Bardet-Biedl syndrome with unique manifestations of congenital giant nevi and refractory anemia: a case report from Palestine.

Introduction and importance: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder impacting multiple organs. Characterized by renal dysfunction, retinal dystrophy, obesity, polydactyly, intellectual disability, and hypogonadism, it lacks targeted treatment. Diagnosis relies on clinical criteria, and management emphasizes early detection, complication screening, and genetic counselling. Case presentation: A 4-year-old boy, born to first-cousin parents, presented with refractory iron-deficiency anaemia (IDA) and recurrent respiratory infections. Prenatal ultrasound revealed renal and limb anomalies. Physical examination showed dysmorphic features, polydactyly, and a giant-congenital naevus. Genetic testing revealed a homozygous MKKS variant. Despite oral iron, severe IDA persisted. Intravenous iron therapy yielded significant improvement. Clinical discussion: BBS, an autosomal recessive ciliopathy, involves various genes. In this case, the MKKS gene variant contributed to the syndrome. The incidence of BBS in the Arab population is discussed, emphasizing its rarity and varied clinical presentations. Incidence in the Arab population, including Palestine, is 1 in 13 500. Diagnostic criteria, encompassing major and minor features, highlight BBS complexity. Renal anomalies, visual disturbances, and cutaneous manifestations are common. Multidisciplinary care addresses systemic involvement with emerging treatments like setmelanotide. Conclusion: This case underscores BBS's rarity and complexity, featuring unique aspects like giant nevi and refractory IDA. Comprehensive management addresses renal, visual, cardiac, and neurologic aspects. Genetic counselling, prenatal testing, and preimplantation genetic diagnosis prevent transmission. Limitations include lacking local epidemiological data and prior studies in Palestine. This case contributes insights, stressing multidisciplinary management and prompting further research in underexplored populations.

Central nervous system magnetic resonance imaging abnormalities and neurologic outcomes in pediatric patients with congenital nevi: A 10-year multi-institutional retrospective study.

BACKGROUND: High-risk congenital melanocytic nevi (CMN) are associated with abnormalities of the central nervous system (CNS), prompting magnetic resonance imaging (MRI) screening guidelines. OBJECTIVE: Describe MRI brain and spine abnormalities in children with CMN and report trends between nevus features, MRI findings, and neurologic outcomes. METHODS: Retrospective review of individuals aged ≤18 years with an MRI of the brain and/or spine and at least 1 dermatologist-diagnosed CMN. RESULTS: Three hundred fifty-two patients were identified. Forty-six children had CMN that prompted an MRI of the brain and/or spine (50% male, average age at first image, 354.8 days). In these children, 8 (17%) had melanin detected in the CNS, of whom all had >4 CMN. One developed brain melanoma (fatal). In patients without CNS melanin, 4 had concerning imaging. Concerning MRI patients had more neurodevelopmental problems, seizures, neurosurgery, and death than individuals with unremarkable imaging. Three hundred six patients received MRIs for other reasons; none detected melanin. No children with only multiple small CMN (n = 15) had concerning imaging. LIMITATIONS: Lack of a control group, cohort size, and retrospective methods. CONCLUSION: MRI of the brain and spine is useful for detecting intervenable abnormalities in high-risk children. Healthy infants with few small CMN may not require screening MRI.

Giant cerebriform melanocytic nevus of the scalp: A case report.

Giant melanocytic nevus is a rare condition caused by benign proliferation of melanocytes. There is a slight risk of malignancy in these lesions which should be noticed especially when they become larger. GCMN can be removed by plastic surgery.

Prevalence and Main Determinants of BRAF V600E Mutation in Dysplastic and Congenital Nevi.

BACKGROUND & OBJECTIVE: Predicting the transformation of dysplastic or congenital nevi into malignant lesions results in a significant increase in the survival of patients. Some specific gene mutations have been reported to be very helpful in this regard. Therefore, this study aimed to evaluate the prevalence of BRAF V600E mutation in dysplastic and congenital nevi. METHODS: This cross-sectional study was conducted on patients with congenital (n=30) or dysplastic (n=30) nevi. For genomic analysis, the BRAF gene mutation (V600E) was evaluated using the real-time polymerase chain reaction. RESULTS: The prevalence of BRAF gene (V600E) mutation was found as 1 case (3.3%) in congenital and 8 cases (26.7%) in dysplastic nevi indicating the higher prevalence of this mutation in patients with dysplastic nevi (P=0.026). Moreover, in the dysplastic nevi group, the presence of BRAF gene mutation (V600E) showed a significant relationship with the severity of dysplasia as the mutation rate was 25% in mild cases, in comparison with 54.5% in moderate dysplasia cases (P=0.009). CONCLUSION: According to the results, 3.3% of the patients with congenital nevi and 26.7% of the subjects with dysplastic nevi were positive for BRAF V600E mutation. Furthermore, the severity of dysplasia could have a positive relationship with the presence of the mutation.

