Laura Z. Fenton

A New Look at XXYY Syndrome : Medical and Psychological Features

XXYY syndrome occurs in approximately 1:18,000–1:40,000 males. Although the physical phenotype is similar to 47,XXY (tall stature, hypergonadotropic hypogonadism, and infertility), XXYY is associated with additional medical problems and more significant neurodevelopmental and psychological features. We report on the results of a cross‐sectional, multi‐center study of 95 males age 1–55 with XXYY syndrome (mean age 14.9 years), describing diagnosis, physical features, medical problems, medications, and psychological features stratified by age groups. The mean age of diagnosis was 7.7 years. Developmental delays and behavioral problems were the most common primary indication for genetic testing (68.4%). Physical and facial features varied with age, although hypertelorism, clinodactyly, pes planus, and dental problems were common across all age groups. Tall stature was present in adolescents and adults, with a mean adult stature of 192.4 cm (SD 7.5; n = 22). Common medical problems included allergies and asthma (>50%), congenital heart defects (19.4%), radioulnar synostosis (17.2%), inguinal hernia and/or cryptorchidism (16.1%), and seizures (15%). Medical features in adulthood included hypogonadism (100%), DVT (18.2%), intention tremor (71%) and type II diabetes (18.2%). Brain MRI (n = 35) showed white matter abnormalities in 45.7% of patients and enlarged ventricles in 22.8%. Neurodevelopmental and psychological difficulties were a significant component of the behavioral phenotype, with developmental delays and learning disabilities universal but variable in severity. Twenty‐six percent had full‐scale IQs in the range of intellectual disability (MR), and adaptive functioning was significantly impacted with 68% with adaptive composite scores <70. Rates of neurodevelopmental disorders, including ADHD (72.2%), autism spectrum disorders (28.3%), mood disorders (46.8%), and tic disorders (18.9%), were elevated with 55.9% on psychopharmacologic medication overall. Recommendations for evaluation and treatment are summarized.

Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes.

OBJECTIVES To assess precision magnetic resonance imaging in the neonate and determine whether there is an early maternal influence on the pattern of neonatal fat deposition in the offspring of mothers with gestational diabetes mellitus (GDM) and obesity compared with the offspring of normal-weight women. STUDY DESIGN A total of 25 neonates born to normal weight mothers (n = 13) and to obese mothers with GDM (n = 12) underwent magnetic resonance imaging for the measurement of subcutaneous and intra-abdominal fat and magnetic resonance spectroscopy for the measurement of intrahepatocellular lipid (IHCL) fat at 1-3 weeks of age. RESULTS Infants born to obese/GDM mothers had a mean 68% increase in IHCL compared with infants born to normal-weight mothers. For all infants, IHCL correlated with maternal prepregnancy body mass index but not with subcutaneous adiposity. CONCLUSION Deposition of liver fat in the neonate correlates highly with maternal body mass index. This finding may have implications for understanding the developmental origins of childhood nonalcoholic fatty liver disease.

Biomarkers of Hypercoagulability and Inflammation in Childhood-Onset Arterial Ischemic Stroke

OBJECTIVE To test the hypothesis that acute elevations of biomarkers of hypercoagulability and inflammation are common in children with arterial ischemic stroke (AIS), particularly among etiologic subtypes that carry an increased risk of recurrent stroke. STUDY DESIGN In this prospective/retrospective institutional-based cohort study of acute childhood-onset AIS (n = 50) conducted between 2005 and 2009, D-dimer, factor VIII (FVIII) activity, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were serially evaluated at the time of clinical blood sampling. Patients were classified by stroke subtype as cardioembolic, moyamoya, non-moyamoya arteriopathy, or other. RESULTS Both D-dimer and CRP were frequently elevated in acute childhood-onset AIS and exhibited a decreasing trend with time. Acute D-dimer levels were significantly higher in cardioembolic AIS compared with noncardioembolic AIS (median, 2.04 microg/mL [range 0.54-4.54 microg/mL] vs 0.32 microg/mL [0.22-3.18 microg/mL]; P = .002). At an optimal threshold of > or = 0.50 microg/mL, the sensitivity and specificity of D-dimer for cardioembolic subtype were 78% and 79%, respectively. CONCLUSIONS Our findings identify D-dimer and CRP as candidate biomarkers for etiology and prognosis in childhood-onset AIS. Further studies should investigate the role of these and other biomarkers of hypercoagulability and inflammation in childhood-onset AIS.

