Rare Causes of Primary XXXX : Genetic and Clinical Characterization of a Large Nationwide Cohort.

@entity1 @entity20719 @entity4788 @entity624 @entity5986 @entity71914 @entity1887 @entity4787 @entity24382 @entity2539 @entity20043 @entity5343 @entity71913 @entity71915 @entity8019 @entity774
CONTEXT: @entity5343 ( @entity5343 ) is a life-threatening condition that is often due to monogenic causes in @entity1 . Although @entity774 occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. OBJECTIVE: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of @entity1 with @entity5343 of unknown etiology. DESIGN: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. @entity1 with @entity774 , @entity8019 , @entity1887 , or obvious syndromic @entity5343 were excluded. SETTING: The study was conducted in 19 tertiary pediatric endocrinology clinics. @entity1 : Ninety-five @entity1 (48 females, aged 0-18 y, eight familial) with @entity5343 of unknown etiology participated in the study. RESULTS: A genetic diagnosis was obtained in 77 @entity1 (81%). The range of etiologies was as follows: @entity4787 (n = 25), @entity2539 (n = 12), @entity624 (n = 11), @entity5986 (n = 9), @entity4788 (n = 9), NNT (n = 7), @entity24382 (n = 2), @entity20043 (n = 1), and @entity20719 (n = 1). Recurrent mutations occurred in several genes, such as @entity71913 in @entity4787 , @entity71914 in @entity5986 , and @entity71915 in @entity4788 . Several important clinical and molecular insights emerged. CONCLUSION: This is the largest nationwide study of the molecular genetics of childhood @entity5343 undertaken. Achieving a molecular diagnosis in more than 80% of @entity1 has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.
