Congenital Deficiency Research Articles

Motorized Plate Lengthening of the Femur in Children: A Preliminary Report.

Limb lengthening by distraction osteogenesis can be performed with motorized internal devices, but intramedullary implants risk avascular necrosis of the femoral head in young children. A method of internal limb lengthening using a motorized expandable plate has been developed and preliminary results are presented. Seven skeletally immature patients (ages 2.7 to 9.7y) with congenital femoral deficiencies underwent femoral lengthening with the use of a magnetic expandable plate. Surgical details, lengthening parameters, Limb Lengthening and Reconstruction Society-Angular deformity, Infection, Motion index, and complications were reviewed and classified according to the modified Clavien-Dindo system. An average lengthening was 4.1cm (range, 3.3 to 4.4cm) comprising 18% of initial femoral segment length (range, 14% to 21%). The average lengthening phase was 50.2 days (range, 40 to 57d) and weight-bearing was initiated at an average of 13 weeks from surgery (range, 8 to 18wk). Limb deformities and length discrepancies were of moderate complexity, with an Limb Lengthening and Reconstruction Society-Angular deformity, Infection, Motion score of 6.57 (range, 6 to 7). Complication rates were comparable to previously reported methods of femoral lengthening. One patient underwent reoperation for patellar instability and 1 patient experienced radiographic hip subluxation which was observed. Small magnitude varus was observed in regenerate in 3 of 7 cases, none requiring treatment. Preoperative planning consisted of careful localization of the corticotomy site, acute deformity correction at the lengthening site in 3 cases, and implant orientation. Limb lengthening with motorized internal plates is feasible for young children with congenital femoral deficiency for whom intramedullary lengthening is unsafe or if external fixation is to be avoided. However, the fundamental principles of distraction osteogenesis and risks of lengthening for congenital discrepancies remain unchanged. Specific considerations herein include: careful planning of implant length and positioning, adjacent joint protection with adjunctive means, and mitigating deformity of the regenerate during distraction. Level IV, retrospective case series.

Evaluation of the ulna lengthening by distraction osteogenesis in congenital radial deficiency

PurposePublications evaluating the results of the ulna lengthening in congenital radial deficiency are based only on small groups of subjects which yield statistical studies of low scientific value. The aim was to examine the effectiveness of ulna lengthening in radial longitudinal deficiency and determine the number and quality of complications based on one of the most numerous study groups described in the literature.MethodsThe material consists of a study group with 31 upper limbs of unmatured patients diagnosed with type III and IV radial longitudinal deficiency. The study group was evaluated based on the parameters known from the literature. The difficulties during elongation were classified according to Paley’s classification.ResultsThe study group contained patients with a mean age of 9 years, and the number of boys and girls was comparable. Ulna length significantly increased after elongation compared to the initial bone length. The patient’s age didn’t affect the ulna lengthening, and the amount of elongation didn’t significantly affect the total stabilization period. However, the total stabilization time increased with increasing patient age. Difficulties affected more than half of the cases.ConclusionsUlna elongation in congenital radial deficiency results in significant lengthening of the ulna, and thus the entire forearm, compared to the initial bone length. This technique has a high percentage of difficulty, so its use should be considered after cautious discussion with the parents and patients.

Effects of Aquatic Physical Therapy in Children With Congenital Femoral Deficiency Who Underwent Bone Lengthening Using an External Fixator: A Case Report

