BEST DTH - PPDIS X LF X CT LNLY FLT CRTKR

P KZN EBV X MALARIA

AUTHORS:
Hannah Wilkerson, BS • Ganesh Maniam, BA, MBA • Ryan E. Dean, BS, MBA • Tosin Bewaji, MD, MPH • Efe Okotcha, MD • Raphael Mattamal, MD

AFFILIATIONS:
Texas Tech University Health Sciences Center at Amarillo, Texas

CITATION:
Wilkerson H, Maniam G, Dean RE, Bewaji T, Okotcha E, Mattamal R. Pediatric coinfection with malaria and Epstein-Barr virus. Consultant. Published online July 30, 2020. doi:10.25270/con.2020.07.00007

Received April 29, 2020. Accepted June 24, 2020.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Hannah Wilkerson, BS, Texas Tech Internal Medicine at Amarillo, 1400 S Coulter St, Amarillo, TX 79106 (h.g.wilkerson@tcu.edu)

An 11-year-old boy presented to his primary care provider (PCP) with a fever of 2 days’ duration. The fever was described as intermittent, particularly occurring in the evenings, and being partially relieved with acetaminophen. The boy’s temperature had not been taken at home. Associated symptoms included intermittent myalgia and reduced appetite, but there had been no vomiting, diarrhea, rash, abdominal pain, night sweats, cough, nasal congestion, sore throat, or fatigue.

The boy had no history of sick contacts, but his travel history was notable for a 1-month visit to Sierra Leone (his native country and an endemic area for chloroquine-resistant malaria). He had returned to the United States approximately 3 weeks prior to presentation. He had been on malaria prophylaxis with mefloquine while in Sierra Leone. He had had a febrile illness a few days after having returned from the trip; he had been taken to see the PCP, who diagnosed a viral illness. The fever had abated after approximately 3 days, until the current episode.

The boy’s current symptoms prompted his mother take him back to his PCP, where the results of a complete blood cell count (CBC) showed pancytopenia with neutropenia. The PCP promptly referred the boy to the hospital for further evaluation.

The patient had no significant medical or surgical history. His family history is significant for sickle-cell disease in his brother, and sickle-cell trait in his mother and his sister. The boy’s hemoglobin electrophoresis test results were unremarkable.

At presentation to the hospital, significant physical examination findings included conjunctival pallor and lymphadenopathy in the left axillary and bilateral anterior cervical nodes. A peripheral blood smear revealed many red blood cells (RBCs) with ring-shaped inclusion bodies, suggestive of malaria. Results of a comprehensive metabolic panel were within normal limits, while a complete blood count revealed anemia (hemoglobin 8.4 gm/dL) and thrombocytopenia (141,000/mcL), with an elevated reticulocyte count at 5% and an absolute neutrophil count of 1359/µL. The C-reactive protein level and erythrocyte sedimentation rate were both elevated at 12 mg/L and 67 mm/hr, respectively, along with the lactate dehydrogenase level at 540 units/L. Serologic test results were positive for Epstein-Barr virus (EBV) IgG and IgM antibodies, consistent with a concurrent EBV infection. Otherwise, urinalysis results were normal, serologic test results for cytomegalovirus were negative, and blood culture and urine culture results were pending.

The patient was started on combination atovaquone/proguanil, 750 mg/300 mg, for 3 consecutive days as per Centers for Disease Control and Prevention guidelines. Due to elevated risk of splenic rupture associated with EBV infection, the patient was discharged with instructions to avoid participation in contact sports for 6 to 8 weeks, with an outpatient follow-up visit to reassess CBC and reticulocyte count.

The final diagnosis was pancytopenia secondary to combined chloroquine-resistant malaria and infectious mononucleosis with EBV.

