Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

In-person validation of the Ichthyosis Scoring System.

BACKGROUND: Ichthyoses are a heterogeneous group of skin disorders characterized by scaling and erythema. Recognizing the variability of scale and erythema by region and ichthyosis subtype, we developed the Ichthyosis Scoring System (ISS) to quantify severity. We previously found ISS to have high inter- and intrarater reliability in evaluating photographic images. To confirm ISS clinical utility, we examined its performance at the 2022 Foundation for Ichthyosis and Related Skin Types conference. METHODS: Sixty-five participants were evaluated by 3 of 9 medical professionals trained to score ichthyosis scale and erythema using ISS. Intrarater and interrater intraclass correlation coefficients (ICC) were analyzed using one-way and two-way random effects models, respectively. RESULTS: Intrarater reliability was excellent (ICC = 0.931, 95% CI, 0.921-0.940) for scale and good (ICC = 0.876, 95% CI, 0.853-0.899) for erythema scoring. Compared to photo validation with excellent intrarater reliability ratings for both scale (ICC = 0.956, 95% CI, 0.925-0.974) and erythema (ICC = 0.913, 95% CI, 0.855-0.949), ISS demonstrated equivalent reliability for live use. Overall interrater reliability for 10 body sites showed excellent (ICC >0.9) and good (ICC >0.75) agreement and consistency for both scale and erythema. Palms were an exception, demonstrating moderate (ICC >0.5) interrater agreement and consistency for erythema evaluation. CONCLUSIONS: ISS is a reliable measure of global and regional ichthyosis severity during in-person evaluations. Ease-of-use, accessibility, and content validity in both live and photographic evaluation endorse ISS as a standard for ichthyosis severity analysis.

Congenital Ichthyosis: A Practical Clinical Guide on Current Treatments and Future Perspectives.

Congenital ichthyoses are a group of hereditary disorders of keratinization that are challenging to treat. Affected individuals suffer not only from thickening of the skin but also associated complications such as growth restriction, hearing and eye complications, infections, and thermodysregulation. This clinical review provides a practical roadmap to the longitudinal care of patients with ichthyosis with both general and age- and disease-specific recommendations. The allure of pathogenesis-based and targeted treatments for these monogenetic severe but orphan conditions shines bright as dermatological therapies enter a new era.

Antimalarials are not Effective as Pre-Exposure Prophylaxis for COVID-19: A Retrospective Matched Control Study.

The early phase of the COVID-19 pandemic prompted a repurposing of antiviral and immunomodulatory drugs as investigational therapeutics, including hydroxychloroquine and chloroquine. While antimalarials have been well-refuted as a treatment for COVID-19, data on these drugs' role in preventing SARS-CoV-2 infection as pre-exposure prophylaxis is more limited. We investigated the efficacy of antimalarial drugs as pre-exposure SARS-CoV-2 prophylaxis in a US tertiary-care center. We identified all adult patients exposed to antimalarials with active prescriptions from July 1, 2019 to February 29, 2020 and exact-matched antimalarial-treated study patients with controls on age, sex, race, and Charleston Comorbidity Index. We used multivariable logistic regression to calculate the odds ratio (OR) of COVID-19 diagnosis by antimalarial exposure, adjusting for demographics, comorbidities, local infection rates, and specific conditions identified in early studies as risk factors for COVID-19. There were 3,074 patients with antimalarial prescriptions and 58,955 matched controls. Hydroxychloroquine represented 98.8% of antimalarial prescriptions. There were 51 (1.7%) infections among antimalarial-exposed and 973 (1.6%) among controls. No protective effect for SARS-CoV-2 infection was demonstrated among antimalarial-exposed patients in the multivariate model (OR=1.06, 95% CI 0.80-1.40, P=0.70). These findings corroborate prior work demonstrating that hydroxychloroquine and related antimalarials do not have a role in protection against SARS-CoV-2.Klebanov N, Pahalyants V, Said JT, et al. Antimalarials are not effective as pre-exposure prophylaxis for COVID-19: a retrospective matched control study. J Drugs Dermatol. 2023;22(8):840-843. doi:10.36849/JDD.6593.

Risk of COVID-19 in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

OBJECTIVE: The aim of this study was to determine the rate of coronavirus disease-19 (COVID-19) among patients with cancer treated with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: This was a retrospective study of 1,545 patients with cancer treated with ICIs between July 1, 2019, and February 29, 2020, and 20,418 age-, sex-, and cancer category-matched controls in a large referral hospital system. Confirmed COVID-19 case and mortality data were obtained with Massachusetts Department of Public Health from March 1 through June 19, 2020. RESULTS: The mean age was 66.6 years, and 41.9% were female. There were 22 (1.4%) and 213 (1.0%) COVID-19 cases in the ICI and control groups, respectively. When adjusting for demographics, medical comorbidities, and local infection rates, ICIs did not increase COVID-19 susceptibility. CONCLUSION: ICIs did not increase the rate of COVID-19. This information may assist patients and their oncologists in decision-making surrounding cancer treatment during this pandemic.

