Newborn-onset chronic urticaria as the first manifestation of NLRP3 mosaicism

Objectives: A 7-month-old boy presented with generalized urticaria since the first week of life, without any other clinical manifestation. Cow's milk allergy was ruled out. His development was normal for his age. Maternal history was significant for COVID-19 infection in the third trimester of pregnancy with mild symptoms. Family history was significant for dermatographism in a maternal uncle. Hives were migratory with no single lesion persisting more than 24 h. There were no recognizable triggers and only relieved for 1-2 days after each vaccination. Patient was treated with optimal doses of antihistamines without improvement. Method(s): Laboratory tests and further studies were performed Results: Laboratory tests were normal including complete blood testing, circulating autoantibodies and infectious studies. C-reactive protein level and erythrocyte sedimentation rate were elevated. Due to chronic urticaria of newborn onset unresponsive to antihistamines a monogenic autoinflammatory disease was suspected. A targeted gene panel covering causative genes revealed the unreported p.Gly307Ala variant in the NLRP3 gene with a variant allele frequency (VAF) of 3% compatible with gene mosaicism. NLRP3 variant was classified as "likely pathogenic" based on its location, where a different variant has been reported as causing a severe form of cryopyrin-associated periodic syndromes (CAPS), and bioinformatic analyses. As expected, the variant was absent in patient's parents supporting for its de novo nature. Vision and hearing exams were normal. Treatment with canakinumab will start soon. Discussion(s): CAPS are dominantly-inherited autoinflammatory diseases caused by gain-of-function NLRP3 variants. These variants are often germline, but in some reported cases the variants are postzygotic causing gene mosaicism as in the patient here described. We believe that the mild presentation in our patient, despite having a likely pathogenic variant, may be explained by the low VAF. The genetic diagnosis in our patient allowed early initiation of anti-IL-1 treatment, which probably will prevent the development of other CAPS manifestations.

Unilateral multiple facial angiofibromas as a solitary manifestation of tuberous sclerosis

We describe the case of a 12-year-old boy who presented via teledermatology with a 5-6-year history of multiple lesions on the right side of his face. They were unchanged since their initial appearance at 6 years of age but were slowly increasing in number across his right cheek and extending onto the chin. Although the lesions were asymptomatic, growing older had made him feel increasingly self-conscious. He was otherwise fit and well, and attended mainstream school, with no past medical history or family history of note. Perinatal and birth history were also uneventful. On examination, he had multiple, 1-2-mm, erythematous papules confined to the right cheek and right chin. Dermoscopy showed an unusual pattern of vessels with nonspecific globules in between. The rest of the skin, hair and nails were entirely normal in appearance. There were no systemic symptoms and a detailed general and systemic examination, as well as radiological imaging, did not reveal any abnormality. An excisional biopsy was taken of one of the lesions, with histological examination demonstrating focal superficial telangiectasia with associated bland round-tospindle cell proliferation, appearances most in keeping with an angiofibroma. This correlated well clinically, apart from unilateral facial angiofibromas being the solitary finding in our patient. Facial angiofibromas - also called adenoma sebaceum - are well described as part of the cutaneous manifestations of tuberous sclerosis (TSC). Classically, these appear as a facial rash in the form of small pink or red spots across the cheeks and nose in a butterfly distribution, at between 3 and 10 years of age, increasing in size and number until adolescence. TSC is an autosomal dominant disorder with defective mammalian target of rapamycin (mTOR) signalling, characterized by hamartomas in many organs, particularly the skin, central nervous system, renal and cardiovascular systems. The clinical presentation is variable, with other well known and frequently reported cutaneous findings such as shagreen patches, ash-leaf macules and periungual fibromas. Unilateral multiple facial angiofibromas in the absence of other cutaneous or systemic manifestations of TSC - as in our patient - are rare, with only 13 reported cases. These may form part of the clinical spectrum of TSC as a probable consequence of cutaneous mosaicism in which a postzygotic genetic mutation has occurred. Our patient was referred for genetic testing, but this has been delayed as a result of the COVID-19 pandemic. Topical sirolimus 1% - an mTOR inhibitor - has been used with good effect for facial angiofibromas, and our patient also responded well to this.

Pulmonary palytoxin poisoning on CT imaging

Background: Palytoxin poisoning is an uncommon exposure in the US, and is most frequently encountered amongst hobbiests and professionals in the aquarium industry. The toxin is produced by the microalgae Ostreopsis as well as the coral Palythoa toxica. Discovered in Hawaii, the name limu-make-o-Hana translates to "seaweed of death from Hana." Palytoxin interrupts Na+/ K+ ATPase pump, resulting in widespread cellular dysfunction. Persons are at highest risk when cleaning a fish tank housing the coral that produces palytoxin, resulting in cutaneous or inhalational exposure. We present a case of palytoxin inhalational exposure with computed tomography (CT) imaging. Case report: A 41-year-old male presented to the emergency department (ED) with dyspnea, cough, and wheezing after cleaning his saltwater fish tank. He reported that he maintains Zoanthid corals in his home saltwater fish tank and typically wears personal protective equipment when cleaning the tank. He had taken off his mask directly after using hot water to clean the tank, and quickly developed shortness of breath. He contacted Poison Control and was instructed to take loratadine with initial improvement in his symptoms. He then developed decreased appetite, nausea, and chills. The following day, in addition to these symptoms, he developed a fever of 102.5 degreeF and an oxygen saturation of 88% measured with an at-home pulse oximeter. He then proceeded to the ED where he was found to be hypoxic to 91% on room air, tachycardic to 120 bpm, hypotensive to 93/ 70mmHg, febrile to 100.9 degreeF and tachypneic at a respiratory rate of 30. Physical exam revealed clear lung sounds. Application of supplemental oxygen at 2 L resulted in improvement in his oxygen saturation and his hypotension and tachycardia responded to intravenous fluids. Significant laboratory results included WBC count of 20.4 with bands of 14%, elevated lactate of 2.4mmol/L, elevated D-dimer of 0.48 mug/mL and a negative COVID PCR test. CTA thorax revealed patchy ground-glass opacities in the bilateral upper and lower lobes with mosaicism. The patient received doxycycline in addition to broad spectrum antibiotics due to concern for inhalational marine toxicity. He was also started on 60mg prednisone, inhaled steroids, and bronchodilators for symptomatic treatment, with improvement in his symptoms. During his hospitalization, a respiratory viral panel was negative for common viruses associated with atypical pneumonia including influenza, coronavirus, metapneumovirus, rhinovirus, enterovirus, adenovirus, parainfluenza, bocavirus, Chlamydophila pneumoniae, and Mycoplasma pneumonia. His dyspnea gradually improved and he was weaned off supplemental oxygen prior to discharge home on hospital day 2. Discussion(s): It is unclear what changes are expected on thoracic imaging in patients with inhalational palytoxin exposure. Chest radiographs in two previous cases displayed scattered infiltrates, and a chest CT in another case showed pleural based consolidations. The ground-glass mosaicism suggests that a more diffuse reactive airway process after an inhalational palytoxin insult. Conclusion(s): Patients with inhalational palytoxin exposure may be found to have reactive airway symptoms along with ground glass opacities with mosaicism on CT imaging.

