, , and Intracranial Calcifications in an 11-Week-Old Boy Inga Aikman, MD, MPH,a,b Kristen Makowski, MD,a Olivia Wenger, MD,a,c Ian Rossman, MD, PHD,a Jeffrey D. Solomon, MDa

An 11-week-old unvaccinated, term Amish boy initially presented with poor abstract feeding, microcephaly, failure to thrive, and developmental delays. His a b fi Akron Children’s Hospital, Akron, Ohio; Division of Critical physical examination was signi cant for both weight and head circumference Care and Hospital Medicine, Department of Pediatrics, being less than the third percentile, and he was noted to have micrognathia, Brody School of Medicine, East Carolina University, Greenville, North Carolina; and cNew Leaf Center, Mount truncal hypotonia, and head lag. He was admitted to the pediatric hospital Eaton, Ohio medicine service for further diagnostic evaluation. Laboratory studies Written consent was obtained from the patient’s assessing for endocrinological and metabolic etiologies yielded negative family before the writing of this case. The case was results, and imaging studies (including a chest radiograph, echocardiogram, also approved by the Akron Children’s Hospital and abdominal ultrasound) were normal. However, intracranial calcifications Institutional Review Board. were noted on a head ultrasound. The etiology of his constellation of Dr Aikman led the initial writing of the manuscript, symptoms was initially thought to be infectious, but the ultimate diagnosis recruited various specialists for writing the manuscript, revised all versions of the manuscript, was not made until after discharge from the pediatric hospital medicine and was involved in the care of the patient; Dr service. Makowski contributed to the writing of the manuscript, revised the manuscript, and was involved in the care of the patient; Dr Wenger contributed to the writing of the manuscript, revised DR MAKOWSKI (PEDIATRIC RESIDENT) the manuscript, and was involved in the care of the (temperature: 37.2°C), with a normal patient; Dr Rossman contributed to the writing of the An 11-week-old unvaccinated Amish heart rate (140 beats per minute) and manuscript, revised the manuscript, and was boy born at term presented to the respiratory rate (44 breaths per involved in the care of the patient; Dr Solomon minute) for age. revised the manuscript and was involved in the care pediatric emergency department with of the patient; and all authors approved the final an 8-week history of poor feeding and His physical examination was pertinent manuscript as submitted and agree to be 3-week history of fussiness and chest for irritability, micrognathia, bilateral accountable for all aspects of the work. “rattling” per his parents. When anterior ear pits, truncal hypotonia, Dr Aikman’s current affiliation is Division of Critical evaluated in the emergency and head lag. His cardiovascular Care and Hospital Medicine, Department of department, he was noted to be fussy examination revealed regular rate and Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC. and not easily consoled and had rhythm, without murmurs, rubs, or DOI: sustained oxygen saturations near 85% gallops. He had strong and equal https://doi.org/10.1542/peds.2019-2795 responsive to supplemental oxygen by femoral pulses. His lung examination Accepted for publication Jun 25, 2020 nasal cannula (0.5 L per minute). Vital was benign, with normal breath sounds Address correspondence to Inga Aikman, MD, MPH, signs were significant for both weight bilaterally and no retractions. His Division of Critical Care and Hospital Medicine, abdomen was soft and nondistended, Department of Pediatrics, Brody School of Medicine, (4.43 kg) and head circumference East Carolina University, 600 Moye Blvd, Room PCMH (37 cm), being less than the third with normal bowel sounds; there was 2CH253, Greenville, NC 27834. E-mail: aikmani18@ percentile for age on the World no hepatomegaly or splenomegaly. His ecu.edu Health Organization (WHO) genital examination was unremarkable, PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, standard male weight-for-age and head with descended testes. 1098-4275). circumference-for-age growth charts, Laboratory studies performed in the Copyright © 2020 by the American Academy of respectively, and length of 57.5 cm emergency department were Pediatrics (at the sixth percentile on the WHO remarkable for an elevated aspartate standard male length-for-age growth aminotransferase of 146 U/L and To cite: Aikman I, Makowski K, Wenger O, et al. fi chart). Blood pressure was elevated at normal alanine aminotransferase of Microcephaly, Hypotonia, and Intracranial Calci cations in an 11-Week-Old Boy. Pediatrics. 2020;146(3):e20192795 120/88 mm Hg. He was afebrile 26 U/L. Lactate was elevated to 4.1

