Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants.

Germline PTEN variants (PTEN hamartoma tumor syndrome [PHTS]) confer up to 85% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk of second primary BCs. Yet, there is no previous investigation into the underlying genomic landscape of this entity. We sought to address the hypothesis that BCs arising in PHTS have a distinct genomic landscape compared to sporadic counterparts. We performed and analyzed exome sequencing data from 44 women with germline PTEN variants who developed BCs. The control cohort comprised of 497 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We demonstrate that PHTS-derived BCs have a distinct somatic mutational landscape compared to the sporadic counterparts, namely second somatic hits in PTEN, distinct mutational signatures, and increased genomic instability. The PHTS group had a significantly higher frequency of somatic PTEN variants compared to TCGA (22.7% versus 5.6%; odds ratio [OR] 4.93; 95% confidence interval [CI] 2.21 to 10.98; p < 0.001) and a lower mutational frequency in PIK3CA (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p = 0.15). Somatic variants in PTEN and PIK3CA were mutually exclusive in PHTS (p = 0.01) but not in TCGA. Our findings have important implications for the personalized management of PTEN-related BCs, especially in the context of more accessible genetic testing.

Genotypic and phenotypic analysis of Korean patients with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder caused by mutations in the TSC1 or TSC2 gene. The aim of this study was to analyze the genotypes and phenotypes of Korean patients diagnosed with TSC and expand our understanding of this disorder. This retrospective observational study included 331 patients clinically diagnosed with TSC between November 1990 and April 2023 at Severance Children's Hospital, Seoul, South Korea. The demographic and clinical characteristics of the patients were investigated. Thirty novel variants were identified. Of the 331 patients, 188 underwent genetic testing, and genotype-phenotype variation was analyzed according to the type of gene mutation and functional domain. Fourty-nine patients (49/188, 26%) were had TSC1 mutations, 103 (55%) had TSC2 mutations, and 36 (19%) had no mutation identified (NMI). Hotspots were identified in exons 8 of TSC1 and exons 35 and 41 of TSC2. Patients with TSC2 mutations exhibited a significantly younger age at the time of seizure onset and had refractory epilepsy. Infantile epileptic spasms syndrome (IESS) was more common in the middle mutation domain of TSC2 than in the hamartin domain. Additionally, retinal hamartoma, cardiac rhabdomyoma, and renal abnormalities were significantly associated with TSC2 compared with other gene types. This study contributes to our understanding of TSC by expanding the genotypic spectrum with novel variants and providing insights into the clinical spectrum of patients with TSC in Korea.

Ictal and interictal epileptic networks of 34 patients with Hypothalamic Hamartoma on scalp electroencephalography.

OBJECTIVE: To investigate ictal and interictal cortical involvement in epilepsy associated with hypothalamic hamartoma. We conducted a retrospective study of 34 patients with epilepsy and hypothalamic hamartoma, using data from long-term video-EEG-monitoring. METHODS: We analyzed onset and propagation of ictal and interictal scalp EEG and visualized the resulting networks of cortical involvement. According to clinical and EEG criteria we grouped patients in: (1) focal disease, (2) focal advanced disease, (3) extended disease. We compared networks between these groups and different seizure types. Eight patients underwent several video-EEGs, and we analyzed all to investigate epilepsy progression. RESULTS: Epileptic activity mainly involved frontal and temporal cortex regions. Involvement of frontal regions was more common in advanced stages of the disease, and strong fronto-temporal connections were observed in the ictal networks of patients in intermediate stages (25.0% (left) and 35.7% (right) of seizures with EEG correlate). Occurrence and timing of EEG-correlate significantly depended on the seizure type (Chi-2-test, p<<0.001). In patients with several EEGs, seizure activity increased by +0.67 seizures/day/month (mean). There were significant differences between patients with normal and impaired cognitive function, with the latter showing pronounced ictal involvement of fronto-temporal cortex areas (p<0.001). CONCLUSION: Overall, in epilepsy due to hypothalamic hamartoma, cortical involvement focuses on frontal and temporal regions and varies systematically with the stage of the disease, different seizure types and presence of impaired cognitive function. We propose that these data may help improve our general understanding of epileptogenesis and potentially provide insights for the surgical therapy of hypothalamic hamartomas.

