Noninferiority and Safety of Nadolol vs Propranolol in Infants With Infantile Hemangioma: A Randomized Clinical Trial.

Importance: Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic ß-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events. Objective: To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH. Design, Setting, and Participants: This double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement. Interventions: Oral propranolol and nadolol in escalating doses up to 2 mg/kg/d. Main Outcomes and Measure: Between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale. Results: The study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions. Conclusions and Relevance: Oral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required. Trial Registration: ClinicalTrials.gov Identifier: NCT02505971.

Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma: Morphological appraisal with a comprehensive review of differential diagnoses.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant syndrome wherein affected individuals are at risk for the development of cutaneous leiomyomas, early-onset multiple uterine leiomyomas, and an aggressive subtype of renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene, which inactivates the enzyme and alters the function of the tricarboxylic acid/Krebs cycle. This article reviews the hitherto described morphologic features of HLRCC-associated renal cell carcinoma (RCC) and outlines the differential diagnosis and ancillary use of immunohistochemistry and molecular diagnostics for these tumors. The morphologic spectrum of HLRCC-associated RCC is wide and histologic features, including tumor cells with prominent nucleoli, perinucleolar halos, and multiple architectural patterns within the same tumor, which are suggestive of this diagnosis. FH immunohistochemistry in conjunction with genetic counseling and germline FH testing are the important parameters for detection of this entity. These kidney tumors warrant prompt treatment as even smaller sized lesions can demonstrate aggressive behavior and systemic oncologic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts.

Polyp Characteristics of Nonsyndromic and Potentially Syndromic Juvenile Polyps: A Retrospective Cohort Analysis.

BACKGROUND: Juvenile polyps (JPs) are the most common gastrointestinal polyps diagnosed in children. There is paucity of evidence differentiating polyp burden groups and the presence and significance of neoplastic changes. METHODS: A retrospective chart review of patients, ages birth through 18 years with nonsyndromic JPs was performed from 2003 to 2017. Abstracted data included basic demographics, age, clinical presentation, colonoscopy findings, and pathology report. Slides of polyps with neoplasia were reviewed by a pathologist. RESULTS: A total of 213 subjects underwent 326 procedures and 435 polypectomies. Subjects with positive family history, positive gene mutations, or numerous (>10) polyps were excluded. Groups were defined by polyp number (1, 2-4, 5-10). Polyp recurrence on repeat colonoscopy was significantly related to polyp burden (1 polyp: 1.5%/2-4 polyps 19.2%/5-10 polyps 82.6%: P < 0.001). Polyp distribution was significantly different amongst different groups with isolated polyps favoring a distal distribution. JPs harboring adenomatous foci were reported in 26 (12%) patients. JPs harboring adenomatous foci were significantly more likely to be proximally distributed but the presence of adenomatous transformation within the polyps did not correlate with polyp number or the likelihood of polyp recurrence on repeat colonoscopy. CONCLUSIONS: JP recurrence is positively and significantly related to polyp burden. JP harbored adenomatous changes independent of polyp number, underscoring a possible malignant potential in JPs. In the absence of a consistent genotype or pedigree, the presence of adenomatous transformation within JPs cannot be construed as a biomarker for syndromic juvenile polyposis.

BMPR1A mutation-positive juvenile polyposis syndrome and atrial septal defect: coincidence or association?

We describe the case of a 16-year-old male patient with BMPR1A mutation and incidentally detected atrial septal defect (ASD). This patient was diagnosed with BMPR1A mutation through genetic testing and was attending for routine surveillance endoscopy when ASD was incidentally diagnosed. He was referred to cardiology outpatient clinic with plans for elective ASD closure. Through this case report we aim to discuss the pathophysiology of juvenile polyposis syndrome (JPS), highlight what we believe to be a novel presentation of comorbid BMPR1A mutation and ASD and hypothesise that patients with BMPR1A mutation and JPS may be at risk of previously unrecognised cardiovascular complications analogous to the previous association of SMAD4 JPS and cardiac abnormalities.

Tumor risk and surveillance for children with hereditary disorders affecting growth.

