Case Report: Two Monochorionic Twins With a Critically Different Course of Progressive Osseus Heteroplasia

Progressive osseous heteroplasia (POH; OMIM 166350) is a rare autosomal-dominant genetic disorder in which extra-skeletal bone forms within skin and muscle tissue. POH is one of the clinical manifestations of an inactivating mutation in the GNAS gene. GNAS gene alterations are difficult matter to address, as GNAS alleles show genetic imprinting and produce several transcript products, and the same mutation may lead to strikingly different phenotypes. Also, most of the publications concerning POH patients are either clinical depictions of a case (or a case series), descriptions of their genetic background, or a tentative correlation of both clinical and molecular findings. Treatment for POH is rarely addressed, and POH still lacks therapeutic options. We describe a unique case of POH in two monochorionic twins, who presented an almost asymptomatic vs. the severe clinical course, despite sharing the same mutation and genetic background. We also report the results of the therapeutic interventions currently available for heterotopic ossification in the patient with the severe course. This article not only critically supports the assumption that the POH course is strongly influenced by factors beyond genetic background but also remarks the lack of options for patients suffering an orphan disease, even after testing drugs with promising in vitro results.

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Screening Children with a Family History of Central Congenital Hypoventilation Syndrome

Case Reports in Pediatrics ◽

10.1155/2020/2713606 ◽

2020 ◽

Vol 2020 ◽

pp. 1-4

Author(s):

Hina Emanuel ◽

Kimberly Rennie ◽

Kelly Macdonald ◽

Aravind Yadav ◽

Ricardo A. Mosquera

Keyword(s):

Family History ◽

Genetic Disorder ◽

Neuropsychological Testing ◽

Clinical Manifestations ◽

Case Series ◽

Blood Gas Analysis ◽

Cor Pulmonale ◽

Gas Analysis ◽

Neuropsychological Evaluations ◽

Hypoventilation Syndrome

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of an autonomic nervous disorder that affects breathing. It is characterized by respiratory insufficiency secondary to insensitivity to hypoxemia and hypercarbia, particularly during sleep leading to persistent apnea. We report four individuals across two generations harboring heterozygous 25 polyalanine repeats mutations (PARMs) in PHOX2B with a varying degree of phenotypic clinical manifestations. Two family members who reported to be “asymptomatic” were subsequently diagnosed with CCHS, based on genetic testing, obtained because of their family history. Genetic studies in the family including a mother and three offsprings revealed in-frame five amino acid PARMs of PHOX2B consistent with CCHS in addition to full clinical assessment. All affected individuals had evidence of hypercapnia on blood gas analysis with PCO2 in the range of 32–70 (mean; 61). Nocturnal polysomnogram revealed evidence of hypoventilation in two individuals (1 offspring and mother) with the end-tidal CO2 median of 54. Magnetic resonance imaging of brain revealed no abnormalities in the brain stem. There was no evidence of cor pulmonale on echocardiograms in all individuals. Neuropsychological testing was conducted on all four patients; two patients (mother and 1 offspring) had normal results, while the other two offspring exhibited some impairments on neuropsychological testing. This case series emphasizes the importance of screening first-degree relatives of individuals with confirmed CCHS to minimize complications associated with long-term ventilatory impairment. It also suggests that some patients with CCHS should undergo neuropsychological evaluations to assess for cognitive weaknesses secondary to their CCHS.

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Clinical findings in five Turkish patients with citrin deficiency and identification of a novel mutation on SLC25A13

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0377 ◽

2020 ◽

Vol 33 (1) ◽

pp. 157-163 ◽

Cited By ~ 3

Author(s):

Melis Demir Köse ◽

Mehtap Kagnici ◽

Taha Reşit Özdemir ◽

Cahit Barış Erdur ◽

Gülin Erdemir ◽

...