Introduction and Objective: Congenital femoral deficiency (CFD) is a malformation that affects 0.2 persons per 10,000 live births. The orthopedic treatment proposed for this disease is bone lengthening using an external fixator (EF). During this treatment, reductions in the range of motion (ROM) of the knee, alterations in the gait speed (GS), and worse quality of life (QOL) commonly occur. Therefore, rehabilitation of patients with CFD receiving this treatment is essential. Aquatic physical therapy (APT) is an innovative approach for this population, however, there are no reports on the effects of APT in patients with CFD after bone lengthening. The objective of this study was to assess the influence of APT on the knee ROM, GS, and QOL of 2 children with CFD implanted with an EF. Case Description: Two children with right-sided CFD implanted with an EF were selected. They received an APT protocol focusing on balance, muscle activation, analgesia and mobility of the right knee, and gait. The right knee ROM, GS, and QOL were measured using right knee goniometry, a 10-m walk test before and after each session, and the Child Health Questionnaire–Parent Form 50 before and after the protocol. Results: An increase in the ROM of the right knee and an improvement in the QOL were observed after the protocol. Only one of the children had an increased GS. Conclusion: The APT protocol increased the knee ROM and improved QOL of the 2 children with CFD implanted with an EF.

Thromboelastometry as an Ancillary Tool for Evaluation of Coagulation Status after rFVIIa Therapy in a Pregnant Woman with Severe Hypoproconvertinemia-A Case Series and Review of the Literature.

Introduction: Factor VII (FVII) deficiency is a rare hemorrhagic diathesis. In females, heavy menstrual and postpartum bleeding can appear as a consequence of its deficiency. Supplementation of the recombinant FVIIa is widely accepted. The supplementation effect in FVII-deficient subjects is difficult to predict, and severe hemorrhage has been described even when FVII levels after supplementation were within normal ranges. The aim of this report is to present the application of thromboelastometry to control the coagulation status in a patient with severe FVII deficiency during pregnancy and delivery, supplemented by rFVIIa per protocol complicated with life-threatening venous thromboembolism. Methods: Rotational thromboelastometry (ROTEM) was performed in 16 pregnant women: in one 28 year old primigravida at 35 weeks of pregnancy with congenital FVII deficiency after rFVIIa administration and 15 healthy women at 38 gestational weeks. The results were compared. Results: The thromboelastometry results showed significant shortening of the clotting time in the extrinsic and the intrinsic pathway in the hypoproconvertinemia patient after rFVIIa administration in relation to healthy pregnant women. A significant reduction in maximum lysis of the clot after FVII supplementation was observed. Conclusions: The thromboelastometry results showed a significant hypercoagulable state with hypoproconvertinemia. Thrombotic complications after delivery might be prevented by the reduction in rFVIIa guided by thromboelastometry. Thromboelastometry performed on a pregnant woman with factor VII deficiency during the supplementation of rFVIIa in peripartum time might be helpful in order to determine an individual, effective dosage regimen of rFVIIa to ensure full correction of clotting disorders without the tendency to develop thrombosis, but further studies are needed.

Use of orthoses and prostheses, physical capacity and satisfaction with the devices in children with congenital lower limb deficiencies

Use of orthoses and prostheses, physical capacity and satisfaction with the devices in children with congenital lower limb deficiencies

Nasolabial and distal limbs dry gangrene in newborn due to hypernatremic dehydration with disseminated intravascular coagulation: a case report

IntroductionGangrene is the death of an organ or tissue due to lack of blood supply or bacterial infection. In neonates, gangrene is usually caused by sepsis, dehydration, maternal diabetes, asphyxia, or congenital anticoagulant deficiency. It commonly occurs in the extremities. Gangrene may lead to death or amputation of the limb. Early diagnosis and prompt management of the underlying cause halts the progression of the disease.Case presentationA 12-day-old neonate presented with a complaint of black discoloration of the nose and feet for 2 days. He was breastfeeding poorly and had signs of dehydration. Upon physical examination, he was tachycardic (pulse rate = 182 beats per minute), tachypneic (respiratory rate = 62 breaths per minute), and hypothermic (temperature = 35.0 oC). He lost 33.3% of his birth weight. He had demarcated cold, dry, and dark discoloration of the entire nose, nasal septum; upper lip; palate; bilateral distal lower limbs; and the left fifth finger. Dorsalis pedis arteries were not palpable on either side. On investigation, the baby had pancytopenia, hypernatremia, elevated creatinine, elevated coagulation profiles, and absent arterial flow in bilateral dorsal pedis arteries. He was treated for hypernatremic dehydration and possible sepsis. He was transfused with whole blood, platelets, and fresh frozen plasma, but finally, the patient passed away on the 7th day of admission.ConclusionThe entire nose, upper lip, soft and hard palate, symmetric lower limb, and fifth finger gangrene due to severe hypernatremic dehydration complicated by disseminated intravascular coagulation may occur in the same patient. To avoid such serious neonatal problems, mothers should be properly educated about optimal breastfeeding techniques and schedule well-child visits 3–5 days after birth.

