Biallelic hexokinase 1 (HK1) variants causative of non-spherocytic haemolytic anaemia: A case series with emphasis on the HK1 promoter variant and literature review.

The hexokinase (HK) enzyme plays a key role in red blood cell energy production. Hereditary non-spherocytic haemolytic anaemia (HNSHA) caused by HK deficiency is a rare disorder with only 12 different disease-associated variants identified. Here, we describe the clinical features and genotypes of four previously unreported patients with hexokinase 1 (HK1)-related HNSHA, yielding two novel truncating HK1 variants. The patients' phenotypes varied from mild chronic haemolytic anaemia to severe infantile-onset transfusion-dependent anaemia. Three of the patients had mild haemolytic disease caused by the common HK1 promoter c.-193A>G variant combined with an intragenic HK1 variant, emphasizing the importance of including this promoter variant in the haemolytic disease gene panels. HK activity was normal in a severely affected patient with a homozygous HK1 c.2599C>T, p.(His867Tyr) variant, but the affinity for ATP was reduced, hampering the HK function. In cases of HNSHA, kinetic studies should be considered in the functional studies of HK. We reviewed the literature of previously published patients to provide better insight into this rare disease and add to the understanding of genotype-phenotype correlation.

Sleep-related breathing disorder in non-infectious pulmonary complications after pediatric allogeneic stem cell transplantation.

BACKGROUND: Chronic lung problems are a rare but serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). We studied clinical phenotypes and polysomnography appearance of breathing abnormality in late onset non-infectious pulmonary complications (NIPS). METHODS: We reviewed Finnish national reference database between the years 1999 and 2016. We identified 12 children with most severely decreased pulmonary function and performed polysomnography and 24 aged-matched controls out of 325 performed pediatric allogeneic HSCTs. RESULTS: All patients with NIPS had severely decreased pulmonary function already at 6 months post HSCT with median FEV1 value 42% (interquartile range (IQR) 30-52%) of predicted normal values. Seven children had obstructive and five children more restrictive lung function. Children with obstructive lung function showed laborious breathing (7/7), decreased oxygenation and ventilation-to-perfusion mismatch (6/7), or REM-sleep-related hypoventilation (4/7) on polysomnography. Children with restrictive lung function (5/12) did not show sleep-related breathing disorder. CONCLUSIONS: Children going through allogeneic HSCT who develop severe chronic obstructive lung function are more likely to present with sleep-related hypoxia and hypoventilation than children with restrictive lung function. IMPACT: Children with severe obstructive lung function and chronic lung graft-versus-host disease following hematopoietic stem cell transplantation are more likely to present with sleep-related mild hypoxia and hypoventilation than children with restrictive lung disease. To our knowledge there are no reports on sleep-related breathing disorders and ventilatory function measured by polysomnography in children with pulmonary complications after allogeneic HSCT. Polysomnography may add to the differential diagnostics between patients with BOS and other non-infectious pulmonary complications.

The ISKDC classification and a new semiquantitative classification for predicting outcomes of Henoch-Schönlein purpura nephritis.

BACKGROUND: Histological findings from primary kidney biopsies were correlated with patient outcomes in a national cohort of paediatric Henoch-Schönlein nephritis (HSN) patients. METHODS: Primary kidney biopsies from 53 HSN patients were re-evaluated using the ISKDC (International Study of Kidney Disease in Children) classification and a modified semiquantitative classification (SQC) that scores renal findings and also takes into account activity, chronicity and tubulointerstitial indices. The ISKDC and SQC classifications were evaluated comparatively in four outcome groups: no signs of renal disease (outcome A, n = 27), minor urinary abnormalities (outcome B, n = 18), active renal disease (outcome C, n = 3) and renal insufficiency, end-stage renal disease or succumbed due to HSN (outcome D, n = 5). For the receiver operating characteristic and logistic regression analyses, outcomes A and B were considered to be favourable and outcomes C and D to be unfavourable. The median follow-up time was 7.3 years. RESULTS: The patients with an unfavourable outcome (C and D), considered together due to low patient numbers, had significantly higher total biopsy SQC scores and activity indices than those who had a favourable one (groups A and B). The chronicity and tubulointerstitial indices differed significantly only between group C + D and group A. The difference in areas under the curve between the total biopsy SQC scores and ISKDC findings was 0.15 [p = 0.04, normal-based 95% confidence interval (CI) 0.007-0.29, bias-controlled 95% CI -0.004 to 0.28]. CONCLUSIONS: Our results suggest that the modified SQC is more sensitive than ISKDC classification for predicting the outcome in HSN cases.