Clinical Spectrum and Science Behind the Hamartomatous Polyposis Syndromes.

The hamartomatous polyposis syndromes are a set of clinically distinct disorders characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumor syndrome. Although each of the syndromes has distinct phenotypes, the hamartomatous polyps can be challenging to differentiate histologically. Additionally, each of these syndromes is associated with increased lifetime risks of gene-specific and organ-specific cancers, including those outside of the gastrointestinal tract. Germline pathogenic variants can be identified in a subset of individuals with these syndromes, which facilitates molecular diagnosis and subsequent gene-enabled management in the setting of genetic counseling. Although the malignant potential of hamartomatous polyps remains elusive, timely recognition of these syndromes is important and enables presymptomatic cancer surveillance and management before symptom exacerbation. Presently, there are no standard agents to prevent the development of polyps and cancers in the hamartomatous polyposis syndromes.

Spindle Cell Lesions with Oncogenic EGFR Kinase Domain Aberrations: Expanding the Spectrum of Protein Kinase-Related Mesenchymal Tumors.

EGFR aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3-14) and occurred subcutaneously in the upper limbs (n = 5), lower limbs (n = 3), back/thorax (n = 5), and the nasal cavity (n = 1). Eleven were cured by surgery, including 1 relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (n = 9) to IFS (n = 1) or lipofibromatosis-like tumors (LFT-like) (n = 2) or dermatofibrosarcoma protuberans-like (DFSP-like) (n = 1) to a predominantly myxoid spindle cell lesion (n = 1). Immunohistochemically, all neoplasms stained with CD34, whereas S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and 1 LFT-like harbored EGFR-KDD, whereas an exon 20 mutation was identified in all FHI, 1 LFT-like, the DFSP-like, and in predominant myxoid spindle cell lesion. By DNAmp, all but 2 cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, EGFR kinase domain aberrations found in FHI, IFS, LFT-like, DFSP-like, and a spindle cell lesion with a predominant myxoid stroma of children and adolescents showed that these neoplasms with a broad morphologic spectrum belong to the group of protein kinase-related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered.

What's new in benign lung tumours?

While lung cancer is one of the most common malignancies routinely encountered by pathologists, benign pulmonary neoplasms are quite rare. However, it is important for pathologists to be familiar with the typical diagnostic features of benign lung tumors to avoid confusing them with malignant morphological mimics. There have also been intriguing discoveries in the genetics of benign pulmonary neoplasms in the past decade. This review will cover several of the most common benign lung tumors, including the diagnostic categories of pulmonary adenomas, bronchial papillomas, and benign mesenchymal tumors, with discussion of the current classification, differential diagnosis, and current knowledge regarding genetic drivers.

Smooth muscle hyperplasia in protein kinase C-fused blue naevi: Report of 12 cases.

BACKGROUND AND AIMS: PKC-fused blue naevi are a recently described group of melanocytic tumours that have distinctive morphological features, including a pigmented epithelioid melanocytoma-like junctional component or a dermal biphasic architecture associating with naevocytoid nests surrounded by dendritic and spindled pigmented melanocytes (so-called 'combined common and blue naevus'). There have been reports of smooth muscle hyperplasia in a hamartoma-like pattern in cases of combined blue naevi without genetic exploration. MATERIALS AND METHODS: Herein, we describe 12 cases of protein kinase C (PKC)-fused blue tumours associated with a co-existing smooth muscle hyperplasia, identified from a total of 98 PKC-fused melanocytic tumours. Archived slides of PKC-fused blue naevi with haematoxylin, eosin and phloxin staining, immunohistochemistry and molecular confirmation of a PKC-fusion by fluorescence in-situ hybridisation (FISH) or RNAseq were re-evaluated for identification of notable smooth muscle hyperplasia. Fifty-one of these slides had already been studied in a previous publication from our group. RESULTS: The hyperplasia ranged from hypertrophic arrector pili muscles to extensive horizontal bundles of disorganised fibres constantly associated and limited within a biphasic dermal melanocytic component. At least one arrector pili muscle was always visible within the tumour, with occasionally direct extension of the hyperplastic fibres from the main muscle body. These muscle fibres were devoid of a PKC-fusion signal by FISH. PKC molecules are involved in the regulation of smooth muscle function, offering an explanatory framework. CONCLUSIONS: These data suggest incorporating smooth muscle hyperplasia as a diagnostic morphological feature of PKC-fused blue melanocytic tumours.

