AAPS J. 2023 Jan 18;25(1):16. doi: 10.1208/s12248-023-00784-8.

ABSTRACT

In August 2021, the US Food and Drug Administration approved Nexviazyme (avalglucosidase alfa-ngpt) for intravenous infusion to treat patients 1 year of age and older with late-onset Pompe disease (LOPD). The effectiveness and safety were studied in patients with LOPD and patients with infantile-onset Pompe disease (IOPD). The dosage(s) tested in clinical trials was 20 mg/kg every other week (qow) in patients with LOPD and 20 mg/kg and 40 mg/kg qow in patients with IOPD. While patients 3 years old and greater with LOPD were eligible for participation in the pivotal trial, the youngest patient enrolled was 16 years old. Therefore, pediatric patients with LOPD were not well represented in the clinical trial. The prevalence of LOPD in pediatrics is extremely low. Thus, conducting a clinical trial in pediatric patients with LOPD would be challenging. Given the similar pathophysiology, mechanism of action, and disease manifestations across the age spectrum of patients with LOPD, the approved dosages for pediatric patients younger than 16 years old with LOPD were based on extrapolation of efficacy using a model-informed exposure bridging strategy, leveraging the safety data from pediatric patients with IOPD. Specifically, the exposure associated with 20 mg/kg qow in adult patients with LOPD was the target exposure for bridging of efficacy. The safety data obtained with 40 mg/kg qow in patients with IOPD was leveraged to support approval in pediatric patients with LOPD aged 1 year and older. This article illustrates a regulatory use of model-informed extrapolation approach for dose selection in pediatric patients with a rare disease.

PMID:36653728 | DOI:10.1208/s12248-023-00784-8

Eur Rev Med Pharmacol Sci. 2023 Jan;27(1):426-430. doi: 10.26355/eurrev_202301_30898.

ABSTRACT

OBJECTIVE: In this study, we have evaluated 12 patients with cerebral alveolar echinococcosis (AE). All patients underwent surgery for cerebral AE. We aimed to demonstrate the relationship between the demographic properties of patients and surgical outcomes as well as surgical suggestions about surgical approaches.

PATIENTS AND METHODS: Patients were analyzed according to demographic properties, hepatic/ pulmonary AE lesion existence, symptoms, neurological and radiological examination, histopathological findings, and outcome after treatment.

RESULTS: Preoperative diagnosis based on the history of the patient, neurological examination, serological tests, and radiology. When enhanced radiological imaging like MR-Tractography and intraoperative neuromonitoring is combined with precision surgical methods cerebral AE is treatable. Ten of twelve cerebral AE patients had favorable outcomes after surgery.

CONCLUSIONS: AE of the brain is a rare but life-threatening parasitic disease. Wherever the primary focus is, surgery for cerebral involvement of AE is challenging but safe with appropriate surgical techniques and the help of radiological examination.

PMID:36647892 | DOI:10.26355/eurrev_202301_30898

Int J Equity Health. 2023 Jan 13;22(1):11. doi: 10.1186/s12939-022-01809-y.

ABSTRACT

Early diagnosis of genetic rare diseases is an unmet need in Brazil, where an estimated 10-13 million people live with these conditions. Increased use of chromosome microarray assays, exome sequencing, and whole genome sequencing as first-tier testing techniques in suitable indications can shorten the diagnostic odyssey, eliminate unnecessary tests, procedures, and treatments, and lower healthcare expenditures. A selected panel of Brazilian experts in fields related to rare diseases was provided with a series of relevant questions to address before a multi-day conference. Within this conference, each narrative was discussed and edited through numerous rounds of discussion until agreement was achieved. The widespread adoption of exome sequencing and whole genome sequencing in Brazil is limited by various factors: cost and lack of funding, reimbursement, awareness and education, specialist shortages, and policy issues. To reduce the burden of rare diseases and increase early diagnosis, the Brazilian healthcare authorities/government must address the barriers to equitable access to early diagnostic methods for these conditions. Recommendations are provided, including broadening approved testing indications, increasing awareness and education efforts, increasing specialist training opportunities, and ensuring sufficient funding for genetic testing.