A study of dermal melanophages in childhood nevi. Reassessing so-called "pigment incontinence".

In inflammatory dermatoses, dermal melanophages (MLP) are ascribed to "pigment incontinence," with melanin "dropping down" from the epidermis. Although this is analogous to the "dropping down" of melanocytic nevus cells (Abtropfung), MLP in ordinary nevi have not been systematically studied-so "pigment incontinence" may not apply to MLP in nevi. A total of 31 childhood nevi identified by pediatricians and family practitioners were evaluated for the distribution of MLP. We tested the hypothesis that a dermal origin of the melanin in MLP is more likely than dropping down from the epidermis. In our cohort, 90.3% (28/31) of childhood nevi had dermal MLP, a significantly higher frequency, compared to 31/60 ordinary adult nevi (P < 0.0001). Superficial dermis was the most common location (P < 0.001). However, only six specimens had MLP restricted to the superficial dermis, significantly less than predicted by the theory that melanin drops down from the epidermis (P < 0.00001). We also evaluated perivascular MLP, since nerves run together with vessels in neurovascular bundles (NVB), and it has been showed that precursors of melanocytes migrate from the neural crest to the skin as nerve sheath stem cells. Superficial NVB MLP correlated with deep NVB bundle MLP (P < 0.05), suggesting that NVB MLP represent "tombstones" for superficial and deep dermal nevus cells. Deep dermal, deep NVB, and deep periadnexal MLP may be valid biological criteria for diagnosis of congenital type (prenatal) nevi. Viewing prenatal nevi in children as a neurocristopathy fits a major principle of pediatric pathology: childhood diseases should be studied and understood based on what happens during tissue development.

Pluripotency markers are differentially induced by IGF1 and bFGF in cells from patients' lesions of large/giant congenital melanocytic nevi.

Factors regulating transcription of pluripotency genes in congenital nevo-melanocytes are not known. Nevo-melanocytes belong somewhere in-between the ends of a spectrum where the normal epidermal melanocyte represents one end and a melanoma cell with multiple genetic abnormalities represents the other. Cells from large/giant congenital nevi (L/GCMN), unlike normal melanocytes, grow colonies on soft agar and express pluripotency markers, similar to melanoma cells. In this study normal melanocytes, SKMEL28 melanoma cells and nevo-melanocytes isolated from three L/GCMN patients were exposed to niche factors bFGF and IGF1 in vitro at physiological doses, and expression of a panel of pluripotency markers was determined by RT-PCR. While normal melanocytes did not show any significant transcriptional change in the genes studied, bFGF induced transcription of Sox2 and Bmi1 in melanoma cells. Patients' cells showed differential expression, with Sox10 being common to C76N and PD1N, while only Sox2 and Bmi1 were upregulated in C139N. IGF1 on the other hand induced unique sets of genes in each individual sample. We conclude that expression of pluripotency genes in L/GCMN cells is affected by niche factors bFGF and IGF1; however, each individual growth factor induced a unique set of genes in a patient's cells.

Neurocutaneous Melanosis with Leptomeningeal Melanoma Involving Supratentorium and Infratentorium.

Neurocutaneous melanoma is a rare congenital syndrome associated with congenital melanocytic nevi with meningeal melanosis or melanoma. The disease is aggressive and has a high propensity for leptomeningeal metastases. We present the case history of a man with neurocutaneous melanoma managed with radical excision followed by hypofractionated adjuvant radiotherapy. One year, eight months later, he had a recurrence of the condition with leptomeningeal spread and was managed with re-excision of the recurrent lesion. Although our patient was disease-free for 20 months after the initial surgery, he survived only approximately five months after the second surgery, which reflects the associated poor prognosis of the disease.

Small Dysplastic Congenital Melanocytic Nevi in Childhood as Possible Melanoma Imitators.

Small pigmented lesions in children can represent a significant diagnostic challenge. If the diagnostic features and therapeutic approach are relatively well established in large and giant nevi, there is still much controversy regarding small and intermediate-sized congenital pigmented lesions that can lead to significant diagnostic challenges, both clinically and dermoscopically, and consequently to difficulty in defining the optimal approach in such cases. Although dermoscopy can be useful in the diagnosis of pigmented lesions, the diversity of clinical and dermoscopic features of pigmented nevi in children usually hinder the differentiation between them and melanoma. Histological findings after resection often show surprising results that do not correspond either to the clinical nor the dermoscopic features. With the present case, we want to emphasise the variable natural behaviour of melanocytic lesions in children, which sometimes leads to unnecessary surgical excisions, which should be avoided in pediatric patients.

