The Association of a Single Nucleotide Variant in COL5A1 to Early Onset Keratoconus and Pectus Excavatum-Convergence of Extracellular Matrix Pathologies.

Keratoconus is a bilateral ocular condition characterized by irregularities and the thinning of the cornea. Decreased central corneal thickness is a hallmark of the condition, and numerous genes have played a role in altering corneal thickness and the subsequent development of keratoconus. Variants in the structural and regulatory genes of the extracellular matrix have been highly associated with keratoconus, as well as with pectus excavatum, a chest wall deformity commonly seen in connective tissue disorders. This report describes a patient with a c.1720-11T>A intronic variant in the collagen-encoding gene, COL5A1, who was diagnosed with early-onset keratoconus and demonstrated a significant pectus excavatum. This report associates a COL5A1 variant with these seemingly unrelated phenotypic associations, further advancing the literature on the topic.

Progressive Keratoconus in a Patient With Severe Pectus Excavatum and a Cartilage Oligomeric Matrix Protein Gene Mutation: A Case Report.

INTRODUCTION: Keratoconus is a progressive ocular disorder associated with numerous systemic diseases, many of which affect the musculoskeletal system. Although the etiology and pathophysiology of the disorder remain elusive, recent studies suggest a significant role of genetic predisposition in the pathogenesis of keratoconus. This case report aims to elucidate a potential genetic association in a patient presenting with keratoconus, severe pectus excavatum, generalized muscular weakness, and skeletal deformities. CASE DESCRIPTION: A 31-year-old Iranian man presented with progressively diminishing vision in both eyes over the years, eventually diagnosed with keratoconus. The patient's history and further examination indicated generalized muscular weakness, skeletal deformities, and severe pectus excavatum with cardiac and large vessel displacement. Whole-exome sequencing identified two heterozygous gene variants: one in the Cartilage Oligomeric Matrix Protein (COMP) gene and another in the Regulating Synaptic Membrane Exocytosis 1 gene. The patient's systemic and ocular symptoms, combined with the gene variants identified, suggested a connective tissue systemic disorder, potentially within the clinical spectrum of COMPopathies. CONCLUSION: This is the first documented case of bilateral progressive keratoconus associated with severe pectus excavatum, generalized musculoskeletal dystrophy, and a COMP gene mutation. It highlights the necessity of continued search into the pathogenic genes of keratoconus, particularly in cases with coexisting systemic manifestations, to further our understanding of the etiology and pathogenesis of this complex disease.

Chest wall deformities and their possible associations with different genetic syndromes.

OBJECTIVE: Our primary objective was to identify discrete and syndromic cases of Pectus excavatum (PE) and Pectus carinatum (PC). We also intended to highlight the significance of further genetic exploration in clinically suspected syndromic cases of PC and PE. Pectus excavatum (PE) and Pectus carinatum (PC) are the most common morphological chest wall deformities. Although various hypotheses have been put forth, the pathogenesis of both entities is largely unknown. Clinicians often refer such cases for further genetic evaluation to exclude an associated underlying connective tissue disorder or a syndrome. Additionally, a detailed anamnesis with focused family history and thorough dysmorphological physical examination was done. PE and PC are considered isolated abnormalities if there is the absence of features of other syndromes, eliminating the need for further genetic evaluations. It is believed that the pattern of inheritance of these non-syndromic isolated PE and PC cases with positive family history could be multifactorial in nature. The recurrence risk of such isolated cases is thought to be low. Further diagnostic studies are indicated as PE and PC could be a part of a syndrome. Among the many syndromes, the most common monogenic syndromes associated with PE and PC are Marfan's and Noonan's. PATIENTS AND METHODS: After obtaining the consent, we compiled a database of the patients who presented with chest wall deformities during the period 2017-2019. We selected 70 cases with PC and PE deformities to identify the discrete and syndromic PC and PE cases. During the study, we perused the cytogenetic and/or molecular analyses, that had been conducted to confirm the clinically suspected syndromic cases. We also scrutinized for the presence of PC and PE cases that are associated with the rare syndrome (s). RESULTS: Various genetic abnormalities were identified in 28 (40%) of the 70 cases that had been diagnosed with chest wall abnormalities. Along with PE and PC, other thoracic wall abnormalities were also identified, such as the broad chest, bell-shaped thorax, and elongated or enlarged thorax. One case of a rare genetic disorder of Morquio syndrome associated with PC was also identified. Novel (previously unpublished) genomic variants are reported here. CONCLUSIONS: It is important to delve deeper when encountering cases of PE and PC by conducting a further genetic exploration of such cases to identify syndromic associations that cause other structural and functional disorders, diagnosis of which might be missed during the early developmental period. Early identification of such disorders may help us correcting the defects, slowing the progression of disease processes, and preparing better to deal with the potential outcome.