A pediatric approach to management of skin growths in basal cell nevus syndrome.

Little guidance on management of basal cell nevus syndrome in children exists. We report a case series of four patients diagnosed with BCNS in early childhood, in whom several highly suspicious lesions were biopsied, but several smaller and questionably concerning lesions were treated with therapies that are more tolerable for children, including topical imiquimod, 5-fluorouracil, cryotherapy, or touch electrodessication following topical anesthetic cream. These therapies were well tolerated, and all residual or persistent lesions were subsequently biopsied and found to be benign. This approach is often preferable for pediatric BCNS patients, in whom concerning lesions can be identified clinically and managed compassionately. However, any lesion that exhibits growth, bleeding, or symptoms should be biopsied for definitive diagnosis.

Novel CARD9 mutation in a patient with chronic invasive dermatophyte infection (tinea profunda).

Caspase Recruitment Domain Family Member 9 (CARD9) is an adaptor molecule that drives antifungal activity of macrophages and neutrophils in the skin. Autosomal recessive loss-of-function mutations in CARD9 confer increased susceptibility to invasive disease with select fungi in non-immunosuppressed patients. We report on a patient with X-linked ichthyosis complicated by chronic cutaneous invasive dermatophyte infection. We identified a previously reported c.271T>C (p.Y91H) mutation and a novel intronic c.1269+18G>A mutation in CARD9 underlying recurrent deep dermatophytosis in this patient despite various antifungals for over three decades. Our case highlights susceptibility to invasive dermatophytosis related to autosomal recessive CARD9 deficiency and illustrates the range of CARD9 mutations to be pursued in immunocompetent patients with unexplained deep dermatophyte infections. Further studies are needed to define the best therapeutic regimen.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years.

Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review.

More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations.

BACKGROUND: Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. OBJECTIVE: We sought to discover characteristics that account for poor outcomes in lethal KID syndrome. METHODS: We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. RESULTS: Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 "lethal" mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V. LIMITATIONS: This clinical review was retrospective. CONCLUSION: GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion.

No Difference in Psychotropic Medication Use in Cosmetic and General Dermatology Patients.

BACKGROUND: Patients presenting for appearance-related concerns are often perceived as being more difficult (ie, more needy, more difficult to satisfy) than patients presenting for medical dermatologic problems. While the reasons for this perception are many, some hypothesize that this may be related to a higher rate of anxiety, depression, or body image issues among these patients.
OBJECTIVE: To determine the prevalence of psychotropic medication use in cosmetic dermatology patients compared to the prevalence of such medication use in general dermatology patients.
METHODS & MATERIALS: The study was a retrospective chart review of female patients, 18 or older, new to a private practice. Exclusion criteria included dermatologic disorders with known psychosocial comorbidity. Psychotropic medication use was recorded.
RESULTS: The percentage of subjects in the medical group (n=156) who reported using psychotropic medications was 22.2% compared to 26.8% in the cosmetic group (n=154; P=0.09).
CONCLUSION: The prevalence of psychotropic medication use among all dermatology patients in our practice was relatively high, but there was no statistically significant difference in the rate of psychotropic medication use in cosmetic dermatology patients compared to general dermatology patients.

J Drugs Dermatol. 2016;15(7):858-861.

Connexin channels in congenital skin disorders.

Gap junctions and hemichannels comprised of connexins influence epidermal proliferation and differentiation. Significant advances in our understanding of the functional role of connexins in the skin have been made by studying the diseases caused by connexin mutations. Eleven clinically defined cutaneous disorders with an overlapping spectrum of phenotypes are caused by mutations in five different connexin genes, highlighting that disease presentation must be deciphered with an understanding of how connexin functions are affected. Increasing evidence suggests that the skin diseases produced by connexin mutations result from dominant gains of function. In palmoplantar keratoderma with deafness, the connexin 26 mutations transdominantly alter the function of wild-type connexin 43 and create leaky heteromeric hemichannels. In keratitis-ichthyosis-deafness syndrome, different connexin 26 mutations can either form dominant hemichannels with altered calcium regulation or increased calcium permeability, leading to clinical subtypes of this syndrome. It is only with detailed understanding of these subtle functional differences that we can hope to create successful pathophysiology driven therapies for the connexin skin disorders.