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 146, number 3, September 2020:e20192795 DIAGNOSTIC DILEMMAS mmol/L, and his ammonia level was they were uncertain. He was admitted context of his hypotonia. Because of normal at 49 µmol/L. A complete to the pediatric hospital medicine his hypotonia and hypoxemia, he blood cell count was unremarkable, service for further evaluation. would not be an ideal candidate for with a white blood cell count of 9.6 3 procedural sedation for a brain MRI Dr Aikman, what would be your 103 cells per µL, hemoglobin of study; however, a head ultrasound differential diagnosis for this patient, 13.5 g/dL, hematocrit of 35%, and could provide some information and what evaluation would you platelet count of 284 3 103 cells per regarding the presence of an acute pursue initially? µL. The remainder of his complete or chronic bleed or metabolic panel included sodium of without exposing the patient to the 142 mEq/L, potassium of 5.3 mEq/L, DR AIKMAN (PEDIATRIC HOSPITAL radiation of a computed tomography chloride of 110 mEq/L, bicarbonate MEDICINE FELLOW) (CT) scan of the head. Reviewing of 21.2 mEq/L, blood urea nitrogen his state metabolic screen and This patient’s respiratory symptoms of ,5 mg/dL, creatinine of 0.24 obtaining urine and serum amino take initial priority in our evaluation, mg/dL, glucose of 121 mg/dL, but his microcephaly, irritability, acids, urine organic acids, and thyroid calcium of 10.1 mg/dL, total bilirubin developmental delay, and studies could further elucidate if of 1.7 mg/dL, alanine phosphatase hypertension raise significant he has an underlying metabolic of 332 U/L, and total protein of concerns. His respiratory symptoms condition. 6.2 mg/dL. Urine and blood cultures began at ∼3 weeks of age, which were performed, and both revealed His chest radiograph was could indicate a persistent, untreated, no growth. A lumbar puncture was unremarkable. On his second hospital or new infectious etiology, such as not performed. day, 4 extremity blood pressures were pneumonia, bronchiolitis, pertussis, elevated in each limb (129/83 mm Hg He was born at 40 weeks’ gestation or multiple viral infections in in right upper, 125/89 mm Hg in left via spontaneous vaginal delivery. His succession. If he had an underlying upper, 136/66 in right lower and birth weight was 2.5 kg (fifth anatomic abnormality such as 129/99 mm Hg in left lower limbs, percentile on the WHO standard male laryngotracheomalacia or other respectively). Cardiology was weight-for-age growth chart). predilection for obstructive apnea, an consulted, and an echocardiogram Maternal screening laboratory acute illness could exacerbate these was performed and unremarkable. results, including for group B conditions. Although his parents did Urine organic and amino acids, Streptococcus, were negative. There not endorse any cyanosis or plasma acylcarnitine, pyruvic acid, were no complications during his worsening respiratory status with thyroid stimulating hormone, and mother’s pregnancy or delivery. His feeds, his hypoxemia on presentation free T4 were obtained and were medical history was significant for and family history of possible normal. His state newborn screen was hospital admission at 2 weeks of age congenital heart disease raise concern reviewed and found to be normal. for a febrile illness; at that time, blood for a congenital cardiac lesion or and urine culture results were vascular ring or sling. His The following day, a pneumogram negative, and a lumbar puncture was developmental delay, coupled with was done and revealed no apneic not performed. He was also noted to his poor weight gain, microcephaly, events. He was transitioned to room have positional desaturations and irritability as well as elevated air and had intermittent unsustained between 86% and 89% during that aspartate aminotransferase and desaturations to the upper 80s, which admission. Additionally, his primary lactate levels, could be due to an did not require supplemental oxygen. care physician was concerned that he underlying genetic, metabolic, or The renal Doppler ultrasound result was not meeting developmental neurologic condition. was negative. Manual blood pressure milestones, including lack of social Given his hypoxemia and concern for readings were obtained and were smile and uncoordinated limb elevated blood pressures, it would be within normal limits for age, so initial movements. prudent to evaluate for an underlying elevated blood pressures were likely He lived with his mother, father, and 3 congenital cardiac anomaly with an secondary to mechanical older siblings, one of whom had echocardiogram. A renal ultrasound measurement. A routine EEG was a history of febrile . There should be performed to rule out renal done and revealed no epileptiform was no known consanguinity artery stenosis as a cause of his activity. A head ultrasound revealed between parents. Otherwise, the hypertension. Characterizing his “extensive parenchymal calcifications, members of his immediate family apnea with a pneumogram may help lenticulostriate calcifications, mild were healthy. His parents reported to delineate if his respiratory distress ventriculomegaly and a large that there were 2 cousins that may is due to anatomic versus central subependymal cyst concerning for have had congenital heart disease, but obstructive events, especially in the CMV.”

Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 AIKMAN et al On the basis of the classic findings for To help narrow the diagnostic congenital cytomegalovirus (CMV) significance of brain calcifications, the infection noted on the ultrasound, the clinician needs to consider prenatal pediatric infectious disease history, perinatal events, family department was consulted for further history, clinical examination, and input. They recommended obtaining laboratory and imaging results. These confirmatory testing, which included data put the findings of brain a urine CMV polymerase chain calcifications into context and allow reaction, urine CMV culture, and a meaningful differential diagnosis to serum CMV and Toxoplasma emerge. Common things being immunoglobulin G and M. Other common, in a patient with infectious considerations included microcephaly and evidence of HIV and the Zika virus (although the FIGURE 1 significant volume loss in addition to Sagittal view of CT of the brain showing fi patient did not have a history of supratentorial and periventricular calcifications. the brain calci cations described travel outside of the state). Each of above, a global intracranial insult these infections has a characteristic would be suspected, with congenital pattern of intracranial calcifications; infection (particularly CMV and CMV results in periventricular Dr Rossman, what are the neurologic toxoplasmosis infection) high on the calcifications,1 whereas diagnoses that you would consider differential.7 In developing nations toxoplasmosis causes diffuse for this patient, given his and unvaccinated populations, parenchymal calcifications.2 HIV can constellation of symptoms, laboratory congenital rubella should also be cause calcifications in the white findings, and radiologic findings? considered. The absence of other matter and basal ganglia, whereas stigmata of these congenital Zika virus leads to calcifications in the infections should prompt a clinician gray-white junction.3 Both CMV and DR ROSSMAN (PEDIATRIC NEUROLOGY) to consider other diagnoses, both toxoplasmosis can be associated with infectious and noninfectious. 1,2 Dystrophic brain calcifications chorioretinitis, whereas CMV is also Localized calcification, with or represent the sequelae of a remote associated with sensorineural hearing without associated volume loss, 1 event, rather than an acute injury, and loss. It is estimated that up to 25% would suggest a focal prenatal can occur from a cerebral insult of of patients with congenital CMV 6 cerebrovascular event within 4 almost any etiology. Their presence develop chorioretinitis, whereas a vascular territory, focal in a neonate is often concerning for 85% to 92% of symptomatic infants hemorrhagic event, vascular an in utero insult such as an infection with congenital toxoplasmosis have malformation, or even a tumor. 5 or cerebrovascular or hypoxic event chorioretinitis. Although conventional MRI may not because a perinatal event would be be as sensitive as CT in identifying too recent to result in calcifications. A hearing screen and dilated eye and delineating calcifications, the Thus, the presence of brain examination were performed to rule inclusion of susceptibility weighted calcifications in a patient like this out these complications, and results imaging MRI and magnetic resonance should yield an investigation, as were negative. There was discussion angiography (MRA) would be helpful reviewed above.6 whether a head CT or brain MRI in the identification and staging of would be a superior imaging study to blood products, vascular anomalies, better characterize the extent of and other brain malformations.8,9 In calcifications, and it was determined our patient, the absence of a clear that head CT was the superior infectious etiology, presence of modality during the acute bilateral periventricular and basal hospitalization. The head CT ganglia calcifications, and degree of fi con rmed the presence of cerebral volume loss identified would fi calci cations in the regions noted in suggest a global insult such as an the ultrasound (Figs 1 and 2). After acute hypoxic event in utero, or an several days, his urine CMV underlying genetic, mitochondrial, or polymerase chain reaction and metabolic disease. culture and serum CMV and Toxoplasma immunoglobulin G and FIGURE 2 In a patient with neonatal immunoglobulin M yielded negative Transverse view of CT of the brain showing encephalopathy, microcephaly, results. supratentorial and periventricular calcifications. dystrophic white matter, and basal