DISCUSSION

Malaria is an infection with protozoan parasites of the Plasmodium genus that causes a flulike illness characterized by cyclical fever, headache, and chills, with potential to cause coma and death.¹ Transferred to humans by the female Anopheles mosquito, the parasite initially infects the liver, then replicates in RBCs, resulting in severe anemia.¹ There are more than 228 million annual malaria cases worldwide, with most occurring in sub-Saharan Africa or South Asia.² Approximately 2000 cases of malaria are diagnosed in the United States each year, generally in patients with a recent history of travel from an endemic country.³

On the other hand, EBV is a human herpesvirus that infects B lymphocytes to cause a variety of conditions, especially in persons who are immunosuppressed or otherwise immunodeficient.⁴ In pediatric patients, acquisition of EBV typically presents as infectious mononucleosis.⁴ However, as a widely disseminated virus, EBV has a wide range of presentations and complications, such as splenic rupture or hematologic abnormalities.⁴

Coinfection with malaria and EBV, as in our patient’s case, is exceedingly rare in the United States. However, a 2015 study found that infection with γ-herpesviruses, including EBV, suppresses the necessary humoral immunity to combat parasitic infections.⁵ This increases the susceptibility of children infected with EBV to acquire malaria, and thus coinfection with both EBV and Plasmodium species is more common in endemic regions.⁵ It is unclear as to which pathogen our patient acquired first—the lack of infectious mononucleosis symptoms and positive serologic test results for EBV IgM and IgG antibodies, in the context of malarial acquisition despite appropriate prophylaxis, suggests that this is a case of EBV infection predisposing the patient to malarial coinfection. A 2004 study determined that the likelihood of malaria coinfection with EBV depends on the stage of viral infection at the time of parasite acquisition,⁶ which further confounds the ability to determine the sequence of infections in our patient’s case.

Regardless of the coinfection timeline, simultaneous infection with EBV and malaria has additional ramifications for the development of oncologic pathologies. Endemic Burkitt lymphoma is the most prevalent pediatric malignancy in Africa, and a 2011 review suggests that one such underlying mechanism includes coinfection with Plasmodium falciparum malaria and EBV.⁷ This may be due to malarial induction of polyclonal B-cell expansion, which may act in combination with lytic EBV reactivation to increase the risk of B cell oncologic transformation through MYC translocation.⁷ A study of 43 children being treated for malaria in Uganda revealed a significant decrease in EBV viral DNA levels after 2 weeks, and this antimalarial-induced reduction of quantitative EBV genome loads suggests a relationship between active malaria infection and EBV reactivation.⁸ Furthermore, the chronic stimulation of a malarial infection may result in repeated EBV reactivation that eventually blunts the T-cell response against EBV; this would enhance its replication as an oncogenic virus and subsequently result in MYC translocation.⁷ A study of 57 EBV-seropositive children in Gambia found that malarial infections caused a significant increase in quantitative viral DNA of EBV, suggesting yet another theory—that malarial infections increase the viremia set point for EBV.⁹ Regardless of the exact mechanism, physicians should be aware of the link between malaria and EBV coinfection with B-cell lymphomas.

Rare coinfections, such as malaria and EBV, present a diagnostic and treatment challenge for clinicians. In this patient’s case, the pancytopenia identified on CBC alarmed the outpatient physician and resulted in hospital admission. The peripheral blood smear was used to diagnose malaria, while serological titers were used to diagnose EBV infection. While the timeline of coinfection remains unclear in this patient’s case, physicians should be aware of the possibility of such presentations despite their relative rarity.

REFERENCES:

1. Cowman A, Healer J, Marapana D, Marsh K. Malaria: Biology and Disease. Cell. 2016; 167(3):610-624. doi: 10.1016/j.cell.2016.07.055

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The Science of Bubbles (Full Science Documentary) | Spark

Morning Talk Part 1 | Ven Ajahn Brahm | Dhamma TV | English Dhamma Talks

India extends ban on international flights till August 31

Earlier this month, in the wake of a surge in Covid-19 cases across the country, the civil aviation ministry had extended the ban on international flights till July 31. Prior to that, the earlier order had said the ban would be in place till July 15.

