Au Lait Research Articles

LGGL-03 TREATMENT OUTCOMES ON OPTIC GLIOMA: A CASE STUDY

Abstract 11 year old male presented in December 2021 with complaints of headache and visual impairment. On examination [he had] multiple freckles in the right axilla and cafe au lait lesions all over his body with largest being 3cm in the inguinal region. Pretreatment MRI showed minimally enhancing mass seen in the optic chiasm extending anteriorly into the distal optic nerves bilaterally and the optic tract posteriorly with extensive vasogenic edema along the optic pathway into the lateral thalamus and extending into the bilateral lentiform nuclei. H-MR spectroscopy of the mass demonstrated a choline peak. Findings in keeping with optic pathway glioma. The baseline fundoscopy showed a normal anterior segment, slightly pale disc on the posterior segment. The patient was commenced on weekly Vinblastine via chemo port. At 24 weeks of treatment patient was assessed MRI and fundoscopy. MRI showed a mild interval decrease in size of lobulated mass lesion involving the optic chiasma, bilateral optic nerves up to intraorbital segments and optic tracts. The lesion also involves the infundibular stalk and tuber cinereum. No interval change in hyperintense T2/FLAIR signal with no enhancement seen at the lateral geniculate bodies, hippocampi, bilateral lentiform nuclei and lateral thalami. He completed 72 weeks of Vinblastine with good clinical Response. NF 1 can cause tumors to form and optic nerve gliomas that may occur in about 15 percent of children with this disease in about 2/3 of the time the tumors stop growing and disappears however there are some tumors that may require treatment.

Comprehensive Assessment of Dermatologic and Dysmorphic Manifestations in Patients With Down Syndrome.

Down syndrome (DS), a common chromosomal anomaly caused by trisomy of chromosome 21, is characterized by a broad spectrum of phenotypic characteristics across multiple organ systems, including cardiac defects and leukemia. Dermatological findings are prevalent among individuals with DS; however, these issues are frequently underrecognized and inadequately researched, resulting in a significant gap in the provision of comprehensive healthcare strategies. Given the increased life expectancy of patients with DS and delayed manifestation of many dermatoses, physicians are increasingly encountering dermatological findings in this population. This study aimed to assess the prevalence and types of dermatological findings in individuals with DS, compare them with those in a control group, and emphasize the necessity of incorporating dermatological evaluations into routine health monitoring. This prospective cross-sectional study was conducted from June 2023 to June 2024 and involved 100 genetically confirmed individuals with DS and 100 age- and sex-matched controls. Comprehensive demographic, clinical, and karyotype data were collected for the DS group, and all the participants underwent detailed morphological evaluations. The DS group had a mean age of approximately 6.37 years, whereas the controls were around 7 years old, with no significant differences in age or sex distribution between the groups. Karyotype analysis showed that trisomy 21 was present in 92% of the cases, mosaicism in 6%, and translocation in 2%. Common dermatological findings in the DS group included xerosis cutis (49%), thin and sparse hair (48%), dental caries (34%), delayed tooth eruption (28%), nail dystrophy (25%), fissured tongue (23%), and cheilitis (18%). Significant differences were noted in the prevalence of scabies, bacterial infections, and café au lait macules between the DS and control groups (p < 0.01). Dysmorphic findings in the DS group included epicanthal folds (97%), upslanted palpebral fissures (97%), brachycephaly (91%), and single transverse palmar crease (89%). Significant gender differences were noted in the prevalence of brachycephaly and the sandal gap (p < 0.01). This study highlights the importance of regular dermatological care in enhancing the health management and quality of life of individuals with DS due to the prevalence and variability of dermatological conditions.

Comprehensive analysis of constitutional mismatch repair deficiency-associated non-Hodgkin lymphomas in a global cohort.

Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non-Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20years. Limited data exist on CMMRD-associated lymphomas and their outcome. We conducted a retrospective study including all CMMRD-associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL). Events considered to define event-free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first. The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T-cell lymphoblastic lymphomas (T-LBL), four B-lymphoblastic lymphomas, and 17 mature B-cell non-Hodgkin lymphoma (B-NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow-up was 8.7years. After the first lymphoma, the 5-year event-free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9-35.1] and 61.5% [95% CI: 49.6-72.1]. The 5-year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%. Standard treatments for sporadic NHL are effective in most CMMRD-associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL.

Neurofibromatosis type 1: short review and clinical case

Neurofibromatosis type 1 (NF1) is acommon (1/3000) autosomal dominant disorder associated with amutation in the NF1 gene, located on the long arm of chromosome 17 (17q11.2). NF1 is diagnosed using well-known clinical criteria: café au lait spots, axillary and inguinal freckles, cutaneous and subcutaneous neurofibromas, optic pathway gliomas, and specific bone abnormalities. The pathognomonic feature of the disease is plexiform neurofibroma (PN), which is abenign peripheral nerve sheath tumor that occurs in 30-50% of patients with NF1. In addition to awide range of clinical manifestations, such as pain, motor, respiratory disorders, neurological deficits, cosmetic defects, etc., there is about a15% risk for the development of malignant peripheral nerve sheath tumors (MPNST). And it should be noted that the treatment of PN is acomplex task that does not have one standard solution. Thus, surgical treatment, which was the “gold standard” and remains one of the main methods of therapy, carries significant risks, such as postoperative neurological deficit, ahigh risk of intraoperative bleeding and is accompanied by ahigh percentage of relapses. Therefore, the emergence of targeted therapy and its use in the Russian Federation since 2021 has made asignificant contribution to the treatment of symptomatic inoperable plexiform neurofibromas.

Cluster of Neurofibromatosis Cases in Remote Area of Northern Karnataka: A Case Series

Abstract Tumours of the nerve system and skin are hallmarks of neurofibromatosis, a neurocutaneous condition. One class of inherited illnesses known as phakomatoses includes neurofibromatosis type 1 (NF1) or von Recklinghausen disease. It may show up anywhere in the body, including the skin, eyes, bones, and organs. We report a visually recorded seven cases of NF1 from same area. Every single patient had some kind of skin symptom. We describe the presence of several isolated neurofibromas, café au lait macules, axillary and inguinal freckling, neurological or cognitive dysfunction, and Lisch nodules in 100% of the eyes as ocular symptoms. Also, a rare occurrence of plexiform neuroma seen. Rare and familial presentation and similar cases in the same region, these findings collectively underscore the complex nature of the patient's medical presentation, necessitating a multidisciplinary approach to management and care.

LZTR1 loss-of-function variants associated with café au lait macules with or without freckling.

Pathogenic variants in the leucine zipper-like transcriptional regulator 1 gene (LZTR1) have been identified in schwannomatosis and Noonan syndrome. Here, we expand the phenotype spectrum of LZTR1 variants. We identified four loss-of-function heterozygous LZTR1 variants in five children with multiple café au lait macules and one adult with multiple café au lait macules and axillar freckling, by applying gene panel analysis in four families. The three LZTR1 variants, namely, c.184del/p.Glu62Serfs*39, c.1927C < T/p.Gln643*, and c.857_858delinsT/p.Gly286Valfs*65, were novel, whereas the variant c.1018C > T/ p.Arg340* had been previously reported in a patient with schwannomatosis. Similar to what is known from other LZTR1-associated conditions, penetrance of the skin manifestations was reduced in two carriers of the familial variants. Our study expands the LZTR1 phenotype to the presence of isolated café au lait macules with or without freckling. Thus, variants in the LZTR1 gene should be considered in patients with multiple café au lait macules.