Phenotypic and genotypic analysis of patients with congenital factor VII deficiency in a multicenter study in Thailand

ObjectiveThe phenotypic and genotypic analysis of patients with congenital factor VII deficiency were retrospectively conducted. MethodsThe study included 26 patients defined as severe (n = 25) and moderate (n = 1) degree by FVII <10% and 10–20%, respectively. ResultsThe diagnosis of factor VII deficiency was based on an isolated prolonged prothrombin time with subsequent factor assay. The median age of first bleed was 7 days (IQR 2–11.2 days). Central nervous system and gastrointestinal tract bleeding were found among all patients with severe degree. Patients with FVII <1–3% exhibited serious bleeding during the first week to the first month of life while patients with FVII >3% did not exhibit serious spontaneous bleeding. The initial bleeding episodes were controlled by administering fresh frozen plasma (FFP) and switched to factor concentrates among a few patients upon definite diagnosis. Subsequent prophylaxis was provided to patients with initial severe bleeding manifestation using FFP (15 ml/kg) 2–3 times weekly or recombinant factor VIIa (90 μg/kg) twice weekly. Genotypic analysis revealed homozygous or double heterozygous mutations among all patients except one patient with heterozygous mutation combined with homozygous polymorphism at codon 413 of G to A substitution (AA) at exon 8 of the FVII gene. The FVII gene mutation was commonly found at IVS6+1G > T (38.3%), followed by p.K376 X (19.2%) and IVS2+2T > C (17.0%). The case fatality rate was 19.2% (5/26) among patients with severe degree. ConclusionEarly diagnosis and appropriate management of congenital factor VII deficiency is essential for favorable outcomes.

Erzincan Bölgesinde Yaşayan Çocuklarda Üçüncü Molar Dişlerin Konjenital Eksikliğinin Araştırılması

Background:In this study, it was planned to retrospectively determine the congenital deficiencies of the third molars in 1460 panoramic films of pediatric patients in the Erzincan region and to examine the distribution according to gender and location in the jaws. Methods:This retrospective study was conducted at Erzincan Binali Yıldırım University, Faculty of Dentistry from June 2018 - January 2020. 1460 patients(752 females and 708 males) between the ages of 10-14 were studied with panoramic radiograph to assess for agenesis of mandibular third molars. Statistical data were analyzed in SPSS 22 program. The Pearson chi-square test was performed for determining the prevalence of congenitally agenesis of the third molar teeth. Results:The prevalence of third molar teeth agenesis was 35.6 %. Total numbers of patients with single third molar missing were 222(15.5 %). The ratio of the prevalence of third molar agenesis for females(38 %) was higher than that for males(33 %). Significantly more third-molar teeth were found to be missing from the maxilla(57 %) than the mandible(43 %). 529 patients(54 %) had agenesis only on the right side and 469 patients(46 %) had agenesis only on the left. Conclusion:The agenesis of the third molars was investigated in pediatric patients living in Erzincan province and its prevalence was found 35.6 %. Congenital deficiency of the third molar teeth is more common in women, while it has been observed more in the maxilla than in the mandible. More comprehensive studies can be done by increasing the number of individuals examined.

