Rare Syndrome Research Articles

Functional and Genetic Analyses Unveil the Implication of CDC27 in Hemifacial Microsomia.

Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible, external ear, and middle ear. The pathogenic genes remain largely unidentified. Whole-exome sequencing (WES) was conducted on 12 HFM probands and their unaffected biological parents. Predictive structural analysis of the target gene was conducted using PSIPRED (v3.3) and SWISS-MODEL, while STRING facilitated protein-to-protein interaction predictions. CRISPR/Cas9 was applied for gene knockout in zebrafish. In situ hybridization (ISH) was employed to examine the spatiotemporal expression of the target gene and neural crest cell (NCC) markers. Immunofluorescence with PH3 and TUNEL assays were used to assess cell proliferation and apoptosis. RNA sequencing was performed on mutant and control embryos, with rescue experiments involving target mRNA injections and specific gene knockouts. CDC27 was identified as a novel candidate gene for HFM, with four nonsynonymous de novo variants detected in three unrelated probands. Structural predictions indicated significant alterations in the secondary and tertiary structures of CDC27. cdc27 knockout in zebrafish resulted in craniofacial malformation, spine deformity, and cardiac edema, mirroring typical HFM phenotypes. Abnormalities in somatic cell apoptosis, reduced NCC proliferation in pharyngeal arches, and chondrocyte differentiation issues were observed in cdc27-/- mutants. cdc27 mRNA injections and cdkn1a or tp53 knockout significantly rescued pharyngeal arch cartilage dysplasia, while sox9a mRNA administration partially restored the defective phenotypes. Our findings suggest a functional link between CDC27 and HFM, primarily through the inhibition of CNCC proliferation and disruption of pharyngeal chondrocyte differentiation.

Patient-led research and displacements of biomedical knowledge production, distribution, and consumption.

Patient and Public Involvement in Research (PPIR) has become an increasingly prevalent and integral part of biomedical research. In this paper, we focus on patient-led research, taking as our case the construction of new biomedical knowledge regarding the rare disease ADNP syndrome. Specifically, we seek to understand how concepts of experiential knowledge and lay expertise become integral to rather than separate from scientific expertise. In the case of ADNP, the parent-led research "mimes" biomedical knowledge practices in a way that, on the one hand, enhances the legitimacy of science and scientific expertise, and on the other displaces and transforms science by the fact that other knowledge agents (patients, next-of-kin) enter these practices.

P015 Nodular skin rash associated with relapsing polychondritis, a challenging diagnostic journey to VEXAS syndrome

Abstract Background/Aims VEXAS syndrome, first described in 2020, is a haemato-inflammatory disease caused by a mutation in the gene-UBA1.This syndrome can coexist with or without Myelodysplastic syndrome. What makes this case interesting is its long and challenging diagnostic journey and the involvement of different clinical specialties such as dermatology, ophthalmology, rheumatology, respiratory, haematology, and stroke teams. Ultimately, two years after the initial presentation, this appeared to be the first case of VEXAS with confirmed genetic mutation in the region. VEXAS being a relatively new entity, treating clinician/s were not aware of the possibility initially. Therefore, spreading awareness regarding the clinical picture of VEXAS is prudent. This case report highlights rheumatological and dermatological manifestations of the disease to aid in the timely diagnosis and management of future cases. Methods We report a 74-year-old previously healthy male presented in 2021 with a rash on his legs, arms, and torso since October 2019. It was progressive, painful, palpable, erythematous, non-pruritic, intermittent rash, cleared with hyperpigmentation. He also had oligoarticular arthritis, constitutional symptoms, recurrent episodes of polychondritis, uveitis, bibasal lung fibrosis, and an ESR and CRP above 100. He also had lymphadenopathy above the diaphragm, but the biopsy only showed necrotic material, and the bone marrow biopsy did not show any features of haematological malignancy. After excluding infections, he was started on high-dose oral prednisolone for relapsing polychondritis. The skin and inflammatory markers improved immediately following high doses of steroids. However, whenever steroids were weaned down, even with the help of Methotrexate, his skin was flaring. He also had unprovoked DVT and, while on anticoagulation, developed occipital infarction. He had extensive skin involvement when he had to stop Methotrexate following a chest infection. Results The skin biopsy was inconclusive. There was no significant cytopenia but persistent macrocytosis even after stopping Methotrexate. As a result, he underwent a repeat bone marrow biopsy, which showed Vacuoles and gene UBA1 mutation in 2023. Conclusion The heterogeneity and complexity of the disease are due to multi-organ involvement, including skin, joints, eyes, lungs, blood vessels, and cartilage, simultaneously or cumulatively. Skin involvement in VEXAS can also be vast, ranging from neutrophilic dermatosis, erythema nodosum-like lesions, leukocytoclastic, or urticarial vasculitis. Cutaneous manifestations develop in the majority with VEXAS syndrome and can be the first presenting symptom in this new rare syndrome. Disclosure M. Gunawardena: None. L. Yalakki: None. R. Moitra: None. E.L. Williams: None. H. Wong: None. D. D'Cruz: None.