The treatment of infantile giant café au lait spot using golden parameter therapy with a high fluence 1064-nm Q-switched Nd: YAG laser

Background Infantile café au lait spot is a brown macule with various sizes (diameter: 0.5 cm–30 cm). Infantile giant café au lait spot (IGCALS) is a huge (diameter >20cm) irregular-shaped benign hyperpigmented skin disorder that arises in infants. There has been no clearly established laser treatment consensus for the treatment of IGCALS because infants are too fragile to receive laser treatment with long hours and broad areas along with the possibility of undesirable cosmetic results. Objectives This study investigated the safety and efficacy of Golden Parameter Therapy (GPT) using a high fluence 1064-nm Q-switched Nd:YAG laser (QSNL) for IGCALS treatment. Methods This study included 24 Korean patients with IGCALS. Twenty-one patients who were treated with a 1064-nm QSNL weekly for 30–50 treatment sessions with GPT. The parameters included a spot size of 7 mm, a fluence of 2.2 J/cm2 and a pulse rate of 10 Hz with one pass using a sliding-stacking technique over the IGCALS. In control group, three patients were treated with a 532-nm picosecond laser monthly for three treatment sessions with a spot size of 3 mm, a fluence of 1 J/cm2 and a pulse rate of 2 Hz. Results After the last treatment, 21 patients with IGCALS reached the complete removal of pigmented lesions, which can be considered optimal cosmetic results without any side effects such as purpura, crust, post-inflammatory hyperpigmentation, iatrogenic punctate leukoderma, and scarring. There are no recurrences in any patients after 6–21 months’ follow-up, but treatment failure occurred in three patients who were treated with 532 nm picosecond laser. Conclusions Convincingly, we argue that early intervention before 12 months of age with GPT using a high fluence 1064 nm QSNL is a safe, applicable and effective treatment for IGCALS, minimizing side effects without any recurrences.

Pigment epithelium derived factor drives melanocyte proliferation and migration in neurofibromatosis café au lait macules.

RASopathies, which include neurofibromatosis type 1 (NF1), are defined by Ras/mitogen-activated protein kinase (Ras/MAPK) pathway activation. They represent a group of clinically related disorders often characterised by multiple Café au Lait Macules (CALMs). To determine, using in depth transcriptomic analysis of NF1 melanocytes from CALM and unaffected skin, (1) the gene(s) responsible for melanocyte proliferation and migration, and (2) the activated signalling pathway(s) in NF1 melanoma. Classical NF1 (n=2, who develop tumours) and 3bp deletion NF1 (p. Met992del, who do not develop tumours) (n=3) patients underwent skin biopsies from CALM and unaffected skin. Melanocytes were isolated and propagated, with five replicates from each tissue sample. DNA and RNA were extracted for mutational analysis and transcriptomic profiling with six replicates per sample. Mechanistic determination was undertaken using melanocyte and melanoma cell lines. All CALMs in NF1 were associated with biallelic NF1 loss, resulting in amplification of Ras/MAPK and Wnt pathway signalling. CALMs were also associated with reduced SERPINF1 gene expression (and pigment epithelium-derived factor (PEDF) levels, the reciprocal protein), a known downstream target of the master regulator of melanocyte differentiation microphthalmia-associated transcription factor (MITF), leading to increased melanocyte proliferation, migration and invasion. In classical NF1 and melanoma, but not 3bp deletion NF1, there was also activation of the PI3K/AKT pathway. Pigment epithelium-derived factor was found to reduce cell proliferation and invasion of NF1 melanoma. Melanocyte proliferation and migration leading to CALMs in NF1 arises from biallelic NF1 loss, resulting in RAS/MAPK pathway activation, and reduced expression of the tumour suppressor PEDF. Activation of the PI3K/AKT pathway in classical NF1 and NF1 melanoma may facilitate tumour growth.

Evaluation of a Novel Dermal Cooling System for the Treatment of Benign Pigmented Lesions in Asians.

