Congenital Deficiency Research Articles

Challenges of Glycemic Control in Patients with Prader–Willi Syndrome Associated with Congenital Leptin Deficiency

Prader–Willi syndrome (PWS) is a rare multisystem genetic disorder and one of the syndromic causes of childhood obesity. It is characterized by learning difficulties and behavioral challenges with subsequent multiple endocrine and multisystem involvement. Congenital leptin deficiency is also a very rare disorder that causes early-onset obesity with hormonal and metabolic disturbances. In this report, we describe the case of an 11- year- old girl who presented to us with uncontrolled blood sugar, significant weight gain, behavioral disturbances and was diagnosed with PWS with congenital leptin deficiency, type 2 diabetes mellitus, hypothyroidism, hypertension and obstructive sleep apnea. The main purpose of this case report is to describe the barriers of glycemic control and lifestyle modification challenges and implement the optimal management plan in such a rare association.

High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor

The long-term clinical outcomes of severe obesity due to leptin signaling deficiency are unknown. We carry out a retrospective cross-sectional investigation of a large cohort of children with leptin (LEP), LEP receptor (LEPR), or melanocortin 4 receptor (MC4R) deficiency (n= 145) to evaluate the progression of the disease. The affected individuals undergo physical, clinical, and metabolic evaluations. We report a very high mortality in children with LEP (26%) or LEPR deficiency (9%), mainly due to severe pulmonary and gastrointestinal infections. In addition, 40% of surviving children with LEP or LEPR deficiency experience life-threatening episodes of lung or gastrointestinal infections. Although precision drugs are currently available for LEP and LEPR deficiencies, as yet, they are not accessible in Pakistan. An appreciation of the severe impact of LEP or LEPR deficiency on morbidity and early mortality, educational attainment, and the attendant stigmatization should spur efforts to deliver the available life-saving drugs to these children as a matter of urgency.

A novel smoothed (SMO) point mutation in congenital tibial hemimelia: a case report

BackgroundCongenital tibial hemimelia (CTH [MIM: 275220]) is a rare congenital limb deficiency that manifests as a shortened, curved, dysplastic or absent tibia with polydactyly. In previous studies, mutations of a distant sonic hedgehog (SHH) cis-regulator (ZRS) and a Shh repressor (GLI3) were identified.Case presentationHere, we admitted a 20-month-old boy who manifested with right tibial deformity, varus foot, ankle dislocation, and ipsilateral preaxial polydactyly. After genetic sequencing and data analysis, the results revealed a 443 A > G mutation in the father and a 536 C > T mutation in the mother in exon 2 of the Smoothed (SMO) gene at 7q32.1, with the coexistence of both mutant alleles in the proband/patient.ConclusionsOur report suggests that even though not previously reported, SMO mutations may be associated with limb anomalies such as tibial hemimelia via Hh signaling in humans and has implications for genetic counseling.

Gene Therapy for Cystic Fibrosis: Recent Advances and Future Prospects.

Gene replacement therapies are novel therapeutic approaches that seek to tackle hereditary diseases caused by a congenital deficiency in a particular gene, when a functional copy of a gene can be delivered to the cells and tissues using various delivery systems. To do this, viral particles carrying a functional copy of the gene of interest and various nonviral gene delivery systems, including liposomes, nanoparticles, etc., can be used. In this review, we discuss the state of current knowledge regarding the molecular mechanisms and types of genetic mutations that lead to cystic fibrosis and highlight recent developments in gene therapy that can be leveraged to correct these mutations and to restore the physiological function of the carrier protein transporting sodium and chlorine ions in the airway epithelial cells. Restoration of carrier protein expression could lead to the normalization of ion and water transport across the membrane and induce a decrease in the viscosity of airway surface fluid, which is one of the pathological manifestations of this disease. This review also summarizes recently published preclinical and clinical data for various gene therapies to allow one to make some conclusions about future prospects for gene therapy in cystic fibrosis treatment.

