This study explored a mother's experience of caring for her child with Jeune syndrome through a phenomenological qualitative approach using letter writing. Data were analyzed inductively, and four major themes emerged: challenges and successes in medical treatment, emotional resilience and family dynamics, overcoming developmental and educational barriers, and hopes and aspirations for the future. The mother described interactions with health care providers, her child's surgeries, treatments, and postoperative care. She emphasized the importance of family support, emotional struggles, and concerns about her child's future health. Developmental delays, social difficulties, and limited access to formal education were noted. Future plans involved tracheostomy closure, dietary improvements, and genetic testing. Despite these challenges, the mother remained hopeful, emphasizing her child's postoperative recovery and potential for greater independence. This analysis highlights the struggles, victories, and aspirations of a mother facing a rare disease and offers inspiration to others in similar circumstances.

Enhancing rare disease detection with deep phenotyping from EHR narratives: evaluation on Jeune syndrome.

Cilia are thin extensions on the cells of eukaryotic organisms. They are formed by a special protein transport mechanism - the intraflagellar transporter (IFT). The IFT consists of two proteins: complex A and complex B. Mutations in the genes of the IFT-A complex (IFT43, IFT121, IFT122, IFT139, IFT140, and IFT144) lead to the development of skeletal ciliopathies. These include Sensenbrenner, Jeune, and short-rib polydactyly syndrome [1,2]. We report two cases of different ciliopathies in a non-related family; both parents are heterozygous carriers of a pathogenic mutation in the IFT122 gene.

IntroductionDYNC2H1-related short-rib thoracic dysplasia with/without polydactyly (SRTD), formerly asphyxiating thoracic dystrophy—Jeune syndrome, is a rare genetic skeletal disorder characterised by a narrow thorax, short ribs, shortened long bones and brachydactyly/polydactyly....

Chest wall deformities encompass a range of structural abnormalities that may be congenital or acquired, impacting various aspects of the thoracic structure and function. This document provides an extensive review of primary chest wall deformities, including Pectus Excavatum (PE), Pectus Carinatum (PC), Poland Syndrome (PS), Jeune Syndrome (JS), and Sternal Cleft (SC). PE, the most prevalent deformity, is characterized by the depression of the anterior chest wall and is often linked to genetic syndromes such as Marfan and Noonan. Its clinical implications, such as exercise intolerance and cardiovascular effects, necessitate careful evaluation through physical examination, imaging, and pulmonary function tests. For severe cases, the Nuss and Ravitch surgical procedures offer corrective options, each with specific indications, benefits, and complications. PC is typified by the protrusion of the sternum and is generally considered a cosmetic issue. However, in severe cases, patients may experience functional impairments. Conservative treatment, including a dynamic compression system, is suitable for mild to moderate cases, while severe cases may require surgical intervention via the modified Ravitch or Abramson procedures. PS involves unilateral absence or hypoplasia of the pectoralis major muscle and may affect rib structures. Treatment focuses on both functional and cosmetic correction, with surgical options including custom implants and reconstructive techniques. JS, primarily congenital, leads to a restricted thoracic volume, posing a significant respiratory risk. Surgical expansion of the thorax is critical in severe cases, utilizing methods like rib grafting and vertical expandable titanium rib placement. SC, a rare condition with incomplete fusion of the sternum, requires early surgical intervention to prevent complications like respiratory distress and mediastinal shift. Across these conditions, individualized treatment plans are essential, balancing surgical benefits with risks, and considering each patient’s unique anatomical, functional, and psychosocial needs. The complexity of chest wall deformities necessitates multidisciplinary management to optimize outcomes and enhance quality of life for affected individuals.

Genotype-phenotype correlations of rare diseases are complicated by low patient number, high phenotype variability, and compound heterozygosity. Mutations may cause instability of single proteins, and affect protein complex formation or overall robustness of a specific process in a given cell. Ciliopathies offer an interesting case for studying genotype-phenotype correlations as they have a spectrum of severity and include diverse phenotypes depending on different mutations in the same protein. For instance, mutations in the intraflagellar transport protein IFT140 cause a vast spectrum of ciliopathies ranging from isolated retinal dystrophy to severe skeletal abnormalities and multi-organ diseases such as Mainzer-Saldino and Jeune syndrome. Here, the quantitative effects of 23 missense mutations in IFT140, which forms part of the crucial IFT-A complex of the ciliary machinery, were analyzed using affinity purification coupled with mass spectrometry (AP-MS). A subset of 10 mutations led to a significant and domain-specific reduction in IFT140-IFT-A complex interaction indicating complex formation issues and potentially hampering its molecular function. Knockout of IFT140 led to loss of cilia, as shown before. However, phenotypically only mild effects concerning cilia assembly were observed for two out of four tested IFT140 missense mutations. Therefore, our results demonstrate the utility of AP-MS in discerning pathogenic MMs from polymorphisms, and we postulate that reduced function is tolerated by the evolutionarily highly conserved IFT-A system.

