Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma.

PURPOSE: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases. METHODS: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6KozakGAL4 allele to assess the expression pattern of dYkt6. RESULTS: Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, developmental delay, and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual is homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] and exhibited neurodevelopmental disorders and optic atrophy. Fly dYkt6 is essential and is expressed in the fat body (analogous to liver) and central nervous system. Wild-type genomic rescue constructs can rescue the lethality and autophagic flux defects, whereas the variants are less efficient in rescuing the phenotypes. CONCLUSION: The YKT6 variants are partial loss-of-function alleles, and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys).

Effects of higher dietary acid load: a narrative review with special emphasis in children.

Metabolic effects of high diet acid load (DAL) have been studied for years in adults, although only recently in children. Contemporary diets, especially those of Western societies, owe their acidogenic effect to high animal-origin protein content and low contribution of base-forming elements, such as fruits and vegetables. This imbalance, where dietary acid precursors exceed the body's buffering capacity, results in an acid-retaining state known by terms such as "eubicarbonatemic metabolic acidosis," "low-grade metabolic acidosis," "subclinical acidosis," or "acid stress". Its consequences have been linked to chronic systemic inflammation, contributing to various noncommunicable diseases traditionally considered more common in adulthood, but now have been recognized to originate at much earlier ages. In children, effects of high DAL are not limited to growth impairment caused by alterations of bone and muscle metabolism, but also represent a risk factor for conditions such as obesity, insulin resistance, diabetes, hypertension, urolithiasis, and chronic kidney disease (CKD). The possibility that high DAL may be a cause of chronic acid-retaining states in children with growth impairment should alert pediatricians and pediatric nephrologists, since its causes have been attributed traditionally to inborn errors of metabolism and renal pathologies such as CKD and renal tubular acidosis. The interplay between DAL, overall diet quality, and its cascading effects on children's health necessitates comprehensive nutritional assessments and interventions. This narrative review explores the clinical relevance of diet-induced acid retention in children and highlights the potential for prevention through dietary modifications, particularly by increasing fruit and vegetable intake alongside appropriate protein consumption.

Risk factors associated with underweight in children aged one to two years: a longitudinal study.

BACKGROUND: Underweight is a prevalent health issue in children. This study aimed to identify factors associated with underweight in children aged 1-2 years in Hamadan city. Unlike the studies conducted in this field, which are cross-sectional and do not provide information on the effect of age changes on underweight, our longitudinal approach provides insights into weight changes over time. On the other hand, this study focuses on the high-risk age group of 1 to 2 years, which has only been addressed in a few studies. METHODS: In this longitudinal study, 414 mothers with 1 to 2 year-old children referred to the health centers of Hamadan city, whose information is in the SIB system, a comprehensive electronic system, were examined to identify factors related to underweight. The response variable was weight-for-age criteria classified into three categories: underweight, normal weight, and overweight. A two-level longitudinal ordinal model was used to determine the factors associated with underweight. RESULTS: Of the children studied, 201 (48.6%) were girls and 213 (51.4%) were boys. Significant risk factors for underweight included low maternal education (AOR = 3.56, 95% CI: 1.10-11.47), maternal unemployment (AOR = 3.38, 95% CI: 1.05-10.91), maternal height (AOR = 0.85, 95% CI: 0.79-0.92), lack of health insurance (AOR = 2.85, 95% CI: 1.04-7.84), gestational age less than 24 years (AOR = 3.17, 95% CI: 16.28-0.97), child age 12-15 months (AOR = 2.27, 95% CI: 1.37-3.74), and child's birth weight (AOR = 0.63, 95% CI: 0.70-0.58). CONCLUSION: Based on the results of the present study, it seems that the possibility of being underweight among children is more related to the characteristics of mothers; therefore, taking care of mothers can control some of the weight loss of children.

Undernutrition in young children with congenital heart disease undergoing cardiac surgery in a low-income environment.