HTRS2023.O8C.4 Subject with infertility due to congenital plasminogen deficiency type 1: results of plasminogen replacement therapy and impact of varying dosage regimen during treatment and maintenance phases

HTRS2023.O8C.4 Subject with infertility due to congenital plasminogen deficiency type 1: results of plasminogen replacement therapy and impact of varying dosage regimen during treatment and maintenance phases

Nicotinamide Adenine Dinucleotide Deficiency and Its Impact on Mammalian Development.

Significance: Nicotinamide adenine dinucleotide (NAD) is an important molecule synthesized from tryptophan or vitamin B3 and involved in numerous cellular reactions. NAD deficiency during pregnancy causes congenital NAD deficiency disorder (CNDD) characterized by multiple congenital malformations and/or miscarriage. Studies in genetically engineered mice replicating mutations found in human patient cases show that CNDD can be prevented by dietary supplements. Recent Advances: A growing number of patient reports show that biallelic loss-of-function of genes involved in NAD de novo synthesis (KYNU, HAAO, NADSYN1) cause CNDD. Other factors that limit the availability of NAD precursors, for example, limited dietary precursor supply or absorption, can cause or contribute to NAD deficiency and result in CNDD in mice. Molecular flux experiments allow quantitative understanding of NAD precursor concentrations in the circulation and their usage by different cells. Studies of NAD-consuming enzymes and contributors to NAD homeostasis help better understand how perturbed NAD levels are implicated in various diseases and adverse pregnancy outcomes. Critical Issues: NAD deficiency is one of the many known causes of adverse pregnancy outcomes, but its prevalence in the human population and among pregnant women is unknown. Since NAD is involved in hundreds of diverse cellular reactions, determining how NAD deficiency disrupts embryogenesis is an important challenge. Future Directions: Furthering our understanding of the molecular fluxes between the maternal and embryonic circulation during pregnancy, the NAD-dependent pathways active in the developing embryo, and the molecular mechanisms by which NAD deficiency causes adverse pregnancy outcomes will provide direction for future prevention strategies. Antioxid. Redox Signal. 39, 1108-1132.

Lack of eosinophil extracellular trap formation due to failure of plasma membrane breakdown in the absence of elastase

AbstractActivated eosinophils are described to release eosinophil extracellular traps (EETs), which consist of the cell’s DNA covered with granule-derived antimicrobial peptides. Upon stimulation of eosinophils with the known EET-inducers phorbol 12-myristate 13-acetate, monosodium urate crystals, or Candida albicans, we observed that their plasma membrane became compromised, resulting in accessibility of the nuclear DNA for staining with the impermeable DNA dye Sytox Green. However, we did not observe any DNA decondensation or plasma membrane rupture by eosinophils, which sharply contrasts with neutrophil extracellular trap (NET) formation and the subsequent cell death known as NETosis. Neutrophil elastase (NE) activity is thought to be essential for the cleavage of histones and chromatin decondensation during NETosis. We observed that the neutrophils of a patient with a mutation in ELANE, leading to congenital neutropenia and NE deficiency, were unable to undergo NETosis. Taken together, we may suggest that the natural absence of any NE-like proteolytic activity in human eosinophils explains why EET formation is not observed, even when eosinophils become positive for an impermeable DNA dye in response to stimuli that induce NETosis in neutrophils.

Proposal of Model for Evaluation of Viral Kinetics of African/Asian/Brazilian-Zika virus Strains (Step Growth Curve) in Trophoblastic Cell Lines.