PMID:36639662 | PMC:PMC9837951 | DOI:10.1186/s12939-022-01809-y

WMJ. 2022 Dec;121(4):297-300.

ABSTRACT

INTRODUCTION: Despite universal newborn screening, there is no comprehensive surveillance system to understand the sickle cell disease population in Wisconsin.

METHODS: We initiated the development of a sickle cell disease surveillance system by linking newborn screening data and electronic health records from 2 large tertiary health care institutions in Wisconsin: Children's Wisconsin and Froedtert Hospital.

RESULTS: There were 1478 individuals within the 3 data sources. One hundred thirty-two (82%) of 159 identified by newborn screening from 2013 through 2019 received care at Children's Wisconsin. The majority of individuals with sickle cell disease at Children's Wisconsin and Froedtert Hospital resided in Milwaukee County.

DISCUSSION: The new surveillance program will increase our understanding of the sickle cell disease population in Wisconsin and help improve quality of care and health outcomes.

PMID:36637841

Neurobiol Dis. 2023 Jan 10:105996. doi: 10.1016/j.nbd.2023.105996. Online ahead of print.

ABSTRACT

Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeats in intron 1 of FXN, while some are compound heterozygotes with an expanded GAA tract in one allele and a missense or nonsense mutation in the other. A missense mutation, changing a glycine to valine at position 130 (G130V), is prevalent among the clinical variants. We and others have demonstrated that levels of mature FXN protein in FRDA G130V samples are reduced below those detected in samples harboring homozygous repeat expansions. Little is known regarding expression and function of endogenous FXN-G130V protein due to lack of reagents and models that can distinguish the mutant FXN protein from the wild-type FXN produced from the GAA-expanded allele. We aimed to determine the effect of the G130V (murine G127V) mutation on Fxn expression and to define its multi-system impact in vivo. We used CRISPR/Cas9 to introduce the G127V missense mutation in the Fxn coding sequence and generated homozygous mice (FxnG127V/G127V). We also introduced the G127V mutation into a GAA repeat expansion FRDA mouse model (FxnGAA230/KO; KIKO) to generate a compound heterozygous strain (FxnG127V/GAA230). We performed neurobehavioral tests on cohorts of WT and Fxn mutant animals at three-month intervals for one year, and collected tissue samples to analyze molecular changes during that time. The endogenous Fxn G127V protein is detected at much lower levels in all tissues analyzed from FxnG127V/G127V mice compared to age and sex-matched WT mice without differences in Fxn transcript levels. FxnG127V/G127V mice are significantly smaller than WT counterparts, but perform similarly in most neurobehavioral tasks. RNA sequencing analysis revealed reduced expression of genes in oxidative phosphorylation and protein synthesis, underscoring the metabolic consequences in our mouse model expressing extremely low levels of Fxn. Results of these studies provide insight into the unique pathogenic mechanism of the FXN G130V mechanism and the tolerable limit of Fxn/FXN expression in vivo.

PMID:36638893 | DOI:10.1016/j.nbd.2023.105996

Orphanet J Rare Dis. 2023 Jan 9;18(1):6. doi: 10.1186/s13023-022-02598-x.

