Rare Disease Research Articles

Unlocking Delivery Strategies for mRNA Therapeutics.

mRNA emerged as an attractive therapy modality with the development of mRNA structure engineering techniques and delivery platforms. mRNA therapeutics, applied for vaccine therapy, protein replacement therapy, and chimeric antigen receptor (CAR) T cell-based therapy, has shown huge potential in treating a wide range of diseases, such as cancer and rare genetic diseases, with successful and exciting preclinical and clinical progress. In mRNA therapeutics, a potent delivery system is key to the success of its application for disease treatment. Herein, different types of mRNA delivery strategies, including nanoparticles produced from lipid or polymer materials, virus-based platforms, and exosome-based platforms, are mainly focused.

Novel monoclonal antibodies: A really specific therapy for light chain amyloidosis.

Light chain amyloidosis is a rare disease caused by clonal plasma cells in the bone marrow generating an excessive amount of immunoglobulin light chains. These chains misfold and produce insoluble fibrils that deposit in various organs, including the heart, kidneys, liver, nervous system, and digestive tract. Life expectancy and symptoms during the course of the disease vary depending on which and how many organs are affected. Targeted plasma cell therapy has significantly advanced the clinical management of amyloidosis, with ongoing progress. However, current clinical studies are investigating innovative targets, drug combinations and treatment strategies to improve therapeutic outcomes by minimizing adverse effects and refining patient prognosis in these challenging hematological conditions. In this paper, we review the state of the art regarding the use of anti-amyloid antibodies, as a revolutionary and innovative approach in the current scenario of amyloid treatment.

De Barsy syndrome due to ALDH18A1 mutation – Expanding the spectrum of a rare neurocutaneous syndrome

De Barsy syndrome is a rare autosomal recessive genetic disorder that manifests with cutis laxa, progeroid appearance, and neurologic and eye abnormalities. It was initially described by De Barsy et al. in 1968. Mutations in the ALDH18A1 gene or PYCR1 genes have been implicated in this syndrome. ALDH18A1 mutations are associated with cutis laxa type IIIA and hereditary spastic paraplegia 9A. We describe an 8-month-old male with cutis laxa, developmental delay and seizures harbouring the ALDH18A1 mutation. Our patient has certain phenotypic manifestations and radiologic findings that make it unique from the other cases described till date.

Understanding Bardet-Biedl Syndrome: Unveiling the Complexities of this Rare Genetic Disorder and its Systematic Review to Identify its Various Variants with Genetic Analysis.

Background: There are a variety of clinical features associated with Bardet-Biedl Syndrome (BBS), a rare genetic disorder affecting several organ systems. First identified in the early 20th century, BBS has since been the subject of extensive research to understand its underlying genetics, clinical presentation, and management. This article provides a comprehensive background on BBS, highlighting its clinical manifestations, genetic basis, and current research efforts. Introduction: BBS is a multisystem, genetic, autosomal recessive heterogeneous cilia structural and functional disorder (occurs when one gene influences two or more seemingly unrelated phenotypic traits) characterized by structural and functional abnormalities of organ and tissues with diverse embryonic derivation. It was first described by Laurence and Moon in 1866. It is caused by loss of proteins coding by the BBS gene. It is characterized by retinal degeneration, post-axial polydactyly, obesity, cognitive deficit, hypogonadism, and cognitive dysfunction. Associated features are diabetes mellitus, hypertension, congenital heart disease, speech defects, dental anomalies, and hepatic fibrosis. In order to diagnose the BBS, molecular genetic tests, such as whole-exome sequencing or whole-genome sequencing is considered useful. Case: A 16 year old girl presented to us in the general medicine ward through the Emergency department with the complaints of dyspnea for six months, fever for three days, and dysuria for three days. Her fever was associated with rigors and chills. On further questioning, her urine was reported to have a bad smell. Past medical history was positive for otitis media and falls. She needed walking support as she was unable to see at night time. On physical examination a young lady was laying in the supine position. She was pale, obese and had high respiratory rate. There was no lymphadenopathy. Extra digits were noted in her upper and lower limbs. Rest of the physical examination was normal. The patient was started on 2 liters of oxygen and blood samples were taken for laboratory investigations. Conclusion: As this was diagnosed on time, so it helped both the family and physcians to check on her weight, respiratory functions, skeletal abnormalities, sexual development, visual acquity, cardiac functioning, hepatic functioning and hematologic stability such as hemoglobin. Being a very rare disease a therefore this disease awareness is necessary among physicians to diagnose the disease early and treat the complications of the disease so that the complications do not progress to the stage where it is irreversible. Early detection of renal problem, visual problems, obesity, and learning disabilities is necessary to be treated on time by involving multidisciplinary approaches.

Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8).

Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials. As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software. Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence. In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials. ANSM Registration Number 2010-A00327-32.

Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy.

Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. Patisiran largely stabilised disease in patients with ATTRv amyloidosis.

Genome-wide analysis identifies MYH11 compound heterozygous variants leading to visceral myopathy corresponding to late-onset form of megacystis-microcolon-intestinal hypoperistalsis syndrome.

Megacystis-microcolon-hypoperistalsis-syndrome (MMIHS) is a rare and early-onset congenital disease characterized by massive abdominal distension due to a large non-obstructive bladder, a microcolon and decreased or absent intestinal peristalsis. While in most cases inheritance is autosomal dominant and associated with heterozygous variant in ACTG2 gene, an autosomal recessive transmission has also been described including pathogenic bialellic loss-of-function variants in MYH11. We report here a novel family with visceral myopathy related to MYH11 gene, confirmed by whole genome sequencing (WGS). WGS was performed in two siblings with unusual presentation of MMIHS and their two healthy parents. The 38years-old brother had severe bladder dysfunction and intestinal obstruction, whereas the 30years-old sister suffered from end-stage kidney disease with neurogenic bladder and recurrent sigmoid volvulus. WGS was completed by retrospective digestive pathological analyses. Compound heterozygous variants of MYH11 gene were identified, associating a deletion of 1.2Mb encompassing MYH11 inherited from the father and an in-frame variant c.2578_2580del, p.Glu860del inherited from the mother. Pathology analyses of the colon and the rectum revealed structural changes which significance of which is discussed. Cardiac and vascular assessment of the mother was normal. This is the second report of a visceral myopathy corresponding to late-onset form of MMIHS related to compound heterozygosity in MYH11; with complete gene deletion and a hypomorphic allele in trans. The hypomorphic allele harbored by the mother raised the question of the risk of aortic disease in adults. This case shows the interest of WGS in deciphering complex phenotypes, allowing adapted diagnosis and genetic counselling.

A mutation in CCDC91, Homo sapiens coiled-coil domain containing 91 protein, cause autosomal-dominant acrokeratoelastoidosis

AbstractAcrokeratoelastoidosis (AKE) is a rare autosomal dominant hereditary skin disease characterized by small, round-oval, flat-topped keratotic papules on the palms, soles and dorsal aspect of hands or feet. The causative gene for AKE remains unidentified. This study aims to identify the causative gene of AKE and explore the underlying biological mechanisms. A large, three-generation Chinese family exhibiting classic AKE symptoms was identified. A genome-wide linkage analysis and whole-exome sequencing were employed to determine the causative gene. shRNA knockdown in human skin fibroblasts and CRISPR/Cas9 knockout in HEK293T cells were utilized to assess gene functions in the progression of elastic fiber biosynthesis. The linkage analysis identified a susceptibility region between rs7296765 to rs10784618 on chromosome 12. Whole-exome sequencing confirmed a splicing mutation of 1101 + 1 G &gt; A in the CCDC91 gene, resulting in exon 11 skipping and a subsequent 59-amino-acid-residue loss (residues L309-Q367del). Further functional analysis revealed distended Golgi cisternae, cytoplasmic vesicle accumulation, and lysosome presence. Immnunostaining of si-CCDC91-HSF cells demonstrated tropoelastin accumulation in the Golgi and abnormal extracellular aggregates. There are no significant changes in Fibrillin-1 microfibril assembly and lysyl oxidase activity. The findings strongly suggest that the protein product of the CCDC91 gene plays a crucial role in elastin transport. This discovery enhances our understanding of CCDC91’s function and broadens the known pathogenic mechanisms of AKE.