P031 An case of cryofibrinogen associated necrotising cutaneous vasculitis on background of aortitis

Abstract Background/Aims Cryofibrinogen is an abnormal protein that forms precipitate in plasma but not in serum. Cryofibrinogenaemia can be detected in healthy individuals and patients with autoimmune diseases, cancer, and infections. Current data suggest that isolated cryofibrinogenaemia can be detected in up to 3% of healthy individuals and it is usually asymptomatic. However, cryofibrinogenaemia can be associated with systemic inflammatory manifestations, of which cutaneous involvement is the most prominent. Methods A 76-year-old male patient presented with acute and progressive necrotising ulcers in the lower limbs along with high inflammatory markers and general decline. He had a background of large vessel vasculitis (aortitis), which was diagnosed with a PET-CT scan three years prior to the current presentation. He was previously treated with oral steroids and eight cycles of cyclophosphamide demonstrating an excellent response with complete resolution of the aortitis on the follow-up PET-CT scan. The patient had remained on maintenance treatment with azathioprine (3mg/kg) as well as therapeutic anticoagulation for atrial fibirillation. Results After thorough investigations for an infective cause and poor response to broad spectrum antibiotics, he was reviewed further for recurrence of large vessel vasculitis. A CT angiogram showed concentric symmetrical soft tissue thickening surrounding the thighs and lower limb arteries without luminal stenosis, suggestive of periarterial inflammation. A further MR angiogram of the aorta did not confirm any evidence of aortic, iliac or visceral artery stenosis. A CT chest/abdomen/pelvis excluded any other pathology or malignancy. Additional investigations showed negative ANA and ENA screen, rheumatoid factor, antiphospholipid antibodies, cryoglobulins, hepatitis virus screen, whilst complement and immunoglobulin levels were normal. However, cryofibrinogen was reported positive and a diagnosis of cryofibrinogen-associated necrotising cutaneous vasculitis was concluded. The patent was started on IV cyclophosphamide (15mg/kg) along with IV methylprednisolone (250mg for the first 3 doses) along with each pulse therapy. After the first two pulses, the patient had a favourable clinical and serological response to the immunosuppressive treatment with improvement in cutaneous lesions and significant reduction in the inflammatory markers. He subsequently underwent an angioplasty for tightly stenotic/occluded tibioperoneal trunk with good recanalisation. Conclusion This is a rare overlap syndrome of new-onset small vessel necrotising cutaneous vasculitis on previous background of large vessel disease (aortitis). In most severe cases with essential cryofibrinogenaemia, the mainstay treatment is with corticosteroids and other immunosuppressive agents in combination with oral anticoagulants and/or low-dose aspirin. Post treatment, the risk of relapse remains high and immunosuppressive therapy may only have a limited impact on the course of thrombotic vasculopathy in the absence of inflammation. More research and longitudinal data are required to optimise treatment protocols and outcomes in patients with cryofibrinogen-associated systemic vasculitis. Disclosure A. Psarras: None. J. David: None. R. Luqmani: None. S. Dubey: Consultancies; Boehringer Ingelheim. Member of speakers’ bureau; Janssen.