Jeune syndrome (JS), first described by Jeune as asphyxiating thoracic dystrophy, is an autosomal recessive osteochondrodysplasia with characteristic skeletal abnormalities and variable renal, hepatic, pancreatic, and ocular complications. Approximately 1 in every 100,000 to 130,000 babies is born with JS. Most patients with JS have respiratory distress due to inadequate lung development and many lose their lives due to respiratory failure. Those who survive have serious comorbidities. In terms of ophthalmological diseases, JS is classified among the hereditary syndromic retinopathies. Most, if not all, hereditary syndromic retinopathies can be analyzed in two main groups: inherited metabolic diseases and ciliopathies. The main cause of ocular pathologies in JS is genetic mutations in ciliary proteins that prevent normal function of retinal photoreceptor cells. Here we describe a patient with JS who presented with the complaint of night blindness. Although Snellen visual acuity was 20/20, the patient’s visual function was severely impaired due to photoreceptor dysfunction caused by ciliopathy secondary to the genetic mutation. This case shows that in patients with syndromic comorbidities accompanying nyctalopia, even those with perfect visual acuity, hereditary retinal dystrophies should be considered and asphyxiating thoracic dystrophy (JS) included in the differential diagnosis. Multimodal retinal imaging, including structural and functional assessments, should be used for the diagnosis and genetic counselling should also be provided.

BackgroundThe dynein cytoplasmic two heavy chain 1 (DYNC2H1) gene encodes a cytoplasmic dynein subunit. Cytoplasmic dyneins transport cargo towards the minus end of microtubules and are thus termed the “retrograde” cellular motor. Mutations in DYNC2H1 are the main causative mutations of short rib-thoracic dysplasia syndrome type III with or without polydactyly (SRTD3). Early diagnosis of SRTD3 prenatally by ultrasound alone is difficult. In this case, a couple who gave birth to three consecutive babies with SRTD3 requested fertility guidance to avoid having another baby with SRTD3.MethodsCytogenetic and molecular genetic analyses of amniotic fluid via whole-genome sequencing (WGS), routine G-banded karyotype analysis, fluorescent quantitative polymerase chain reaction, and whole-exome sequencing (WES) were performed at 19 weeks. Peripheral blood samples from the parents were also screened by Sanger sequencing for SRTD3-related mutations.ResultsTwo compound heterozygous mutations, c.10,594 C > T and c.7720G > A, in the DYNC2H1 gene were identified, which were inherited from the mother and father, respectively. The foetus’s mother is heterozygous for the c.10,594 C > T variant, and the foetus’s father is heterozygous for the c.7720G > A variant. The mutation c.10,594 C > T, which is a nonsense mutation believed to be pathogenic, has been previously reported. The mutation c.7720G > A, which is a missense mutation, has yet to be reported. Moreover, no chromosomal abnormalities or pathogenic copy number variations (CNVs) were detected in the foetus. The patient did not become pregnant after PGT-M and IVF-ET. This family subsequently accepted donated eggs; a successful pregnancy occurred, and a healthy girl was born.ConclusionThe compound heterogeneous mutations in DYNC2H1 ultimately accounts for the diversity of disease phenotypes reported in this study and can be used to guide future pregnancies. Our findings expand the mutation spectrum of DYNC2H1 in this rare disease and highlight the value of WES in the diagnosis of skeletal dysplasia with unclear prenatal indications.

Asphyxiating Thoracic Dysplasia (ATD), marked by chest wall depression and cardiopulmonary dysfunction, poses therapeutic challenges in secondary cases due to concurrent primary pathologies. This report details the Wang procedure with Matrix-RIB bar in a 66-year-old female with osteomalacia-induced secondary ATD. Prolonged prone positioning and glucocorticoid-induced osteoporosis led to bilateral rib fractures, severe chest wall collapse, and respiratory failure. Surgical correction involved rib osteotomy, preshaping, and fixation using the Wang procedure with Matrix-RIB bar to reconstruct the chest wall. Postoperatively, the patient transitioned to non-invasive ventilation with improved cardiopulmonary function. The Wang procedure demonstrates efficacy and safety in complex secondary ATD, particularly in osteomalacia-related cases, emphasising tailored surgical strategies for diverse etiologies. This approach enhances treatment outcomes, offering a valuable framework for similar cases.

Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. In this retrospective study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with recessive Jeune syndrome. We detected twelve variants, eight of which were novel, including c.373+91A>G, which led to aberrant splicing. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Analysis of all reported and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.

Ellis Van Creveld syndrome is a rare genetic disorder with approximately 150 reported cases worldwide, inherited as an autosomal recessive trait. It is caused by mutations in the EVC and EVC2 genes on chromosome 4p16. Common features include narrow thorax, limb shortening, hexadactyly, and cardiac defects. We present a case detected by ultrasound in early pregnancy. Mrs. A.R., aged 38, had a consanguineous marriage and a previous child with Ellis Van Creveld syndrome. Ultrasound in the first trimester revealed signs suggestive of recurrence, including cystic hygroma, short curved limbs, polydactyly, and syndactyly. The pregnancy was terminated. Macroscopic examination revealed features consistent with Ellis Van Creveld syndrome, including cystic hygroma, narrow thorax, tetramicromelia, and limb anomalies. The fetus had a cardiac septation anomaly. Histological examination showed delayed placental villous maturation, but normal bone and visceral histology. Neurological examination was unremarkable. Although some features resembled Jeune syndrome, the presence of gingival frenulums and ectodermal abnormalities suggested Ellis Van Creveld syndrome, consistent with the sibling's phenotype. Early ultrasound detection of morphological abnormalities is essential. Further research is needed to understand the genetic basis of Ellis Van Creveld syndrome fully. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. The implementation of next-generation sequencing in routine diagnostics, together with advanced clinical phenotyping including multimodal retinal imaging, have contributed to the increase of reports describing novel genotype-phenotype associations and phenotypic expansions. In this study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with syndromic recessive Jeune syndrome. The most common retinal phenotypes were cone-rod and rod-cone dystrophies, but the clinical presentations were unified by their early onset as well as the severe impact on central visual function. Twelve variants were detected (three pathogenic, seven likely pathogenic, two of uncertain significance), eight of which were novel. One deep intronic change, c.373+91A>G, led to the creation of a cryptic splice acceptor site in intron four, followed by the inclusion of a 200- base pair pseudoexon and subsequent premature stop codon formation. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Meta-analysis of all published and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.

Asphyxiating thoracic dystrophy type Jeune is a rare, potentially fatal, autosomal recessive skeletal dysplasia characterized by a small and narrow thorax, lung hypoplasia, limb shortness, and facultative congenital abnormalities (e. g. polydactyly and ocular, hepatic, or renal complications) (de Vries et al., Eur J Pediatr 2010; 169: 77–88). Despite the identification of at least 17 associated genes since its first description (Jeune et al., Arch Fr Pediatr 1955; 12: 886–891), prenatal diagnosis and prognostic counseling remain challenging due to substantial clinical heterogeneity and limited genotype-phenotype correlations (Stembalska et al., Genes 2022; 13). We present a newborn with antenatally confirmed and postnatally relatively mild Jeune syndrome.

The pancreas has two functions: Exocrine and endocrine. The exocrine function involves the secretion of digestive enzymes. The endocrine function includes secreting insulin, glucagon, etc., which help regulate blood glucose. Exocrine Pancreatic Insufficiency (EPI) refers to impaired production of digestive enzymes and bicarbonate, which can cause maldigestion and malabsorption. Cystic fibrosis, chronic pancreatitis, Schwachman-Diamond syndrome, Pearson syndrome, and Johanson-Blizzard syndrome are more common causes of EPI in the pediatric population. Pancreatic aplasia or hypoplasia, Jeune syndrome, pancreatectomy, and isolated pancreatic enzyme deficiencies are less common etiologies [1-3]. Moreover, EPI may occur in inflammatory bowel disease, celiac disease, diabetes, and Sjogren’s syndrome.

P432: An adult with Kagami-Ogata syndrome misdiagnosed as Freeman-Sheldon: The importance of genetics follow-up

BackgroundShort-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias.MethodsSystemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues.ResultsThe major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively.ConclusionOur findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.