Coronary Artery Bypass Grafting in a Patient With Multivessel Disease and Dextrocardia With Situs Inversus Totalis.

Dextrocardia with situs inversus totalis is a rare hereditary condition characterized by reversed orientation of the major thoracic and abdominal organs. Though dextrocardia itself is not believed to increase the risk of coronary artery disease, the workup and surgical management of patients with this condition may be technically challenging to heart team clinicians. This report describes the case management of a high-risk 56-year-old man with dextrocardia who presented with multivessel coronary artery disease.

How should we differentiate hypoglycaemia in non-diabetic patients?

Hypoglycaemic syndromes are rare in apparently healthy individuals and their diagnosis can be a difficult challenge for clinicians as there are no shared guidelines that suggest how to approach patients with a suspect hypoglycaemic disorder. Since hypoglycaemia symptoms are common and nonspecific, it's necessary to document the Whipple Triad (signs and/or symptoms compatible with hypoglycaemia; relief of symptoms following glucose administration; low plasma glucose levels) before starting any procedure. Once the triad is documented, a meticulous anamnesis and laboratory tests (blood glucose, insulin, proinsulin, C-peptide, β-hydroxybutyrate and anti-insulin antibodies) should be performed. Results can guide the physician towards further specific tests, concerning the suspected disease. In this review, we consider all current causes of hypoglycaemia, including rare diseases such as nesidioblastosis and Hirata's syndrome, describe appropriate tests for diagnosis and suggest strategies to differentiate hypoglycaemia aetiology.

Clinical and epidemiological features of cutaneous mastocytosis among the pediatric population of Moscow

BACKGROUND: Cutaneous mastocytosis is a rare disease that primarily develops in childhood.&#x0D; AIM: This study aimed to determine the clinical and epidemiological characteristics and frequency of detection of cutaneous mastocytosis among children in Moscow.&#x0D; MATERIALS AND METHODS: A single-center epidemiological retrospective study was conducted. Data from Form № 12 of the federal statistical observation "Information on the number of diseases registered in patients living in the service area of a medical organization" were used as a statistical source of information. To calculate the incidence rate in intensive indicators per 100 thousand population, data on the population of Moscow for the period 2019–2022 were used.&#x0D; RESULTS: Over the period 2019–2022, a gradual trend towards an increase in the number of newly identified cases of cutaneous mastocytosis in children and adolescents in Moscow was revealed. Number of initial applications from children and adolescents (0–17 years old) for this period increased by 4.8 times. The share of cutaneous mastocytosis in the structure of skin diseases and congenital anomalies (malformations) of the skin increases every year. In 2019, for every 1,834 pediatric visits (age category 0–17 years) regarding skin diseases, there was 1 case of mastocytosis; in 2020 the ratio was 1,863:1; in 2021 ― 491:1; in 2022 ― 376:1. Since 2019, there has been an increase in the primary incidence of cutaneous mastocytosis from 3.63 cases per 100,000 child population to 16.61 cases per 100,000 child population in 2022.&#x0D; CONCLUSION: The increase in incidence in the pediatric population and the share of cutaneous mastocytosis in the structure of skin diseases in recent years demonstrates the need to generate interest and attention of the medical community to this pathology.

Cardiac amyloidosis, features of diagnosis and treatment

Cardiac amyloidosis is considered a rare disease, but as diagnostic capabilities increase, so does the assessment of its prevalence. Cardiac amyloidosis manifests itself with symptoms of restrictive cardiomyopathy, leading to progressive heart failure. However, the underlying pathogenetic mechanisms of the disease differ. This literature review provides an overview of cardiac amyloidosis, from classification to molecular mechanisms and modern treatment options.

Late‐onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?