PURPOSE OF REVIEW: Hereditary disorders affecting growth (both overgrowth and growth retardation) are frequently associated with heightened risk of neoplastic disease. This review summarizes the tumor spectra associated with these conditions and identifies disease-specific screening approaches. RECENT FINDINGS: An understanding of the molecular events underlying many of these growth disorders has evolved significantly over the past several years. Recognition of genotype-phenotype associations, in many cases, informs the cancer risk profile. Additionally, accumulating data suggest a benefit of rational presymptomatic surveillance for at-risk individuals, with a reduction in tumor-associated morbidity. Recent clinical practice recommendations have established risk-driven paradigms for tumor surveillance in the context of hereditary tumor predisposition syndromes, including those affecting growth. SUMMARY: Clinicians caring for children with growth disorders should be aware of syndromic associations and the associated cancer risks. Knowledge of tumor spectra and recommended surveillance strategies may facilitate tumor diagnosis at an early stage and reduce morbidity of the disease and associated treatments.

Infantile hemangioma status by dynamic infrared thermography: A preliminary study.

BACKGROUND: Infantile hemangiomas (IH) are initially warm due to increased proliferation and perfusion then involute with apoptosis and reduced perfusion. Objective quantitative evaluation of IH treatment response is essential for improving outcomes. We applied a functional imaging method, dynamic infrared (IR) thermography, to investigate IH status versus control skin and over time. MATERIALS AND METHODS: A preliminary prospective observational study was conducted among 25 subjects with superficial or mixed IHs (< 19 months) over 59 clinic visits. Infrared images of IHs and control sites, standardized color images, and three-dimensional images were obtained. Tissue responses following application and removal of a cold stress were recorded with video IR thermography. Outcomes included areas under the curve during cooling (AUCcool ) and rewarming (AUCrw ) and thermal intensity distribution maps. RESULTS: AUCcool and AUCrw were significantly higher and cooling rate slower for IHs versus uninvolved tissue indicating greater heat, presumably due to greater perfusion and metabolism for the IH. IR distribution maps showed specific areas of high and low temperature. Significant changes in IH thermal activity were reflected in the difference (AUCcool - AUCrw ), with 6.2 at 2.2 months increasing to 37.6 at 12.8 months. IH cooling rate increased with age, indicating slower recovery, and interpreted as reduced proliferation and/or involution. CONCLUSIONS: Dynamic IR thermography was a well-tolerated, quantitative functional imaging modality appropriate for the clinic, particularly when structural changes, i.e., height, volume, color, were not readily observed. It may assist in monitoring progress, individualizing treatment, and evaluating therapies. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (Identifier NCT02061735).

Gastrointestinal Findings in the Largest Series of Patients With Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium.

OBJECTIVES: Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data. METHODS: The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates. RESULTS: Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed. CONCLUSIONS: The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.

Scoring the therapeutic effects of oral propranolol for infantile hemangioma: A prospective study comparing the Hemangioma Activity Score (HAS) with the Hemangioma Severity Scale (HSS).

BACKGROUND: Validated and reliable instruments to measure disease severity are needed to substantiate the benefit of therapies for infantile hemangioma. Two purpose-made systems have been described: the Hemangioma Activity Score (HAS) and the Hemangioma Severity Scale (HSS). OBJECTIVE: We sought to compare the HAS with the HSS in terms of ease of use, accuracy, and outcome in infants treated with oral propranolol. METHODS: A prospective study of 54 infants with infantile hemangioma was conducted from October 2009 to December 2012. Propranolol was initiated at 0.5 mg/kg/d and increased to 2 mg/kg/d on day 3. The HAS and the HSS were applied independently by 2 observers. RESULTS: Intraclass correlation coefficients of the HAS and HSS between the observers was comparable but HSS scores often remained the same upon improvement of the infantile hemangioma and therefore did not reflect disease severity. HAS decreased over time, with a dramatic drop in the first week reflecting an immediate therapeutic response. LIMITATIONS: This is a single-institution study and there may have been some selection bias in the patients who were referred for treatment. CONCLUSIONS: This study suggests that the HAS is preferable to the HSS in evaluating infantile hemangioma response to treatment.