Keyword(s):

Novel Mutation ◽

Genetic Disorder ◽

Laboratory Data ◽

Clinical Manifestations ◽

Case Series ◽

Clinical Findings ◽

First Case ◽

Age Related ◽

Citrin Deficiency ◽

Turkish Patients

AbstractBackgroundCitrin deficiency (CD) is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. Three clinical manifestations have been described until today.Case presentationWe reported 5 CD patients from two families. Four patients were male and one patient was female. Two of them have NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency); three of them have CTLN2 (adult-onset type II citrullinemia). Both NICCD patients showed typical clinical and biochemical changes with a diagnosis confirmed by mutations in the SLC25A13 gene. We detected a previously unreported homozygous novel mutation c.478delC (L160Wfs*36 ) on the SLC25A13 gene. All of the CTLN2 patients were siblings. Proband was a 15-year-old mentally retarded and autistic male who had admitted to our emergency with disorientation. Laboratory data showed hyperammonemia and citrullinemia.ConclusionsTwo different profiles of age-related CD have been depicted with this article. It has been aimed to underline that the CD can be observed in different forms not only in neonatals or little infants but also in adolescents. This article is the first case series that covers both NICCD and CTLN2 cases together and that has been published in Turkey. Considering the fact that especially the majority of CTLN2 cases have been identified in Asian countries, our article has vital importance in terms of defining phenotypic features of the disease.

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Allergy to Gibberellin-Regulated Proteins (Peamaclein) in Children

International Archives of Allergy and Immunology ◽

10.1159/000517413 ◽

2021 ◽

pp. 1-6

Author(s):

Benedetta Biagioni ◽

Leonardo Tomei ◽

Claudia Valleriani ◽

Giulia Liccioli ◽

Simona Barni ◽

...

Keyword(s):

Pediatric Patients ◽

Immunoglobulin E ◽

Clinical Manifestations ◽

Case Series ◽

In Vitro Test ◽

Eligibility Criteria ◽

Positive Skin ◽

Vitro Test ◽

Pru P 3

Background: Gibberellin-regulated proteins (GRPs, Peamaclein) are allergens recently identified in plant-derived food allergy (FA), and little is known about the clinical manifestations of this allergic condition in the European population, especially in children. Objective: Our study aimed to identify and characterize pediatric patients with pollen-FA due to GRP sensitization. Methods: We retrospectively analyzed the charts of patients referred to the Allergy Unit of the Meyer Children’s Hospital in Florence for suspected FA. Three main eligibility criteria based on the actual knowledge of GRP allergy were used to select patients deserving further investigations: (1) systemic reactions after consumption of fruit or an unknown culprit food, (2) positive skin prick tests to both cypress pollen and Pru p 3-enriched peach peel extracts, (3) negative in vitro test results for Pru p 3 serum-specific Immunoglobulin E (sIgE). We performed the in vitro test to determine the anti-rPru p 7 (Peamaclein) sIgE levels in the selected patients. Results: We identified 10 pediatric patients with Pru p 7 allergy and described their characteristics. The use of our eligibility criteria showed a high accuracy in identifying these patients: 100% of the selected patients had positive in vitro results for Pru p 7. We therefore proposed a diagnostic algorithm for Pru p 7 allergy. Conclusion: This is the first case series of European pediatric patients with a demonstrated Peamaclein allergy. These findings broaden our knowledge on GRP allergy in pediatric populations and could help clinicians to suspect, diagnose, and manage this recently discovered plant-derived FA.

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Kartagener’s syndrome: review of a case series

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2015.294 ◽

2015 ◽

Vol 10 ◽

Author(s):

Nicola Ciancio ◽

Maria Margherita De Santi ◽

Raffaele Campisi ◽

Laura Amato ◽

Giuseppina Di Martino ◽

...