ABSTRACT

The "diagnostic odyssey" describes the process those with undiagnosed conditions undergo to identify a diagnosis. Throughout this process, families of children with undiagnosed conditions have multiple opportunities to decide whether to continue or stop their search for a diagnosis and accept the lack of a diagnostic label. Previous studies identified factors motivating a family to begin searching, but there is limited information about the decision-making process in a prolonged search and how the affected child impacts a family's decision. This study aimed to understand how families of children with undiagnosed diseases decide whether to continue to pursue a diagnosis after standard clinical testing has failed. Parents who applied to the Undiagnosed Disease Network (UDN) at the National Institutes of Health (NIH) were recruited to participate in semi-structured interviews. The 2015 Supportive Care Needs model by Pelenstov, which defines critical needs in families with rare/undiagnosed diseases, provided a framework for interview guide development and transcript analysis (Pelentsov et al in Disabil Health J 8(4):475-491, 2015. https://doi.org/10.1016/J.DHJO.2015.03.009 ). A deductive, iterative coding approach was used to identify common unifying themes. Fourteen parents from 13 families were interviewed. The average child's age was 11 years (range 3-18) and an average 63% of their life had been spent searching for a diagnosis. Our analysis found that alignment or misalignment of parent and child needs impact the trajectory of the diagnostic search. When needs and desires align, reevaluation of a decision to pursue a diagnosis is limited. However, when there is conflict between parent and child desires, there is reevaluation, and often a pause, in the search. This tension is exacerbated when children are adolescents and attempting to balance their dependence on parents for medical care with a natural desire for independence. Our results provide novel insights into the roles of adolescents in the diagnostic odyssey. The tension between desired and realistic developmental outcomes for parents and adolescents impacts if, and how, the search for a diagnosis progresses.

PMID:36624503 | PMC:PMC9830697 | DOI:10.1186/s13023-022-02598-x

Int J Environ Res Public Health. 2022 Dec 27;20(1):395. doi: 10.3390/ijerph20010395.

ABSTRACT

Rare diseases are a subject of great scientific and health interest that has been on the rise in recent years [...].

PMID:36612717 | PMC:PMC9819633 | DOI:10.3390/ijerph20010395

Phys Chem Chem Phys. 2023 Jan 6. doi: 10.1039/d2cp03012h. Online ahead of print.

ABSTRACT

In silico strategies offer a reliable, fast, and inexpensive, way compared to the clumsy in vitro approaches to boost understanding of the effect of amino acid substitution on the structure and consequently the associated function of proteins. In the present work, we report an atomistic-based, reliable in silico structural and energetic framework of the interactions between the receptor-binding domain of the Interleukin-15 (IL-15) protein and its receptor Interleukin-15α (IL-15α), consequently, providing qualitative and quantitative details of the key molecular determinants in ligand/receptor recognition. Molecular dynamics simulations were used to investigate the dynamic behavior of the specific binding between IL-15 and IL-15α followed by estimation of the free energies via molecular mechanics/generalized Born surface area (MM/GBSA). In particular, residues Y26, E46, E53, and E89 of the IL-15 protein receptor-binding domain are identified as main hot spots, shaping and governing the stability of the assembly. These results can be used for the development of neutralizing antibodies and the effective structure-based design of protein-protein interaction inhibitors against the so-called orphan disease, vitiligo.

PMID:36607223 | DOI:10.1039/d2cp03012h

Orphanet J Rare Dis. 2023 Jan 4;18(1):1. doi: 10.1186/s13023-022-02606-0.

ABSTRACT

Alkaptonuria is a rare inherited disorder for which there was no disease-modifying treatment. In order to develop a successful approved therapy of AKU multiple barriers had to be overcome. These included activities before the conduct of the study including deciding on the drug therapy, the dose of the drug to be used, clarify the nature of the disease, develop outcome measures likely to yield a positive outcome, have a strategy to ensure appropriate patient participation through identification, build a consortium of investigators, obtain regulatory approval for proposed investigation plan and secure funding. Significant barriers were overcome during the conduct of the multicentre study to ensure harmonisation. Mechanisms were put in place to recruit and retain patients in the study. Barriers to patient access following completion of the study and regulatory approval were resolved.

PMID:36600285 | DOI:10.1186/s13023-022-02606-0

Indian J Pathol Microbiol. 2023 Apr-Jun;66(2):385-387. doi: 10.4103/ijpm.ijpm_316_21.