Punctal Atresia As a Clinical Indicator of Systemic Genetic Anomalies

ABSTRACT Background Punctal atresia or agenesis (PA) is a rare congenital anomaly characterized by the absence or closure of the tear duct puncta, potentially linked to systemic genetic anomalies. The necessity of a genetic workup based solely on the presence of PA remains uncertain. This study investigates a cohort of PA patients, examining the prevalence and types of associated syndromes. Methods A retrospective medical records review of all patients diagnosed with PA at the Children’s Hospital of Philadelphia between 2009–2023 was conducted, analyzing medical histories and genetic testing results. Primary outcomes included the prevalence of systemic syndromes, while secondary outcomes focused on the variety of associated syndromes. Results Forty-four patients were included, of which 31 were male (70%) with a mean ± SD age 3.3 ± 3.3 years. Overall, 87 puncta in the study cohort were affected, and 26 cases (59%) were bilateral. Systemic abnormalities or genetic syndromes were identified in 19 patients (43%), with the most common being Ectodermal Dysplasia and Down syndrome. Additional rare syndromes were demonstrated. No significant association was found between systemic abnormalities and gender, bilaterality, or the number of puncta involved. Conclusions A high incidence of systemic syndromes (43%) was observed in the study cohort. In individuals with PA who also exhibit extraocular disease, systemic evaluation and genetic workup should be considered. Syndromic diagnoses identified in our cohort also include: Branchio-oto-renal syndrome, 22q11.2 deletion syndrome, 1q21.1 microdeletion syndrome, NF1, monosomy 4q and trisomy 6q, which represent novel associations. The lack of correlation between PA’s phenotypic severity and systemic abnormalities highlights the need to obtain a comprehensive medical history and consider a systemic workup in PA patients.

Rapidly Progressive Osteoarthritis of the Hip: A Prospective Study.

Background: Rapidly progressive osteoarthritis of the hip (RPOH) is a rare syndrome that involves the femoral head and acetabulum. Methods: We analyzed the incidence of RPOH in 2022. The inclusion criteria included a clinical history of pain for 1-6 months and a decrease in joint space of > 2 mm within one year or a decrease in joint space by 50% in that time accompanied by femoral and/or acetabular bone destruction. Exclusion: There are no other destructive arthropathies and no evolutionary radiological image sequence. Results: There were 15 patients, 16 hips, an incidence around 3.17%, a 1:1 laterality ratio, and 1 bilateral affected. The mean average age is 77.35 years. The male/female ratio is 1:2. The average BMI is 31.2. The time of the onset of the symptoms to the patient's diagnosis is 5 months. The functionally modified Harris scale (MHS) had an average score of 30 points. They had surgery hip arthroplasty with a cementless cup in all cases, a revision cup in one of them, and a double mobility cup in the other, with the stem cemented three times. There were no post-surgical complications. Functionally was achieved at 3 months. The average MHS is 70 at 12 months. The average MHS is 85. Conclusions: RPOH is an idiopathic entity characterized by great clinical involvement and rapid radiological evolution. It is most common in women around 77 years of age. The bone quality requires surgical alternatives to implants, and it has good functional recovery post-surgery.

ANTXR1 deficiency promotes fibroblast senescence: implications for GAPO syndrome as a progeroid disorder

ANTXR1 is one of two cell surface receptors mediating the uptake of the anthrax toxin into cells. Despite substantial research on its role in anthrax poisoning and a proposed function as a collagen receptor, ANTXR1’s physiological functions remain largely undefined. Pathogenic variants in ANTXR1 lead to the rare GAPO syndrome, named for its four primary features: Growth retardation, Alopecia, Pseudoanodontia, and Optic atrophy. The disease is also associated with a complex range of other phenotypes impacting the cardiovascular, skeletal, pulmonary and nervous systems. Aberrant accumulation of extracellular matrix components and fibrosis are considered to be crucial components in the pathogenesis of GAPO syndrome, contributing to the shortened life expectancy of affected individuals. Nonetheless, the specific mechanisms connecting ANTXR1 deficiency to the clinical manifestations of GAPO syndrome are largely unexplored. In this study, we present evidence that ANTXR1 deficiency initiates a senescent phenotype in human fibroblasts, correlating with defects in nuclear architecture and actin dynamics. We provide novel insights into ANTXR1's physiological functions and propose GAPO syndrome to be reconsidered as a progeroid disorder highlighting an unexpected role for an integrin-like extracellular matrix receptor in human aging.