Mutations in COL1A1 and COL27A1 Associated with a Pectus Excavatum Phenotype in 2 Siblings with Osteogenesis Imperfecta.

BACKGROUND Osteogenesis imperfecta is a skeletal disease with a range of phenotypes, depending on the genetic mutation. Individuals with osteogenesis imperfecta type I often have mutations in COL1A genes. This disease can be associated with chest wall deformities such as pectus excavatum, but the number of patients with this presentation is limited, and genetic variants associated with this phenotype have not been reported. CASE REPORT We studied the Skeletal Disorders Genetic Panel of 2 siblings with osteogenesis imperfecta type I and severe pectus excavatum requiring surgical correction. Both had severe respiratory symptoms secondary to the chest wall deformity, and the male patient had evidence of mitral valve insufficiency on an echocardiogram. Results of the genetic panel were remarkable for a homozygous copy number gain in exons 2 to 51 in gene COL1A1. Additionally, both had a heterozygous pathogenic variant in exon 7 of gene COL27A1 (replacement of a glycine with arginine in codon 697 of the protein). CONCLUSIONS Gene COL27A1 plays a role during the calcification of cartilage to bone and is associated with Steel syndrome, a skeletal disorder mainly found in the Puerto Rican population. Heterozygous carriers of the p.Gly697Arg variant in COL27A1 have not been described to have a phenotype with chest wall deformities. Additionally, a genotype-phenotype relationship regarding pectus excavatum in patients with osteogenesis imperfecta has not been described, suggesting that having COL1A gene mutations and simultaneous haploinsufficiency of COL27A1 can result in a phenotype of osteogenesis imperfecta with pectus excavatum and predispose these patients to additional phenotypic features.

The Epidemiology behind Pectus Excavatum: Clinical Study and Review of the Literature.

INTRODUCTION: Pectus excavatum (PE) is a funnel-shaped indentation of the sternum and is the most common deformity of the chest wall. It is associated with syndromic diseases but can occur as an isolated form. Familial occurrence is assumed in up to 40% of cases, but large-scale studies are lacking. Most of the data are obtained from case reports which postulate autosomal recessive, dominant with reduced penetrance, X-linked, and multifactorial patterns of inheritance. No monogenetic cause has been identified to date. This study was designed to provide basic information on the epidemiology, family history, and comorbidity for a large cohort of isolated PE and to show that there is an inheritance pattern for PE that indicates a genetic background. MATERIALS AND METHODS: A retrospective study was done using a paper-based questionnaire for all PE patients attending two specialized centers for chest wall deformities. Patients with isolated PE were included and asked to provide information on family history and comorbidities. RESULTS: Family history was available for 78 patients. A positive family history was found in 42 patients (54%) with a total of 53 affected family members. CONCLUSION: The described family histories indicate an underlying genetic cause for PE. Identification of the genetic factors may contribute to characterize patients who are at risk of inheriting isolated PE.

Association between pectus excavatum and congenital genetic disorders: A systematic review and practical guide for the treating physician.