INDIA Updated: Jul 31, 2020 17:57 IST

hindustantimes.com | Edited by Sohini Sarkar

Hindustan Times, New Delhi

During the suspension of international flights due to the Covid-19 outbreak in India, more than 2,500 repatriation flights by foreign carriers to evacuate stranded passengers to and from India were approved. (PTI PHOTO.)

     

India on Friday extended the ban on international commercial passenger flights till August 31. But the restriction shall not apply to international cargo operations and flights specifically approved by aviation regulator, the Directorate General of Civil Aviation (DGCA).

“The government has decided to extend the suspension on the Scheduled International Commercial Passenger Services to/from India up to 2359 hours IST of 31st August,” the statement read.

Earlier this month, in the wake of a surge in Covid-19 cases across the country, the civil aviation ministry had extended the ban on international flights till July 31. Prior to that, the earlier order had said the ban would be in place till July 15. The ban on international flights was extended even as capacity on domestic routes has been hiked to 45% from the earlier 33%.

ALSO READ | India extends ban on international flights till July 31

To allow gradual movement of passenger traffic during the Covid-19 health crisis, ‘Transport Bubble’ agreements have been signed with the United States, France and Germany. Air France and United Airlines of the US will operate a limited number of international flights under the “air bubble” arrangements with India.

The country has also signed a travel bubble agreement with Kuwait to evacuate stranded passengers both to and from India. Further similar arrangements are likely to be put in place by the aviation ministry to ease passenger movements from different countries. On July 9, India had announced an air bubble with the United Arab Emirates that would be in place from July 12 to 26.

A bilateral air bubble refers to a travel corridor between two countries that wish to reopen their borders and re-establish connections with each other. International flights to and from India have been suspended since March 23 as the Covid-19 pandemic spread across the world to nearly 185 countries. Limited domestic flights have since resumed on certain sectors from May 25.

ALSO READ | France, US establish ‘air bubbles’ for flights to India

During the suspension of international flights due to the Covid-19 outbreak in India and other countries, more than 2,500 repatriation flights by foreign carriers to evacuate stranded nationals to and from India were approved by the government.

Under the Centre’s massive Vande Bharat Mission, national carrier Air India and its subsidiary Air India Express have evacuated 2,67,436 stranded passengers and other flights have brought back 4,86,811 passengers between May 6 to July 30.

REASON FOR R IN BJR X KARMA X B GTA 2.20

Bhagavad Gita WISDOM CODE 7: The soul is never created, nor does it ever die. The soul is without birth, eternal, immortal, and ageless. It is not destroyed when the body is destroyed. USE: This code addresses the universal human fear of annihilation and the primal fear of nonexistence. SOURCE: Bhagavad Gita, chapter 2, verse 20


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RD BK WSDM CD

Five hundred years before the birth of Jesus, a mysterious group of healerscholars formed communities near the present-day Dead Sea in an area known as Qumran. The community included many religious sects, including the Nazarenes and the Ebionites, people known collectively as the Essenes. While the origin and nature of the Essenes remains controversial today, their existence is undisputed. Some of the first references to the lineage of the Essenes are found on clay tablets of ancient Sumer dating as far back as 3500 B.C.E. They’re also recorded in historic writings that range from those of 1st-century Roman scholars Flavius Josephus and Pliny the Elder, where Essenes are referred to as a “race by themselves, more remarkable than any other in the world” in manuscripts preserved today in libraries and museums that include the Austrian National Library in Vienna, the British Museum in London, and the Vatican Library in Vatican City. Elements of nearly every major religion of the world today, including those indigenous to China, Tibet, Egypt, India, Palestine, Greece, and the American desert Southwest, may be traced back to the original wisdom preserved by the Essenes. Many mystical traditions from the Western world, in particular, have roots in this body of information, such as the traditions of the Freemasons, Gnostic Christians, and Kabbalists. Wisdom Code 8 is derived from a collection of Essene texts that found their way safely from Palestine before the advance of the Mongol forces between 1299 and 1300 C.E., then into the hands of Nestorian priests in Asia, and ultimately into the Vatican Library. It was there, in the early 1920s, that student and scholar Edmond Bordeaux Szekely was given special access to the library for a research project. In the course of exploring the library for his thesis, he discovered the forgotten Aramaic gospel of Jesus’s teachings. Although he was not allowed to remove the documents from the Vatican, he transcribed and later published excerpts of these documents as the book series the Essene Gospel of Peace.