BACKGROUND: Malnutrition (undernutrition) in children with congenital disease (CHD) is a notable concern, with preoperative and persistent growth failure post-cardiac surgery contributing to poorer outcomes. Poor growth in children with CHD in low-income environments is exacerbated by feeding difficulties, poverty, delayed diagnosis, and late corrective surgery. This study describes and compares the growth of young children with CHD undergoing cardiac surgery in central South Africa from before to 6-months after cardiac surgery. METHODS: Children 30 months and younger, with their mothers, were included in this prospective observational descriptive study. Weight- height-, and head circumference-for-age z-scores were used to identify children who were underweight, stunted and microcephalic. Z-scores for growth indices were compared from baseline to 3-months and 6-months post-cardiac surgery. Changes in growth over time were calculated using a 95% confidence interval on the difference between means. Linear regression was used to determine the association between growth and development, health-related quality of life and parenting stress respectively. RESULTS: Forty mother-child pairs were included at baseline. Most children (n = 30) had moderate disease severity, with eight children having cyanotic defects. A quarter of the children had Down syndrome (DS). Twenty-eight children underwent corrective cardiac surgery at a median age of 7.4 months. Most children (n = 27) were underweight before cardiac surgery [mean z-score - 2.5 (±1.5)], and many (n = 18) were stunted [mean z-score - 2.2 (±2.5)]. A quarter (n = 10) of the children had feeding difficulties. By 6-months post-cardiac surgery there were significant improvements in weight (p = 0.04) and head circumference (p = 0.02), but complete catch-up growth had not yet occurred. Malnutrition (undernutrition) was strongly associated (p = 0.04) with poorer motor development [Mean Bayley-III motor score 79.5 (±17.5)] before cardiac surgery. Growth in children with cyanotic and acyanotic defects, and those with and without DS were comparable. CONCLUSION: Malnutrition (undernutrition) is common in children with CHD in central South Africa, a low-income environment, both before and after cardiac surgery, and is associated with poor motor development before cardiac surgery. A diagnosis of CHD warrants regular growth monitoring and assessment of feeding ability. Early referral for nutritional support and speech therapy will improve growth outcomes.

Prevalence and determinants of failure to thrive in children with vesico-ureteral reflux.

AIM: To assess the prevalence and determinants of failure to thrive (FTT) among patients with vesico-ureteral reflux (VUR) and evaluating the effects of supplementation on growth in patients with urinary solute losses. METHODS: We retrospectively enrolled 1277 patients with VUR (mean age at diagnosis = 6.5 months). Patients with FTT were screened for renal tubular function impairment (TFI). If fractional excretion of sodium (FENa) >2% or blood bicarbonate <20 mmol/L, supplementation was provided. RESULTS: Among 1277 patients, 56 (4.4%) had FTT. Of these, 42 (75%) presented extrarenal causes of FTT, 3 (5.4%) had chronic kidney disease (CKD), 9 (16.1%) had TFI, and 2 (3.5%) had CKD and TFI. FTT occurred in 8/208 patients (3.8%) with and in 48/1069 patients (4.5%) without (p = 0.68) recurrent urinary tract infections (UTIs). At multiple logistic regression, birthweight <10th percentile, preterm birth, TFI, identified or suspected syndromes and other diseases were predictors of FTT. Eleven (19.6%) patients with FTT had TFI; five with increased FENa and/or acidosis received supplementation and showed catch-up growth. The remaining six patients exhibited spontaneous catch-up growth. CONCLUSION: FTT was found in <5% of children with VUR. It was not determined by recurrent UTIs and was mainly associated with extrarenal causes. Supplementation with sodium and bicarbonates could be useful in selected cases.

The social work discipline in the management of Failure to thrive in infants and children: an integrated behavioral health approach to pediatric programming.

Failure to thrive (FTT) is a DSM-5/ICD-10 diagnosis which describes infants and children who fail to grow within expected norms. The causes for poor growth are multifactorial and often include psychosocial factors. Social workers are important players in an interdisciplinary team approach to this diagnosis. This research and manuscript focus on the use of an integrated infant mental health pediatric model of practice, and outcomes for one case study. The article will review the social worker's role in the treatment of FTT, effective social work services provided in an integrated behavioral health approach, and a review of a cost-benefit analysis of treatment of FTT in a Primary Care Facility verses a hospital setting.