BACKGROUND: Pectus excavatum (PE) could be part of a genetic disorder, which then has implications regarding comorbidity, the surgical correction of PE, and reproductive choices. However, referral of a patient presenting with PE for genetic analysis is often delayed because additional crucial clinical signs may be subtle or even missed in syndromic patients. We reviewed the literature to inventory known genetic disorders associated with PE and create a standardized protocol for clinical evaluation. METHODS: A systematic literature search was performed in electronic databases. Genetic disorders were considered associated with PE if studies reported at least five cases with PE. Characteristics of each genetic disorder were extracted from the literature and the OMIM database in order to create a practical guide for the clinician. RESULTS: After removal of duplicates from the initial search, 1632 citations remained. Eventually, we included 119 full text articles, representing 20 different genetic disorders. Relevant characteristics and important clinical signs of each genetic disorder were summarized providing a standardized protocol in the form of a scoring list. The most important clinical sign was a positive family history for PE and/or congenital heart defect. CONCLUSIONS: Twenty unique genetic disorders have been found associated with PE. We have created a scoring list for the clinician that systematically evaluates crucial clinical signs, thereby facilitating decision making for referral to a clinical geneticist.

TINAG mutation as a genetic cause of pectus excavatum.

To investigate the possible involvement of germline mutations in pectus excavatum (PE). We investigated a four-generation pedigree with PE. Whole-exome sequencing (WES)was performed to identify potential mutations for PE formation. Sanger sequencing was used to validate these mutations. hFOB1.19 cell proliferation was measured with a Celigo imaging cytometry system. There were four PE patients in this four-generation pedigree. In the four patients, we identified a novel heterozygous stop-gain variant in Tubulointerstitial Nephritis Antigen (TINAG) through exome sequencing: c.G2A, p.W2*. This mutation was validated by Sanger sequencing. Knockdown of TINAG inhibited the proliferation of hFOB1.19 cells. Based on these results, we hypothesize that the TINAG c.G2A mutation is a loss-of-functionmutationthat reduces TINAG expression. Increasing TINAG warrants further investigation as a potential novel anabolic mechanism of PE treatment.

Solución del caso 14. Dolor abdominal en paciente joven con fenotipo característico / Solution to case 14. Abdominal pain in young patient with characteristic phenotype

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[Loeys-Dietz syndrome (TGFßR2 mutation) in a 4-year-old child with thoracic aortic aneurysm]. / Syndrome de Loeys-Dietz (mutation TGFßR2) chez une enfant de 4ans avec anévrysme de l'aorte thoracique.

Loeys-Dietz syndrome is a rare form of connective tissue disorder, whose clinical features can resemble those of Marfan syndrome, but with a more unpolished appearance. Recently brought out, this pathology remains little known; however, its consequences may be dramatic. We report on the case of a 4-year-old girl followed for a congenital hip dislocation, in which a systematic exam found increased cutaneous elasticity and a bifid uvula, suggesting a connective tissue disorder. Symptoms were unpolished, as the child's height was normal, without any positive cardiac, rheumatological, or ophthalmological family history. Cardiovascular tests found a thoracic aortic aneurysm at the Valsalva sinus (26mm, Z-score=+4.24). A genetic investigation found a TGFßR2 gene mutation, leading to the diagnosis of Loeys-Dietz syndrome type 2. Skeletal damage associated with bifid uvula and/or hypertelorism and an aneurysm of the ascending aorta should guide the genetic investigation to the search for TGF-ß vasculopathy such as Loeys-Dietz syndrome.

Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice.