Our study aimed to evaluate the efficacy of this novel dermal cooling system (DCS) in reducing pigmentation in benign pigmented lesions in Asian patients and its potential side effects. It was a prospective open-label single-center study. Asian patients, with the presence of benign pigmented lesions mainly including lentigines, melasma, nevus spilus, ephelides, café au lait, and seborrheic keratosis were recruited for a novel DCS. The DCS provided localized cooling of the epidermal layer below freezing but was less intense than cryotherapy. Each patient received DCS at Week 0 and repeated at 4-week intervals up to 10 sessions. Global aesthetic improvement scores (GAIS) by blinded physicians and subjects were recorded at 2, 6, and 12 months posttreatment follow-up. Eighty-one patients were recruited with a total of 305 sessions performed and 1716 lesion sites treated. At 2-month posttreatment, 76.5% and 58.6% treatment sites showed obvious to marked improvement respectively and the improvement sustained at 6 and 12 months. Only minor adverse events were reported. Erythema and edema were the most commonly anticipated effects immediately after treatment. The pain was minimal. Postinflammatory hyperpigmentation was only reported in 2.2% (38/1716) treated sites. To our knowledge, this study was the first study to demonstrate that this novel DCS was an effective, safe, and well-tolerated treatment for benign pigmented lesions in Asians.

LMIC-20. REAL-WORLD EXPERIENCE IN DEALING WITH CHILDREN WITH SUSPECTED CENTRAL NERVOUS SYSTEM (CNS) TUMORS AT THE CHILDREN’S HOSPITAL LAHORE (UCHS), PAKISTAN

Abstract BACKGROUND CNS tumors are the leading cause of cancer-related deaths in children in HICs, but data from LMICs are scarce. The objectives of this study were to document the trajectory of children with CNS tumors at a tertiary-care hospital in Pakistan. METHODS This prospective, analytic, cohort study recorded all new cases of suspected CNS tumors (birth to 16 years) presented from 2023/01/01 to 2023/12/31 at UCHS, Lahore. RESULTS A total of 145 cases were included. Median age at presentation was 7.0 years (1.5 months–15 years); male-to-female ratio was 1.4:1. Median time to presentation was 2 months (0.1 – 96 months); delay of &amp;gt;6 months was observed in 30.5% cases due to delayed presentation to medical facility (74%) and healthcare delay (26%). Headaches and vomiting (56%), focal neurological deficit (23%), and seizures (15%) were the most common presenting complaints. Consanguinity (46%), and family history of cancers (19%) were frequent; café au lait macules were observed in 9.7%. 50% tumors were infratentorial, 46% supratentorial and 4% spinal. Tumor excision was done in 45%, VP-shunts in 42%, and upfront chemotherapy in 2%. Only 60% had a final diagnosis. Tissue diagnosis in 39% cases showed Medulloblastoma (18 patients, 32%), Pilocytic Astrocytoma (27%), and High-grade glioma (16%) as the commonest diagnoses, while 21% had a radiological diagnosis based on CT/MRI features: DIPG/DMG (12%), Craniopharyngioma (7.6%), and Optic Pathway Glioma (1.4%). Of 18 medulloblastoma patients, only 7 received postoperative radiotherapy. Seventy (48%) patients expired (including 38 before surgery), 27% are on follow-up and 25% are LAMA/LTFU/defaulted treatment. One-year survival was 36% with median survival of 4 months (0.07-96 months). CONCLUSION Less than half of the patients with CNS tumors undergo active treatment, a large proportion leave treatment/follow-up and have poor overall survival. Considerable cases with cancer predisposition syndromes were suspected.