AbstractMethionine synthase reductase deficiency (cblE) is a rare autosomal recessive inborn error of cobalamin metabolism caused by pathogenic variants in the methionine synthase reductase gene (MTRR). Patients usually exhibit early‐onset bone marrow failure with pancytopenia including megaloblastic anemia. The latter can remain isolated or patients may present developmental delay and rarely macular dysfunction. Treatment mostly includes parenteral hydroxocobalamin to maximize the residual enzyme function and betaine to increase methionine concentrations and decrease homocysteine accumulation. We report herein 2 cblE siblings diagnosed in the neonatal period with isolated pancytopenia who, despite treatment, exhibited in adulthood hemolytic anemia (LDH &gt;11 000 U/L, undetectable haptoglobin, elevated unconjugated bilirubin) which could finally be successfully treated by hydroxocobalamin dose escalation. There was no obvious trigger apart from a parvovirus B19 infection in one of the patients. This is the first report of such complications in adulthood. The use of LDH for disease monitoring could possibly be an additional useful biomarker to adjust hydroxocobalamin dosage. Bone marrow infection with parvovirus B19 can complicate this genetic disease with erythroblastopenia even in the absence of an immunocompromised status, as in other congenital hemolytic anemias. The observation of novel hemolytic features in this rare disease should raise awareness about specific complications in remethylation disorders and plea for hydroxocobalamin dose escalation.

Abnormal performance of peroral endoscopic myotomy (POEM): a case misdiagnosed as achalasia of cardia.

Pseudoachalasia is a rare disease that behaves similarly to achalasia (AC), making it sometimes difficult to differentiate. We report a case of 49-year-old male with adenocarcinoma of the gastroesophageal junction misdiagnosed as achalasia. No obvious abnormalities were found in his initial examinations including upper digestive endoscopy, upper gastrointestinal imaging and chest computed tomography (CT). During the subsequent introduced-peroral endoscopic myotomy (POEM), it was found that the mucosal layer and the muscular layer had severe adhesion, which did not receive much attention, delayed the clear diagnosis and effect treatment, and ultimately led to a poor prognosis for the patient. This case suggests that when patients with AC found mucosal and muscular adhesions during POEM surgery, the possibility should be considered that the lesion may be caused by a malignant lesion.

Symptomatic duodenal intramural hematoma caused by weight training: a report of two cases.

Symptoms of traumatic duodenal intramural hematoma, a rare disease caused by trauma, blood disease, or antithrombotic therapy, can include abdominal pain. Case 1 is that of a 35-year-old man at a gym who dropped a 100kg barbell on his abdomen. It was diagnosed as a duodenal obstruction caused by a traumatic intestinal wall hematoma. In Case 2, a 16-year-old male adolescent performing deadlift training at a gym had subsequent abdominal pain. It was diagnosed as intestinal wall hematoma. Both patients improved with conservative treatment. Malignancy is sometimes suspected from imaging findings. Detailed patient history and imaging studies can avoid unnecessary surgery.

Isolated calvarial aneurysmal bone cyst in a pediatric patient: illustrative case.

Aneurysmal bone cysts (ABCs) are benign, osteolytic lesions that can occur in long bones, vertebrae, or rarely, the skull. Here the authors present the case of a 15-year-old male with a primary ABC of the left frontoparietal skull along with a review of the literature to provide insight into the nature of this rare disease. An otherwise healthy 15-year-old male presented with a tense, painful lesion of the left frontoparietal scalp. He could not identify any inciting trauma, but first noted the lesion less than 2 weeks prior to presentation with progressive enlargement. Cranial imaging revealed a lytic skull lesion with fluid-fluid levels suggestive of ABC. Curative therapy was provided via wide excision of the lesion and calvarial reconstruction of the resultant skull defect. This was performed without complication, and histopathological evaluation confirmed the diagnosis of primary ABC. ABCs of the skull are rare entities and most often arise in the skull base versus the calvaria. Typically, these lesions are associated with an underlying bone pathology (secondary ABCs) but can be rarely seen as isolated lesions (primary ABCs). Clinical management consists of excision and adjuvant therapy for underlying pathology where appropriate.

Issues, Challenges and Opportunities for Economic Evaluations of Orphan Drugs in Rare Diseases: An Umbrella Review.