////////////////////////////GRF A SOLO JRNY
A SOLO JOURNEY Through the grief that follows loss, we temporarily experience emotional and physiological shock. And even when we’re surrounded by the bestintentioned friends and loved ones, and receiving support, just as it is with fear, as described in Part Two, we ultimately go through the gauntlet of grief alone. No one can grieve for us. Grief is a solo journey. And that journey often leads us to a battleground within ourselves where we discover conflicting emotions and the feeling of being empty, numb, and isolated. With our conflicted emotions come the seemingly endless questions that loop tirelessly in our mind: among them, Will I ever feel better? What do I do now? Why is this happening? There is a strength that can only be known in the presence of loss and grief. And with that strength comes the reward of life’s deepest levels of personal mastery.


//////////////////////////////The Gospel of Peace WISDOM CODE 8: One day your body will return to the Earthly Mother; even also your ears and your eyes. But the Holy Stream of Life, the Holy Stream of Sound, and the Holy Stream of Light, these were never born, and can never die. USE: This code addresses the primal fear of nonexistence and our relationship to a greater presence. SOURCE TEXT: The Essene Gospel of Peace


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-///////////////////////THIS IS JOW IT ENDS - LONELY FLAT WITH CARETAKER


////////////////////////ORANGUTANG SOLITARY CF CHIMP BONOBOS


///////////////////////The Essene Gospel of Peace is a record of Jesus describing the relationship between our “Mother Earth” and our “Father in Heaven.”

PRAKRITI X PURUSH

/////////////////////From a place of heart/brain harmony, recite this code line by line, either silently in your mind or out loud, until you feel a shift in your sense of fear. The key is to embrace this code with a focus of awareness, breath, and feeling in the heart rather than the mind. One day your body will return to the Earthly Mother; even also your ears and your eyes. But the Holy Stream of Life, the Holy Stream of Sound, and the Holy Stream of Light, these were never born, and can never die.



//////////////////////////Loss is a universal experience. It’s inevitable. It’s inescapable. And it’s natural. We all lose something each day of our lives. Sometimes our losses are so subtle that they’re almost imperceptible. From the time we’re young, for example, we see “progress” changing the faces of the homes, streets, grocery stores, and movie theaters that we grew up with. While the incremental change of a new mall or the loss of our favorite late-night café may seem insignificant as it occurs, when we put those changes together and look backward in time, we find that the way we remember our neighborhood is barely recognizable when compared to the current version of our surroundings.



///////////////////////And just as a really great batch of cacao peanut butter cookies reflects the quality, as well as the quantity, of the ingredients that we place into the mix, it’s that sparkle, smile, glow, and tingle that reveals the one-of-a-kind energy that we create in the presence of our loved ones. And it’s precisely because this field of energy is so very real that when it dissolves with their passing we experience so much hurt. When we lose a loved one, the field of energy that we’ve created together begins to disintegrate. It has to, because the energy from the body that once held it together no longer exists.



///////////////////////////There’s an unspoken potential that each of us will lose the people and the ways of life that we cherish and hold most dear. It’s inevitable because nothing lasts forever. It’s this fact that promises we will experience loss in our lives, and the grief that is the consequence, as well as the path to healing from loss. Whether it’s the loss of a friend or loved one, or the loss of a community and an entire way of life, the result is the same. Grief is nature’s support system for reconciling loss and helping us to move forward with life in a healthy way. It’s also nature’s way to get us to feel our grief even when we may be reluctant to do so.



/////////////////////////////KALI YUGA

একদিন পঞ্চপাণ্ডব দ্বাপর যুগের শেষ প্রান্তে, ভগবান শ্রীকৃষ্ণের কাছে প্রশ্ন করেন যে "কলিযুগ কেমন হবে" ?