Bilateral Congenital Anorchidism: Case Study

Embryonic testicular regression syndrome (ETRS) or congenital bilateral anorchidism (CBA) is a highly rare syndrome defined by the complete absence of testicular tissue in a patient with a male karyotype. The phenotype varies depending on when gonadal regression occurs in utero. Clinically, a micropenis, hypoplastic scrotum, empty, without perceived testicles are observed. Hormonal assessments reveal collapsed or completely absent testosterone levels and AMH (anti-Mullerian hormone) levels. Diagnosis is confirmed by laparoscopic exploration. Management relies on androgen supplementation and placement of testicular prostheses.

CINCA/NOMID is a rare autoinflammatory syndrome in rheumatological practice. Experience of diagnosis, management and therapy with interleukin-1 inhibitors

Objective: to present the experience of diagnosis, management and therapy with interleukin-1 inhibitors (iIL1) in patients with Chronic Infantile Onset Neurologic Cutaneous Articular/Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID) according to the Russian Federal Rheumatological Center data.Material and methods. From 2007 to 2023, eight patients were included in the study (7 men) aged 10 months to 33 years, including 3 with a disease duration of more than 10 years (13, 17 and 33 years). Genetic testing was performed in all patients and mutations in the NLRP3 gene were identified in 6 cases.Results and discussion. The age of onset of the disease ranged from 0 to 6 months. The delay in diagnosis and prescription of therapy ranged from 10 months to 33 years. All patients had the classic manifestations of CINCA/NOMID, including fever, rash, central nervous system (CNS) involvement, elevated ESR and CRP levels, 6 patients had articular manifestations, 7 had ocular manifestations and 6 had sensorineural hearing loss. Amyloidosis was detected in 1 case. All patients were prescribed iIL1. Anakinra was used in 6 patients (in 5 as the first line, in 1 as the second line therapy) with a positive response; subsequently 2 of these patients were switched to canakinumab once every 4 weeks (1 patient deteriorated and was readministered anakinra). Five patients received canakinumab (3 as first-line therapy, 2 as second-line therapy), 1 patient was switched to anakinra due to insufficient CNS response. The response to iIL1 therapy was positive in all patients, but incomplete in some of them due to the severity of the manifestations and the presence of irreversible organ damage.Conclusion. Patients with CINCA/NOMID have a severe disease and a poor prognosis. In this context, early administration of iIL1 is necessary. In the case of CNS involvement, the use of anakinra is preferable, as it is characterized by better penetration of the blood-brain barrier and is therefore more effective. Later it is possible to switch the patient to canakinumab, however, to achieve a complete response, it is sometimes necessary to increase the dose of the drug and reduce the interval between doses.

Exploring an objective measure of overactivity in children with rare genetic syndromes