The Zika virus (ZIKV) epidemic brought new discoveries regarding arboviruses, especially flaviviruses, as ZIKV was described as sexually and vertically transmitted. The latter shows severe consequences for the embryo/fetus, such as congenital microcephaly and deficiency of the neural system, currently known as Congenital ZIKV Syndrome (CZS). To better understand ZIKV dynamics in trophoblastic cells present in the first trimester of pregnancy (BeWo, HTR-8, and control cell HuH-7), an experiment of viral kinetics was performed for African MR766 low passage and Asian-Brazilian IEC ZIKV lineages. The results were described independently and demonstrated that the three placental cells lines are permissive and susceptible to ZIKV. We noticed cytopathic effects that are typical in in vitro viral infection in BeWo and HTR-8. Regarding kinetics, MR766lp showed peaks of viral loads in 24 and 48 hpi for all cell types tested, as well as marked cells death after peak production. On the other hand, the HTR-8 lineage inoculated with ZIKV-IEC exhibited increased viral production in 144 hpi, with a peak between 24 and 96 hpi. Furthermore, IEC had peak variations of viral production for BeWo in 144 hpi. Considering such in vitro results, the hypothesis that maternal fetal transmission is probably a way of virus transmission between the mother and the embryo/fetus is maintained.

A Successful Treatment Approach in 2 Patients With Type 1 Plasminogen Deficiency: Intratracheal Application of Fresh Frozen Plasma and Tissue Plasminogen Activator.

Respiratory system involvement is common in congenital plasminogen deficiency. Although many treatment approaches have been tried, there is still no definitive treatment for respiratory system involvement. We report 2 congenital plasminogen deficiency cases, who presented with severe respiratory symptoms, for whom a novel treatment modality was tried. After intravenous administration of FFP (fresh frozen plasma), tissue plasminogen activator and FFP were administered intratracheally, and respiratory system findings improved. Intratracheal administration of tissue plasminogen activator and FFP is an available treatment modality for patients with lung involvement. Fibrin plaques should be carefully removed and new lesion formation should be prevented.

Congenital IGF-1 deficiency protects from cancer: lessons from Laron syndrome.

Many clinical and experimental studies have implicated the growth hormone (GH)-insulin-like growth factor (IGF-1) axis with the progression of cancer. The epidemiological finding that patients with Laron syndrome (LS), the best-characterized disease under the spectrum of congenital IGF-1 deficiencies, do not develop cancer is of major scientific and translational relevance. The evasion of LS patients from cancer emphasizes the central role of the GH-IGF-1 system in cancer biology. To identify genes that are differentially expressed in LS and that might provide a biological foundation for cancer protection, we have recently conducted genome-wide profiling of LS patients and normal controls. Analyses were performed on immortalized lymphoblastoid cell lines derived from individual patients. Bioinformatic analyses identified a series of genes that are either over- or under-represented in LS. Differential expression was demonstrated in a number of gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT and PI3K-AKT signaling, etc. Major differences between LS and controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. The identification of novel downstream targets of the GH-IGF-1 network highlights the biological complexity of this hormonal system and sheds light on previously unrecognized mechanistic aspects associated with GH-IGF-1 action in the cancer cell.

The establishment, maintenance, and adaptation of high- and low-impact chronic pain: a framework for biopsychosocial pain research.

The establishment, maintenance, and adaptation of high- and low-impact chronic pain: a framework for biopsychosocial pain research.

Management of Neonatal Isolated and Combined Growth Hormone Deficiency: Current Status.

Congenital growth hormone deficiency (GHD) is a rare disease caused by disorders affecting the morphogenesis and function of the pituitary gland. It is sometimes found in isolation but is more frequently associated with multiple pituitary hormone deficiency. In some cases, GHD may have a genetic basis. The many clinical signs and symptoms include hypoglycaemia, neonatal cholestasis and micropenis. Diagnosis should be made by laboratory analyses of the growth hormone and other pituitary hormones, rather than by cranial imaging with magnetic resonance imaging. When diagnosis is confirmed, hormone replacement should be initiated. Early GH replacement therapy leads to more positive outcomes, including reduced hypoglycaemia, growth recovery, metabolic asset, and neurodevelopmental improvements.