তখন ভগবান শ্রীকৃষ্ণ পরামর্শ দেন পাঁচ ভাইকে এক জঙ্গলের ভেতর পাঁচটি ভিন্ন ভিন্ন পথ দিয়ে হেঁটে আবার তাঁর কাছে ফেরত আসতে।

পাঁচ ভাই জঙ্গলের ভেতরে দেখলেন ---

যুধিষ্ঠির ওই পথে হেঁটে যাওয়ার সময় একটা অদ্ভুত জিনিস লক্ষ্য করলেন - একটা হাতি কিন্তু তার দুটি শুঁড়।

এই অদ্ভুত লক্ষ্যের কথা জানালেন শ্রীকৃষ্ণের কাছে।

উত্তরে শ্রীকৃষ্ণ বলেন, "কলিযুগের মানুষ হবে ঠিক এই রকম। তারা মুখে বলবে এক, কিন্তু তাদের কাজ গুলো হবে সম্পূর্ণ আলাদা।"

ভীম দেখতে পেলেন, একটা গরু তার বাছুর কে আদর করছে চেটে চেটে, কিন্তু এত বেশি চাটছে যে বাছুরটির গায়ের ছাল উঠে গিয়ে রক্তপাত শুরু হয়েছে।

ভীম এই কথাটা শ্রীকৃষ্ণের কাছে জানালেন।

উত্তরে শ্রীকৃষ্ণ বলেন, "কলি যুগের মাতা, পিতা হবে ঠিক এইরকম। মাতা, পিতার অন্ধ স্নেহ ও অতিরিক্ত ভালোবাসাই, তাদের সন্তানদের ক্ষতির কারণ হয়ে উঠবে। যেমন এতে সন্তানদের বিচার বুদ্ধিহীনতা ও পরনির্ভরশীল করে তুলবে। যা আগামীতে স্বাভাবিক ও সুস্থ জীবন যাপনে তাদের বাঁধা হয়ে দাঁড়াবে।"

অর্জুন দেখতে পেলেন, একটি নদীতে একটি পচাগলা মৃত ছাগল আর ওই ছাগলের উপর বসে আছে একটা শকুন। কিন্তু ওই শকুনের ডানায় লেখা আছে বেদ মন্ত্র।

উত্তরে শ্রীকৃষ্ণ বলেন, "কলিযুগের কিছু ভন্ড সাধকেরা হবে ঠিক এই রকমের। অর্থাৎ দেশ ও সমাজের বুকে যাদের ধার্মিক ও জ্ঞানী হিসেবে খ্যাতি থাকবে, কিন্তু তাদের প্রকৃত মানসিকতা হবে শকুনের ন্যায়।"

নকুল দেখতে পেলেন, যে এক বিশালাকার পাথরের খন্ড পাহাড় থেকে গড়িয়ে পড়ছে, কিন্তু কোন বিশালবৃক্ষ তাকে আটকাতেই পারছে না। অবশেষে সামান্য একটা দুল্পা(গুল্ম) গাছের তলায় এসে আটকে যায়।

উত্তরে শ্রীকৃষ্ণ বলেন, "কলিযুগের মানুষের পাপের পরিমাণ বেড়ে হবে ওই পাথরের সমান। কিন্তু কোনো মানুষ যদি এই হরিনাম রূপী দুল্পা গাছটিকে ধরতে পারে, তাহলে সর্ব বিপদ থেকে রক্ষা পাবে।"

সহদেব দেখতে পেলেন একটা বিশাল গভীর কূয়া। কিন্তু অবাক হয়ে দেখলেন ওই কূয়ার শেষ প্রান্তে বিন্দুমাত্র জল নেই।

উত্তরে শ্রীকৃষ্ণ বলেন, "কলিযুগের কিছু বাড়ি হবে বিশাল আকৃতির ও মানুষের ধনসম্পত্তি থাকবে ওই গভীর কূয়ার সমান কিন্তু ওই বাড়ি ও ধনসম্পত্তি মালিকের মধ্যে থাকবেনা বিন্দু মাত্র সুখ।"