Keyword(s):

Cross Sections ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Case Series ◽

Central Position ◽

Specialized Center ◽

Clinical Presentations ◽

Pathological Differentiation ◽

Dynein Arms

Background: Kartagener Syndrome (KS) is a rare autosomal recessive genetic disorder, resulting in a group of clinical manifestations, including bronchiectasis, chronic pansinusitis and situs inversus. Methods: We hereby reviewed eight cases of this rare entity selected from patients attending our outpatients Respiratory Unit since 2006. Samples of respiratory epithelium were obtained with the method of nasal brushing and sent to a specialized center in order to be studied with electron microscopy. At least 50 cross sections of different cilia from different cells were observed in each specimen to study the axonemal structure. Electron micrographs were taken at a magnification of X 50,000 to determine the orientation of the cilia and at a magnification of X 110,000 to study the axonemal pattern. The incidence of abnormal cilia was expressed as a percentage. Results: We observed different ultrastructural defects in our KS patients, including absence of outer dynein arms, absence of outer and inner dynein arms, and absence of the central pair with transposition of a peripheral doublet into the central position. Patient’s follow up lasted till 2014, however two patients with more severe clinical behavior died before. Conclusions: This is a review of a case series, yet our data has shown that nasal brushing with ultrastructural pathological differentiation may be useful to identify patients with high risk and to develop more complex clinical presentations.

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629 CPVT and complete atrio-ventricular block: two faces of the same coin?

European Heart Journal Supplements ◽

10.1093/eurheartj/suab127.031 ◽

2021 ◽

Vol 23 (Supplement_G) ◽

Author(s):

Mattia Petrungaro ◽

Martina Nesti ◽

Elena Cavaretta ◽

Zefferino Palamà ◽

Antonio Scarà ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Cardiac Mri ◽

Genetic Test ◽

Genetic Disorder ◽

Stress Test ◽

Pacemaker Implantation ◽

Clinical Manifestations ◽

Case Series ◽

Polymorphic Ventricular Tachycardia ◽

Av Block

Abstract Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an electrical genetic disease characterized by induction of malignant ventricular arrhythmias during adrenergic stress in structurally normal hearts. CPVT is correlated to syncope or sudden cardiac death (SCD). Usually, it is caused by an autosomal dominant mutation in the cardiac ryanodine receptor (RyR2), an essential gene for Ca2+ homeostasis. Methods and results Our case series refers to: a man (59 years) who came to our attention for a clinical check-up 4 years after implanting bicameral pacemaker at the age of 55 years for complete AV block; and his three sons (E. female 27 years; D. male 25 years; and B. female 17 years) who had evidence of polymorphic non-sustained ventricular tachycardia (NSVT) with increasing effort during stress test. The three sons performed cardiac MRI and underwent genetic test. All three were found to be carriers of the same microdeletion of the RYR 2 gene (1q43- extended for about 49 kb) at the genetic test. They also have non-compacted myocardium at cardiac MRI. The father was also found to be a carrier of the same genetic microdeletion, while the mother was negative to the genetic test. The man was diagnosed to be a carrier of the mutation 4 years after pacemaker implantation. Conclusions Mutation of the RyR2 may have different phenotypic expressions and can be correlated to various clinical manifestations. CPVT is the most common one, and its prompt identification is crucial to prevent subjects from sport-related risks and to plan an efficient therapy. Our case series provides evidence for a careful consideration of such a genetic disorder even in presence of a major AV conduction disease in a relatively young subject. In the present case series, no major adverse events occurred. However, we can, in the aftermath, speculate that if a genetic disorder had been suspected when AV block occurred, a timely diagnosis could have been made earlier also for the sons.

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P.079 4H leukodystrophy: a case series of siblings with an unusually mild phenotype

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.177 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S35

Author(s):

SM DeGasperis ◽

G Bernard ◽

D Pohl

Keyword(s):

Medical Records ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Case Series ◽