Surgical treatment of a massive soft tissue neurofibroma in neurofibromatosis type 1

Introduction. Neurofibromas developing in neurofibromatosis type 1 rarely grow to a large size. However, in cases of massive lesions, selection of optimal treatment tactics can be complicated. Clinicians usually resort to surgical treatment which currently serves as an effective instrument for improving patients’ quality of life and for achieving good cosmetic results.Aim. To describe a successful experience of surgical treatment in a patient with giant neurofibroma type 1 affecting a massive pool of soft tissues.Clinical case. Patient, 22 years, sought medical help at the N.N. Blokhin National Medical Research Center of Oncology with diagnosis of neurofibromatosis type 1 with massive lesions in the tissues of the lower third of the back, gluteal region, thighs. The disease has existed since birth, family medical history is fraught: father died of malignant manifestation of a neurogenic tumor. The younger sister is also diagnosed with neurofibromatosis affecting the brain and manifesting through cafe au lait spots on the body. Due to massive tumors significantly decreasing the patient’s quality of life, cytoreductive surgical treatment was prescribed aimed at maximally radical resection of all available tumors to alleviate the patient’s condition.Conclusion. The presented clinical case demonstrates successful experience of surgical treatment of a patient with giant neurofibroma affecting a massive pool of soft tissues.

Immediate Nipple Areolar Complex Reconstruction in A Patient With von Recklinghausen's Neurofibromatosis: A Clinical Case Report

Von Recklinghausen's neurofibromatosis is an autosomal dominant condition commonly characterized by café au lait patches, axillary freckling, multiple neurofibromas, and Lisch nodules. In this context, we present a complex case involving a 32-year-old female who suffered from severe neurofibromatosis, leading to a significant impact on her bilateral nipple-areolar complexes. Furthermore, we illuminate the subsequent outcome of her immediate reconstruction procedure.

Nitrogen Management and Virus Incidence on Cut Flower Production of Dahlia

Abstract Cut flower production, particularly of dahlia, has a strong profit potential for small farms. This study evaluated the field response of dahlia ‘Café au Lait’ to nitrogen (N) rates and implemented routine testing for common viruses. Yield was measured over a three-year field trial with five N application rates: 0, 56, 112, 168, and 224 kg N·ha−1 (0, 50, 100, 150, 200 lb N·A−1) in North Logan, Utah (USDA Hardiness Zones 5). A grower-participant study was also conducted in Northern Utah (USDA Hardiness Zones 5 – 7) to understand cultural practices and challenges. Application of 168 and 224 kg N·ha−1 (150 and 200 lb N·A−1) produced the greatest yields of stems per plant, while 168 kg N·ha−1 (150 lb N·A−1) was the most economically efficient from partial economic budgets. Viruses were highly prevalent in stock, resulting in cull rates of nearly 50% in 2019 and 2020. After sourcing lab-cultured stock in 2021, 0% of plants were culled, indicating a strong need for management of viruses in dahlia. Soil survey results from the grower-participant study revealed widespread levels of elevated macronutrients and salinity that increased annually and correlated with decreasing yield across farms. This study helps determine optimal N rates, increase awareness of virus management, as well as supporting fertility outreach with small growers to promote soil sustainability. Species used in this study: Dahlia, Dahlia pinnata ‘Café au Lait’.

Sleep, Behavioral, and Cognitive Complaints in Children with Neurofibromatosis Type 1: A Public Health Challenge