BackgroundOveractivity is prevalent in several rare genetic neurodevelopmental syndromes, including Smith-Magenis syndrome, Angelman syndrome, and tuberous sclerosis complex, although has been predominantly assessed using questionnaire techniques. Threats to the precision and validity of questionnaire data may undermine existing insights into this behaviour. Previous research indicates objective measures, namely actigraphy, can effectively differentiate non-overactive children from those with attention-deficit hyperactivity disorder. This study is the first to examine the sensitivity of actigraphy to overactivity across rare genetic syndromes associated with intellectual disability, through comparisons with typically-developing peers and questionnaire overactivity estimates.MethodsA secondary analysis of actigraphy data and overactivity estimates from The Activity Questionnaire (TAQ) was conducted for children aged 4-15 years with Smith-Magenis syndrome (N=20), Angelman syndrome (N=26), tuberous sclerosis complex (N=16), and typically-developing children (N=61). Actigraphy data were summarized using the M10 non-parametric circadian rhythm variable, and 24-hour activity profiles were modelled via functional linear modelling. Associations between actigraphy data and TAQ overactivity estimates were explored. Differences in actigraphy-defined activity were also examined between syndrome and typically-developing groups, and between children with high and low TAQ overactivity scores within syndromes.ResultsM10 and TAQ overactivity scores were strongly positively correlated for children with Angelman syndrome and Smith-Magenis syndrome. M10 did not substantially differ between the syndrome and typically-developing groups. Higher early morning activity and lower evening activity was observed across all syndrome groups relative to typically-developing peers. High and low TAQ group comparisons revealed syndrome-specific profiles of overactivity, persisting throughout the day in Angelman syndrome, occurring during the early morning and early afternoon in Smith-Magenis syndrome, and manifesting briefly in the evening in tuberous sclerosis complex.DiscussionThese findings provide some support for the sensitivity of actigraphy to overactivity in children with rare genetic syndromes, and offer syndrome-specific temporal descriptions of overactivity. The findings advance existing descriptions of overactivity, provided by questionnaire techniques, in children with rare genetic syndromes and have implications for the measurement of overactivity. Future studies should examine the impact of syndrome-related characteristics on actigraphy-defined activity and overactivity estimates from actigraphy and questionnaire techniques.

De Barsy syndrome due to ALDH18A1 mutation – Expanding the spectrum of a rare neurocutaneous syndrome

De Barsy syndrome is a rare autosomal recessive genetic disorder that manifests with cutis laxa, progeroid appearance, and neurologic and eye abnormalities. It was initially described by De Barsy et al. in 1968. Mutations in the ALDH18A1 gene or PYCR1 genes have been implicated in this syndrome. ALDH18A1 mutations are associated with cutis laxa type IIIA and hereditary spastic paraplegia 9A. We describe an 8-month-old male with cutis laxa, developmental delay and seizures harbouring the ALDH18A1 mutation. Our patient has certain phenotypic manifestations and radiologic findings that make it unique from the other cases described till date.

VEXAS syndrome: Focus on dermatological manifestations and their histopathological correlate

AbstractBackgroundVEXAS ‘Vacuoles, E1 Enzyme, X‐linked, Autoinflammatory, Somatic syndrome’ is a rare autoinflammatory syndrome, first described in October 2020 by Beck et al. It is caused by somatic mutations in the UBA1 gene, coding for the E1 enzyme, responsible for ubiquitination. It manifests in adulthood, mainly in men, with constitutional symptoms, haematological abnormalities and often skin lesions with neutrophilic dermatoses most frequently reported. Since skin lesions are a frequent and early manifestation, recognising these may prove very useful for diagnosis.ObjectivesTo focus on the dermatological manifestations of VEXAS and their histopathological correlate.MethodsWe retrospectively collected data and revised skin biopsies of VEXAS patients diagnosed in our tertiary care centre, and compared those with the literature.ResultsWe identified nine men between 62 and 84 years old. The most frequently encountered UBA1 mutation was p.Met41Thr. Skin manifestations occurred in all patients; mostly as erythematous to purpuric papules/plaques, often with annular pattern. Histopathological, early VEXAS lesions showed a gradient in infiltrate with neutrophils being concentrated in the superficial interstitium and lymphocytes situated deeper around the blood vessels. Later in the disease course, the pattern became more variable and less specific with more nuclear debris, histiocytes, neutrophils and ulceration. Haematological and constitutional manifestations were present in all patients, followed by musculoskeletal (88.8%), eye (77.7%) and cardiovascular manifestations (66.6%). Polychondritis was present in 6/9 (66.6%) patients, as were respiratory symptoms, though only 33.3% had proven lung disease. The mortality rate was 22% 10 months after diagnosis.ConclusionsThis is the first cohort which describes in detail VEXAS skin manifestations with revision of all available skin biopsies, which led to the conclusion that early histopathological abnormalities in VEXAS syndrome may be easy to recognise, while the histopathological image becomes less specific over time and mimics other diseases as VEXAS progresses.