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হরে কৃষ্ণ হরে কৃষ্ণ কৃষ্ণ কৃষ্ণ হরে হরে

হরে রাম হরে রাম রাম রাম হরে হরে

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(সংগৃহীত)

//////////////////////IP B MONK

Otagaki Rengetsu WISDOM CODE 9: The impermanence of this floating world I feel over and over. It is hardest to be the one left behind. USE: This code reminds us that even in the knowledge that all things are temporary, enduring the loss of a loved one is still one of hardest things we will face. SOURCE TEXT: Otagaki Rengetsu, renowned Buddhist nun

////////////////////////////////LOSS FROM THE BUDDHIST PERSPECTIVE To ease our suffering in times of loss, Buddhist teachings invite us to consider our pain within the larger context of a universal template for human experience. The template is known as the three marks of existence, which are identified as follows: Impermanence Suffering The non-self Briefly stated, when we are suffering, the cause of our pain is attachment: our expectation that something, some place, or someone will continue to exist in a way that meets our expectations. The third mark of existence, embracing the non-self, is the solution to transcend our suffering. The nonself is defined as a state of enlightenment that is achieved through the release of our personal identity—the ego self—in exchange for a greater allinclusive identity. In this expanded identity, we view ourselves as part of, rather than separate from, the world around us. By embracing this more mindful version of ourselves, we are freed from the suffering that is the result of attachment.

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/////////////////////////OWN BODY IS A TEMPLE X OF IMPERMANENCE X WALKING IS MY PRAYER  X   OBIAT WIMP X  

////////////////////////OM SAD GATI

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THAKURDA KHARAGPUR DREAM INCIDENT

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/////////////////////////IP S OS  IMPERMANENCE X SUFFRING X O SELF 

B MIND IPSOS

////////////////////////////Buddha WISDOM CODE 10: You only lose what you cling to. USE: This code reminds us that our suffering in times of loss is the result of our attachment to what is impermanent. SOURCE: A widely used, colloquial summary of the Buddhist principle of nonattachment



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GOD YAHWEH X WSDM CD

The second of God’s hidden names is the word Almighty and is typically translated by Near Eastern scholars from Aramaic as Shaddai (meaning “Almighty”) or El Shaddai (meaning “God Almighty”). This is one of the seven names of God that are substituted for God’s actual name over 6,800 times in the Hebrew Bible. The other six names are Ehyeh, meaning “I will be”; Tzevaot, meaning “host”; Elohim, meaning “gods”; El, meaning “God”; and Eloah, also meaning “God.”


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Five hundred years before the birth of Jesus, a mysterious group of healerscholars formed communities near the present-day Dead Sea in an area known as Qumran. The community included many religious sects, including the Nazarenes and the Ebionites, people known collectively as the Essenes. While the origin and nature of the Essenes remains controversial today, their existence is undisputed. Some of the first references to the lineage of the Essenes are found on clay tablets of ancient Sumer dating as far back as 3500 B.C.E. They’re also recorded in historic writings that range from those of 1st-century Roman scholars Flavius Josephus and Pliny the Elder, where Essenes are referred to as a “race by themselves, more remarkable than any other in the world” in manuscripts preserved today in libraries and museums that include the Austrian National Library in Vienna, the British Museum in London, and the Vatican Library in Vatican City. Elements of nearly every major religion of the world today, including those indigenous to China, Tibet, Egypt, India, Palestine, Greece, and the American desert Southwest, may be traced back to the original wisdom preserved by the Essenes. Many mystical traditions from the Western world, in particular, have roots in this body of information, such as the traditions of the Freemasons, Gnostic Christians, and Kabbalists. Wisdom Code 8 is deri