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 146, number 3, September 2020 3 ganglia brain calcifications with genetic counselor is vital to guide DR WENGER (GENERAL PEDIATRICS associated brain atrophy resembling appropriate molecular genetic testing WITH EMPHASIS ON THE CARE OF a congenital infection, several rare for individual patients found to have AMISH PATIENTS) genetic disorders should be congenital or other dystrophic brain Autosomal recessive disorders must 12 considered. Aicardi-Goutières calcifications and their families. be considered in any infant with syndrome (AGS) represents a family developmental stagnation and of genetic primary interferonopathies neurologic irritability; awareness of in which systemic innate immune DR MAKOWSKI genetic heritage can catalyze effective system activation results in diagnostic evaluation. Our patient’s After discharge, the patient was seen multiorgan tissue injury mimicking case demonstrates how population- by Dr Wenger at the New Leaf Center viral pathology. Several genes have focused genetic expertise streamlines (a nonprofit clinic providing care to been associated with AGS, leading to medical decision-making, lessens children with inherited disorders), some distinct clinical features across health care costs, and improves and analysis for SAMHD1 the AGS spectrum, although, in some quality of life. As generations pass, was sent, which confirmed the cases, no clear molecular diagnosis is the common ancestry and relative 10 diagnosis of AGS. Appointments were made. AGS associated with cultural isolation of America’s Amish made with both the ophthalmology homozygous in the increases the risk for certain and neurology departments. He was SAMHD1 gene has been described in inherited conditions.13 Conditions 11 found to have congenital glaucoma at the Midwest Amish population. In like AGS occur globally, but certain 4 months of age, requiring medical the clinical context of such a patient causative mutations are more and surgical management. His and in the absence of clear infectious common in isolated groups. or other metabolic abnormalities, this irritability was managed with Targeted gene amplification allows for diagnosis becomes more likely. It gabapentin and clonidine. Because of grounded, cost-effective application of should be noted that within SAMHD1- his increased tone and decreased genetic testing to primary care related AGS, there is a spectrum of right-sided movements noted at his settings. An informal network of clinical presentation and age of neurology visit, MRI and MRA of the clinics across America aims to symptom onset; some patients with brain and MRA of the neck were expedite diagnosis of inherited disease SAMHD1 mutations will be mildly recommended for concern of left- in Amish populations from medical affected until later in life and present sided infarcts. MRI and MRA of the home models. Such clinics offer with medium- and large-vessel brain revealed diffuse cortical volume targeted mutation analysis for the cerebrovascular disease.11 loss (most prominent in the temporal lobes bilaterally) and a persistent same cost as a complete metabolic Other rare genetic right trigeminal artery. Furthermore, panel or complete blood cell count, leukoencephalopathies could be focal cystic change was present coupled with useful awareness of fi considered including Krabbe disease, adjacent to the temporal horn of the population-speci c risks. X-linked , right lateral ventricle. No infarcts When providers are less familiar with leukoencephalopathy with were detected. He continued to have population-specific risks, other calcifications and cysts, Coates plus global developmental delay, although options are available to confirm syndrome associated with mutations the encephalopathic phase had a suspected diagnosis. If a child is in the CTC1 gene, COL4A1-related resolved. Palliative care, physical affected by neurodevelopmental congenital small vessel disease, and therapy, and occupational therapy impairment from birth, has Cockayne syndrome, were involved in his management. dysmorphic facial features, or a hypomyelinating disease associated The cause of his self-resolving manifests multiorgan disease (for with intracranial calcifications hypoxemia during admission was not instance, a congenital cardiac lesion typically affecting basal ganglia and fully elucidated, but we speculate that combined with a kidney anomaly), presenting with distinct dysmorphic it could have been a result