ADAMTS13 levels in a plasma-derived FVIII concentrate: A potential therapeutic option for patients with congenital thrombotic thrombocytopenic purpura

IntroductionTreatment of congenital thrombotic thrombocytopenic purpura (cTTP), a disease characterized by the congenital deficiency of ADAMTS13, remains a challenge as there are no specific treatments available yet, other than therapy based on the use of fresh frozen plasma (FFP). Since cTTP is caused by low levels of ADAMTS13 protein, commercially available coagulation factor concentrates have been considered as potential ADAMTS13 source in place of FFP. The study aimed to validate the therapeutic potential of a plasma-derived factor VIII (FVIII) product as a source of ADAMTS13. MethodsThe quantitation of ADAMTS13 activity levels in eight lots of a plasma-derived FVIII product, (Koāte®) was carried out with three different methodologies: a Fluorescence Resonance Energy Transfer (FRET) assay, a chemiluminescence assay, and a chromogenic ELISA. ADAMTS13 protein antigen levels were measured by the FRET technique as well. In addition, von Willebrand factor (VWF) activity (VWF ristocetin cofactor, VWF:RCo, and VWF collagen binding, VWF:CB) and antigen (VWF:Ag) were measured using chemiluminescence assays. Qualification protocols were applied to the methods used. ResultsThe results showed high levels of ADAMTS13 in all eight Koāte® lots analyzed, with antigen and activity levels respectively of 10.72 IU/ml ± 3.94 and 5.62 IU/ml ± 1.39. Despite the significant content of ADAMTS13, VWF integrity seems not to be affected (0.81 ± 0.15 VWF:RCo/VWF:Ag and 0.75 ± 0.15 VWF:CB/VWF:Ag ratios). ConclusionsThese findings suggest that Koāte® could be a potential candidate for the treatment of cTTP, warranting evaluation in a clinical trial.

Mutations of TFPI-binding exosites on factor VII cause bleeding phenotypes in factor VII deficiency

AbstractTissue factor (TF) pathway inhibitor (TFPI) is a Kunitz-type anticoagulation protein that inhibits activated factor VII (FVIIa)/TF complex. Incidentally, many different F7 gene variants, including TFPI-binding exosite mutations, have been reported in patients with congenital FVII deficiency and clinical bleeding variabilities. Here, TFPI-binding exosites (R147 and K192) on FVII zymogen were selectively disrupted to understand their roles in the pathogenesis of bleeding phenotypes. Expression of recombinant FVII variants (R147A, K192A, and R147A/K192A) demonstrated markedly reduced secretion of FVII owing to intracellular retention in the endoplasmic reticulum, as demonstrated by upregulation of the unfolded protein response genes in all FVII variants. FVII variants showed a similar FVII activation pattern and FVIIa amidolytic activity than FVII wild-type (WT). In contrast to FVII activation, R147A and K192A showed a 90% reduction in FX activation relative to WT, whereas the R147A/K192A variant demonstrated a 99% decrease in FX activation. The clotting time was markedly prolonged with R147A and K192A than WT, and no FVII coagulant activity was detected in R147A/K192A. In addition, the thrombin generation assay revealed a significant prolongation of lag time in all FVII variants. Our study explains how mutations of TFPI-binding exosites of FVII can lead to bleeding phenotypes in individuals carrying these aberrancies.

Severe pathogenic variants of intestinal sucrase-isomaltase interact avidly with the wild type enzyme and negatively impact its function and trafficking