Pathology and genomics of pediatric melanoma: A critical reexamination and new insights.

The clinicopathologic features of pediatric melanoma are distinct from those of the adult counterpart. For example, most childhood melanomas exhibit a uniquely favorable biologic behavior, save for those arising in large/giant congenital nevi. Recent studies suggest that the characteristically favorable biologic behavior of childhood melanoma may be related to extreme telomere shortening and dysfunction in the cancer cells. Herein, we review the genomic profiles that have been defined for the different subtypes of pediatric melanoma and particularly emphasize the potential prognostic value of telomerase reverse transcriptase alterations for these tumors.

Giant Congenital Melanocytic Nevus (GCMN) - A New Hope for Targeted Therapy?

We present a 6-month-old male patient, who was consulted with dermatologist by his parents, because of a pigmented lesion, present since birth, covering almost the all skin of the back and buttocks. A sharply bordered, unequally coloured congenital pigmented nevus, measuring approximately 21 cm in diameter was observed in the whole body skin examination. The lesion was affecting the lower 2/3 of the skin of the back and the top half of the gluteus area, extending to the lateral part of the tors, forward the abdomen and the upper lateral part of the hips, composed by multiple darker-pigmented nests and several lighter areas, with single depigmented zones, hairy surface, irregularly infiltrated on palpation. Congenital melanocytic nevi are presented in approximately 1% of newborns, while giant congenital melanocytic nevi (GCMN) are the most uncommon subtype of them; with occurrence rate 1 in 50,000 births. They affect 2% of a total body surface or presenting in a diameter larger than 20 cm in older children. Although not common, the possible malignant transformation remains one of the most important considerations related to them, as the related lifetime risk of melanoma is 4% to 10%. Treatment recommendations include non-surgical methods as dermabrasion only within the first two weeks of life, for prevention the possible melanocytic deeper migration, while serial surgical excisions or tissue expanders could be useful treatment tool even in later stages. Nevertheless, cosmetic result is not always satisfactory, and the risk of malignant changes remains, in cases of previous melanocytic migration in deeper layer. Recent article suggests the potential role in the treatment of GCMN with NRAS inhibitor trametinib, approved for treatment of advanced melanoma, associated with underlying NRAS mutations. Although promising, the drug could be useful in paediatric patients, only with associated NRAS gene mutation. It is still unclear whether it could be helpful, independent of the NRAS status.

A mutation in the Cdon gene potentiates congenital nevus development mediated by NRAS(Q61K).

Congenital nevi develop before birth and sometimes cover large areas of the body. They are presumed to arise from the acquisition of a gene mutation in an embryonic melanocyte that becomes trapped in the dermis during development. Mice bearing the Cdk4(R24C) ::Tyr-NRAS(Q) (61K) transgenes develop congenital nevus-like lesions by post-natal day 10, from melanocytes escaping the confines of hair follicles. We interbred these mice with the collaborative cross (CC), a resource that enables identification of modifier genes for complex diseases (those where multiple genes are involved). We examined variation in nevus cell density in 66 CC strains and mapped a large-effect quantitative trait locus (QTL) controlling nevus cell density to murine chromosome 9. The best candidate for a gene that exacerbates congenital nevus development in the context of an NRAS mutation is Cdon, a positive regulator of sonic hedgehog (Shh) that is expressed mainly in keratinocytes.

Characteristics, treatment, and survival of invasive malignant melanoma (MM) in giant pigmented nevi (GPN) in adults: 976 cases from the National Cancer Data Base (NCDB).

BACKGROUND: Malignant melanoma (MM) arising in a giant pigmented nevus (GPN) is a rare disease in adults with no large series published to our knowledge. OBJECTIVE: We sought to describe the characteristics, treatment, and survival of MM in GPN for adults. METHODS: Adults with invasive MM in GPN (n = 976) reported to the National Cancer Data Base from 1998 to 2012 were evaluated for patient and tumor characteristics, treatment, and survival. For comparison, data from adults with invasive superficial spreading melanoma (SSM) (n = 111,870) and nodular melanoma (n = 35,962) were used. RESULTS: Compared with patients with SSM, patients with MM in GPN had a thicker Breslow depth, more positive lymph nodes, and distant metastasis more frequently. Multivariate analysis identified age older than 65 years, Breslow thickness greater than 2 mm, presence of ulceration, presence of distant metastasis, and positive margins as independent predictors of survival in patients with MM in GPN. At all stages, having MM in GPN has similar overall survival compared with SSM. LIMITATIONS: The study is retrospective and registry-based. CONCLUSIONS: Invasive MM in GPN occurs in adults, with overall survival similar to SSM. Clinicians should be aware of the continued risk of MM in adults with GPN with low threshold for biopsy.

