Search

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans. Five of 6 patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora, while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC, and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital, and craniofacial imaging. Lay Summary: Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by overactivity of the parathyroid hormone type 1 receptor, a receptor that is important for regulating bone development. Some patients report eye problems, but these have not been well-described. We therefore performed extensive eye examinations in 6 individuals with JMC. One had progressive right-sided facial paralysis associated with eye-tearing and dryness. A second individual had decreased central vision. Using optical coherence tomography (OCT), a method which takes detailed pictures of the retina, we found thinning of the retina's nerve layers (RNFL). Computed tomography (CT) of the skull showed narrowing of the bony canal through which the optic nerve passes. A third individual had normal vision but RNFL thinning just on the sides. Analysis of ganglion cells, the nerve cells carrying signals from the retina to the brain, showed localized deterioration of the optic nerve; skull CT also revealed optic canal narrowing. These findings suggest that JMC is associated with progressive damage to the optic nerve. Thus, patients with JMC would benefit from regular eye exams including OCT and visual field testing, in addition to routine imaging. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle–brachial index (ABI). Methods: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. Results: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. Conclusions: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort. (ClinicalTrials.gov Identifier NCT01585402) [ABSTRACT FROM AUTHOR]

The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next‐generation sequencing results, and providing a basis for novel advances in biology and medicine. [ABSTRACT FROM AUTHOR]

Background: The Achilles tendon (AT) is the widest and most resistant of the osteoarticular system and has the greatest load-bearing capacity. It is involved in daily functioning and sports activities performance. Exposure to excessive stress on the calcaneus tendon (CT) can prevent an effective repair process and favor permanent injuries. Tendinopathy is a clinical syndrome resulting from disorientation of AT fibers, and inflammatory signs characteristic of tendinitis or tissue degeneration present in tendinosis can be found. The condition can manifest itself through functional changes accompanied by clinical signs such as crackling, tenderness, pain and edema. Infrared thermography is used to trace thermographic profiles, capable of detecting thermal changes related to pathologies. Objectives: The main goal of this study was to correlate AT region thermograms with clinical and functional characteristics in healthy individuals with CT pathology. Methods: The present work consists of a double-blind pilot randomized trial, of qualitative and quantitative nature. Individuals with TC tendinopathy, classified in the Tendinopathy Group (TG) and individuals without tendinopathy, classified in the Control Group (CG) participated. Assessments were performed to characterize the subjects belonging to the TG and CG: anamnesis, infrared thermography, referred pain, crepitation and thickness on palpation, algometry, arch sign test and Royal London Hospital test, pain on passive dorsiflexion, pain on lifting the heel and long jump. Results: The results obtained in infrared thermography were consistent with those obtained in the clinical evaluation for TG and GC. The results demonstrate that healthy tendons presented an average temperature difference of 0.24 ± 0.15 °C between legs with a maximal difference of 0.4 °C. On the other hand, unilateral tendinopathy presented an average temperature difference of 1.2 ± 0.9 °C, however, this difference could be as big as 5.1 °C. Conclusion: It is concluded that infrared thermography can be used safely and non-invasively to aid in the diagnosis of Achilles tendon tendinopathy. [ABSTRACT FROM AUTHOR]

