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Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia
Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited β-globin mutation (HBB:c.93-21G>A, IVS-I-110:G>A), a known cause of β-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire α-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of β-thalassemia intermedia resulting from a single β-thalassemia mutation in combination with an α-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis
Case report: Anorexia nervosa and unspecified restricting-type eating disorder in Jewish ultra-orthodox religious males, leading to severe physical and psychological morbidity
BackgroundYoung Jewish Ultra-Orthodox women usually show less disturbances in body image and eating in comparison to less religious communities. By contrast, problems with eating are highly unknown and unrecognized in Jewish Ultra-Orthodox males.AimTo investigate whether in Ultra-Orthodox males, restricting-type AN (AN-R) with highly obsessional physical activity and unspecified restricting eating disorder (ED) in the context of obsessive–compulsive disorder (OCD) would lead to severe physical and emotional morbidity.ResultsThe study included two groups: the first, 3 adolescents with AN-R developing severely increased ritualized obsessional physical activity in addition to restricting eating, requiring inpatient treatment because of severe bradycardia. These youngsters ignored the severity of their obsessional physical activity, continuing with it in hospital despite their grave medical condition. One student began extensive training for triathlon, whereas another student, upon remitting from AN, developed severe muscle dysmorphia. These findings suggest that young Ultra-Orthodox males with AN may develop obsessional physical activity to increase their muscle mass rather than to lose weight Another four Jewish Ultra-Orthodox males developed malnutrition in the context of severe OCD, with no evidence of dieting or body-image disturbances. These individuals developed highly obsessional adherence to different Jewish religious rules, including prolonged praying, asceticism, and overvalued strict adherence to Jewish Kashrut rules of eating, leading in all cases to severe food restriction. They were highly unaware of their severe weight loss and required hospitalization because of severe physical disturbances associated with malnutrition. Moreover, most did not cooperate with their treatment, and their ED-related obsessionality was mostly resistant to psychopharmacotherapy.ConclusionOwing to their highly ritualistic rigid way of life, combined with the need for excellency in studying, Jewish Ultra-Orthodox adolescent males with AN might be at a specific risk of developing severe physical disturbances if their illness is associated with highly perfectionistic obsessional physical activity. Second, Jewish Ultra-Orthodox religious males with OCD might be at a specific risk for severe undernutrition, as their rigid relentless observance of Jewish everyday laws might highly interfere with their eating