The role for ambulatory electrocardiogram monitoring in the diagnosis and prognostication of Brugada syndrome: a sub-study of the Rare Arrhythmia Syndrome Evaluation (RASE) Brugada study.

Brugada syndrome (BrS) diagnosis and risk stratification rely on the presence of a spontaneous type 1 (spT1) electrocardiogram (ECG) pattern; however, its spontaneous fluctuations may lead to misdiagnosis and risk underestimation. This study aims to assess the role for repeat high precordial lead (HPL) resting and ambulatory ECG monitoring in identifying a spT1, and evaluate its prognostic role. HPL resting and ambulatory monitoring ECGs of BrS subjects were reviewed retrospectively, and the presence of a spT1 associated with ventricular dysrhythmias and sudden cardiac death (SCD). Three-hundred and fifty-eight subjects (77 with spT1 pattern at presentation, Group 1, and 281 without, Group 2) were included. In total, 1651 resting HPL resting and 621 ambulatory monitoring ECGs were available for review, or adequately described. Over a median follow-up of 72 months (interquartile range - IQR - 75), 42/77 (55%) subjects in Group 1 showed a spT1 in at least one ECG. In Group 2, 36/281 subjects (13%) had a newly detected spT1 (1.9 per 100 person-year) and 23 on an HPL ambulatory recording (8%). Seven previously asymptomatic subjects, five of whom had a spT1 (four at presentation and one at follow-up), experienced arrhythmic events; survival analysis indicated that a spT1, either at presentation or during lifetime, was associated with events. Univariate models showed that a spT1 was consistently associated with increased risk [spT1 at presentation: hazard ratio (HR) 6.3, 95% confidence interval (CI) 1.4-28, P = 0.016; spT1 at follow-up: HR 3.1, 95% CI 1.3-7.2, P = 0.008]. Repeated ECG evaluation and HPL ambulatory monitoring are vital in identifying transient spT1 Brugada pattern and its associated risk.

Decoding the dilemma of antenatal ventral body wall defects: A case report and literature review

We are presenting the case of a rare fetal polymalformative syndrome known as the limb body wall complex (LBWC) and its antenatal diagnosis. The level II Anomaly ultrasound of a primigravida female detected exencephaly, thoracoabdominoschisis, club foot, kyphoscoliosis, fetoplacental adherence, and a deficient umbilical cord, classically described in LBWC. It is imperative for radiologists to be familiar with this rare fatal entity of sporadic occurrence and to differentiate it from other non-lethal counterparts for appropriate maternal counseling and timely termination of pregnancy.

Complex therapy of kaposiform hemangioendothelioma complicated by Kasabach-Merritt syndrome. A case report and review of the literature

Background: Kasabach-Merritt syndrome is an infrequent complication of large hemangiomas that could be life-threatening. Ninety percent of this phenomenon is associated with kaposiform hemangioendothelioma. Aim of the study: To present the therapeutic process of a child with kaposiform hemangioendothelioma complicated by this rare syndrome. Case report: The patient was admitted to the hospital during the first month of life due to a lesion on the head and neck. After many attempts with pharmacological treatment, surgery was the only effective treatment.Conclusions: We want to emphasize that operative management of these tumors should be considered in cases of treatment resistance or rapidly progressive growth of the hemangioendothelioma.

The paradox of platypnoea-orthodeoxia syndrome.

Platypnoea-orthodeoxia is a rare clinical syndrome characterised by dyspnoea and oxygen desaturation in the upright position which improves when supine. It requires two components: a sufficiently sized anatomical vascular defect (typically intra-cardiac or intra-pulmonary) combined with a functional component that promotes positional right-to-left shunting. We describe the rare occurrence of a patient with platypnoea-orthodeoxia syndrome (POS) because of a paradoxical shunt through a patent foramen ovale caused by a large right atrial line-associated thrombus in a male with metastatic oesophageal cancer undergoing chemotherapy. This case is a timely reminder to consider POS amongst differentials for hypoxia as it is often treatable if recognised.