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N KZN NN SZR

Neonatal Seizures: Diagnosis, Etiologies, and Management 31/07/2020 https://www.medscape.com/viewarticle/929063_print https://www.medscape.com/viewarticle/929063_print 2/12 hypothermia. [14] Identification of seizures in HIE is imperative, as they occur in 25 to 50% of neonates with HIE and may exacerbate the underlying brain injury. [15–17] Seizure semiology varies based on the region of brain injury, but there is a high prevalence of subclinical seizures in neonates, which underscores the need for electroencephalography (EEG) recording as discussed later. Table 1. Causes of neonatal seizures Etiology Frequency a Seizure onset Hypoxic–ischemic encephalopathy 38% First 24 h Ischemic stroke 18% First week Intracranial hemorrhage 12% First week Genetic syndrome (including benign familial neonatal epilepsy) 9% In utero to weeks Intracranial infection 4% Days to weeks Brain malformation 4% Variable Transient metabolic 4% First few days Inborn errors of metabolism 3% Day 2+ Others/unknown 9% variable aAmong a large cohort of 426 consecutive neonates with seizures. 53 Cerebrovascular events are the second most common cause of neonatal seizures. Arterial ischemic perinatal strokes are typically the result of embolism from the placenta or umbilical cord, carotid artery, or heart. Maternal risk factors include oligohydramnios, chorioamnionitis, premature rupture of membranes, preeclampsia, diabetes, and smoking. Neonatal risk factors include congenital cardiac abnormalities, systemic infection, coagulation disorders, placental abnormalities, and male sex. Seizures resulting from focal strokes often present somewhat later than those caused by neonatal HIE, frequently up to 24 to 48 hours after birth or later. [18–20] The seizure semiology among neonates with perinatal arterial ischemic strokes is classically focal clonic seizures due to involvement of the motor cortex in the middle cerebral artery territory. ICH can cause acute symptomatic seizures, with severity and semiology determined by the size and location of the hemorrhage. Subdural hemorrhage in the anterior and middle cranial fossae may have associated subarachnoid hemorrhage and may result in seizures. Parenchymal hemorrhages frequently cause seizures, and are often caused by underlying vascular malformations. Intraventricular hemorrhages rarely cause seizures in term infants unless the hemorrhage is large and involves parenchymal injury. [19] However, ICH is the second most common etiology of seizures in preterm infants (<32 02789176="" 1.="" 100="" 13="" 15="" 1="" 2.="" 20="" 24="" 25="" 28="" 2="" 3.="" 30="" 31="" 3="" 4.="" 40="" 41="" 48="" 4="" 4th="" 50="" 5="" 60="" 66="" 6="" 6th="" 7.5="" 75="" 7="" 80="" 8="" 96="" 9="" a="" abate="" abbreviations:="" abnormal="" abnormalities.="" abnormalities="" abnormality="" about="" access="" accompanied="" accurate="" accurately="" acid="" aciduria="" acquired="" active="" activity.="" acute="" addition="" additional="" additionally="" adequate="" administered="" administration.="" administration="" advancement="" advances.="" advances="" adverse="" affect="" affected="" affecting="" after="" age-specific="" age.="" age="" agent.="" agent="" agents.="" agents="" aid="" albumin="" aldh7a1="" algorithm="" algorithms="" all="" allocation="" allow="" alone.="" along="" also="" alteration="" alters="" american="" amino="" among="" amt="" an="" and="" animal="" anomalies="" 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PHORSHA NA KALO TYPE 5 NA 6 X FITZPATRICK SKIN TYPES

DWM women who were overweight between 20 and 49 years of age had nearly twice the risk of dementia after age 70. And older men and women who were obese in those earlier years saw their risk jump 150%

women who were overweight between 20 and 49 years of age had nearly twice the risk of dementia after age 70. And older men and women who were obese in those earlier years saw their risk jump 150%

P KZN “Doll #135 with vitiligo”

P KZN FILS SYNDROME

F

ACIAL DYSMORPHISM, IMMUNODEFICIENCY, LIVEDO, AND SHORT STATURE; FILS

Phenotype-Gene Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key	Gene/Locus	Gene/Locus MIM number
12q24.33	FILS syndrome	615139	AR	3	POLE	174762

Clinical Synopsis

   

 

▼ TEXT

A number sign (#) is used with this entry because of evidence that facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) is caused by homozygous mutation in the POLE gene (174762) on chromosome 12q24.

