the involved parenchyma. They were made aware about the results' variability. However, the relatives refused the surgery and the patient was discharged at their request. We counseled the parents of the child for mutational analysis to investigate the underlying cause; however, the patient's family refused the same, predominantly because of financial constraints. Currently, the patient is lost to follow-up.

Discussion

HME is a rare neurological malformation resulting from disorganized parenchymal overgrowth due to excessive cellular proliferation as well as decreased apoptosis. Occurrence of subsequent radial neuroblast migration and postmigrational organization often results in associated MCDs.⁵

Excessive parenchymal overgrowth may involve one cerebral hemisphere (HME) or, less commonly, both cerebral hemispheres (dysplastic megalencephaly). Coexisting enlargement of the ipsilateral cerebellar hemisphere and the ipsilateral half of the brainstem is referred to as total HME.⁵ Involvement of the partial area of one cerebral hemisphere, as in our case, has been described in only a few manuscripts in the available literature, variously referred to as localized megalencephaly, hemi-hemimegalencephaly or focal megalencephaly.^6,7 Nakahashi et al. studied 43 patients with HME, of whom 11 showed signs of localized megalencephaly.⁶

Localized HME is often associated with extensive MCDs. These anomalies can be frontal predominant (anterior quadrantic dysplasia), occipital predominant (posterior quadrantic dysplasia) or almost diffuse type.⁶ D'Agostino and colleagues reported 19 patients with posterior quadrantic dysplasia, of whom 14 had localized megalencephaly.⁷ The present case showed an enlarged parietal, temporal and occipital lobe and enlarged right occipital horn along with extensive cortical malformations (posterior quadrantic dysplasia) in the form of pachygyria, polymicrogyria, cortical hypertrophy, hippocampal dysplasia and SLD. SLD is an extremely rare entity with fewer than 10 cases reported to date.⁸ There is debate as to whether SLD originates from an anomaly of stem cell differentiation or neuronal migration. The observation in the present case leads us to believe it to be a migrational anomaly.⁸ Our case also lends support to the views of Barkovich and Peacock, who initially reckoned SLD as a localized variant of HME.⁹

To the best of our knowledge, our case is the first to report the association of GCMN with localized HME and posterior quadrantic dysplasia. This association may be because both of these are migrational anomalies with subsequent deregulated proliferation of melanocytes and neuroblasts, respectively. Previously, an association of GCMN with lissencephaly has been reported.² Shih et al. reported a case of neurocutaneous melanocytosis with multiple intracranial anomalies including HME and a myxoid mesenchymal cerebral tumor.³ Ahmed and colleagues described an infant presenting with GCMN in association with encephalocraniocutaneous lipomatosis who had HME in association with extensive MCD.⁴

HME and its localized variants have been observed to be associated with various neurocutaneous syndromes such as epidermal nevus syndrome, Proteus syndrome, Klippel-Trenaunay syndrome, hypermelanosis of Ito, neurofibromatosis I with incontinentia pigmenti syndrome and tuberous sclerosis.⁵ Mutation of the AKT1 gene is implicated in HME with Proteus syndrome, whereas the AKT3 gene mutation is associated in those not associated with Proteus syndrome.¹⁰ Apart from AKT3, somatic activating point mutations in PIK3CA and mTOR have been identified in HME and a subset of focal cortical dysplasia. Moreover, germline and somatic point mutations in the AKT3, PIK3R2, and PIK3CA genes have been associated with megalencephaly-capillary malformation syndrome and megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.¹¹ The association of HME with GCMN in the present case points toward a somatic mutation that affects the cutaneous epithelium as well as the neuroepithelium. This leads to the possibility that this child is affected with a mutation that lies in the PIK3CA-related overgrowth spectrum range that includes AKT1/AKT3/PTEN, or rather extends the spectrum of anomalies that are more directly related to the MAPK signaling pathway. Although GCMN in this patient points toward BRAF and NRAS mutations, possibilities of NF1 or KRAS mutations also exist, which can lead to skin lesions similar to CMN such as neurofibromatosis and encephalocraniocutaneous lipomatosis.¹² Unfortunately we could not perform mutational analysis on our patient, predominantly because of financial constraints of the family.

Neurological complications are a well-established association of CMN and are characterized by neurocutaneous melanocytosis that show the foci of melanin-containing cells in the leptomeninges as well as the brain parenchyma, commonly basal ganglia, dentate nucleus, cerebellar hemispheres, pons, thalamus and amygdala.¹³ Studies show that melanin in these lesions is produced within neurons and glia rather than melanocytes, and there are subtle signs of focal cortical dysplasia within these lesions.¹³ It has been observed that the risk of congenital neurological abnormalities in children with CMN increases with the size of the largest CMN and the total number of nevi.¹³ A study by Waelchli et al. shows that a routine MRI of the CNS in children with two or more CMN at birth undertaken within the first year of life is the best predictor of neurodevelopmental abnormalities and the requirement for neurosurgery in childhood. MRI should be performed ideally within the first six months, as myelination obscures the signal for melanin. Patients with normal MRI do not usually need repeat neurological assessment or MRI unless there is an alteration in neurological status. Those with only neurocutaneous melanocytosis need regular annual neurodevelopmental follow-up, and those with other neurological abnormalities need regular follow-up by MRI.¹³

Surgery is the most reasonable therapeutic option for patients with quadrantic dysplasia and localized HME; however, surgical results are variable and overlapping of eloquent areas, poor delineation of the edge of lesions and independent contralateral ictal focus can lead to treatment failure. Surgical planning should be guided by preoperative MRI, prolonged scalp electroencephalogram, neurocognitive evaluation and positron emission tomography scan.⁷

It is imperative to recognize the localized form of this dysplasia on MRI as the local quadrantic hemispheric resection may be a more appropriate surgical option rather than hemispherectomy, which carries a high risk of mortality and morbidity. In long-standing cases of uncontrolled seizures, sometimes areas of atrophy may be present in localized hemimegalencephalies. Such cases are difficult to differentiate from multilobar cortical dysplasia, which is characterized by focal cortical dysplasia involving multiple lobes. Absence of extracerebral anomalies such as enlarged olfactory nerve, vascular enlargement, cerebellar enlargement and dysplasia may help differentiate them from localized megalencephaly. Also, seizure onset in MCDs is milder and of later onset than localized megalencephaly.⁷

To the best of our knowledge, this is the first case report of GCMN occurring in association with posterior quadrantic dysplasia, which itself is a very rare disorder. Also, SLD present in the index case is a rare abnormality with fewer than 10 cases reported in the literature.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.