ABSTRACT

Fibrolamellar hepatocellular carcinoma is a rare primary hepatic tumor that usually occurs in youth. The common presenting features are vague abdominal pain, nausea, vomiting and weight loss. We present a case report of a young male who presented with cholestatic jaundice and on evaluation was diagnosed to have fibrolamellar hepatocellular carcinoma. He underwent successful surgical resection of the tumor. In young individuals presenting with unexplained cholestasis, fibrolamellar hepatocellular carcinoma should be considered.

PMID:37077092 | DOI:10.4103/ijpm.ijpm_316_21

Turk J Pediatr. 2022;64(6):1161-1164. doi: 10.24953/turkjped.2022.342.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a multisystemic, autosomal recessive disease, which is caused by a mutation in the transmembrane conduction regulator protein (CFTR) gene. We present a patient who was diagnosed with CF and later diagnosed with Niemann-Pick type-A (NPA) disease, which is an autosomal recessive lysosomal lipid storage disease.

CASE: A 2-month-old Syrian refugee patient was diagnosed with CF due to a high sweat test and two homozygous CFTR-related pathogenic gene mutations in our pediatric pulmonology clinic, where she was referred due to a high immunoreactive trypsinogen (IRT) value as a result of newborn screening. As the patient had neurological symptoms and hepatosplenomegaly that could not be explained by CF in the clinical follow-up, the patient was diagnosed with NPA was made with a cherry red spot on eye examination, foam cells in the bone marrow, and low sphingomyelinase activity, in addition to CF.

CONCLUSIONS: Although CF and NP have common systems of involvement in both diseases, pathological symptoms have different origins. If a patient with CF has simultaneous neuromotor delay, other autosomal recessive diseases that may accompany it should be suspected. In studies, similar pathological pathways related to abnormal cholesterol accumulation in the cell were detected between NP type C and CF. But our case was NPA. As case reports on the coexistence of the two diseases increase, we believe that a better understanding of similar pathological pathways may lead to new therapeutic targets for both diseases.

PMID:36583901 | DOI:10.24953/turkjped.2022.342

Cancer Med. 2022 Dec 30. doi: 10.1002/cam4.5587. Online ahead of print.

ABSTRACT

BACKGROUND: Prostate cancer (PCa) is a major cause of cancer morbidity and mortality for men globally, and androgen signaling clearly drives its onset and progression. Androgen receptor (AR) regulation is complex and remains elusive, despite several studies tackling these issues. Therefore, elucidating the mechanism(s) underlying AR regulation is a potentially promising approach to suppressing PCa.

METHODS: We report that Par14, one isoform of the prolyl isomerases homologous to Pin1, is a critical regulator of AR transcriptional activity and is essential for PCa cell growth.

RESULTS: Par14 was shown to be overexpressed in PCa, based on analyses of deposited data. Importantly, overexpression of Par14 significantly enhanced androgen-sensitive LNCap cell growth. In contrast, silencing of Par14 dramatically decreased cell growth in LNCap cells by causing cell cycle arrest. Mechanistically, silencing of the Par14 gene dramatically induced cyclin-dependent kinase inhibitor p21 at both the mRNA and the protein level through modulating the localization of p53. In addition, suppression of Par14 in LNCap cells was shown to downregulate the expressions of androgen response genes, at both the mRNA and the protein level, induced by dihydrotestosterone. Par14 was shown to directly associate with AR in nuclei via its DNA-binding domain and augment AR transcriptional activity.

CONCLUSION: Thus, Par14 plays a critical role in PCa progression, and its enhancing effects on AR signaling are likely to be involved in the underlying molecular mechanisms. These findings suggest Par14 to be a promising therapeutic target for PCa.

PMID:36583514 | DOI:10.1002/cam4.5587

BMJ Open. 2022 Sep 1;12(9):e060394. doi: 10.1136/bmjopen-2021-060394.

