Noonan syndrome and related disorders: Alterations in growth and puberty

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548–555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465–468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652–662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413–427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42–48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038–1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet,2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294–296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in this group, most notably Noonan syndrome and Costello syndrome. CFC is genetically heterogeneous and caused by gene mutations in the Ras/mitogen-activated protein kinase pathway. the major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. It is essential that this condition be differentiated from other RASopathies, as a correct diagnosis is important for appropriate medical management and determining recurrence risk. Children and adults with CFC require multidisciplinary care from specialists, and the need for comprehensive management has been apparent to families and health care professionals caring for affected individuals. To address this need, CFC International, a nonprofit family support organization that provides a forum for information, support, and facilitation of research in basic medical and social issues affecting individuals with CFC, organized a consensus conference. Experts in multiple medical specialties provided clinical management guidelines for pediatricians and other care providers. These guidelines will assist in an accurate diagnosis of individuals with CFC, provide best practice recommendations, and facilitate long-term medical care.CFC International, Vestal, New YorkNational Institutes of HealthNational Institutes of Health (NIH)Univ Minnesota, Dept Pediat & Ophthalmol, Div Genet & Metab, Minneapolis, MN 55454 USAUniv Minnesota, Dept Pediat, Div Clin Behav Neuroscience, Minneapolis, MN 55454 USAChildrens Hosp & Clin Minnesota, St Paul, MN USATexas Childrens Hosp, Dept Mol & Human Genet, Houston, TX 77030 USABaylor Coll Med, Houston, TX 77030 USABenioff Childrens Hosp, Madison Clin Pediat Diabet, San Francisco, CA USAUniv Calif San Francisco, San Francisco, CA 94143 USAUniversidade Federal de São Paulo, Med Genet Ctr, São Paulo, BrazilCatholic Univ, A Gemelli Sch Med, Inst Med Genet, Rome, ItalyUniv Kentucky, Dept Pediat, Lexington, KY USAUniv Texas Hlth Sci Ctr San Antonio, Dept Orthoped, San Antonio, TX 78229 USABoston Childrens Hosp, Dept Cardiol, Boston, MA USABoston Childrens Hosp, Div Genet, Boston, MA USAHarvard Univ, Sch Med, Boston, MA USAEmory Univ, Sch Med, Dept Human Genet, Atlanta, GA USAEmory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USAUniv Calif San Francisco, Dept Neurol, San Francisco, CA USAYoungstown State Univ, Special Educ & Sch Psychol, Dept Counseling, Youngstown, OH 44555 USACFC Int, Vestal, NY USAUniv Calif Davis, UC Davis MIND Inst, Dept Pediat, Div Genom Med, Sacramento, CA 95817 USAUniversidade Federal de São Paulo, Med Genet Ctr, São Paulo, BrazilNational Institutes of Health: R01-AR062165Web of Scienc

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Sclerosing Polycystic Adenosis of the Parotid Gland: Report of a Bifocal, Paucicystic Variant with Ductal Carcinoma in situ and Pronounced Stromal Distortion Mimicking Invasive Carcinoma

We present a case (female patient, age 45 years) with a bifocal, paucicystic variant of sclerosing polycystic adenosis of the parotid gland with cribriform ductal carcinoma in situ (DCIS) and pronounced stromal distortion affecting the in situ component to such an extent that it gave a distinct impression of intralesional invasive adenocarcinoma. P63–and calponin-positive myoepithelial cells were present in the periphery of the acini and ducts in the benign component, somewhat discontinuously in the DCIS-component, and even in the periphery of the small irregular atypical cell nests that appeared infiltrative on the haematoxylin and eosin stained sections. Strong cytoplasmic immunoreactivity for GCDFP-15 was detected in the benign component with a variable, patchy and mostly weak positivity in the DCIS. More than 90% of the cells in the DCIS component displayed strong nuclear immunoreactivity for androgen receptors and 10% of the benign ducts showed positivity. Weak to moderate nuclear immunoreactivity for estrogen receptors was seen in 30% of cells in the benign ductal component whereas the DCIS was negative. Occasional cells in the adenosis-component were weakly positive for PR. The proliferative activity (Mib-1/Ki-67) was low (1–2%) in the benign component whereas increased proliferation was seen in the DCIS and in the areas with pseudoinfiltration which also featured atypical mitoses