Loss‐of‐function variants in the ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) cause ENPP1 Deficiency, a rare disorder characterized by pathological calcification, neointimal proliferation, and impaired bone mineralization. The consequence of ENPP1 Deficiency is a broad range of age dependent symptoms and morbidities including cardiovascular complications and 50% mortality in infants, autosomal recessive hypophosphatemic rickets type 2 (ARHR2) in children, and joint pain, osteomalacia and enthesopathies in adults. Recent research continues to add to the growing clinical presentation profile as well as expanding the role of ENPP1 itself. Here we review the current knowledge on the spectrum of clinical and genetic findings of ENPP1 Deficiency reported in patients diagnosed with GACI or ARHR2 phenotypes using a comprehensive database of known ENPP1 variants with associated clinical data. A total of 108 genotypes were identified from 154 patients. Of the 109 ENPP1 variants reviewed, 72.5% were demonstrably disease‐causing, a threefold increase in pathogenic/likely pathogenic variants over other databases. There is substantial heterogeneity in disease severity, even among patients with the same variant. The approach to creating a continuously curated database of ENPP1 variants accessible to clinicians is necessary to increase the diagnostic yield of clinical genetic testing and accelerate diagnosis of ENPP1 Deficiency. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor‐23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23‐mediated hypophosphatemia, such as X‐linked hypophosphatemia (XLH) and tumor‐induced osteomalacia (TIO), in whom pathology‐driving FGF23 levels can be in the "normal range." To determine FGF23 levels that are diagnostic for the identification of patients with FGF23‐mediated hypophosphatemic disorders, we studied 149 patients with various disorders of FGF23‐mediated and FGF23‐independent hypophosphatemia and defined cut‐off levels for both intact FGF23 (iFGF23) and C‐terminal FGF23 (cFGF23) that can accurately distinguish between FGF23‐mediated and FGF23‐independent hypophosphatemia. In addition, to demonstrate the relationship between FGF23 and phosphate across the spectrum of human physiology, we assessed blood levels of FGF23 and phosphate in 434 patients with various forms of hypophosphatemia, hyperphosphatemia, and normophosphatemia. An intact FGF23 cut point of 27 pg/mL was 100% sensitive and specific in distinguishing FGF23‐mediated from FGF23‐independent hypophosphatemia, and a cFGF23 cut point of 90 RU/mL was 100% sensitive and specific in distinguishing specifically TIO from FGF23‐independent hypophosphatemia. There was overlap in the cFGF23 range of 45–90 RU/mL between genetic forms of FGF23 excess and FGF23‐independent hypophosphatemia, substantiating the superiority of iFGF23 over cFGF23 in making the diagnosis of FGF23‐mediated hypophosphatemia. In this cohort, using the laboratory upper limit of normal for cFGF23 (180 RU/mL) would result in a misdiagnosis in more than half of patients with FGF23‐mediated hypophosphatemia. In this, the largest study of FGF23 in chronic hypophosphatemia to date, we established iFGF23 and cFGF23 cut‐off values to assist in the evaluation and diagnosis of hypophosphatemic conditions. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Hemivertebra is a congenital vertebral malformation caused by unilateral failure of formation during embryogenesis that may be associated with additional abnormalities. A systematic review was conducted to investigate genetic etiologies of non‐isolated hemivertebra identified in the fetal, neonatal, and infant periods using PubMed, Cochrane database, Ovid Medline, and ClinicalTrials.gov from inception through May 2022 (PROSPERO ID CRD42021229576). The Human Phenotype Ontology database was accessed May 2022. Studies were deemed eligible for inclusion if they addressed non‐isolated hemivertebra or genetic causes of non‐isolated hemivertebra identified in the fetal, neonatal, or infant periods. Cases diagnosed clinically without molecular confirmation were included. Systematic review identified 23 cases of non‐isolated hemivertebra with karyotypic abnormalities, 2 cases due to microdeletions, 59 cases attributed to single gene disorders, 18 syndromic cases without known genetic etiology, and 14 cases without a known syndromic association. The Human Phenotype Ontology search identified 49 genes associated with hemivertebra. Non‐isolated hemivertebra is associated with a diverse spectrum of cytogenetic abnormalities and single gene disorders. Genetic syndromes were notably common. Frequently affected organ systems include musculoskeletal, cardiovascular, central nervous system, genitourinary, gastrointestinal, and facial dysmorphisms. When non‐isolated hemivertebra is identified on prenatal ultrasound, the fetus must be assessed for associated anomalies and genetic counseling is recommended. [ABSTRACT FROM AUTHOR]

Ocular manifestations are observed in approximately one third of all inherited metabolic disorders (IMDs). Although ocular involvement is not life-threatening, it can result in severe vision loss, thereby leading to an additional burden for the patient. Retinal degeneration with or without optic atrophy is the most frequent phenotype, followed by oculomotor problems, involvement of the cornea and lens, and refractive errors. These phenotypes can provide valuable clues that contribute to its diagnosis. In this issue we found 577 relevant IMDs leading to ophthalmologic manifestations. This article is the seventh of a series attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement. [ABSTRACT FROM AUTHOR]

Understanding the genetic architecture of metabolic epilepsies is of paramount importance, both to current clinical practice and for the identification of further research directions. The main goals of our study were to identify the scope of metabolic epilepsies and to investigate their clinical presentation, diagnostic approaches and treatments. The International Classification of Inherited Metabolic Disorders and IEMbase were used as a basis for the identification and classification of metabolic epilepsies. Six hundred metabolic epilepsies have been identified, accounting for as much as 37% of all currently described inherited metabolic diseases (IMD). Epilepsy is a particularly common symptom in disorders of energy metabolism, congenital disorders of glycosylation, neurotransmitter disorders, disorders of the synaptic vesicle cycle and some other IMDs. Seizures in metabolic epilepsies may present variably, and most of these disorders are complex and multisystem. Abnormalities in routine laboratory tests and/or metabolic testing may be identified in 70% of all metabolic epilepsies, but in many cases they are non-specific. In total, 111 metabolic epilepsies (18% of all) have specific treatments that may significantly change health outcomes if diagnosed in time. Although metabolic epilepsies comprise an important and significant group of disorders, their real scope and frequency may have been underestimated. [ABSTRACT FROM AUTHOR]