ABSTRACT

OBJECTIVES: Rare diseases are characterised by low incidence, often with little evidence for effective treatments. Isolated patients and specialist centres for rare diseases are increasingly connected, thanks to the internet. This scoping review aimed to identify issues facing people with a rare disease that authors report may be addressed by electronic resources (mobile applications, websites, social media platforms, telehealth and online portals).

DESIGN: Scoping review guided by the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines.

DATA SOURCES: Medline, Embase and PsycInfo were searched, supplemented by hand searches of selected journals, in July 2021.

ELIGIBILITY CRITERIA: Peer-reviewed literature in English was searched using terms for rare disease (incidence <1:2000), electronic modalities (eg, mobile phone) and patient support terms. No date limit was set. Conference abstracts were included.

DATA EXTRACTION AND SYNTHESIS: Data extracted: rare disease/group of diseases, name of the e-resource, need identified in the patient cohort, features of the e-resource, any other findings or observations of interest. From this, a framework was developed synthesising features across diseases and resources.

RESULTS: Seventy-two papers were found (from 383). Fifty-six electronic resources were described in 64 papers, while 12 papers were exploratory studies. Cystic fibrosis (n=28) was the most frequently addressed, followed by haemophilia (n=16).Four domains and 23 subdomains of needs were extracted from the papers. The domains of needs were: support for self-management, access to high-quality information, access to appropriate specialist services, and social support. Subdomains are sometimes related to needs of individual rare diseases (eg, social isolation due to infection risk in people with cystic fibrosis). Fifteen electronic resources were identified that supported parents of children with rare disorders.

CONCLUSIONS: While it can be argued that rare diseases, per se, may be no less distressing or onerous to care for than a high prevalence disease, rare diseases have unique features: the lengthy odyssey to find a diagnosis, then appropriate specialists, the lack of evidence around effective treatments, guidelines or access to knowledgeable general health service providers. Designers of electronic resources are urged to consult key stakeholders to enhance the effectiveness and usability of resources for people with a rare disease.

PMID:36581982 | PMC:PMC9438091 | DOI:10.1136/bmjopen-2021-060394

JAAPA. 2023 Jan 1;36(1):25-27. doi: 10.1097/01.JAA.0000885156.01681.46.

ABSTRACT

This article describes an unusual presentation of a blue finger in a middle-aged woman with no significant past medical history. The patient was diagnosed with Achenbach syndrome, a rare condition that is generally considered transient and benign. The underlying pathophysiology of this condition is unclear, but may be related to transient subcutaneous ecchymosis, possibly from microtrauma. If the condition recurs, a workup can include laboratory tests for autoimmune diseases such as rheumatoid arthritis. Clinician awareness of this presentation may reduce patient anxiety and unnecessary testing.

PMID:36573813 | DOI:10.1097/01.JAA.0000885156.01681.46

Orphanet J Rare Dis. 2022 Dec 26;17(1):449. doi: 10.1186/s13023-022-02595-0.

ABSTRACT

BACKGROUND: The COVID-19 pandemic is affecting many areas of life and has posed additional strains on the highly vulnerable group of caregivers of children with rare diseases (RDs). The psychosocial situation of the family caregivers deserves more attention, both in research and practice. The current study explores the distress level of caregivers of children with RDs, their psychosocial information needs, and caregiver-reported health-related quality of life (HRQoL) of children with RDs in times of the COVID-19 pandemic.

METHODS: Data from a cross-sectional online survey conducted within the German CARE-FAM-NET project (children affected by rare diseases and their families-network) between March and August 2020 were examined. The study sample included 149 family caregivers, mostly mothers (83.2%) of 167 children with RDs. The survey assessed demographic and disease-related characteristics, distress and everyday problems of caregivers (Distress Thermometer for Parents; scale 0-10), psychosocial information needs (self-developed items; scale 0-100), and caregiver-reported HRQoL of the children with RDs (DISABKIDS Chronic Generic Measure, short-form; scale 0-100). Using descriptive statistics, we analyzed the psychosocial situation of families during the COVID-19 pandemic. We further conducted correlation analysis to investigate interrelations.