Abstract Background: Neurofibromatosis type I (NF1) is a genetic and neurodevelopmental condition impacting the peripheral nervous system. Predominant clinical features include "café au lait" spots, neurofibromas, and cognitive challenges. While some clinical reports suggest a link between NF1 and alterations in sleep, there is a lack of studies exploring this connection specifically in children. This becomes crucial, given that sleep significantly influences a child's neurobehavioral, neurocognitive, and psychosocial development. Objective: To describe sleep, cognitive, and behavioral complaints in Brazilian children diagnosed with Neurofibromatosis type 1. Methods: Parents of children within the age range from 1 to 12 years old answered an online questionnaire composed of 24 questions related to sleep habits, sleep patterns, and cognitive and behavioral complaints. Results: Data was collected from 41 children, who were categorized between preschoolers (32%) and school-aged (68%). 63% of the entire sample reported sleep complaints. 66% of the children slept less than 10 hours a day, 26% of them being preschoolers and 74% school-aged. 85% of the children used electronics devices at night, and more than half (54%) of the sample had more than 2 hours of daily screen time. 66% of the children had a late bedtime. Easy crying (31%) was the most reported behavioral complaint in preschoolers, and anxiety (32%) was more prevalent in school-aged children. Alterations in attention and focus (44%) was the most frequent cognitive issue in the entire sample. Conclusion: This is the first study carried out in Brazil that assesses sleep, behavioral and cognitive complaints, and sleep patterns in children with NF1. It was reported that children with NF1 have significant sleep complaints and insufficient sleep duration. Additionally, behavioral, and cognitive complaints were widely reported. We reinforce the relevance of sleep assessment during routine clinical examination of patients with NF1. Keywords: Neurofibromatosis 1, Child, Sleep, Cognition, Behavior.

Plexiform Neurofibroma: Case Report

Plexiform neurofibroma (PNF) is a benign nerve tumor, most often developing in the cephalic region. It is usually considered pathognomonic for neurofibromatosis type 1 (NF1) or Von Recklinghausen disease. We report the case of a patient treated in our training for plexiform neurofibroma on NF1. This is a 28-year-old patient, without any particular ATCD, who consulted for a left scalpo-fronto-palpebral subcutaneous swelling that had been present for 12 years, causing major aesthetic discomfort. Furthermore, it presented numerous (&gt; 6) café au lait spots greater than 15mm in diameter. The patient underwent excision of the left scalpo-fronto-palpebral tumor under general anesthesia with direct closure. The pathological examination confirmed the diagnosis of plexiform neurofibroma. The postoperative course was simple and the result satisfactory. Surgical excision remains the only treatment for plexiform neurofibomas in Von Recklinghausen disease.

Ophthalmologic Findings in Children with Neurofibromatosis Type 1

ABSTRACT The purpose of this study was to evaluate the ophthalmologic findings in children with neurofibromatosis type 1 (NF1) and compare these findings in eyes with and without optic pathway gliomas (OPGs). We carried out a retrospective chart review of children with NF1. We recorded demographic characteristics, clinical manifestations of disease, and ophthalmologic findings including visual acuity, intraocular pressure, cup-to-disc ratio, visual field testing, and optical coherence tomography findings. Ophthalmologic findings were examined for the cohort for initial and final appointments. These findings were also compared between eyes with and without OPGs. The study included 119 participants with 238 total eyes. The most common clinical manifestations of NF1 in this cohort were café au lait macules (98%), axillary or inguinal freckling (91%), Lisch nodules (66%), and cutaneous neurofibromas (57%). Thirty-seven participants had imaging that allowed evaluation for choroidal abnormalities, and 28 (76%) had choroidal lesions. Twenty-seven participants (23%) had OPGs, and 44 eyes were affected. On initial assessment, eyes with OPGs had worse visual acuity. On final examination, eyes with OPGs were more likely to have a worse visual acuity and a thinner generalised retinal nerve fibre layer (RNFL) thickness, inferior RNFL thickness, and temporal RNFL thickness. This study provides longitudinal follow-up of children affected by NF1 with and without OPGs. Eyes with OPGs were found to be associated with worse visual acuity and thinner RNFLs overall on final testing.