Developmental and behavioral phenotypes of pediatric patients with PTEN hamartoma tumor syndrome.

Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life-impacting neurodevelopmental features of PHTS. Our study recruited 20 children/adolescents with PHTS, who were then administered assessments for autism spectrum disorder (ASD) and other neurocognitive measures, including assessment of IQ, executive and adaptive functioning, and health-related quality of life. Thirteen individuals (65%) were identified as having ASD, of which five were newly diagnosed during the study. Of those, ASD symptom severity was in the mild-moderate range for 77%. Overall, IQ was in the average range, with a mean of 92.61 (SD 24.45, p = 0.5), though there was a non-statistically significant trend toward individuals without ASD having a higher mean IQ (102.7 vs 82.3; p = 0.1). Subjects had significant impairment in processing speed (mean 75.38, SD 24.75, p < 0.05), decreased adaptive functioning skills across all domains, and a trend toward having more executive functioning problems. Individuals with PHTS are at increased risk of neurodevelopmental disorders, including ASD and impaired executive and adaptive functioning. Although clear guidelines exist for cancer surveillance for individuals with PHTS, additional guidelines and screening for neurodevelopmental disorders are warranted.

Neuropsychological functioning of adults with PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) might be associated with a distinct cognitive and psychological profile. However, previous studies are limited, predominantly based on small and pediatric cohorts, likely affected by selection bias, and show a broad range of findings. We aimed to characterize the neuropsychological functioning of adults with PHTS. A total of 40 participants, with intellectual disability as exclusion criterium, completed an extensive clinical neuropsychological assessment including cognitive tasks, questionnaires, and a clinical diagnostic interview. The cognitive tasks and questionnaire data were categorized as below and above average based on 1.5 SD. About 80% of participants showed an average level of intelligence. In addition, 30% and 24% of participants scored below average on immediate memory recall and speed of information processing, respectively. Furthermore, about 25% reported above average scores on the majority of the questionnaires, indicating psychological distress, signs of alexithymia, and cognitive complaints. Personality of participants was characterized by inflexibility, social withdrawal, and difficulties in recognizing and describing their own emotions. Adults with PHTS demonstrate a heterogeneous yet distinct neuropsychological profile that is characterized by slower information processing, psychological problems, and specific personality traits. These findings provide directions on how to optimize the care and daily lives of adults with PHTS.

Sirolimus for vascular anomalies associated with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a rare condition associated with vascular anomalies and increased tumor risk. Sirolimus, an mTOR inhibitor used for managing vascular anomalies is underexplored in PHTS. A single-institution retrospective review of children with PHTS and vascular anomalies treated with sirolimus identified seven patients. Median age at sirolimus initiation was 10 years. After a median 2.5-year follow-up, six of seven patients (86%) showed significant clinical improvement. No significant adverse effects were observed, except mild buccal ulcers and acne. This study supports sirolimus as an effective and safe treatment for vascular anomalies in a small group of children with PHTS.

Hypothalamic Hamartoma related epilepsy: A systematic review exploring clinical, neuropsychological, and psychiatric outcome after surgery.