There are significant challenges when obtaining clinical and economic evidence for health technology assessments of rare diseases. Many of them have been highlighted in previous systematic reviews but they have not been summarised in a comprehensive manner. For all stakeholders working with rare diseases, it is important to be aware and understand these issues. The objective of this review is to identify the main challenges for the economic evaluation of orphan drugs in rare diseases. An umbrella review of systematic reviews of economic studies concerned with orphan and ultra-orphan drugs was conducted. Studies that were not systematic reviews, or on advanced therapeutic medicinal products, personalised medicines or other interventions that were not considered orphan drugs were excluded. The database searches included publications from 2010 to 2023, and were conducted in MEDLINE, EMBASE and the Cochrane library using filters for systematic reviews, and economic evaluations and models. These filters were combined with search terms for rare diseases and orphan drugs. A hand search supplemented the literature searches. The findings were reported by a compliant Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Two hundred and eighty-two records were identified from the literature searches, of which 64 were duplicates, whereas five reviews were identified from the hand search. A total of 36 reviews were included after screening against inclusion/exclusion criteria, 35 from literature searches and one from hand searching. Of those studies 1, 27 and 8 were low, moderate and high quality, respectively. The reviews highlight the scarcity of evidence for health economic parameters, for example, clinical effectiveness, costs, quality of life and the natural history of disease. Health economic evaluations such as cost-effectiveness and budget-impact analyses were scarce, and generally low-to-moderate quality. The causes were limited health economic parameters, together with publications bias, especially for cost-effectiveness analyses. The results highlighted issues around a considerable paucity of evidence for economic evaluations and few cost-effectiveness analyses, supporting the notion that a paucity of evidence makes economic evaluations of rare diseases more challenging compared with more prevalent diseases. Furthermore, we provide recommendations for more sustainable approaches in economic evaluations of rare diseases.

Carnitine palmitoyltransferase II (CPT II) deficiency responsible for refractory cardiac arrhythmias, acute multiorgan failure and early fatal outcome

BackgroundCarnitine palmitoyltransferase II (CPT II) deficiency is a rare inborn error of mitochondrial fatty acid metabolism with autosomal recessive pattern of inheritance. Its phenotype is highly variable (neonatal, infantile, and adult onset) on the base of mutations of the CPT II gene. In affected subjects, long-chain acylcarnitines cannot be subdivided into carnitine and acyl-CoA, leading to their toxic accumulation in different organs. Neonatal form is the most severe, and all the reported patients died within a few days to 6 months after birth. Hereby, we report on a male late-preterm newborn who presented refractory cardiac arrhythmias and acute multiorgan (hepatic, renal, muscular) injury, leading to cerebral hemorrhage, hydrocephalus, cardiovascular failure and early (day 5 of life) to death. Subsequently, extended metabolic screening and target next generation sequencing (NGS) analysis allowed the CPT II deficiency diagnosis.Case presentationThe male proband was born at 36+ 4 weeks of gestation by spontaneous vaginal delivery. Parents were healthy and nonconsanguineous, although both coming from Nigeria. Family history was unremarkable. Apgar score was 9/9. At birth, anthropometric measures were as follows: weight 2850 g (47th centile, -0.07 standard deviations, SD), length 50 cm (81st centile, + 0.89 SD) and occipitofrontal circumference (OFC) 35 cm (87th centile, + 1.14 SD). On day 2 of life our newborn showed bradycardia (heart rate around 80 bpm) and hypotonia, and was then transferred to the Neonatal Intensive Care Unit (NICU). There, he subsequently manifested many episodes of ventricular tachycardia, which were treated with pharmacological (magnesium sulfate) and electrical cardioversion. Due to the critical conditions of the baby (hepatic, renal and cardiac dysfunctions) and to guarantee optimal management of the arrythmias, he was transferred to the Pediatric Cardiology Reference Center of our region (Sicily, Italy), where he died 2 days later. Thereafter, the carnitines profile evidenced by the extended metabolic screening resulted compatible with a fatty acid oxidation defect (increased levels of acylcarnitines C16 and C18, and low of C2); afterwards, the targeted next generation sequencing (NGS) analysis revealed the known c.680 C > T p. (Pro227Leu) homozygous missense mutation of the CPTII gene, for diagnosis of CPT II deficiency. Genetic investigations have been, then, extended to the baby’s parents, who were identified as heterozygous carriers of the same variant. When we meet again the parents for genetic counseling, the mother was within the first trimester of her second pregnancy. Therefore, we offered to the couple and performed the prenatal target NGS analysis on chorionic villi sample, which did not detect any alterations, excluding thus the CPT II deficiency in their second child.ConclusionsCPTII deficiency may be suspected in newborns showing cardiac arrhythmias, associated or not with hypertrophic cardiomyopathy, polycystic kidneys, brain malformations, hepatomegaly. Its diagnosis should be even more suspected and investigated in cases of increased plasmatic levels of creatine phosphokinase and acylcarnitines in addition to kidney, heart and liver dysfunctions, as occurred in the present patient. Accurate family history, extended metabolic screening, and multidisciplinary approach are necessary for diagnosis and adequate management of affected subjects. Next generation sequencing (NGS) techniques allow the identification of the CPTII gene mutation, essential to confirm the diagnosis before or after birth, as well as to calculate the recurrence risk for family members. Our report broads the knowledge of the genetic and molecular bases of such rare disease, improving its clinical characterization, and provides useful indications for the treatment of patients.