Genetic Mutation ◽

Neurological Deficits ◽

Motor Deficits ◽

Severe Phenotype ◽

Mild Phenotype ◽

History Of

Background: 4H leukodystrophy is a genetic disorder typically characterized by hypomyelination, hypodontia and hypogonatotropic hypogonadism. Previously reported patients had considerable cognitive and motor deficits. We present a pair of siblings with a less severe phenotype. Methods: Patient data was obtained from medical records from the Children’s Hospital of Eastern Ontario. Results: The first patient was diagnosed with 4H leukodystrophy at the age of 21 years after genetic testing revealed a POLR3B mutation with a homozygous V523E variant. She has hypomyelination on MRI and a history of optic neuritis, as well as intermittent sensory and motor symptoms in the context of a diagnosis of multiple sclerosis. She has no clinical manifestations of 4H leukodystrophy. The patient is now 26 years old and has only mild neurological deficits. Her younger brother was diagnosed with 4H leukodystrophy at the age of 18 years and found to have the same genetic mutation as his sister. He has a history of seizures and mild learning disabilities. He is now 23 years old with no typical symptoms of 4H leukodystrophy. Conclusions: 4H leukodystrophy is usually associated with a severe, disabling phenotype and a poor prognosis. Our patients illustrate that a much milder phenotype exists.

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Pediatric Visual Snow Syndrome (VSS): A Case Series

Vision Development & Rehabilitation ◽

10.31707/vdr2019.5.4.p249 ◽

2019 ◽

pp. 249-254

Author(s):

Kenneth J. Ciuffreda ◽

MH Esther Han ◽

Barry Tannen

Keyword(s):

Visual Field ◽

Case Series ◽

Therapeutic Interventions ◽

Visual Condition ◽

Visual Phenomena ◽

Entire Visual Field ◽

The Individual ◽

Vision Therapy ◽

Abnormal Visual

Visual snow syndrome (VSS) is a relatively rare, unusual, and disturbing abnormal visual condition. The individual perceives “visual snow” (VS) throughout the entire visual field, as well as other abnormal visual phenomena (e.g., photopsia). Only relatively recently has treatment been proposed (e.g., chromatic filters) in adults with VSS, but rarely in the pediatric VSS population (i.e., medications). In this paper, we present three well-documented cases of VSS in children, including their successful neuro-optometric therapeutic interventions (i.e., chromatic filters and saccadic-based vision therapy)

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Recent Patents on Anti-Cancer Potential of Helenalin

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892815666200702142601 ◽

2020 ◽

Vol 15 (2) ◽

pp. 132-142

Author(s):

Priyanka Kriplani ◽

Kumar Guarve

Keyword(s):

Synergistic Effects ◽

Therapeutic Interventions ◽

Active Constituent ◽

Scientific Impact ◽

Isolation Techniques ◽

Anti Cancer ◽

Prevention Of Cancer ◽

Synthetic Derivatives

Background: Arnica montana, containing helenalin as its principal active constituent, is the most widely used plant to treat various ailments. Recent studies indicate that Arnica and helenalin provide significant health benefits, including anti-inflammatory, neuroprotective, antioxidant, cholesterol-lowering, immunomodulatory, and most important, anti-cancer properties. Objective: The objective of the present study is to overview the recent patents of Arnica and its principal constituent helenalin, including new methods of isolation, and their use in the prevention of cancer and other ailments. Methods: Current prose and patents emphasizing the anti-cancer potential of helenalin and Arnica, incorporated as anti-inflammary agents in anti-cancer preparations, have been identified and reviewed with particular emphasis on their scientific impact and novelty. Results: Helenalin has shown its anti-cancer potential to treat multiple types of tumors, both in vitro and in vivo. It has also portrayed synergistic effects when given in combination with other anti- cancer drugs or natural compounds. New purification/isolation techniques are also developing with novel helenalin formulations and its synthetic derivatives have been developed to increase its solubility and bioavailability. Conclusion: The promising anti-cancer potential of helenalin in various preclinical studies may open new avenues for therapeutic interventions in different tumors. Thus clinical trials validating its tumor suppressing and chemopreventive activities, particularly in conjunction with standard therapies, are immediately required.