The post-surgical outcome for Hypothalamic Hamartoma (HH) related epilepsy in terms of seizure freedom (SF) has been extensively studied, while cognitive and psychiatric outcome has been less frequently reported and defined. This is a systematic review of English language papers, analyzing the post-surgical outcome in series of patients with HH-related epilepsy (≥5 patients, at least 6 months follow-up), published within January 2002-December 2022. SF was measured using Engel scale/equivalent scales. We looked at the outcome related to different surgical techniques, and HH types according to Delalande classification. We evaluated the neuropsychological and neuropsychiatric status after surgery, and the occurrence of post-surgical complications. Forty-six articles reporting 1318 patients were included, of which ten pediatric series. SF was reported in 686/1222 patients (56,1%). Delalande classification was reported in 663 patients from 24 studies, of which 70 were type I HH (10%), 320 were type II HH (48%), 189 were type III HH (29%) and 84 were type IV HH (13%). The outcome in term of SF was reported in 243 out of 663 patients. SF was reported in 12 of 24 type I HH (50%), 80 of 132 type II HH (60,6%), 32 of 59 type III HH (54,2%) and 12 of 28 type IV HH (42,9%). SF was reached in 129/262 (49,2%) after microsurgery, 102/199 (51,3%) after endoscopic surgery, 46/114 (40,6%) after gamma knife surgery, 245/353 (69,4%) after radiofrequency thermocoagulation, and 107/152 (70,4%) after MRI-guided laser interstitial thermal therapy. Hyperphagia/weight gain were the most reported surgical complications. Others were electrolyte alterations, diabetes insipidus, hypotiroidism, transient hyperthermia/poikilothermia. The highest percentage of memory deficits was reported after microsurgery, while hemiparesis and cranial nerves palsy were reported after microsurgery or endoscopic surgery. Thirty studies reported developmental delay/intellectual disability in 424/819 (51,7%) patients. 248/346 patients obtained a global improvement (72%), 70/346 were stable (20%), 28/346 got worse (8%). 22 studies reported psychiatric disorders in 257/465 patients (55,3%). 78/98 patients improved (80%), 13/98 remained stable (13%), 7/98 got worse (7%). Most of the patients had non-structured cognitive/psychiatric assessments. Based on the available data, the surgical management in patients with HH related epilepsy should be individualized, aiming to reach not only the best epilepsy result, but also the optimal cognitive and psychiatric outcome.

Comprehensive review of status gelasticus: Diagnostic challenges and therapeutic insights.

Status gelasticus is a rare form of status epilepticus characterized by prolonged and/or clustered gelastic seizures. The review encompasses an analysis of cases reported in the literature, focusing on causes, clinical-electroencephalographic features, and therapeutic interventions. The study reveals the challenges in defining and understanding status gelasticus due to its diverse etiologies and limited reported cases. The association with hypothalamic hamartomas and other brain abnormalities underscores the importance of thorough evaluations. The review also discusses new treatments, including medications and less invasive surgeries. While progress has been made, the study points out challenges in diagnosing and managing this complex condition, highlighting the importance of ongoing research.

Neuromodulation strategies in developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are a group of childhood-onset epilepsy syndromes characterized by frequent seizures, severe cognitive and behavioral impairments, and poor long-term outcomes. These conditions are typically refractory to currently available medical therapies, prompting recent exploration of neuromodulation treatments such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), which aim to modulate epileptic networks spanning cortical and subcortical regions. These advances have occurred alongside an improved understanding of syndrome-specific and interictal epileptiform discharge/seizure-specific brain networks. By targeting key nodes within these networks, DBS and RNS hold promise for influencing seizures and associated cognitive and behavioral comorbidities. Initial experiences with centromedian (CM) thalamic DBS for Lennox-Gastaut syndrome (LGS) have shown modest efficacy across multiple seizure types. Reports also indicate the application of DBS and RNS across various genetic and structural etiologies commonly associated with DEEs, with mixed success. Although DBS and RNS are increasingly used in LGS and other DEEs, their mixed efficacy highlights a knowledge gap in understanding why some patients with LGS do not respond and which neuromodulation approach is most effective for other DEEs. To address these issues, this review first discusses recent neuroimaging studies showing similarities and differences in the epileptic brain networks underlying various DEEs, revealing the common involvement of the thalamus and the default-mode network (DMN) across multiple DEEs. We then examine thalamic DBS for LGS to illustrate how such network insights may be used to optimize neuromodulation. Although network-based neuromodulation is still in its infancy, the LGS model may serve as a framework for other DEEs, where optimal treatment necessitates consideration of the underlying epileptic networks. Lastly, the review suggests future research directions, including individualized connectivity assessment and biomarker identification through collaborative efforts, which may enhance the therapeutic potential of neuromodulation for individuals living with DEEs.

Pediatric nasal chondromesenchymal hamartomas: a case series.