of his a microarray is generally and other clinical features.11 There acute encephalopathic period or recommended to rule out are numerous other rare genetic autonomic instability because he had chromosomal anomalies.14,15 conditions in which some patients a normal EEG, echocardiogram, and Metabolic screening tests (serum and have been reported to have pneumogram. The family received urine amino acids and urine organic congenital or acquired brain genetic counseling. acids) are often done at the same calcifications thought to be related to time, depending on the clinical the pathology of the disease. In Dr Wenger, what are some of the features of the case. If microarray or considering a diagnostic evaluation, special considerations for this patient metabolic testing does not reveal an consultation with a geneticist and population? underlying cause, whole exome

Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 AIKMAN et al sequencing can be pursued.16 elevated liver enzymes in the either agenesis or dysgenesis of the Although costlier than targeted neonatal period make AGS difficult to , infantile spasms, genetic tests, the above approach will distinguish from acquired congenital and chorioretinal lacunae.23 reveal pathogenic mutations causing infections, which have similar each of the inherited conditions in presentations. Unlike CMV and DIAGNOSIS our patient’s differential. toxoplasmosis (which have ocular manifestations of retinal scarring1 The diagnosis should be considered 2 SUMMARY (DR AIKMAN) and chorioretinitis), patients with on the basis of clinical features and AGS have no retinal changes.21 Their laboratory findings and is ultimately AGS is a rare disorder marked by vision can range from normal to confirmed with genetic testing. In encephalopathy, microcephaly, cortical blindness,21 and they are also addition to the clinical manifestations fi cerebral calci cations (especially in at risk for congenital or acquired noted above, patients have classic the basal ganglia), leukodystrophy, glaucoma.22 Our patient’s preliminary radiologic findings, which include 17 and cerebral atrophy. It is eye examination during his intracranial calcifications, white transmitted via a heterogeneous hospitalization did not reveal any matter changes, and cerebral group of gene mutations in autosomal evidence of glaucoma, but he was atrophy.17 Although patients may recessive (most common), autosomal noted to have this on subsequent have calcifications extending to the dominant, and, possibly, de novo outpatient ophthalmology para- and periventricular white 17,18 inheritance patterns. examination at 4 months of age. matter, calcifications in the basal Like our patient, most with AGS have Although there are no large studies ganglia (putamen, globus pallidus, an uneventful delivery and newborn detailing when glaucoma appears in thalamus, and caudate nucleus) are 17,19–21 period and then develop symptoms the disease course, in a case series of a diagnostic clue for AGS. The within the first year of life, usually 3 patients with AGS, researchers absence of calcifications does not ∼4 months of age.19 The initial noted the diagnosis of glaucoma preclude a diagnosis of AGS because 22 manifestation is encephalopathy, between 10 and 12 months of age. calcifications may develop after the 17 marked by irritability, jitteriness, Another key difference between AGS onset of symptoms. CT scans poor sleep-wake cycles, difficulty and congenital CMV is the lack of remain an expedient neuroimaging feeding, and, occasionally, hearing loss in the former. modality with high sensitivity for 21 seizures.17–21 Decreased head growth, detecting intracranial calcifications. Patients tend to have a broad range of leading to acquired microcephaly, is However, MRI with susceptibility other neurologic symptoms, including also a hallmark of AGS.20 Other weighted imaging is becoming as truncal hypotonia, poor head control, laboratory findings include elevated sensitive as, if not more sensitive dystonia, an exaggerated startle liver enzymes, anemia, and than, CT in detecting pediatric 21 response, and pyramidal as well as calcifications and differentiating these thrombocytopenia. 