Downregulation of the GHRH/GH/IGF1 axis in a mouse model of Börjeson-Forssman-Lehman syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 (PHF6) mutations. Individuals with BFLS present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared with control mice. Growth hormone (GH) levels were reduced in the absence of PHF6. Phf6-/Y animals displayed a reduction in the expression of the genes encoding GH-releasing hormone (GHRH) in the brain, GH in the pituitary gland and insulin-like growth factor 1 (IGF1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating a neuroendocrine contribution to the phenotype. Loss of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of growth hormone signaling partially rescued body size, supporting a reversible deficiency in GH signaling. These results demonstrate that PHF6 regulates the GHRH/GH/IGF1 axis.

Clinical features, epidemiology, and treatment of Shwachman-Diamond syndrome: a systematic review.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic dysfunction and diverse clinical phenotypes. In the present study, we reviewed the internationally published reports on SDS patients, in order to summarize the clinical features, epidemiology, and treatment of SDS. METHODS: We searched the WangFang and China National Knowledge Infrastructure databases with the keywords "Shwachman-Diamond syndrome," "SDS," "SBDS gene" and "inherited bone marrow failure" for relevant articles published from January 2002 to October 2022. In addition, studies published from January 2002 to October 2022 were searched from the Web of Science, PubMed, and MEDLINE databases, using "Shwachman-diamond syndrome" as the keyword. Finally, one child with SDS treated in Tongji Hospital was also included. RESULTS: The clinical features of 156 patients with SDS were summarized. The three major clinical features of SDS were found to be peripheral blood cytopenia (96.8%), exocrine pancreatic dysfunction (83.3%), and failure to thrive (83.3%). The detection rate of SDS mutations was 94.6% (125/132). Mutations in SBDS, DNAJC21, SRP54, ELF6, and ELF1 have been reported. The male-to-female ratio was approximately 1.3/1. The median age of onset was 0.16 years, but the diagnostic age lagged by a median age of 1.3 years. CONCLUSIONS: Pancreatic exocrine insufficiency and growth failure were common initial symptoms. SDS onset occurred early in childhood, and individual differences were obvious. Comprehensive collection and analysis of case-related data can help clinicians understand the clinical characteristics of SDS, which may improve early diagnosis and promote effective clinical intervention.

Diencephalic syndrome-like presentation of brainstem tumor: a series case-based review.

PURPOSE: Russel described a rare clinical entity known as diencephalic syndrome (DS) in 1951, which was traditionally caused by a neoplasm in the hypothalamic-optic chiasmatic region. DS is characterized by severe emaciation despite adequate or slightly reduced caloric intake, locomotor hyperactivity, euphoria and other minor features. Current evidence suggests that a rare population of children with a similar phenotype may have their tumor located in the posterior fossa instead, defining the DS-like presentation, a rare entity with few cases reported in the literature. METHODS: A thorough search of three databases (PubMed, Ovid Medline, and Ovid Embase) was conducted to identify relevant papers reporting children with DS associated with brainstem tumors. To our knowledge, only seven cases have been documented in the literature. Moreover, we present four of our own cases, focusing on the unusual clinical presentation, the diagnosis process, and the lag time between the initial symptoms and the definitive diagnosis. RESULTS: In this review, the mean lag time between the onset of symptoms and diagnosis was 20.9 months (median: 16 months; range: 1.5-72 months), whereas in our series of cases, the time was 32.5 months (median: 33 months; range: 7-57 months). CONCLUSION: Despite recent significant advances in neuro-oncology diagnostic tools, this mean lag time did not improve when compared with the previous literature review from 1976. Throughout these data, we aim to raise awareness in the hopes of detecting intracranial neoplasms earlier in cases of children with profound emaciation of unknown cause.

Biopsychosocial characteristics of children admitted with failure to thrive.