Cavernous Sinus Thrombosis in Children: Imaging Characteristics and Clinical Outcomes.

Background and Purpose— Cavernous sinus thrombosis (CST) is a rare life-threatening cerebrovascular disease known to cause carotid artery narrowing (CAN) and arterial ischemic stroke. The imaging features of CST and related complications have been reported in adults, but rarely in children. Methods— We performed a retrospective review of children with imaging confirmed CST from 2003 to 2014, describing presenting symptoms, imaging findings, and treatment. Results— Ten patients with CST were identified. All had CAN and 6 of 10 developed infarcts. Of 8 patients treated with anticoagulation therapy, 3 developed new infarcts. None required discontinuation of anticoagulation therapy because of bleeding. Visual impairment secondary to infectious neuritis was common. Imaging characteristics include cavernous sinus expansion, filling defects, restricted diffusion, arterial wall enhancement, empyema, superior ophthalmic vein enlargement and thrombosis, orbital cellulitis, and pituitary inflammation. CAN resolved in 60% of cases. Outcomes were mostly good, with a modified Rankin Scale score of ⩽1 for 7 of 10 patients at discharge and 1 death. Conclusions— CAN and infarcts were common in this modest cohort of children with CST. Despite the high incidence of CAN and infarction, outcomes were often favorable. Although this is the largest cohort of childhood CST reported to date, large multicenter cohorts are needed to confirm our findings and determine the preferred therapeutic strategies for childhood CST.

A new mutation in MT-ND1 m.3928G>C p.V208L causes Leigh disease with infantile spasms

New mutations in mitochondrial DNA encoded genes of complex I are rarely reported. An infant developed Leigh disease with infantile spasms. Complex I enzyme activity was deficient and response to increasing coenzyme Q concentrations was reduced. Complex I assembly was intact. A new mutation in MT-ND1 m.3928G>C p.V208L, affecting a conserved amino acid in a critical domain, part of the coenzyme Q binding pocket, was present at high heteroplasmy. The unaffected mother did not carry measurable mutant mitochondrial DNA, but concern remained for gonadal mosaicism. Prenatal testing was possible for a subsequent sibling. The ND1 p.V208L mutation causes Leigh disease.

Congenital paraesophageal hiatal hernia

A healthy newborn baby with a left cleft lip and palate presented to our institution at 18 hours of life because of persistent emesis after feeds. Initial evaluation with chest radiography and a contrast swallow at the outside facility demonstrated an intrathoracic stomach (A, arrows outline the stomach with retained contrast). A repeat contrast swallow, performed at our institution to help better define the anatomy of the esophagus, stomach, and duodenum revealed a congenital paraesophageal hiatal hernia with an intrathoracic stomach without any evidence of gastric volvulus (B, arrow outlines gastroesophageal junction). The stomach appeared to be herniating through a posterior midline defect in the diaphragm. At laparotomy, a large paraesophageal hiatal hernia with an intrathoracic stomach and hernia sac was identified. The hernia sac was resected, the stomach was returned to its intraabdominal position, and closure of the large hiatal hernia was accomplished by reapproximating the crura using interrupted nonabsorbable sutures. On the second postoperative day, oral feeds were initiated and the baby was advanced to full feeds by the fourth postoperative day. Congenital paraesophageal hiatal hernia is a rare condition in neonates and infants. Clinical presentation is nonspecific and usually consists of persistent emesis or pulmonary infections. Diagnostic workup usually includes chest radiograph with confirmation by a barium swallow study. Once the diagnosis is established, prompt surgical repair is mandatory to avoid potentially lethal complications, such as gastric volvulus and perforation. Operative repair consists of resecting the hernia sac, reduction of the stomach, and repair of the hiatal defect with reapproximation of the crura. Because this is such a rare entity, the addition of a fundoplication, gastropexy, or both remains controversial.