[Orbital congenital nevi: Principles of treatment about 51 cases]. / Nævi orbitaires congénitaux: principes de prise en charge thérapeutique à propos de 51 cas.

INTRODUCTION: The incidence of congenital nevi is one over 20,000 newborns per year, 14 % of them are located in the head and neck area. Nevi of the orbital region are particularly difficult to handle on the aesthetic and functional side. The objectives of this study were to conduct an analysis of different clinical presentations of congenital nevi of the eyelid orbital region in children to establish a treatment algorithm. MATERIEL AND METHODS: We realised a bi-centric retrospective study including 51 children with orbito-palpebral congenital nevi. We analysed the different clinical presentations, their treatments and their results. RESULTS: Nineteen underwent direct suture excision; three a total skin graft; 15 a combination of treatments, among them four underwent tissular expansion and 14 patients were not operated and clinically followed-up. The average follow-up time was 6.6 years. In 33 cases residual nevic area was still present. The postoperative sequelae were: dyschromia (n=17), anatomical deformation of the eye (n=10), nevi outbreaks (n=8), internal canthus deformation (n=5) and ectropion (n=1). CONCLUSION: The results of our study show that therapeutic abstention is preferred when the aesthetic wrong is accepted by the patient and when there is not a higher risk of malignant degeneration. In order to minimise the risk of postoperative sequelae, we propose a therapeutic algorithm for the management of congenital orbital nevi.

Complications of nonbreast tissue expansion: 9 Years experience with 44 adult patients and 119 pediatric patients.

BACKGROUND: Tissue expansion is a common reconstructive technique that has been associated with significant complications since its inception. However, the existing literature mostly focuses on complications associated with pediatric tissue expansion only or describes a combined population of adult and pediatric patients, including breast tissue expansion; despite the fact that each of these groups of patients has different characteristics that may affect tissue expansion. OBJECTIVE: In this study we present a critical review of our experience with complications of nonbreast tissue expansion in adult and pediatric patients and compare between these groups. METHODS: The charts of patients who underwent nonbreast tissue expansion at Hadassah Medical Center between January 2003 and July 2012 were reviewed. Data were collected including the age of the patient, anatomical site of the expansion, indication and complications. RESULTS: A total of 202 expansion procedures were performed on 119 pediatric patients (<16 years) and 56 expansion procedures on 44 adult patients. The overall complication rate was 18.2%, with 40 pediatric procedures having complications (19.8%) and 7 adult procedures (12.5%). The difference in complication rates between the two groups was not found to be statistically significant. There was no statistically significant difference in complication rate between the different anatomical areas of expansion in both adult and pediatric patients or between the indications for operation. Most (68%) of the cases with complications underwent subsequent successful reconstruction. CONCLUSIONS: Despite the consistent high complication rate, tissue expansion can be used as a good reconstructive method in both adult and pediatric patients in all anatomic areas and for different indications.

A newborn with neurocutaneous melanocytosis and Dandy-Walker malformation.

BACKGROUND: Neurocutaneous melanocytosis is a rare congenital dysplasia of the neuroectodermal melanocyte precursor cells that leads to proliferation of melanin-producing cells in the skin and leptomeninges. PATIENT: We describe a newborn with a giant congenital melanocytic nevus on his back, buttocks, and thighs. His brain magnetic resonance imaging study revealed bilateral T1 hyperintense lesions in the cerebellum and in the amygdala, hydrocephalus, and a Blake's pouch cyst, consistent with neurocutaneous melanocytosis and Dandy-Walker malformation. CONCLUSION: Neurocutaneous melanocytosis has a wide clinical spectrum that includes hydrocephalus, epilepsy, cranial nerve palsy, increased intracranial pressure, and sensorimotor deficits.

Problematic lesions in children.

Melanoma in childhood is rare, and appears more commonly either in association with a preexisting (congenital) nevus, or with spitzoid features than de novo. Thus, problematic melanocytic lesions in children are essentially represented by congenital nevi and Spitz nevi that can be regarded as melanoma precursors and melanoma simulators, respectively. As a consequence, clinical and dermoscopic features of melanoma in children differ from those in an adult population. Herein we describe common clinical and dermoscopic features of problematic lesions in children, focusing on congenital and Spitz/Reed nevi, and including other problematic lesions, such as atypical, blue, acral, and scalp nevi.