AIMS: The aim of this study was to characterise and compare the biopsychosocial characteristics of children admitted with failure to thrive (FTT), subdivided into those with underlying medical complexities (categorised as organic FTT - OFTT) and those with none (categorised as non-organic FTT - NOFTT), with a focus on the medical, nutritional, feeding skills and psychosocial domains. METHODS: A retrospective review of medical records was conducted in children admitted with FTT from January 2010 to December 2020. Descriptive statistics were used for data analysis. RESULTS: A total of 353 children were included, with the mean age of presentation 0.82 ± 2.05 years (OFTT 1.16 ± 2.50 years, NOFTT 0.49 ± 1.41 years, P = 0.002). Approximately, half of the children were classified as having OFTT. These children had lower birth weights, were more likely to have a history of intrauterine growth restriction and had longer hospital stays. The NOFTT group had significantly more abnormal feeding strategies identified in their caregivers, whereas the OFTT group had more delayed feeding skills and oral aversion. There was no significant difference in psychosocial domains, with both groups having a comparably high risk of abuse and neglect. CONCLUSIONS: The classification of FTT as non-organic or organic based purely on psychosocial parameters did not reflect the complex nature of FTT within our local population. These groups had different medical variables, and caregiver feeding strategies. A multidisciplinary team approach is recommended for the assessment and intervention for children with FTT to address these domains and the complex interactions between them.

Prevalence and predictive factors of malnutrition in Thai children with congenital heart disease and short-term postoperative growth outcomes.

Background: Growth restriction is still a common problem in children with congenital heart disease (CHD). Evidence demonstrates that performing cardiac surgery in appropriate timing may result in better growth outcome. Aim: To investigate prevalence and associated factors of malnutrition in pediatric patients with CHD who underwent cardiac surgery. In addition, post-operative growth outcomes at two weeks following cardiac surgery were also assessed. Methods: A retrospective cohort study was conducted in pediatric patients who underwent cardiac surgery at Chiang Mai University Hospital between January and September 2014. Results: One hundred patients with a median age of 28.5 months (range 14-62 months) were enrolled. Two-third of these patients had at least one form of malnutrition before receiving surgical treatment while wasting, stunting and combined wasting-stunting accounted for 23%, 28%, and 15% of patients, respectively. Multiple logistic regression analysis demonstrated that congestive heart failure-related symptoms were significantly associated with increasing risk of malnutrition (adjusted OR 4.4; 95% CI 1.78-11.26, p = 0.001). Two weeks after hospital discharge, wasting patients with regardless of stunting had significantly improved weight for height (WHZ) and weight for length Z-scores (WLZ) compared to growth parameters at the time of cardiac surgery, p = 0.012 and p < 0.001, respectively. Conclusion: The prevalence of acute and chronic malnutrition in pediatric patients with CHD who underwent cardiac surgery was very high in this study. Children with congestive heart failure had a four-time at risk of undernutrition. In short-term, cardiac surgery may mitigate acute malnutrition of these patients.

Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency.

PURPOSE: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. METHODS: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. RESULTS: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). CONCLUSION: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.

Diencephalic syndrome in a female child due to intracranial germinoma: a case report.

INTRODUCTION: Diencephalic syndrome (DS) is a rare syndrome with failure to thrive (FTT) as the primary manifestation, which is often associated with astrocytoma or glioma and rarely caused by germinoma. To our knowledge, there are no reports of female patients presenting with DS secondary to germinoma. CASE REPORT: we report a case (an 11-year-old girl) of diencephalic syndrome presenting with FTT. She was diagnosed with severe malnutrition in the local hospital two years before admission and still did not show normal development after long-term nutritional support. Finally, after ruling out increased metabolism, inadequate caloric intake, and nutrient absorption, intracranial MRI showed a space-occupying lesion in the suprasellar cisterna-hypothalamus area. After excluding other causes of FTT, a biopsy was performed for pathological examination and demonstrated a germinoma. An excellent therapeutic effect was achieved during the three-month follow-up after radiotherapy. CONCLUSION: This case reminds us that intracranial tumors should be considered an indispensable etiology for patients with suspicious FTT, and early diagnosis and intervention may achieve a good prognosis.