21st ESPD Annual Meeting

The proceedings contain 169 papers. The topics discussed include: GNAQ/11 mosaicism causes aberrant calcium signaling and drives systemic hypocalcemia;pediatric obesity and skin disease (PicoSkin-study): cutaneous findings and associated quality of life in 86 children and adolescents with obesity;what gives them the shivers? two new cases of infantile transient smooth muscle contraction of the skin;dermatologic manifestations of multisystem inflammatory syndrome in children during the COVID-19 pandemic;clinical characteristics and management of cutaneous lymphangioma circumscriptum;different shades of grey! infantile black hairy tongue- a case series and review of the literature;descriptive series of cases of pediatric linear morphea in a tertiary hospital in Barcelona;the prevalence of itch in German schoolchildren: a population-based study;neurocognitive functioning, physical health, and mental health of school-aged children treated with propranolol or atenolol for infantile hemangioma;and efficacy and safety of tralokinumab in adolescents with moderate-to-severe atopic dermatitis: results of the phase 3 ECZTRA 6 trial.

DOES ZYMOT SPERM SEPARATION IMPROVE EM- BRYO DEVELOPMENT OUTCOMES WHEN APPLIED TO ALL INFERTILITY PATIENTS COMPARED TO DENSITY GRADIENT WASHING OR SURGICALLYATTAINED SPERM?

OBJECTIVE: The ZyMot sperm separation device has proven favorable for use in elevated DNA fragmentation index (DFI) male factor patients, as an alternative to density gradient (DG) washing or surgically attained testicular sperm. In 2020, without fully understanding the infectivity and transmission potential of SARS-CoV2 in semen, a more liberal application of a timed ZyMot microfluidic swim-up was applied to our IVF patients to dilute out and minimize potential pathogens. This study aimed to evaluate whether the use of ZyMot sperm improved normal embryo development. MATERIALS AND METHODS: Retrospective analysis of PGT-A/ICSI cycles (N= 3219) between 2016-2020 was conducted to assessed fertilization rates (FR), blastocyst development/utilization rates (BUR) and genetic outcomes. Sperm preparations were performed per standard operating or manufacturer advised (i.e., ZyMot) procedures. Cumulus oocyte complexes were harvested 36h post-hCG, stripped and ICSI performed 3-5hr later. Zygotes were assessed at 16-18hr post-ICSI, and embryos cultured under humidified tri-gas incubation for up to 7 days. Blastocyst (BL) development as evaluated, and expanded BL or greater were biopsied on Days 5, 6 or 7. All BL were vitrified and genetics determinations for euploidy, aneuploidy and mosaicism were contrast. Applying Chi-squared analysis, we compared potential differences (p<0.05) between oocytes inseminated by DG wash (n=23,549), ZyMot wash (n=7,331) or testicular sperm (n=815). RESULTS: No difference in FR (76%), D5 BL formation (52-56%) or BUR (52-53%) was detected between DG and ZyMot washed sperm, respectively. Meanwhile, testicular sperm had a lower FR (70%;p<0.05), fewer BL forming on D5 (48%;p<0.05) and a lower overall BUR (41%;p<0.05). In addition, fewer testicular-derived BL were euploid (39%;p<0.05) with more aneuploidy (54%;p<0.05) than DG wash (50%, 39%;respectively) or ZyMot swim-up (45%, 37%;respectively) derived-embryos. No difference in potentially viable BL (Euploidy+Mosiac outcome) was observed between DG or ZyMot wash groups (63-64%). CONCLUSIONS: Application of the ZyMot device in the general IVF population offered no benefit to embryo development outcomes compared to standard sperm wash procedures. Our data does support that microfluidic separation of sperm using ZyMot for male factor patients with elevated DFI is a more favorable and cost-effective approach to surgically attaining testicular sperm when ejaculated sperm is possible. However, when insufficient motile and or morphologically normal sperm are available in an ejaculate further analysis is needed to elucidate the benefit of testicular biopsy treatment, as our assessments in this study may be biased by including men with non-obstructive azoospermia. IMPACT STATEMENT: The timed selection of morphologically normal, highly progressive sperm by ICSI, PVP-swim-out likely mimics the potential benefits the ZyMot device may offer infertile men with elevated sperm DNA fragmentation generating similar blastocyst development and euploidy outcomes.