RESULTS: The distress level among caregivers was high (M = 6.84, SD = 2.43); 89.6% reported clinical distress (≥ 4). Everyday problems (e.g., sleep problems, fatigue, being out of shape, fears, feeling tense or nervous, and worry) were frequent. Caregivers reported a wide range of psychosocial information needs. In about half of the children (49.5%), caregiver-reported HRQoL was low, while average HRQoL (M = 58.7, SD = 19.5) was comparable to parent-reported norm data of children with severe clinical conditions. Distress correlated positively with psychosocial information needs (r = 0.40), and negatively with the caregiver-reported HRQoL of the children (r = - 0.46).

CONCLUSIONS: This study indicates a high psychosocial burden on family caregivers of children with RDs during the early COVID-19 pandemic, characterized by high distress levels and wide-ranging everyday problems, unmet psychosocial information needs, and reduced caregiver-reported HRQoL in children with RDs. The findings highlight the ongoing need for target group-specific, low-threshold support services (e.g., websites) during and after the pandemic.

PMID:36572906 | DOI:10.1186/s13023-022-02595-0

Ital J Pediatr. 2022 Dec 26;48(1):202. doi: 10.1186/s13052-022-01391-7.

ABSTRACT

BACKGROUND: The spread of knowledge on the important implications of a diagnosis of genetic disease does not correspond to a sharing of the knowledge and equal rights of children.

MAIN BODY: It is estimated that about 5% of newborns may have a rare disease that in some cases, if diagnosed early, could have specific treatments that may be able to modify the natural history of the disease. However, in most countries the diagnosis during the first hours of life is limited to a few diseases, due to the high costs and time required for genetic investigations with classical methods. Recently, experimental projects to subject all newborns to a complete DNA analysis, with Next Generation Sequencing techniques, to detect any genetic pathologies as early as possible, have been reported in some countries. The late diagnosis of some genetic diseases that have treatment plans, such as spinal muscular atrophy, can be a serious damage, for anyone who has seen and accompanied the life of a child with this disease and his/her family, before and after, the recent availability of therapies which, if started very early, can lead to an almost normal life. Rapid sequencing and genetic diagnosis are a crucial part of directing inpatient management and this resource should be accessible not only to academic medical centers but also in community settings.

CONCLUSIONS: It is time for a profound reflection that places in Italy, as in other countries, the use of genetic tests in neonatal and pediatric age based on principles of evidence, ethics, and democracy and on clear national guidelines, which also consider organizational aspects.

PMID:36572899 | PMC:PMC9793583 | DOI:10.1186/s13052-022-01391-7

Medicina (Kaunas). 2022 Dec 13;58(12):1835. doi: 10.3390/medicina58121835.

ABSTRACT

Background and Objectives: Recent findings demonstrate that the transmigration of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) to the nervous system implicates severe neurotropic pathologies, including the onset of the rare disease called Guillain-Barré syndrome (GBS) which is characterized by immune-mediated polyneuropathy. This study aimed to identify the predisposing factors and the clinical features of coronavirus disease 2019 (COVID-19)-induced GBS. Materials and Methods: We have performed an analysis of 147 cases. A systematic review of the published research work was performed per the PRISMA statement to obtain individual participant data (IPD) for the meta-analysis. The search was conducted through PubMed, using the combined search terms "Guillain-Barré syndrome" and "COVID-19". All case reports and series in the English language with accessed full text were included in the search. Results: A systematic database search led to the retrieval of 112 peer-reviewed articles published between 1 April 2020, and 8 February 2022. The articles comprised 16 case series and 96 case reports containing IPD for 147 patients. Our findings showed that 77.6% of all cases were 40 years or older. Males comprised most of the cases (65.3%; n = 96). The intensive care unit (ICU) admission was 44.9%, and the need for mechanical ventilation (MV) was 38.1%. The patients presented with hyporeflexia or areflexia (84.4%; n = 124), lower limb strength and sensation impairment (93.2%; n = 138), upper limb strength and sensation impairment (85.7; n = 126), and somatic sensation impairment (72.8%; n = 107). The patients presented with increased cerebral spinal fluid (CSF) protein levels (92%; n = 92) and the presence of CSF albuminocytological dissociation (83.5%; n = 71). The most common variant of GBS observed was acute inflammatory demyelinating polyneuropathy (AIDP). We found that predisposing factors concomitant with COVID-19 and GBS were male gender and older age. Among the cases, patient mortality was 10.9%. Conclusions: A gap of knowledge exists regarding the complete spectrum of clinical characteristics of COVID-19-related GBS. Recent findings suggest that SARS-CoV-2 triggers GBS, as it follows a similar para-infectious pattern as the other viral agents contributing to the onset of GBS.

