Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders.

BACKGROUND AND AIMS: Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) are characterized by very short telomeres and multisystem organ involvement including liver disease. Our study aimed to characterize baseline hepatic abnormalities in patients with DC/TBD and determine risk factors associated with liver disease progression. APPROACH AND RESULTS: A retrospective review was performed on a cohort of 58 patients (39 males) with DC/TBD who were prospectively evaluated at a single institute from 2002 to 2019. The median age at initial assessment was 18 (1.4-67.6) years, and median follow-up duration was 6 (1.4-8.2) years. Patients with autosomal or X-linked recessive inheritance and those with heterozygous TINF2 DC were significantly younger, predominantly male, and more likely to have DC-associated mucocutaneous triad features and severe bone marrow failure compared with autosomal dominant-non- TINF2 DC/TBD patients. Liver abnormality (defined at baseline assessment by laboratory and/or radiological findings) was present in 72.4% of patients with predominantly cholestatic pattern of liver enzyme elevation. Clinically significant liver disease and portal hypertension developed in 17.2% of patients during the 6-year follow-up; this progression was mainly seen in patients with recessive or TINF2 -associated DC. Significant risk factors associated with progression included the presence of pulmonary or vascular disease. CONCLUSIONS: Our experience shows a high prevalence of cholestatic pattern of liver abnormality with progression to portal hypertension in patients with DC/TBD. Presence of pulmonary and/or vascular disease in patients with recessive or TINF2 DC was an important predictor of liver disease progression, suggesting the need for increased vigilance and monitoring for complications in these patients.

Disease progression and clinical outcomes in telomere biology disorders.

Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs, and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR), or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs (144 male, 86.6% known genotype, median age at diagnosis 19.4 years [range 0 to 71.6]), enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up (median follow-up 5.2 years [range 0 to 36.7]). Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure (BMF), severe liver disease, and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival (OS) of 52.8 years (95% confidence interval [CI] 45.5-57.6), and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better OS was present in AD vs AR/XLR/TINF2 disease (P < .01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines and risk stratification in patients with DC/TBDs. This trial was registered at www.clinicaltrials.gov as #NCT00027274.

Gender Disparities in Reimbursement Among Dermatologists and Dermatologic Surgeons.

BACKGROUND: Previous literature supports a disparity in income between male and female physicians across multiple specialties, even when controlling for variables such as working hours, maternity leave, and productivity. OBJECTIVE: To understand if income disparity exists between male and female general dermatologists (GDs), and in dermatologists who completed a dermatologic surgical fellowship. MATERIALS AND METHODS: The authors surveyed members of the American Academy of Dermatology, including 66 dermatologic surgeons (DSs) (34 male and 32 female DSs) and 252 GDs (119 male and 133 female GDs), on questions related to total annual income, demographics, current employment, and time spent providing patient care. A logarithmic ordinal regression model was used to analyze income and the effect of different variables. RESULTS: Male GDs were 2.46 times more likely than female GDs to be in a higher income category (95% confidence interval [CI]: 1.44-4.23). There was no significant difference between the incomes of male and female DSs (male-to-female odds ratio: 1.46, CI: -0.44 to 1.23). These findings did not change when variables of age, median patient visits, and hours worked were controlled for. CONCLUSION: Income gender inequality exists among GDs. However, this inequality does not seem to extend to DSs.

Understanding the evolving phenotype of vascular complications in telomere biology disorders.

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.

Reduced anti-Müllerian hormone levels in males with inherited bone marrow failure syndromes.

Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond-Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and post-pubertal males with FA, DC/TBD or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median 5 ng/mL, range: 1.18-6.75) compared with unaffected male relatives (median 7.31 ng/mL, range: 3.46-18.82, P=0.03) or healthy male volunteers (median 7.66 ng/mL, range: 3.3-14.67, P=0.008). Males with DC/TBD had lower levels of AMH (median 3.76 ng/mL, range: 0-8.9) compared with unaffected relatives (median 5.31 ng/mL, range: 1.2-17.77, P=0.01) or healthy volunteers (median 5.995 ng/mL, range: 1.57-14.67, P<0.001). Males with DBA had similar levels of AMH (median 3.46 ng/mL, range: 2.32-11.85) as unaffected relatives (median 4.66 ng/mL, range: 0.09-13.51, P=0.56) and healthy volunteers (median 5.81 ng/mL, range: 1.57-14.67, P=0.10). Our findings suggest a defect in the production of AMH in post-pubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.

Incidence of Benign Meningiomas in the United States: Current and Future Trends.

Background: Benign meningiomas are the most frequently reported central nervous system tumors in the United States, with increasing incidence in past decades. However, the future trajectory of this neoplasm remains unclear. Methods: We analyzed benign meningioma incidence of cases identified by any means (eg, radiographically with or without microscopic confirmation) in US Surveillance, Epidemiology, and End Results cancer registries among groups aged 35 to 84 years during 2004-2017 by sex and race and ethnicity using age-period-cohort models. We employed age-period-cohort forecasting models to glean insights regarding the etiology, distribution, and anticipated future (2018-2027) public health impact of this neoplasm. Results: In all groups, meningioma incidence overall increased through 2010, then stabilized. Temporal declines were statistically significant overall and in most groups. JoinPoint analysis of cohort rate-ratios identified substantial acceleration in White men born after 1963 (from 1.1% to 3.2% per birth year); cohort rate-ratios were stable or increasing in all groups and all birth cohorts. We forecast that meningioma incidence through 2027 will remain stable or decrease among groups aged 55-84 years but remain similar to current levels among groups aged 35-54 years. The case count of total meningioma burden in 2027 is expected to be approximately 30 470, similar to the expected case count of 27 830 in 2018. Conclusions: Between 2004 and 2017, overall incidence of benign meningioma increased and then stabilized or declined. For 2018-2027, our forecast is incidence will remain generally stable in younger age groups but decrease in older age groups. Nonetheless, the total future burden will remain similar to current levels because the population is aging.

CNS manifestations in patients with telomere biology disorders.

OBJECTIVE: We systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology. METHODS: Forty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board-approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age. RESULTS: In this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population (p < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings (p = 0.02) and neurodevelopmental abnormalities (p < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease. CONCLUSIONS: Structural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.