Sucrase-isomaltase (SI) is the major disaccharidase of the small intestine, exhibiting a broad α-glucosidase activity profile. The importance of SI in gut health is typified by the development of sucrose and starch maldigestion in individuals carrying mutations in the SI gene, like in congenital sucrase-isomaltase deficiency (CSID). Common and rare defective SI gene variants (SIGVs) have also been shown to increase the risk of irritable bowel syndrome (IBS) with symptoms and clinical features similar to CSID and also in symptomatic heterozygote carriers. Here, we investigate the impact of the most abundant and highly pathogenic SIGVs that occur in heterozygotes on wild type SI (SIWT) by adapting an in vitro system that recapitulates SI gene heterozygosity. Our results demonstrate that pathogenic SI mutants interact avidly with SIWT, negatively impact its enzymatic function, alter the biosynthetic pattern and impair the trafficking behavior of the heterodimer. The in vitro recapitulation of a heterozygous state demonstrates potential for SIGVs to act in a semi-dominant fashion, by further reducing disaccharidase activity via sequestration of the SIWT copy into an inactive form of the enzymatic heterodimer. This study provides novel insights into the potential role of heterozygosity in the pathophysiology of CSID and IBS.

A Literature Review of the Causes of Congenital Limb Deficiencies Over the Last 20 Years

ABSTRACT Introduction Despite the prevalence of congenital limb deficiencies (CLDs) occurring in around 7.9/10,000 births (Am J Med Genet A. 2011;155A:1225–1235), there is still a gap in the knowledge regarding the etiology of a large proportion of cases, and literature addressing this topic is sparser compared with other conditions. Objective The aim of this study is to assess the literature surrounding the causes of CLDs and use this to suggest the area in which a potential gap in the information on the causes of CLDs lies. Study Design This study is a literature review on articles published from the year 2000 onward. Methods A search was conducted on five databases (CINAHL, Scopus, PubMed, Embase, Cochrane Library) and the ProQuest platform resulting in 18 articles to be discussed, after inclusion and exclusion criteria were applied and critical appraisals were completed. Results and Discussion The main findings could be separated into four themes including genetics, environment, drugs, and vascular. Comparisons were made among similar literature, although within some topics, this was less effective, given the specificity and reduced volume of research. Positive correlations were seen in all studies; however, the biggest underlying factor for most causes seemed to originate from a vascular disruption. Conclusions Future studies should focus on an underlying vascular disruption as a base for further research to attempt to find reasoning for the proportion of CLDs with an unknown cause. Further attempts should be made into creating a consensus on classifying and recording CLDs to ensure a more uniform approach to this topic worldwide, allowing comparisons to be drawn more easily. Clinical Relevance Understanding relevant terminology is vital to ensure that families experiencing CLD receive accurate information about their child's condition. This understanding will also lead to improvements in the quality of recorded data, such as clinical notes and registry inputs.

Effects of color-enhancing glasses on color vision in congenital red-green color deficiencies.

As commercially available glasses for color vision deficiency (CVD) are classified as low risk, they are not subject to stringent marketing regulations. We investigate how EnChroma and VINO glasses affect performance on the Colour Assessment and Diagnosis (CAD) test in individuals with CVD. Data were obtained from 51 individuals with red-green CVD. Blood or saliva samples were collected to examine the structure of the OPN1LW/OPN1MW array. Individuals completed the CAD test twice without glasses and once with each pair of glasses. Although there was a statistically significant effect of both glasses, only that of VINO could be considered functionally meaningful.

Hematuria in Patients with Congenital Coagulation Factor Deficiencies

Hematuria in Patients with Congenital Coagulation Factor Deficiencies

A large population study reveals a novel association between congenital color vision deficiency and environmental factors

The molecular genetics underlying color-vision deficiencies (CVD) has been established and widely studied. The aim of this study is to assess the associations between the prevalence of CVD and both genetics (place of origin) and environment (place of birth).

Physiological Function and Congenital Deficiency of α-TTP, a Determinant of Vitamin E Transport in the Body -One Portion of the Research for Which the Pharmaceutical Society of Japan Award Was Given

This review summarizes one portion of the research for which the author received the Pharmaceutical Society of Japan Award. The complete title of the awarded research is "Pharmacological Studies on Metabolism and Functions of Biomembrane Lipids". Because the awarded research is a very broad study, this review describes the discovery, physiological functions, and congenital defects of α-tocopherol transfer protein (α-TTP), a critical factor in determining the transport of vitamin E in the body, which has been the focus of the author's work throughout his research career.

