Biallelic PI4KA variants cause neurological, intestinal and immunological disease.

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.

Liver transplantation for acute liver failure: are there thresholds not to be crossed?

Factors predicting survival after liver transplantation (LT) for irreversible acute liver failure (ALF) are rare. The aim of this study was to identify prognostic preoperative factors of patients with ALF that predict mortality after LT to avoid futile transplantation. From chart review, we identified 57 patients receiving transplants for ALF from 12/2000 to 09/2010. Recipient and donor data were analyzed and correlated with in-hospital mortality and patient survival by univariable/multivariable logistic regression and Cox proportional hazards. The survival rates at 30 days and 12 months were 77.2% and 64.9%, respectively. The in-hospital mortality rate was 29.8%. Follow-up of patients discharged from the hospital alive showed 30-day and 12-month survivals of 100% and 92.5%, respectively. Multivariable analysis of factors known preoperatively showed that the lowest pH of the recipient before LT (P = 0.03) was independently associated with in-hospital mortality, and the recipient's BMI (P = 0.03) and the lowest pH before LT (P = 0.03) were independently associated with patient survival. A pH of 7.26 was the calculated cutoff (ROC) for increased in-hospital mortality. Donor factors did not affect patient survival. Patients with ALF and a pH ≤ 7.26 have the worst outcome after liver transplantation. Therefore, emergency liver transplantation should be critically discussed for each individual.

Prevalence of osteopathologies in a single center cohort of survivors of childhood primary brain tumor.

Background: Childhood primary brain tumors (CPBT) are the second largest group of childhood malignancies and associated with a high risk for endocrine late effects. Objective: To assess endocrine late effects and their relevance for the development of osteopathologies in survivors. Methods: This single center cross sectional study investigated data from 102 CPBT survivors with a mean age of 13.0 years and a mean age at diagnosis of 8.7 years. Clinical, biochemical, radiographic, and anamnestic data regarding endocrine and bone health were obtained at study visits. In addition, data regarding tumor stage and therapy was obtained by chart review. An expert opinion was applied to define presence of osteopathologies. Results: Impaired bone health, defined by at least one pathological screening parameter, was present in 65% of patients. 27.5% were found to have overt osteopathologies per expert opinion. 37.8% displayed a severe vitamin D deficiency (25-OH vitamin D < 10 ng/ml) and 11% a secondary hyperparathyroidism. Patients with osteopathologies had lower 25-OH vitamin D levels compared to patients without osteopathologies. Multiple endocrine late effects were present: diabetes insipidus in 10.8%, aberrant pubertal development in 13.7%, central hypocortisolism in 14.9%, thyroid dysfunction in 23.8% and growth hormone deficiency in 21.8%. A total of 31.3% of survivors displayed any endocrinopathy. Tumors located near hypothalamic structures and patients who received irradiation had a higher likelihood of endocrine morbidity. Conclusion: This study indicates that endocrine deficiencies are common in pediatric survivors of CPBTs. Osteopathologies are present in this cohort. A prominent effect of hormonal deficiencies on bone health was not detected, possibly because patients were sufficiently treate for their endocrine conditions or indicating resilience of the childhood bone remodeling process. Vitamin D deficiency is frequent and should be treated as recommended.

Increased Prevalence of Subclinical Hypothyroidism and Thyroid Autoimmunity in Depressed Adolescents: Results From a Clinical Cross-Sectional Study in Comparison to the General Pediatric Population.

OBJECTIVE: The study was undertaken to determine the prevalence of subclinical and overt thyroid dysfunction as well as thyroid autoimmunity in depressed adolescents in comparison to the general pediatric population. Additionally, the relationship between parameters of thyroid function and Beck Depression Inventory-II (BDI-II) scores was examined. METHODS: Parameters of thyroid function (thyrotropin, free thyroxine, thyroid peroxidase antibodies) and prevalence of thyroid dysfunction and autoimmunity were determined in 360 adolescents (11-19 years) with at least mild depression (BDI-II score > 13) between June 2016 and December 2019 and in a representative reference cohort without evidence of impaired mental health from a nationwide survey (German Health Interview and Examination Survey for Children and Adolescents [KiGGS], 2003-2006). RESULTS: There was a higher prevalence of thyroid peroxidase antibody positivity in depressed adolescents (mean ± SD BDI-II, 30.0 ± 10.4) compared to KiGGS participants (depressed adolescents: 5.8%, 95% CI [3.7-8.6]; odds ratio [OR] 1.9, P = .009, d = 0.36; KiGGS participants: 3.1%, 95% CI [2.5-3.9]). The prevalence of subclinical hypothyroidism was likewise higher in depressed adolescents (9.1%, 95% CI [6.3-12.4] vs KiGGS participants: 2.1%, 95% CI [1.6-2.7]; OR 4.7, P < .001, d = 0.85), but no other types of thyroid dysfunction had a higher prevalence. There was no significant relationship between parameters of thyroid function and BDI-II scores, as examined by multiple regression considering relevant covariates. The positive results were verified in a subsample of patients with a confirmed diagnosis of depression (N = 284). CONCLUSIONS: The prevalence of subclinical hypothyroidism and of thyroid autoimmunity in depressed adolescents is increased. The etiology of these observations is not well understood, and further studies to examine the underlying relationship are required. Moreover, thyroid autoimmunity may constitute an additional risk factor for depression on its own.

Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood.

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families.

Prevalence of Osteopathologies in Children and Adolescents After Diagnosis of Acute Lymphoblastic Leukemia.

Background: Impaired bone health is a late effect of childhood malignancies which can be difficult to detect in juvenile survivors. It may, however, lead to compromised quality of life, or even permanent disability later in life due to osteoporosis, pain or fractures if left untreated. Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy with an over 85% five-year survival. ALL and its treatment cause bone alterations in adults, but little information on the bone health status in juvenile survivors is available. Objective: To report data on skeletal late effects in juvenile survivors of childhood ALL based on a comprehensive assessment of bone health and to assess the influence of a vitamin D deficiency on bone health in this cohort. Methods: In a single center cross sectional study 128 pediatric patients (11.9 ± 4.76 years) with a mean follow up of 5.88 ± 3.75 years after diagnosis of ALL were recruited. The bone health status of the survivors was assessed based on clinical examination, review of medical records, biochemical and radiographic analyses, by clinical experts. A score which utilized 8 different parameters was formed and used to assess the effect of a vitamin D deficiency on bone health. Results: In this cohort, 18% of survivors displayed overt osteopathologies as defined by clinical expert assessment. Impaired bone health, defined by at least one pathological screening parameter, was detected in 77%. Despite recommendations for adequate vitamin D supplementation, 15% displayed a vitamin D deficiency associated with hyperparathyroidism. The applied score identified survivors with osteopathologies with high sensitivity and specificity. The median score did not differ between patients without and with severe vitamin D deficiency. Conclusion: Our findings suggest that impaired bone health and osteopathologies are common skeletal late effects following treatment of childhood ALL. Major contributing factors are BMT, irradiation and older age at diagnosis. Vitamin D deficiency likely accounts for hyperparathyroidism in some patients but does not seem to further affect bone health in this cohort. Survivors of ALL need thorough surveillance to investigate bone health, since bone morbidity is common and still poorly understood. Early detection and appropriate intervention may improve bone health.

Resistance to GHRH but Not to PTH in a 15-Year-Old Boy With Pseudohypoparathyroidism 1A.

Pseudohypoparathyroidism 1A (PHP1A) consists of signs of Albright hereditary osteodystrophy (AHO) and multiple, variable hormonal resistances. Elevated PTH levels are the biochemical hallmark of the disease. Short stature in PHP1A may be caused by a form of accelerated chondrocyte differentiation leading to premature growth plate closure, possibly in combination with GH deficiency in some patients. Treatment of short stature with recombinant growth hormone (rhGH) in pediatric patients may improve final height if started during childhood. The 10 11/12-year-old boy with clinical signs of AHO presented for evaluation of short stature [height standard deviation score (SDS) -2.72]. Clinically his mother was affected by AHO as well. A heterozygous mutation c.505G>A (p.E169K) in exon 6 of the GNAS gene confirmed a diagnosis of PHP1A in the boy. However, hormonal assessment was unremarkable except for low serum IGF-1 (SDS -2.67). On follow-up, GH deficiency due to GHRH resistance was suspected and confirmed by clonidine and arginine stimulation tests. Treatment with rhGH (0.035 mg/kg) for 2 years resulted in catch-up growth (height SDS -1.52). At age 15 years the PTH levels and bone age of the patient remain within the normal range. In patients with PHP1A, short stature is caused by the effects of Gs-α deficiency on the growth plate. However, resistance to GHRH and the resulting GH deficiency might also contribute. Recombinant GH treatment increases growth in these patients. Diagnostic workup for GH deficiency as a factor contributing to short stature is recommended even in the absence of other hormonal resistances.