Clinical Profile of Congenital Factor XIII Deficiency in Children.

Congenital Factor 13 Deficiency (FXIIID) is a rare bleeding disorder (RBD) of autosomal recessive inheritance, with an incidence of 1 in 3-5million. The clinical symptomatology, diagnosis, and management of FXIIID are described. A retrospective chart review of children with FXIIID was performed from January 2000 through October 2021 at a tertiary care center in Southern India. The diagnosis was performed by the Urea clot solubility test (UCST) and Factor XIII antigen assay. Twenty children (representing 16 families) were included. Male: Female ratio was 1.5:1. The median age of symptom onset was 6 mo, and the median age of diagnosis was 1 y, demonstrating a delay in diagnosis. Consanguinity was present in 15 (75%) with 4 children having affected siblings. Clinical symptomatology ranged from mucosal bleeds to intracranial bleeds and hemarthrosis, with many children having a history of prolonged umbilical bleeding in their neonatal period. Fourteen children were on cryoprecipitate prophylaxis. Four children had breakthrough bleeds due to irregular prophylaxis, including one intracranial bleed due to a delay in cryoprecipitate prophylaxis during the covid pandemic. Congenital FXIIID presents with a wide range of bleeding manifestations. The high prevalence of consanguinity in Southern India can be a cause of FXIIID's high prevalence in this region. There is a propensity for intracranial bleeding with a significant number having this at first presentation. Regular prophylaxis is required and feasible to prevent potentially fatal bleeds.

Safety and efficacy of an anti–human APC antibody for prophylaxis of congenital factor deficiencies in preclinical models

AbstractRebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia. We engineered a humanized chimeric antibody, SR604, based on a previously published murine antibody, HAPC1573, which selectively blocks the anticoagulant activity of human activated protein C (APC). SR604 effectively blocked the anticoagulation activities of APC in human plasma deficient in various coagulation factors in vitro with affinities ∼60 times greater than that of HAPC1573. SR604 exhibited prophylactic and therapeutic efficacy in the tail-bleeding and knee-injury models of hemophilia A and B mice expressing human APC (humanized hemophilic mice). SR604 did not interfere with the cytoprotection and endothelial barrier function of APC, nor were there obvious toxicity effects in humanized hemophilic mice. Pharmacokinetic study showed a high bioavailability (106%) of subcutaneously injected SR604 in cynomolgus monkeys. These results demonstrate that SR604 is expected to be a safe and effective therapeutic and/or prophylactic agent with a prolonged half-life for patients with congenital factor deficiencies including hemophilia A and B.

An unlucky WHIMsical child – A case report

Immunodeficiency in children often has the worst prognosis and there are varied primary and secondary causes for immunodeficiency. Warts Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a congenital immune deficiency that increases the likelihood of human papillomavirus infection (Warts), a low white blood cell count, hypogammaglobulinemia, and bone marrow myelokathexis. We present the case of a 3-year-old child brought by an orphanage caretaker with a history of recurrent swelling in both eyelids, multiple skin lesions all over the body, and recurrent respiratory tract infections. The child has been treated with native medications elsewhere with no improvement noted. Work up done for immune deficient states and bone marrow evaluation revealed myelokathexis with neutropenia/lymphopenia which made the possibility of WHIM syndrome. Treatment with colony stimulating factor has been initiated but could not be continued due to financial constraints. This report emphasis on the need for work-up to make early diagnosis and intervention of the disease as such than treating only their manifestations.

Case Report: Tibial Hemimelia

Unilateral tibial hemimelia is an anomaly characterized by the absence of the tibia. Tibial hemimelia is the rarest form of congenital longitudinal deficiency of the tibia with an incidence of 1 in 1,000,000 live births. It is characterized by deficiency of tibia with relatively intact fibula. It causes marked shortening of the limb with a severe equinovarus deformity. It may occur in isolated form or combined with other congenital anomalies. Some cases of tibia hemimelia are genetically transmitted as autosomal dominant or recessive, whereas others are sporadic. The treatment is always difficult and challenging. Amputation was the preferred treatment option specially in complete tibial absence; however, a conservative management is used in other types of the deformity.