Atopic dermatitis leading to failure to thrive: A case report.

We present an infant with severe atopic dermatitis, protein loss, and subsequent failure to thrive. With proper management, the patient's laboratory findings normalized, and he gained weight appropriately. In this report, we highlight the impact that severe atopic dermatitis may have growth and development and review the genetic conditions that can result in a similar clinical presentation.

Serial Long-Term Growth and Neurodevelopment of Very-Low-Birth-Weight Infants: 2022 Update on the Korean Neonatal Network.

BACKGROUND: We aimed to evaluate the long-term growth and neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs, birth weight < 1,500 g) born between 2013, the establishment of the Korean Neonatal Network (KNN), and 2018, both at 18-24 months of corrected age and three years of age, using a nationwide large cohort, and to evaluate whether these outcomes have improved over time since 2013. METHODS: This study used data from the annual reports of the KNN for 18-24 months of corrected age (follow-up 1) and three years of age (follow-up 2). Follow-up 1 data were collected from 10,065 eligible VLBWIs born between January 1, 2013, and December 31, 2018. Follow-up 2 data were collected from 8,156 eligible VLBWIs born between January 1, 2013, and December 31, 2017. RESULTS: The overall follow-up rates of VLBWIs at follow-ups 1 and 2 were 74.6% (7,512/10,065) and 57.7% (4,702/8,156), respectively. The overall mortality rate between discharge from the neonatal intensive care unit and follow-up 1 was 1% (104/10,065). The overall mortality rate between follow-ups 1 and 2 was 0.049% (4/8,156). Growth restrictions decreased over time, especially weight growth restrictions, which significantly decreased according to era (17% in infants born in 2013-2014 and 13% in infants born in 2017-2018). Fewer infants were re-hospitalized and required rehabilitative support according to era at follow-up 1. More infants had language developmental delays and required language support according to era, both at follow-ups 1 and 2. The incidence of cerebral palsy has significantly decreased over time, from 6% in infants born in 2013-2014 to 4% in infants born in 2017-2018 at follow-up 1, and from 8% in infants born in 2013-2014 to 5% in infants born in 2017 at follow-up 2. CONCLUSION: Long-term outcomes of VLBWIs regarding weight growth and cerebral palsy, the most common motor disability in childhood, have improved serially according to era since 2013. However, the rate of infants with language delays requiring language support has increased according to era. Further studies are required on the increased trends of language delay and language support while improving motor outcomes.

A late diagnosis of Pseudohypoaldosteronism type I in an infant with hypoplastic left heart syndrome presenting with failure to thrive.

Pseudohypoaldosteronism type I is caused by a peripheral resistance to aldosterone and can present with electrolyte abnormalities, poor growth, or dehydration. Although a rare disease, several case reports have been published regarding Pseudohypoaldosteronism type I in neonates and infants. We report a case of failure to thrive and hyponatremia in an infant with hypoplastic left heart syndrome who was subsequently found to have Pseudohypoaldosteronism type I.

A novel screening tool to predict severe acute malnutrition through automated monitoring of weight-for-age growth curves.

Weight-for-age (WFA) growth faltering often precedes severe acute malnutrition (SAM) in children, yet it is often missed during routine growth monitoring. Automated interpretation of WFA growth within electronic health records could expedite the identification of children at risk of SAM. This study aimed to develop an automated screening tool to predict SAM risk from WFA growth, and to determine its predictive ability compared with simple changes in weight or WFA z-score. To develop the screening tool, South African child growth experts (n = 30) rated SAM risk on 100 WFA growth curves, which were then used to train an artificial neural network (ANN) to assess SAM risk from consecutive WFA z-scores. The ANN was validated in 185 children under five (63 SAM cases; 122 controls) using diagnostic accuracy methodology. The ANN's performance was compared with that of changes in weight or WFA z-score. Even though experts' SAM risk ratings of the WFA growth curves differed considerably, the ANN achieved a sensitivity of 73.0% (95% confidence interval [CI]: 60.3; 83.4), specificity of 86.1% (95% CI: 78.6; 91.7) and receiver-operating characteristic curve area of 0.795 (95% CI: 0.732; 0.859) during validation with real cases, outperforming changes in weight or WFA z-scores. The ANN, as an automated screening tool, could markedly improve the identification of children at risk of SAM using routinely collected WFA growth information.