Superior mesenteric artery syndrome in oncology: Report of two cases and review of the literature

A rare cause of abdominal pain is the superior mesenteric artery syndrome (SMAS), characterized by an extrinsic compression of the third portion of the duodenum by the superior mesenteric artery. It occurs in the context of rapid weight loss, because of the decrease of intra-abdominal fat causing a reduction in the exit angle of this important vascular structure. Cancer patients frequently present with weight loss, often severe, making them a population at risk of presenting this syndrome. Because symptoms are vague and could be secondary to oncologic treatments, the diagnosis of SMAS is often overlooked. We present two cases of oncology patients evaluated in the National Cancer Institute in Chile who presented with symptoms suggestive of SMAS, weight loss greater than 5 kg in a short period of time associated with abdominal pain and vomiting. Both cases were confirmed by images [computed tomography (CT) scan] and treated with nutritional support only. We present both cases along with a brief review of the literature on this rare syndrome, which is usually a diagnostic challenge.

The interplay between X-chromosome functional dosage and circadian regulation in females.

Biological factors and mechanisms that drive higher prevalence of insomnia in females are poorlyunderstood. This study focused on the neurological consequences of X-chromosome functional imbalancesbetween sexes. Benefited from publicly available large-scale genetic, transcriptional and epigenomic data, we curated andcontrasted different gene lists: (1) X-liked genes, including assignments for X-chromosome inactivation patterns anddisease associations; (2) sleep-associated genes; (3) gene expression markers for the suprachiasmatic nucleus. We show that X-linked markers for the suprachiasmatic nucleus are significantly enriched for clinicallyrelevant genes in the context of rare genetic syndromes and brain waves modulation. Considering female-specific patterns on brain transcriptional programs becomes essential whendesigning health care strategies for mental and sleep illnesses with sex bias in prevalence.

Encephalocraniocutaneous Lipomatosis: A Case Report.

Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome and subclassification of oculoectodermal syndrome. Encephalocraniocutaneous lipomatosis may be associated with postzygotic mutations. However, absence of an identifiable mutation does not preclude a diagnosis of ECCL. Encephalocraniocutaneous lipomatosis commonly causes skin, eye, and central nervous system anomalies. Diagnosis can be made through genetic sequencing or standardized clinical criteria. One clinically apparent major criterion for the diagnosis of ECCL is nevus psiloliparus (NP), a fatty nevus with overlying nonscarring alopecia. In this case, a 50-day-old female infant with uncomplicated birth history presented to dermatology clinic for evaluation of 2 superficial cranial masses that had been present since birth without regression or evolution. One of the masses was located within the hairline and demonstrated overlying nonscarring alopecia, suspicious of NP. Because of concern for ECCL, brain magnetic resonance imaging was ordered and revealed 2 intracranial lipomas. Genetic testing was inconclusive. Excision of the masses was performed at the request of the parents for cosmetic purposes. Histologic evaluation of the surgical specimens confirmed the diagnosis of NP and ECCL. A suspected NP should raise concern for ECCL and prompt further evaluation for systemic involvement. In particular, patients with suspected ECCL should be screened for ocular and CNS involvement. Early identification and diagnosis are important for prognostication because patients with ECCL are at increased risk of developing neoplasms of the head and neck and may require more frequent screening examinations.

UNVEILING A RARITY: LIGHT CHAIN DISEASE COINCIDING WITH PURE RED CELL APLASIA

This paper presents a unique case report of concurrent Light Chain Disease (LCD) and Pure Red Cell Aplasia (PRCA), two rare hematological disorders seldom observed together. Light Chain Disease is a plasma cell disorder characterized by the overproduction of abnormal immunoglobulin light chains, while Pure Red Cell Aplasia is a rare bone marrow failure syndrome resulting in the selective reduction or absence of red blood cell precursors. The co-occurrence of these conditions poses diagnostic and therapeutic challenges due to their distinct pathophysiologies and clinical presentations. Through a detailed examination of the patient's medical history, diagnostic workup, and treatment outcomes, this case sheds light on the complexities associated with managing rare hematological disorders with overlapping manifestations.