PMID:36557036 | PMC:PMC9788175 | DOI:10.3390/medicina58121835

Medicina (Kaunas). 2022 Dec 9;58(12):1810. doi: 10.3390/medicina58121810.

ABSTRACT

Kimura's disease (KD) is a rare chronic inflammatory disorder that commonly occurs in Asian males. It mainly presents as painless subcutaneous masses or lymphadenopathy in the head and neck region. The incidence of KD in the oral cavity is quite rare. We reported a rare case of a 53-year-old male who had KD in his soft palate, hard palate and bilateral tonsils associated with severe sleep apnea. This patient underwent radiotherapy and exhibited a good response to the treatment. Throughout the 12-month follow-up period, the patient's condition remained satisfactory. Of the other 14 reviewed cases of KD in the oral cavity, the lesions can occur in the buccal mucosa, hard and soft palate, and mouth floor with specific clinical features. We further summarized their manifestations and treatments in order to guide the future identification and management of KD with lesions in the oral cavity.

PMID:36557012 | PMC:PMC9783615 | DOI:10.3390/medicina58121810

Genes (Basel). 2022 Dec 10;13(12):2327. doi: 10.3390/genes13122327.

ABSTRACT

To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term "ectodermal dysplasia", referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options.

PMID:36553593 | PMC:PMC9778228 | DOI:10.3390/genes13122327

Rev Invest Clin. 2022;74(6):328-339. doi: 10.24875/RIC.22000234.

ABSTRACT

BACKGROUND: Severe congenital neutropenia type 4 (SCN4) is a rare autosomal recessive granulopoiesis disorder caused by G6PC3 gene pathogenic variants. The estimated prevalence is 1/10,000,000 people. Over 90% of patients present a syndromic form with variable multisystemic involvement, including congenital heart defects, increased visibility of superficial veins (IVSV), inflammatory bowel disease, and congenital urogenital defects as prominent symptoms.

OBJECTIVES: The objective of the study was to study non-hematological phenotypic findings that suggest a clinical diagnosis of SCN4.

METHODS: We examined medical records of patients diagnosed with neutropenia from January 2000 to December 2020, selecting cases with non-hematologic manifestations for phenotypic description and G6PC3 gene sequencing.

RESULTS: We found 11 cases with non-hematologic features: congenital heart defects in 8, IVSV in 6, inflammatory bowel disease in 4, urogenital defects in 4, and similar facial appearance. In addition, Sanger sequencing confirmed 3 homozygous cases for the c.210delC variant, a compound heterozygous harboring this variant, and a c.199_218+1 deletion.

CONCLUSIONS: Our findings of the c.210delC variant in very close geographical settings, to date, have only been reported among Mexicans, and a mutual uncommon surname in two families strongly supports a founder effect for the variant in the studied population. Furthermore, the described non-hematologic symptoms in patients with severe primary neutropenia should be explored, confirming SCN4 by investigating G6PC3 gene mutations.

PMID:36546889 | DOI:10.24875/RIC.22000234