Deficiency of acyl-CoA synthetase 5 is associated with a severe and treatable failure to thrive of neonatal onset.

Failure to thrive (FTT) causes significant morbidity, often without clear etiologies. Six individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Standard diagnostic work up did not ascertain an etiology. Autozygosity mapping and whole exome sequencing identified homozygosity for a novel genetic variant of the long chain fatty acyl-CoA synthetase 5 (ACSL5) shared among the affected individuals (NM_203379.1:c.1358C>A:p.(Thr453Lys)). Autosomal recessive genotype-phenotype segregation was confirmed by Sanger sequencing. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss-of-function mutation without any remaining activity. ACSL5 belongs to an essential enzyme family required for lipid metabolism and is known to contribute the major activity in the mouse intestine. Based on the function of ACSL5 in intestinal long chain fatty acid metabolism and the gastroenterological symptoms, affected individuals were treated with total parenteral nutrition or medium-chain triglyceride-based formula restricted in long-chain triglycerides. The patients responded well and follow up suggests that treatment is only required during early life.

Biallelic deletion in a minimal CAPN15 intron in siblings with a recognizable syndrome of congenital malformations and developmental delay.

Calpainopathies constitute a heterogeneous group of disorders resulting from deficiencies in calpains, calcium-specific proteases that modulate substrates by limited proteolysis. Clinical manifestations depend on tissue-specific expression of the defective calpain and substrate specificity. CAPN15, encoding the Drosophila small optic lobes (sol) homolog, was recently found to cause various eye defects in individuals carrying bi-allelic missense variants. Here we report on two siblings with manifestations reminiscent of Johanson-Blizzard syndrome including failure to thrive, microcephaly, global developmental delay, dysmorphic features, endocrine abnormalities and congenital malformations, in addition to eye abnormalities. Exome sequencing identified a homozygous 47 base-pair deletion in a minimal intron of CAPN15, including the splice donor site. Sequencing of cDNA revealed single exon skipping, resulting in an out-of-frame deletion with a predicted premature termination codon. These findings expand the phenotypic spectrum associated with CAPN15 variants, and suggest that complete loss-of-function is associated with a recognizable syndrome of congenital malformations and developmental delay, overlapping Johanson-Blizzard syndrome and the recently observed brain defects in Capn15 knockout (KO) mice. Moreover, the data highlight the unique opportunity for indel detection in minimal introns.

Aldosterone synthase (CYP11B2) deficiency among Palestinian infants: Three novel variants and genetic heterogeneity.

Aldosterone synthase deficiency (ASD) is a rare potentially life-threatening genetic disorder that usually presents during infancy due to pathogenic variants in the CYP11B2 gene. Knowledge about CYP11B2 variants in the Arab population is scarce. Here, we present and analyze five Palestinian patients and their different novel pathogenic variants. Data on clinical presentation, electrolytes, plasma renin activity, and steroid hormone levels of five patients diagnosed with ASD were summarized. Sequencing of the CYP11B2 gene exons was followed by evolutionary conservation analysis and structural modeling of the variants. All patients were from highly consanguineous Palestinian families. The patients presented at 1-4 months of age with recurrent vomiting, poor weight gain, hyponatremia, hyperkalemia, and low aldosterone levels. Genetic analysis of the CYP11B2 gene revealed three homozygous pathogenic variants: p.Ser344Profs*9, p.G452W in two patients from an extended family, and p.Q338stop. A previously described pathogenic variant was found in one patient: p.G288S. We described four different CYP11B2 gene pathogenic variants in a relatively small population. Our findings may contribute to the future early diagnosis and therapy for patients with ASD among Arab patients who present with failure to thrive and compatible electrolyte disturbances.