▼ Description

FILS syndrome is characterized by mild facial dysmorphism, mainly malar hypoplasia, livedo on the skin since birth, immunodeficiency resulting in recurrent infections, and short stature (summary by Pachlopnik Schmid et al., 2012). 

▼ Clinical Features

Pachlopnik Schmid et al. (2012) reported a large multigenerational consanguineous French kindred in which 11 individuals showed a constellation of features, including mild facial dysmorphism, immunodeficiency, livedo, and short stature. Three additional family members displayed 2 or 3 of these 4 features. Facial dysmorphism included high forehead and malar hypoplasia. Livedo, usually present from birth, was present on the skin of the cheeks, forearms, and/or legs of all except 1 patient. With increasing age, telangiectasia became apparent on the cheeks. Growth impairment was observed during early childhood and resulted in variable short stature in adulthood. Head circumference was normal, resulting in relative macrocephaly. Three patients had bone dysplasia with pain, and studies showed lacunar bone lesions, cortical thickening, and modeling defects at the long bone diaphyses. All but 2 patients had immunodeficiency resulting in recurrent respiratory tract infections, and meningitis. Laboratory studies showed decreased IgM and IgG2 levels, reduced isohemagglutinin titers, a lack of antibodies to polysaccharide antigens, and low memory B cell counts. In addition, several patients had low naive T cell counts and decreased T cell proliferation. Allergies, autoimmunity, opportunistic infections, and malignancies were not observed. Sister chromatid exchange was normal. 

Thiffault et al. (2015) studied a Palestinian girl (CMH812) who exhibited intrauterine growth retardation (IUGR) and had postnatal short stature and microcephaly. Dysmorphic features included malar and mandibular hypoplasia, prominent nasal bridge and columella, downslanting palpebral fissures, small mouth, and low-set posteriorly rotated ears. Over several months, lacy reticular pigmentation was noted on the face and extremities. Erupted teeth were small and dysplastic. She experienced chronic rhinosinusitis and pulmonary infections with purulent otitis media. At 20 months of age, she was hospitalized with pancytopenia, splenomegaly, hepatitis, and acute cytomegalovirus infection. She was found to have low IgM, IgG2, and IgG4, and showed no serologic response to pneumococcal vaccine or lymphocytic response to pertussis or Candida antigens. 

▼ Inheritance

The transmission pattern of FILS in the family reported by Pachlopnik Schmid et al. (2012) was consistent with autosomal recessive inheritance. 

▼ Mapping

By genomewide homozygosity mapping of a large consanguineous French family with FILS, Pachlopnik Schmid et al. (2012) identified a common 2-Mb region on chromosome 12q (lod score of 11). 

▼ Molecular Genetics

By homozygosity mapping followed by candidate gene sequencing of a consanguineous French family with FILS, Pachlopnik Schmid et al. (2012) identified a homozygous splice site mutation in the POLE gene (174762.0002). PCR analysis of patient T cells showed 2 types of POLE transcripts, wildtype (10%) and a mutant transcript lacking exon 34 (90%). Studies of patient T cells, B cells, chondrocytes, and osteoblasts showed an impairment in cell proliferation and in G1- to S-phase progression of the cell cycle. 

In a 2-year-old Palestinian girl (CMH812) with FILS, Thiffault et al. (2015) performed exome sequencing and identified homozygosity for the same POLE splice site mutation previously found in a French family with FILS by Pachlopnik Schmid et al. (2012). Noting that the girl had more significantly impaired growth and immunity than the French patients with the same mutation, Thiffault et al. (2015) suggested that rare variants in other POLE subunits or MMR genes might act as genetic modifiers; however, no additional rare variants were detected in MMR genes, POLE1-interacting proteins, or other DNA breakage/instability syndrome genes.