17,18,20 extrapyramidal signs. It is from blood products.9 Patients may have sterile estimated that one-quarter to one- cerebrospinal fluid (CSF) pleocytosis, half17,19,21 of patients develop Patients with AGS have chronic CSF which can lead to the misdiagnosis seizures. The ultimate developmental leukocytosis, which can range from 5 3,17 of infectious meningitis and outcomes for these patients vary,21 to 100 lymphocytes/mm. encephalitis.17 Additionally, patients but most patients have significant Lymphocyte count tends to be the can present with fevers without an delays in language, gross motor skills, most elevated early in the disease identifiable source of infection and intellectual ability.17,21 course, although not always, then (sterile pyrexia).18 Of note, our decreases over several years.21 patient was evaluated for fever Chilblains are a characteristic feature Interferon-a levels are also elevated 2 weeks before admission to our that can be helpful in diagnosis. in the CSF of patients with AGS (.2 facility. Although only blood and Approximately 40% of affected IU/mL); similar to the CSF 21 urine cultures were performed, it is patients have these erythematous, leukocytosis, it is highest early in the 18 possible that this was an episode of painful, pruritic, skin lesions that disease course, then normalizes fi 17,21 sterile pyrexia. Practitioners should are commonly localized to the ngers, within 3 to 4 years. be mindful of this presentation, toes, helixes of the ears, and other 17 Most patients with AGS acquire the especially in patients with concurrent pressure points. disease through an autosomal recessive microcephaly or hypotonia. It is important to note that AGS is inheritance pattern (TREX1, Microcephaly, intracranial a separate entity from Aicardi RNASEH2A, RNASEH2B, RNASEH2C, calcifications, hepatosplenomegaly, syndrome, which occurs almost ADAR,andSAMHD1 mutations), thrombocytopenia, anemia, and always in females and is marked by although some mutations (TREX1,

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 146, number 3, September 2020 5 IFIHI,andADAR) are acquired in an TREATMENT tocilizumab, has been used to treat autosomal dominant or de novo The treatment of AGS is mostly cerebrovascular disease in at least 21 SAMHD1 fashion. Once a patient is diagnosed supportive and best provided by one patient with the -related AGS.24,25 Thus, early recognition of with AGS, his or her parents and a multidisciplinary team. Physical, siblings should undergo genetic testing AGS symptoms and prompt diagnosis occupational, and speech therapists and counseling.24 If the genetic variant may allow future patients with AGS assist in maximizing patient mobility is not found in the parents, the patient’s and their families earlier treatment and feeding. Patients should be mutation is de novo.24 Ifinheritedinan opportunities that could prevent or managed closely by their primary autosomal recessive pattern, both blunt neurologic sequelae. care physicians as well as parents are asymptomatic carriers, and the patient’ssiblingshavea25% a neurologist, geneticist, and chance of inheriting the disease, 25% ophthalmologist, who should screen ABBREVIATIONS for the development of glaucoma. At chance of not having the disease and AGS: Aicardi-Goutières syndrome present, there are no targeted not being a carrier, and 50% chance of CMV: cytomegalovirus 24 being an asymptomatic carrier. immunomodulatory therapies for CSF: cerebrospinal fluid Prenatal testing and preimplantation AGS, although some patients with AGS CT: computed tomography genetic diagnosis are available for the with intracranial vasculopathies will MRA: magnetic resonance 13 parents of affected individuals, and be corticosteroid responsive. angiography most patients with AGS do not have Recently, the interleukin-6 receptor WHO: World Health Organization offspring.24 targeted monoclonal antibody,

FINANCIAL DISCLOSURE: Dr Rossman is a member of the Novartis speakers’ bureau for Gilenya in pediatric-onset multiple sclerosis; the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2020/08/18/peds.2 019-2795 References This article cites 21 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2020/08/18/peds.2 019-2795#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Hospital Medicine http://www.aappublications.org/cgi/collection/hospital_medicine_su b Neurology http://www.aappublications.org/cgi/collection/neurology_sub Neurologic Disorders http://www.aappublications.org/cgi/collection/neurologic_disorders_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 26, 2021 Microcephaly, Hypotonia, and Intracranial Calcifications in an 11-Week-Old Boy Inga Aikman, Kristen Makowski, Olivia Wenger, Ian Rossman and Jeffrey D. Solomon Pediatrics originally published online August 20, 2020;

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