PURPOSE: Nasal chondromesenchymal hamartomas (NCMH) are rare, predominantly benign tumors of the sinonasal tract. The distinction from higher grade malignancy may be challenging based on imaging features alone. To increase the awareness of this entity among radiologists, we present a multi-institutional case series of pediatric NCMH patients showing the varied imaging presentation. METHODS: Descriptive assessment of imaging appearances of the lesions on computed tomography (CT) and magnetic resonance imaging (MRI) was performed. In addition, we reviewed demographic information, clinical data, results of genetic testing, management, and follow-up data. RESULTS: Our case series consisted of 10 patients, with a median age of 0.5 months. Intraorbital and intracranial extensions were both observed in two cases. Common CT findings included bony remodeling, calcifications, and bony erosions. MRI showed heterogeneous expansile lesion with predominantly hyperintense T2 signal and heterogenous post-contrast enhancement in the majority of cases. Most lesions exhibited increased diffusivity on diffusion weighted imaging and showed signal drop-out on susceptibility weighted images in the areas of calcifications. Genetic testing was conducted in 4 patients, revealing the presence of DICER1 pathogenic variant in three cases. Surgery was performed in all cases, with one recurrence in two cases and two recurrences in one case on follow-up. CONCLUSION: NCMHs are predominantly benign tumors of the sinonasal tract, typically associated with DICER1 pathogenic variants and most commonly affecting pediatric population. They may mimic aggressive behavior on imaging; therefore, awareness of this pathology is important. MRI and CT have complementary roles in the diagnosis of this entity.

Nevus lipomatosus superficialis: A series of six cases.

Nevus lipomatosus still imposes diagnostic, categorization, and etiologic challenges. Even though an intradermal adipose tissue is a histopathologic prerequisite, the lesions are clinically divided into classic multiple forms and a solitary variant, which some consider a separate so-called lipofibroma clinicopathologic entity. This further complicates the true prevalence, classification and etiopathogenesis of nevus lipomatosus. Case reports and series studies have reflected either consistent or variable and sometimes conflicting clinicopathologic findings. A few have reported electron microscopic findings. Immunohistochemistry is lacking. We report two multiple and four solitary forms of nevus lipomatosus in six patients, highlighting their salient histopathologic features and immunohistochemical profile. Both forms showed intradermal groups of perivascular S100+ lipogenic and CD34+ mesenchymal cells intermixed with scattered CD1a+ and FXIIIa+ dendrocytes, CD3 lymphocytic and CD117 mast cells in a fibromyxoid milieu. Epidermal nevoid and comedonal follicular alterations, attenuated dermal connective tissue and adnexal structures were variably present in both forms. We compared our findings with seven series of studies reporting classic and solitary forms. Both forms showed similar histopathologic findings, comparable clinicopathologic features, predominantly pelvic, and shoulder girdle distribution patterns in bimodal age onsets. Even though some lipomatous skin lesions clinically and histopathologically overlap with nevus lipomatosus, certain findings are helpful distinguishing features. Small intradermal islands of lipocytic fibroplasia have characteristic perivascular milieu that may function as a niche of preadipose CD34 mesenchymal stem cells. They are most likely represented in the dermis of the pelvic and shoulder areas in certain individuals prone to maintain these embryonic reservoirs, which are clinically manifested at different ages. Some may have unifocal or multifocal residues reflecting multiple and solitary forms.

Asymptomatic CD34+ plaque on the scalp of a child.

Fibroblastic connective tissue nevus (FCTN) is a rare, benign dermal mesenchymal lesion of fibroblastic and myofibroblastic lineage. We report a case of a 2-year-old male who presented with an 18-month history of an erythematous, asymptomatic, unchanging dermal plaque on the right medial frontal scalp. A punch biopsy showed a disorderly, bland, dermal fibroblastic spindle cell proliferation extending to the superficial subcutis. It stained positive for CD34, and concern for dermatofibrosarcoma protuberans was raised. However, FISH was negative for PDGFB rearrangement, and the constellation of findings was most consistent with FCTN. This case underscores the importance of distinguishing CD34+ mesenchymal tumors for both dermatologists and dermatopathologists. As these represent a rather diverse group of lesions with different biological behaviors, a knowledge of the differential diagnosis of these entities is critical for proper patient management.

Third Trimester Stillbirth Associated With Hamartoma of Mature Cardiac Myocytes (HMCM).