Prevalence of congenital sucrase-isomaltase deficiency in Turkey may be much higher than the estimates

Prevalence of congenital sucrase-isomaltase deficiency in Turkey may be much higher than the estimates

The Effects of Piracetam and Noopept on NMDA- and 5-HT2A-Receptors in the Brains of Mice with Congenital β-Arrestin Deficiency

The Effects of Piracetam and Noopept on NMDA- and 5-HT2A-Receptors in the Brains of Mice with Congenital β-Arrestin Deficiency

LIMBDREAM: THE LIMB RECONSTRUCTION REGISTRY OF EXPERIENCE, ASPIRATION, AND MEASURES

IntroductionPatient-reported outcome measures (PROMs) has gained momentum in the orthopaedic literature. The GOAL-LD (Gait Outcomes Assessment List for Limb Deformity) incorporates the framework of The WHO International Classification of Functioning, Disability and Health and correlates highly with the Paediatric Outcomes Data Collection Instrument (PODCI) when applied in a limb reconstruction setting. The Royal Children's Hospital Melbourne, Australia, supported by The University of Melbourne is designing and implementing a Limb Reconstruction Registry, prospectively enrolling patients with a number of key conditions and provide a mechanism for capturing surgical data and PROMs at regular follow-up intervals. LimbDREAM (The Limb Reconstruction Registry of Experience, Aspiration and Measures) has begun recruiting participants, and this paper serves as a narrative review of our design and implementation process.Materials & MethodsAfter provision of a research grant, audit was conducted to examine local case mix and estimate recruitment based on conditions selected. Literature review was focussed on (i) registries in the paediatric limb reconstruction domain and (ii) use of PROMs across conditions selected. A high-level process-flow chart was constructed in order to inform governance and staffing requirements in addition to REDCap Database structure. Local as well as scalable deployment was considered. Alpha and beta testing was performed by principal and associate investigators prior to participant recruitment.ResultsAudit identified 6 condition streams for inclusion: Congenital limb deficiencies, congenital pseudarthrosis of the tibia, bone dysplasias, bone tumours, amputation, and complex deformity of other etiology. Literature review identified 20 PROMs used across these conditions, with limited validation studies and significant implementation heterogeneity. REDCap database design took longer than anticipated (planned 10 months, actual 18 months) before being recruitment ready, due to the complexity of ensuring data collection logic would work across highly diverse patient journeys. Initial recruitment across all streams has been promising. Email and text message reminders have proved helpful in increasing survey return rates.ConclusionsProspective collection of PROMs as well as surgical data via a standardized dataset will provide the basis for future condition-specific research, with the ability to support nested trials. Implementation requires forethought with regard to time frames and staffing for non-automated steps as well as data integrity review. The next phase of the LimbDREAM project will be to integrate use of the Registry into our weekly Limb Reconstruction Meeting to ensure that operative plans and data are captured close to the point of care.

Traumatic rupture of anterolateral papillary muscle in a patient with congenital deficiency of left hemi-pericardium: case report

Abstract Congenital absence or deficiency of the pericardium or hemi-pericardium is uncommon. When it happens, the protection given to the heart is greatly reduced, and blunt or penetrating trauma to the chest is transmitted directly to the heart. Valvular injuries from these traumas are however rare with a case of tricuspid valve rupture reported. Traumatic papillary muscle rupture in all patients group is also rare. Co-existing rupture of papillary muscle in patients with congenital absence of the pericardium is extremely rare. We report the rare case of a patient with deficient left hemi-pericardium who had a traumatic rupture of the anterolateral papillary muscle from a road traffic accident.