Cytogenetic analysis of fanconi anemia patients: An hospital based study

: Fanconi anemia is a rare genetic disorder caused by mutations in genes whose protein products are involved in replication, cell cycle control and DNA repair and is associated with a very high frequency of bone marrow failure and many other manifestations including, but not restricted to, severe birth defects.The diagnosis of FA is confirmed by a specific test known as chromosomal breakage study, a differential technique in which clastogenic substances, such as DEB (diepoxy butane) or MMC (mitomycin C), lead to sections of the chromosome being deleted, added, or rearranged.In this retrospective study, peripheral blood smears of patients with Aplastic Anemia were analyzed to diagnose Fanconi Anemia.: A total of 135 cases of Aplastic anemia were analyzed and screened by chromosomal breakage analysis for ruling in/out Fanconi anemia.: A total of 9 (6.66%) out of 135 patients showed a significant increase in the number of chromosomal breaks in comparison to their control. An analysis of the variable clinical manifestations was also done and correlated to the diagnosis of Fanconi Anemia. : This study throws light on the importance of cytogenetic analysis as being the most classical test for FA which involves detection of chromosomal breakage or aberrations in metaphase spreads. This relatively inexpensive assay may be useful for screening patients for whom FA is in the differential diagnosis, such as those with radial ray anomalies, short stature, hypogonadism, or café au lait spots, or for population-based FA incidence studies.

Spontaneous Primary Pneumothorax as A Complication of Neurofibromatosis Type 1.

NF1 is a genetic disease that results in cutaneous conditions, including neurofibroma, axillary, inguinal lentigines and café au lait spots. In some cases (5-20%) it can also affect the lungs, causing neurofibroma, infiltrative and cystic lesions, emphysema or bullae, leading to chronic respiratory failure.SSP is a clinical presentation of NF1 caused by the rupture of lung cysts or bullae, with an unclear relationship to smoking.Early diagnosis of pulmonary manifestations in patients with NF1 is crucial as surgical removal of lung cysts and bullae seems to prevent recurrence of SSP.

THU614 Neurofibromatosis Type 1 Presenting With Pheochromocytoma And Severe Vascular And Hematological Manifestations Due To A Novel NF1 Mutation

Abstract Disclosure: L.A. Alobaid: None. O. Alsagheir: None. M. Alswailem: None. B. Alghamdi: None. A.S. Alzahrani: None. Neurofibromatosis (NF) type 1 is an autosomal dominant condition caused by germline mutations in NF1, a tumor suppressor gene encoding neurofibromin. Pheochromocytomas (PCC) and paragangliomas can develop in up to 8% of patients with NF type 1. Vasculopathy leading to vascular narrowing and malformations are also well described manifestations of NF. Finally, a number of hematological manifestations have been described including thrombocytosis, leukocytosis, myelodysplastic syndrome, acute myeloid leukemia, and lymphoma. We present a young woman who has NF type 1 and presented with all of these unusual manifestations including PCC, leukemoid reaction, severe thrombocytosis, vascular malformations and narrowing, extensive skin freckling and café au lait spots. She was found to have a novel truncating NF1 mutation, which explains the severity of her disease. Case description: A 21-year-old lady referred to our hospital with a 4-year history of episodic headaches, blurred vision, on/off palpitations, sweating, and facial redness. She was found to be severely hypertensive at 200-230/95-140 mm Hg. Family history was positive for skin freckling, nodules and café au let spots in her father, two aunts and four siblings. On examination, BP 195/100 mmHg, Pulse 120 bpm. She has widespread skin freckling, and cafe au lait spots of different sizes and shapes. Systemic examination was otherwise normal. Urine metanaphrine was 9.34 umol/day (0-1.49) and normetanephrine 42.16 umol/day (0-3.43). A CT scan of the abdomen showed an 8-cm left adrenal heterogeneously enhancing hypervascular mass and narrowing of the infrarenal abdominal aorta with sever stenosis of celiac artery origin and severe diffuse narrowing of the left external iliac artery. Gallium 68 PET CT scan revealed an uptake at the same mass without other foci of uptake. Laboratory investigations: HbA1c 11.9%, WBC 18-24x109/L, Platelets 850-1,350x109/L. Bone marrow examination was refused by the patient so the exact underlying hematological disorder could not be accurately diagnosed. She was prepared with phenoxybenzamine and labetalol and underwent an open left adrenalectomy. Post operatively, she developed a large right anterior cerebral artery ischemic stroke as a complication of narrow cerebral vessels and the severe thrombocytosis. Histopathological examination confirmed the diagnosis of PCC with Ki67∼20%. Molecular testing revealed a novel truncating NF1 mutation (c.7606C&amp;gt;T, p.Gln2536X). Conclusion: We describe unusually severe haematological and vascular manifestations of NF type 1 in a young girl who presented with a large PCC. These severe manifestations reflect the broad manifestations of NF type 1 due to the important role of neurofibromin in different organs and the significant effects of the underlying NF1 truncating mutation in this patient. Presentation: Thursday, June 15, 2023