High Prevalence of Congenital Factor VII (FVII) Deficiency in Adolescent Females with Heavy Menstrual Bleeding and Iron Deficiency Anemia

To examine the clinical characteristics and prevalence of congenital bleeding disorders (CBDs), with emphasis on congenital factor VII (FVII) deficiency and other rare bleeding disorders, in adolescent and young adult females referred to a hemophilia treatment center (HTC) for evaluation and management of heavy menstrual bleeding (HMB) and iron deficiency anemia (IDA) DESIGN: In this single-center retrospective study, we reviewed the clinical characteristics and prevalence of CBDs in postmenarchal females, younger than 22 years of age, referred to an HTC from 2015 to 2021 for evaluation of HMB with or without IDA. One hundred females, with a mean age of 15 years (range 9-20 years), met initial study criteria, and 95 were included in the final analysis. Forty-five (47%) females were ultimately diagnosed with a CBD. The most prevalent diagnoses were FVII deficiency and type 1 von Willebrand disease (VWD) (42.3%, n=19 each). Forty-two percent of patients with FVII deficiency had a low-for-age FVII activity level, 21.1% were only positive for the FVII R353Q variant associated with borderline FVII levels, whereas 36.8% had both a low-for-age FVII activity level and a positive R353Q variant. Eighty percent of patients with a CBD were found to have relatives with abnormal bleeding symptoms. Congenital FVII deficiency is prevalent among female adolescents experiencing HMB with or without IDA. In addition to VWD, evaluation for this specific factor deficiency should be considered as part of the initial CBD workup. Presence of abnormal bleeding history in the family could also help to predict presence of a CBD.

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V.

The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.

Non-syndromic familial congenital dental deficiency: two cases report.

Congenital dental deficiency can lead to aesthetic and masticatory dysfunction, which have a great effect on the quality of life of patients. Genetic inheritance is the determining factor of congenital dental deficiency, which may follow the pattern of autosomal dominant, recessive, or sex chromosome inheritance. However, the specific genetic mechanisms are not clear. The prevalence of congenital absence of permanent teeth in the general population worldwide are not high, and familial oligodontia in clinically healthy patients is rare. This paper reported two cases of familial non-syndromic congenital teeth loss and included a review of literature referring to the etiology, clinical manifestations, and treatment of congenital dental deficiency.

Phenotypic and genotypic characterization of two factor VII deficiency patients from southeastern China.

The congenital factor VII deficiency (FVIID) is a rare autosomal recessive haemorrhagic disease caused by mutations in the F7 gene. The aim of this study was to identify the mutations causing FVII deficiency and explain the genotype-phenotype association in two unrelated Chinese patients. Mutation detection was conducted by sequencing the whole F7 gene coding exons, exon-intron boundaries and the untranslated regions of 3' and 5'. Then, the genetic information was analyzed to predict the structures of the mutated proteins. A total of four different mutations were detected, including three missense mutations (c.64G>A, c.286A>G, and c.722C>A, predicting p.Gly22Ser, p.Arg96Gly, p.Thr241Asn, respectively) and one insertion mutation (c.204_205insCGGC, predicting p. Leu68Argfs ∗ 37), among which two were reported for the first time (p.Arg96Gly, p.Leu68Argfs ∗ 37). Multiple sequence alignments of FVII protein revealed that the residues p.Arg96 and p.Thr241 were highly conserved. The novel missense mutation p.Arg96Gly was determined as damaging with online software Polyphen-2 and SIFT. We investigated two asymptomatic patients diagnosed with severe FVII deficiency and identified two novel mutations (the mutation p.Arg96Gly and p.Leu68Argfs ∗ 37). Identification of the F7 mutations was important for genetic counseling and accurate prediction of the inheritance pattern.