Fetal primary cardiac tumors (FPCTs) are very rare. The majority of them correspond to cardiac rhabdomyomas, followed by other benign neoplasms or hamartomas. We describe the case of a third trimester female stillborn with an incidental autopsy finding of Hamartoma of Mature Cardiac Myocytes (HMCM), a rare benign cardiac tumor previously unreported in the fetal or neonatal period. The intrauterine demise occurred at 32 + 6 weeks gestation after an uneventful pregnancy. The fetal autopsy revealed a structurally normal heart with a small subendocardial nodule just below the membranous septum. Microscopically, the nodule was well-demarcated from the surrounding penetrating bundle of the conduction axis and the adjacent left ventricular myocardium and consisted of disorganized mature cardiac myocytes in a haphazard arrangement with patchy mild interstitial fibrosis, consistent with HMCM. Awareness that HMCM can occur in the fetus is important in order to consider it among the differential diagnosis of FPCTs.

Autopsy case of linear nevus sebaceous syndrome with KRAS (G12D) mutation.

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous syndrome associated with systemic complications that involve multiple organs, including the skin, central nervous system, eyes, and skeleton. LNSS is considered to be caused by mosaic RAS gene mutation. In this report, we present an autopsy case of LNSS in a Japanese boy. The affected neonate had hydrops fetalis and was born at 28 weeks and 4 days of gestation, weighing 2104 g. He had bilateral inverted eyelids, verrucous linear nevus separated along Blaschko's line, myocardial hypertrophy, and pharyngeal constriction, and underwent intensive treatment in NICU for arrhythmia, hydrocephalus, and respiratory distress. The hydrocephalus progressed gradually and he died at the age of 181 days, 12 days after a sudden cardiac arrest and recovery. KRAS G12D mutation was found in a skin biopsy specimen but not in blood cells, suggesting a postzygotic mosaicism. Autopsy revealed novel pathological findings related to LNSS, including intracranial lipomatous hamartoma and mesenteric lymphangioma, in addition to previously reported findings such as multicystic dysplastic kidney. There was the limited expression of mutated KRAS protein in kidneys.

Case of a Newborn with a Neurocristic Hamartoma in a Congenital Melanocytic Naevi.

We present the case of a newborn female that was referred for review of a large melanocytic lesion on the lower back and multiple smaller lesions. Two biopsies were taken which showed features of congenital naevus and a small component of spindled dendritic cells that showed no positivity with melanocytic markers. As such, the histopathological findings of these biopsies were consistent with a diagnosis of a congenital naevus with areas resembling a neurocristic hamartoma. This case serves to highlight this rare condition and its clinical presentation, histopathological features and the importance of its early diagnosis and surveillance.

Multimodal Approach for the Treatment of Complex Hypothalamic Hamartomas.

Hypothalamic hamartomas (HHs) are rare congenital lesions formed by heterotopic neuronal and glial cells attached to the mammillary bodies, tuber cinereum, and hypothalamus.They often present with an intractable epilepsy typically characterized by gelastic seizures but commonly associated with other types of refractory seizures. The clinical course is progressive in most of the cases, starting with gelastic seizures in infancy and deteriorating into complex seizure disorders that result in catastrophic epilepsy associated with cognitive decline and behavioral disturbances.Hamartomas are known to be intrinsically epileptogenic and the site of origin for the gelastic seizures. As antiepileptic drugs are typically ineffective in controlling HH-related epilepsy, different surgical options have been proposed as a treatment to achieve seizure control. Resection or complete disconnection of the hamartoma from the mammillothalamic tract has proved to achieve a long-lasting control of the epileptic syndrome.Usually, symptoms and their severity are typically related to the size, localization, and type of attachment. Precocious puberty appears mostly in the pedunculated type, while epileptic syndrome and behavioral decline are frequently related to the sessile type. For this reason, different classifications of HHs have been developed based on their size, extension, and type of attachment to the hypothalamus.The bigger and more complex hypothalamic hamartomas typically present with severe refractory epilepsy, behavioral disturbances, and progressive cognitive decline posing a formidable challenge for the control of these symptoms.We present here our experience with the multimodal treatment for complex hypothalamic hamartomas. After an in-depth review of the literature, we systematize our approach for the different types of hypothalamic hamartomas.