18F-FDG PET/CT evaluation of children and young adults with suspected spinal fusion hardware infection

BackgroundEvaluation of the child with spinal fusion hardware and concern for infection is challenging because of hardware artifact with standard imaging (CT and MRI) and difficult physical examination. Studies using 18F-FDG PET/CT combine the benefit of functional imaging with anatomical localization.ObjectiveTo discuss a case series of children and young adults with spinal fusion hardware and clinical concern for hardware infection. These people underwent FDG PET/CT imaging to determine the site of infection.Materials and methodsWe performed a retrospective review of whole-body FDG PET/CT scans at a tertiary children’s hospital from December 2009 to January 2012 in children and young adults with spinal hardware and suspected hardware infection. The PET/CT scan findings were correlated with pertinent clinical information including laboratory values of inflammatory markers, postoperative notes and pathology results to evaluate the diagnostic accuracy of FDG PET/CT. An exempt status for this retrospective review was approved by the Institution Review Board.ResultsTwenty-five FDG PET/CT scans were performed in 20 patients. Spinal fusion hardware infection was confirmed surgically and pathologically in six patients. The most common FDG PET/CT finding in patients with hardware infection was increased FDG uptake in the soft tissue and bone immediately adjacent to the posterior spinal fusion rods at multiple contiguous vertebral levels. Noninfectious hardware complications were diagnosed in ten patients and proved surgically in four. Alternative sources of infection were diagnosed by FDG PET/CT in seven patients (five with pneumonia, one with pyonephrosis and one with superficial wound infections).ConclusionFDG PET/CT is helpful in evaluation of children and young adults with concern for spinal hardware infection. Noninfectious hardware complications and alternative sources of infection, including pneumonia and pyonephrosis, can be diagnosed. FDG PET/CT should be the first-line cross-sectional imaging study in patients with suspected spinal hardware infection. Because pneumonia was diagnosed as often as spinal hardware infection, initial chest radiography should also be performed.

Sonography of pediatric blunt scrotal trauma: what the pediatric urologist wants to know

Pediatric blunt scrotal trauma is most often the consequence of sports injury and presents a diagnostic challenge because swelling and pain make a scrotal physical exam difficult. US with color flow and duplex Doppler is the first-line imaging modality with the goal of accurate and timely diagnosis of injury requiring surgery to preserve fertility and hormonal function. US imaging findings following blunt scrotal trauma include hydrocele, hematocele, testicular hematoma, testicular fracture, testicular rupture, compromised perfusion/testicular torsion and testicular dislocation. Importantly, several of these findings may coexist. Our goal is to present the pertinent intrascrotal anatomy, US imaging findings for each testicular injury, and contemporary management for each, with emphasis on what our pediatric urology colleagues need to know for optimal patient care.

John D. Strain, MD (1951–2018)