The Phenotypic Spectrum of Desanto-Shinawi Syndrome: A Comparative Report of the First Reported Case in Turkey.

DeSanto-Shinawi syndrome (DESSH, OMIM #616708) is a rare genetic disorder caused by pathogenic variants in the WAC gene. This syndrome is characterized by a wide range of physical and neurological symptoms including dysmorphic features, developmental delay, intellectual disability, and behavioral abnormalities. DESSH was described by DeSanto in 2015, and since then, only a few dozen cases have been reported worldwide. Recent research has focused on identifying the underlying genetic cause of the syndrome as well as exploring potential treatments. In this report, we describe a female case who had dysmorphic features including long palpebral fissures, depressed nasal root, mild bulbous nasal tip, thin upper lip, hypertrichosis, short fingers, and intellectual disability, speech delay, and motor retardation. In addition, she had behavioral abnormalities such as agitation, anxiety, and attention deficit hyperactivity disorder (ADHD). Clinical exome sequencing showed a pathogenic heterozygous nonsense variant in exon 13 of the WAC gene c.1837C>T, p.(Arg613Ter) with de novo inheritance. To the best of our knowledge, this is the first case of DESSH reported from Turkey. We aimed to report this rare syndrome and compare the clinical findings of our case with previously reported cases in the literature.

Anesthesia management for a child with the Koolen-de Vries syndrome: a case report

BackgroundThe Koolen-de Vries syndrome (KdVS) is a relatively new rare disease caused by micro-deletion of 17q21.31 which was first reported by Koolen in 2006. Typical phenotypes for KdVS include hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Up to now, there was only one case report about anesthesia management of patient diagnosed KdVS. It was a 2-year-old girl who experienced an MRI exam under anesthesia.Case presentationWe described a 21-month-old boy who planned to undergo an orchidopexy under general anesthesia diagnosed with KdVS. He had an intellectual disability, characteristic facial dysmorphism, tracheo/laryngomalacia, patent foramen ovale, and cryptorchidism related to KdVS. Due to the complex condition especially the presence of tracheo/laryngomalacia, we took some special measures, including reducing the amount of long-acting opioid, keeping the spontaneous breath, performing a caudal block, and applying the laryngeal mask. But the laryngeal mask was changed to an endotracheal tube because it failed to provide adequate ventilation. The boy experienced mild laryngeal spasm and hypoxia after extubation, but lateral position and etomidate eased his breathing problem and re-intubation was avoided. It is indicated that anesthesia management for patients with orphan disease is a real challenge for all anesthesia providers.ConclusionsThe Koolen-de Vries syndrome is a relatively new orphan disease involving multiple systems. Keeping spontaneous breath, evaluating airway potency to anesthetics, applying endotracheal tube, and post-extubation lateral or prone position may be helpful for airway management for patient with hypotonia and tracheo/laryngomalacia. KdVS patient needs prolonged post-anesthesia monitoring and/or medication for airway complications.