THU143 A Novel Maternally Inherited GNAS Variant In A Family With Hyperphagia And Obesity

Abstract Disclosure: P. Purushothaman: None. A. Ramakrishnan: None. E.F. Gevers: None. Introduction: Heterozygous inactivating mutations in the maternal allele of the GNAS gene typically result in pseudohypoparathyroidism (PHP) characterized by developmental delay, short stature, obesity, hormone resistance and bone abnormalities. Recently, GNAS variants were also described in 1% of patients in the UK Genetics of Obesity cohort, resulting in reduced MC4R signalling. Here, we report another novel GNAS variant in family with hyperphagia and obesity and only mild features of PHP. Case: The proband presented at 6 years with hyperphagia and obesity from age 3 years. BMI was 30.4 (4.1 SDS) with height +1.9 SDS, and head circumference (HC) + 3.0 SDS. She had subtle brachydactyly, short toes and a café au lait patch. Developmental milestones and cognitive achievements were mildly delayed. Her 12-year-old brother [ height +2.1 SDS, weight +3.1 SDS, BMI 29.55 (2.9 SDS), HC +3.6 SDS] had been followed in an obesity clinic for a few years with hyperphagia, obesity, delayed developmental milestones and a recent diagnosis of autism. He also had subtle brachydactyly, as did the mother who was also obese (BMI 38.9) with a normal height but had normal cognition. Results: In the proband, initial investigations did not suggest hormone resistance. However, at 8.7 years, PTH was high [9.5 pmol/L (0.7-5.6)] with normal calcium and Vitamin D; TSH 6.6 mU/L (&amp;lt;6), FT4 11.8 pmol/L (10.8 - 19.0). She had hyperlipidaemia and fatty liver. X-ray hand showed generalised mild brachydactyly with a short right fifth metacarpal. In the brother, PTH tested for the first time at 12.9 years was 18.4 pmol/L (1.6-6.9), calcium and vitamin D were normal; TSH 4.04 mU/L (&amp;lt;4.2) and FT4 13.4 pmol/L. Next Generation Sequencing using the Cambridge Obesity gene panel detected a novel heterozygous (c.791A&amp;gt;C, p.(Asn264Thr) variant in exon 10 of GNAS in the proband and subsequently in the mother and brother confirming maternal inheritance. This variant has not been reported in control databases (1000 Genomes, ESP, ExAC and gnomAD, Human Gene Mutation Database and ClinVar). The variant is in a highly conserved region susceptible to missense mutations and has been classified as pathogenic using ACMG and ACGS guidelines. Discussion: In conclusion, we describe a novel heterozygous inactivating GNAS variant c.791A&amp;gt;C, p.Asn264Thr resulting in hyperphagia, obesity, developmental delay, macrocephaly, mild brachydactyly, tall stature and variable biochemical mild hormone resistance in 2 siblings and resulting in obesity, mild brachydactyly without cognitive impairment in the mother. These cases demonstrate the clinical heterogeneity of the monogenic disease. Clinical and biochemical screening for PHP and genetic screening for GNAS variants should be performed in patients presenting with obesity, even in the absence of classical signs of PHP, to reduce diagnostic delay. Presentation: Thursday, June 15, 2023