Dr. John D. Strain, a leader in the pediatric imaging community, died June 22, 2018, after a courageous battle with advanced-stage esophageal cancer. He was 67 years old. John is remembered as an innovator with the utmost common sense and perseverance. He would be delighted, grinning broadly, when complex ideas came to fruition, but he would be equally amazed when the simplest tasks would falter, when he would sigh and exclaim, “We’ll just keep at it!” He was limitless in his curiosity and energy. John was a Denver native who grew up in a loving family with three siblings, an influential physician father and an encouraging and supportive stay at-home mother. John’s father, Dr. James E. Strain, is an acclaimed pediatrician and former president of the American Academy of Pediatrics. John was a tremendous athlete. He began swimming at age 4, competed in his first out-of-state swim meet at age 8 and held every state record in freestyle throughout high school. He was a distinguished three-sport athlete, also playing football (all-state quarterback) and baseball (all-state pitcher). He even led the National Association of Intercollegiate Athletics (NAIA) in strikeouts and earned run average (ERA) on a talented all-star baseball team. The Minnesota Twins were planning to draft him out of high school, but when his mom received the call, she simply told them not to bother because “Johnny was going to college!” John’s passion for baseball continued throughout his life, and he held season tickets for the Colorado Rockies from the beginning of the franchise. John attended the University of Northern Colorado on a baseball scholarship, earning a Bachelor of Science in chemistry. Upon graduation, he attended the University of Colorado School of Medicine, where his first love was surgery. After completing a surgical internship, he knew it was not a good fit and instead did emergencymedicine locums for a year. During that time, he honed his golf game and even competed in the PGA qualifying tournament in Chicago! John’s final elective in medical school was radiology. He credits the strong mentoring and teaching of Dr. Paul Siebert, chair of radiology at the Denver U.S. Department of Veterans Affairs (VA) hospital, as the spark to his career. John discovered he had a keen eye, could identify abnormalities quickly, and remembered patients through their imaging. A monthlong rotation during residency at Denver Children’s Hospital (now Children’s Hospital Colorado) under Dr. Jack Campbell clarified his career path. Upon completing pediatric radiology fellowship training at Denver Children’s Hospital, he accepted his first and only job — at Denver Children’s Hospital. He was promoted to chairman after 5 years, a position he excelled in for the next 28 years. Through the Society for Pediatric Radiology (SPR), he was mentored by the best pediatric radiologists, including Drs. * Laura Z. Fenton laura.fenton@childrenscolorado.org

Lethal neonatal hyperammonemia in severe ornithine transcarbamylase (OTC) deficiency compounded by large hepatic portosystemic shunt

A term male infant presented at 48 h of age with apnea, lethargy, and seizures. Plasma ammonia was 1180 μmol/ L, and biochemical studies (plasma citrulline <2 μM; urine orotate 1142 μg/ng creatinine) were consistent with a proximal urea cycle disorder (UCD). Initially, hyperammonemia improved with continuous renal replacement therapy (cRRT) and ammonia scavengers. Upon discontinuation of cRRT, hyperammonemia worsened and lactic acidosis developed, with coexistent fulminant hepatic and renal failure. Color Doppler ultrasound of the liver (Fig. 1a–d identified a large congenital intrahepatic portosystemic shunt (PSS) with enlarged middle hepatic vein (MHV) with abnormal tortuous portosystemic shunt to the left portal vein (LPV). Congenital PSS occurs in approximately 1:25,000 births and is classified as either intraor extrahepatic (Stringer 2008). Shunts bypassing hepatic circulation can be associated with hyperammonemia and encephalopathy, even in the setting of normal urea cycle function (Witters et al. 2008; Kim et al. 2012; Sokollik et al. 2013; Van Straten et al. 2014). Plasma glutamine was initially massively elevated (>3000 μM), but it normalized with cRRT and ammonia scavengers despite persistence of recalcitrant hyperammonemia. OTC deficiency was confirmed by identification of a 4.3-Mb hemizygous deletion involving Xp21.1–Xp11.4 and incorporating the entire OTC locus, portending absent functional OTC enzymes and severe disease. The hemizygous Xp deletion, also involving other key genes (including CYBB and XK, associated with chronic granulomatous disease and McLeod syndrome, respectively), together with the PSS, caused recalcitrant, fatal hyperammonemia and lactic acidosis off cRRT. Autopsy revealed extensive hepatic centrilobular necrosis and dilated vascular spaces. This case illustrates the devastating effects of hepatic vascular anomalies in patients with coexistent UCD.