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Pediatric leukemia susceptibility disorders: manifestations and management

Hematology ◽

10.1182/asheducation-2017.1.242 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 242-250 ◽

Cited By ~ 6

Author(s):

Lisa J. McReynolds ◽

Sharon A. Savage

Keyword(s):

Early Onset ◽

Ribosome Biogenesis ◽

De Novo ◽

Disease Risk ◽

Bone Marrow Failure ◽

Clinical Manifestations ◽

Cancer Surveillance ◽

Therapeutic Interventions ◽

Pediatric Leukemia ◽

Inherited Susceptibility

Abstract The clinical manifestations of inherited susceptibility to leukemia encompass a wide phenotypic range, including patients with certain congenital anomalies or early-onset myelodysplastic syndrome (MDS) and some with no obvious medical problems until they develop leukemia. Leukemia susceptibility syndromes occur as a result of autosomal dominant, autosomal recessive, or X-linked recessive inheritance, or de novo occurrence, of germline pathogenic variants in DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, and other critical cellular processes. Children and adults with cytopenias, MDS, dysmorphic features, notable infectious histories, immunodeficiency, certain dermatologic findings, lymphedema, unusual sensitivity to radiation or chemotherapy, or acute leukemia with a family history of early-onset cancer, pulmonary fibrosis, or alveolar proteinosis should be thoroughly evaluated for a leukemia susceptibility syndrome. Genetic testing and other diagnostic modalities have improved our ability to identify these patients and to counsel them and their family members for subsequent disease risk, cancer surveillance, and therapeutic interventions. Herein, the leukemia susceptibility syndromes are divided into 3 groups: (1) those associated with an underlying inherited bone marrow failure syndrome, (2) disorders in which MDS precedes leukemia development, and (3) those with a risk primarily of leukemia. Although children are the focus of this review, it is important for clinicians to recognize that inherited susceptibility to cancer can present at any age, even in older adults; genetic counseling is essential and prompt referral to experts in each syndrome is strongly recommended.

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Pan-American Lancehead Pit-Vipers: Coagulotoxic Venom Effects and Antivenom Neutralisation of Bothrops asper and B. atrox Geographical Variants

Toxins ◽

10.3390/toxins13020078 ◽

2021 ◽

Vol 13 (2) ◽

pp. 78

Author(s):

Lachlan A. Bourke ◽

Christina N. Zdenek ◽

Edgar Neri-Castro ◽

Melisa Bénard-Valle ◽

Alejandro Alagón ◽

...

Keyword(s):

Evolutionary Biology ◽

Current Knowledge ◽

Clinical Manifestations ◽

In Vivo Studies ◽

Factor X ◽

Clotting Factors ◽

Bothrops Asper ◽

Species Specific

The toxin composition of snake venoms and, thus, their functional activity, can vary between and within species. Intraspecific venom variation across a species’ geographic range is a major concern for antivenom treatment of envenomations, particularly for countries like French Guiana that lack a locally produced antivenom. Bothrops asper and Bothrops atrox are the most medically significant species of snakes in Latin America, both producing a variety of clinical manifestations, including systemic bleeding. These pathophysiological actions are due to the activation by the venom of the blood clotting factors Factor X and prothrombin, thereby causing severe consumptive coagulopathy. Both species are extremely wide-ranging, and previous studies have shown their venoms to exhibit regional venom variation. In this study, we investigate the differential coagulotoxic effects on human plasma of six venoms (four B. asper and two B. atrox samples) from different geographic locations, spanning from Mexico to Peru. We assessed how the venom variation of these venom samples affects neutralisation by five regionally available antivenoms: Antivipmyn, Antivipmyn-Tri, PoliVal-ICP, Bothrofav, and Soro Antibotrópico (SAB). The results revealed both inter- and intraspecific variations in the clotting activity of the venoms. These variations in turn resulted in significant variation in antivenom efficacy against the coagulotoxic effects of these venoms. Due to variations in the venoms used in the antivenom production process, antivenoms differed in their species-specific or geographical neutralisation capacity. Some antivenoms (PoliVal-ICP, Bothrofav, and SAB) showed species-specific patterns of neutralisation, while another antivenom (Antivipmyn) showed geographic-specific patterns of neutralisation. This study adds to current knowledge of Bothrops venoms and also illustrates the importance of considering evolutionary biology when developing antivenoms. Therefore, these results have tangible, real-world implications by aiding evidence-based design of antivenoms for treatment of the envenomed patient. We stress that these in vitro studies must be backed by future in vivo studies and clinical trials before therapeutic guidelines are issued regarding specific antivenom use in a clinical setting.

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