Abstract Disclosure: P. Choudhari: None. S. Mootha: None. Background: Hyperglycemic hyperosmolar state (HHS) without ketosis is rare in children. While the crux of management of HHS is extensive hydration followed by insulin, this management can be difficult for children with kidney failure. Clinical Case: A 6-year-old female with complex medical history including Jeune syndrome (asphyxiating thoracic dystrophy), end stage renal disease status post kidney transplant, currently with rejection, now on peritoneal dialysis (PD), and history of steroid induced hyperglycemia was admitted for altered mental status. Several days prior to the current admission, she was admitted for an upper respiratory infection and found to have hyponatremia, which improved with fluid restriction and sodium supplementation. Subsequent worsening of hyponatremia led to adjustments in her PD to include higher amounts of dextrose in the dialysate (1.5% to 2.5%). At the current admission, she was found to have a blood glucose of 2096 mg/dL, uncorrected sodium of 121 mg/dL, corrected to 153 mg/dL, serum osmolality of 406 mOsm/kg, and hemoglobin A1c of 11.3%. She had mild acidemia and beta-hydroxybutyrate of 0.5 mmol/L. She was transferred to the Pediatric Intensive Care Unit (PICU) and intubated given her waxing and waning mental status and complex history. Since she was anuric, fluid resuscitation was carefully managed. She received a total of 14 mL/kg normal saline boluses, which lowered blood glucose by about 240 mg/dL. Multidisciplinary conversations between PICU, Endocrinology, and Nephrology culminated with a plan to attempt to slowly reduce blood glucose levels via PD prior to using regular insulin infusion. 24-hour PD was restarted with lower dextrose in the dialysate (1.5%). Due to persistent hypotension, she required norepinephrine infusion and stress dose hydrocortisone. With PD, blood glucose levels decreased by 20-30 mL/kg/hr in the first day. Regular insulin infusion was started, while continuing 24-hour PD, after blood glucoses stagnated at 1400-1500 mg/dL. After 4-5 days of PD and insulin infusion, the child’s blood glucoses decreased to 300-400 mg/dL. After tolerating her g-tube feeds, she was transitioned to an insulin pump as she was requiring high doses of insulin (1.8 units/kg/hr). Conclusion: We present a child with complex medical history, including history of steroid induced hyperglycemia, end stage renal disease status post renal transplant, anuria, currently on PD, who developed hyperglycemic hyperosmolar state (HHS). PD helped to lower her significant hyperglycemia, initially without insulin. There are few case reports on the use of PD or hemodialysis to improve hyperglycemia or hypernatremia in children with renal failure. This case demonstrates dialysis can be an effective strategy to attempt for children in a hyperosmolar state in whom aggressive fluid management can be detrimental. Presentation: Thursday, June 15, 2023

Jeune syndrome, also known as asphyxiating thoracic dystrophy, was first described by Jeune et al in a couple of siblings back in 1955. He described 2 boys with certain distinctive characteristics, particularly a severely narrow thorax [1]. We now know it is a rare genetic condition presented in only 1 per 1000 000 130 000 live births in the USA [1].

Jeune's syndrome, or asphyxiating thoracic dystrophy (ATD), is a rare autosomal recessive disorder characterized by skeletal dysplasia. Ribs are typically short and horizontal resulting-in lethal variant-in severe lung hypoplasia, progressive respiratory failure, and death. Lateral thoracic expansion (LTE) consists in staggered bilateral ribs osteotomy leading to chest expansion and lung development. Studies on LTE in ATD patients report encouraging data, but the rarity of ATD implies the lack of a standardized surgical path. The aim of this report is to present our experience with LTE, the technical modification we adopted, and patients' clinical outcome. We retrospectively reviewed data of 11 LTE performed in 7 ATD patients with lethal variant. Information regarding pre- and postoperative clinical conditions and surgical details was collected. We adopted a single-stage or a two-stage approach based on patient clinical condition. Computed tomography (CT) scan was performed before and after surgery and lung volume was calculated. Five patients are alive, while two died in intensive care unit for other than respiratory cause (sepsis). Most patients experienced clinical improvement in terms of decreased respiratory infections rate, need for ventilation, and improved exercise tolerance. Postoperative CT scan demonstrated a median lung volume increase of 88%. Mortality in ADT patients is high. However, LTE is a feasible and safe surgical approach, which could improve clinical conditions and survival rate. Survived patients showed postoperatively less oxygen requirement and improved clinical conditions.

ABSTRACTThe primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal dysplasias. The motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport, respectively, in the cilium. WDR34 (also known as DYNC2I2), a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, short-rib polydactyly syndrome and asphyxiating thoracic dysplasia patients. There is a poor correlation between genotype and phenotype in these cases, making diagnosis and treatment highly complex. We set out to define the biological impacts on cilia formation and function of WDR34 mutations by stably expressing the mutant proteins in WDR34-knockout cells. WDR34 mutations led to different spectrums of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, localization of intraflagellar transport complex-B proteins, transition zone integrity and Hedgehog signalling were also affected.