Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl À /H þ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and-genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.

About half the cases of energy drink-related toxicity involved unintentional exposures by children < 6 years old. Educational campaigns and legal restrictions on the sale of energy drinks were associated with decreasing calls to poison centers for energy drink toxicity and are encouraged.

Patient now 19 years old has intellectual disability, developmental delay, absent speech, seizures, hypotonia, severe motor disability (non-ambulatory), short stature, relative macrocephaly. Patient uses gastric tube for feeding and has gastroesophageal reflux. Facial dysmorphisms include short palpebral fissures, large incisors, full eyebrows. Fingers are short and trident-shaped.Brain MRI revealed progressive cerebral and cerebellar volume loss, hypodensity in the left basal ganglia, unchanged and consistent with a lacune infarct (remote). There is a less conspicuous area of hypodensity on the contralateral side. There are hypodense white matter changes along the periventricular white matter and bilateral centrum semiovale.

Drowning is a leading cause of injury-related death in children. In 2017, drowning claimed the lives of almost 1000 US children younger than 20 years. A number of strategies are available to prevent these tragedies. As educators and advocates, pediatricians can play an important role in the prevention of drowning. BACKGROUND Drowning is the leading cause of injury death in US children 1 to 4 years of age and the third leading cause of unintentional injury death among US children and adolescents 5 to 19 years of age. 1 In 2017, drowning claimed the lives of almost 1000 US children. Fortunately, childhood unintentional drowning fatality rates have decreased steadily from 2.68 per 100 000 in 1985 to 1.11 per 100 000 in 2017. Rates of drowning death vary with age, sex, and race and/or ethnicity, with toddlers and male adolescents at highest risk. After 1 year of age, male children of all ages are at greater risk of drowning than female children. Overall, African American children have the highest drowning fatality rates, followed in order by American Indian and/or Alaskan native, white, Asian American and/or Pacific Islander, and Hispanic children. For the period 2013-2017, the highest drowning death rates were seen in white male children 0 to 4 years of age (3.44 per 100 000), American Indian and/or Alaskan native children 0 through 4 years (3.58), and African American male adolescents 15 to 19 years of age (4.06 per 100 000). 1 Drowning is also a significant source of morbidity for children. In 2017, an estimated 8700 children younger than 20 years of age visited a hospital emergency department for a drowning event, and 25% of those children were hospitalized or transferred for further care. 1 Most victims of nonfatal drowning recover fully with no neurologic deficits, but severe long-term neurologic deficits are seen with extended submersion times (.6 minutes), prolonged resuscitation efforts, and lack of early bystander-initiated cardiopulmonary resuscitation (CPR). 2-4 The American Academy of Pediatrics issues this revised policy statement because of new information and research regarding (1) populations at

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

The circumstances involved in the type 1 homicides (beatings by caretakers) suggested that those attacks occurred impulsively, death was unintended, and emergency care was summoned, often with a false story. Previous abuse was suspected in more than one half of those incidents.

This study used linked, official data for population-based surveillance of homicides, suicides, and homicide–suicides in four U.S. states and four counties. Among 1,503 homicide incidents, less than 5% ( n = 74) were followed by the perpetrator's suicide and 1% ( n = 18) by a nonfatal suicide attempt. However, among men who killed their female intimate partner with a firearm, 59% also took their own life. Homicide–suicide perpetrators did not test positive for an antidepressant more often than other male suicide decedents (15% vs. 19%). Most (54%) perpetrators of nonfirearm homicides who attempted suicide lived; nearly all (93%) firearm perpetrators who attempted suicide died. Among men who killed their female intimate partner with a firearm, homicide–suicide was the norm. Better enforcement of existing laws designed to protect abuse victims by removing firearms from domestic abusers may also prevent abusers' suicides.

In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). METHODS: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. RESULTS: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogendependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. CONCLUSION: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.