Adolescent idiopathic scoliosis (AIS) and pectus excavatum (PE) are common pediatric musculoskeletal disorders. Little is known about the tissue of origin for either condition, or about their genetic bases. Common variants near GPR126/ADGRG6 (encoding the adhesion G protein-coupled receptor 126/adhesion G protein-coupled receptor G6, hereafter referred to as GPR126) were recently shown to be associated with AIS in humans. Here, we provide genetic evidence that loss of Gpr126 in osteochondroprogenitor cells alters cartilage biology and spinal column development. Microtomographic and x-ray studies revealed several hallmarks of AIS, including postnatal onset of scoliosis without malformations of vertebral units. The mutants also displayed a dorsal-ward deflection of the sternum akin to human PE. At the cellular level, these defects were accompanied by failure of midline fusion within the developing annulus fibrosis of the intervertebral discs and increased apoptosis of chondrocytes in the ribs and vertebrae. Molecularly, we found that loss of Gpr126 upregulated the expression of Gal3st4, a gene implicated in human PE, encoding Galactose-3-O-sulfotransferase 4. Together, these data uncover Gpr126 as a genetic cause for the pathogenesis of AIS and PE in a mouse model.

An intragenic deletion of the gene MNAT1 in a family with pectus deformities.

Pectus carinatum and excavatum have multiple genetic associations. We report on a novel association of these deformities in a 34-month-old male and his father, likely due to a small intragenic deletion of MNAT1 (ménage a trois 1 gene). Both individuals share a deletion of MNAT1 located at 14q23.1 and an interstitial duplication of CHRNA7 located at 15q13.3. Deletion of MNAT1 has been associated with connective tissue abnormalities and is likely the etiology of the malformations, whereas the duplication of CHNRA7 is unlikely related due to the lack of association with any such connective tissue abnormalities.

A mother and daughter with a novel phenotype of hand and foot abnormalities and severe pectus excavatum.

A mother and daughter with an overlapping Catel-Manzke and Temtamy preaxial brachydactyly hyperphalangism syndrome phenotype are reported. We describe a phenotype with a previously undescribed genetic basis. .

Dismorfología de las deformidades de la pared torácica: distribución de frecuencias de los subtipos de pectus excavatum típico y subtipos poco comunes / Dysmorphology of Chest Wall Deformities: Frequency Distribution of Subtypes of Typical Pectus Excavatum and Rare Subtypes

Antecedentes/Objetivo: Más del 40% de los pacientes con pectus excavatum tienen antecedentes familiares de una deformidad torácica. Sin embargo, no se han publicado estudios de la frecuencia de los diferentes fenotipos de pectus excavatum. Métodos: Se estudió una muestra aleatoria de 300 pacientes con pectus excavatum no sindrómico de la clínica de deformidades de la pared torácica del Children's Hospital of the King's Daughters de Norfolk (Virginia, Estados Unidos) y se clasificó a los pacientes según un sistema descrito con anterioridad. Se utilizaron para ello fotografías e imágenes de tomografía computarizada (TC). Resultados: Pectus excavatum típico. Datos fotográficos: se observó una deformidad con depresión profunda localizada (forma de taza) en el 67% de los casos, difusa (en forma de platillo) en el 21%, de tipo trinchera (en forma de surco) en el 10%, y de tipo Currarino-Silverman (deformidad mixta de pectus excavatum/pectus carinatum condromanubrial) en el 1%. El punto más profundo se encontraba a la derecha de la línea media en el 80% de los casos, a la izquierda en el 10% y en el centro en el 10%. En las fotografías, el punto más profundo se encontraba en la parte inferior del esternón en el 75% de los casos. Cuando había asimetría, el punto más profundo de la deformidad estaba a la derecha de la línea media en el 90% de los casos. Datos de TC: la media del índice de Haller fue de 4,9. La torsión esternal intensa (>30 grados) se asoció a un índice de Haller más alto (6,3) que el observado en la torsión leve (4,5). El punto más profundo de la depresión se encontraba en la parte media o baja del esternón en más del 99% de los casos. Resultó imposible estimar la anchura o la longitud de la depresión, ya que los límites estaban mal definidos (AU)

Conclusiones: El pectus excavatum típico tiene forma de copa en el 67% de los casos, se encuentra a la derecha de la línea media en el 80% y afecta a la parte media o baja del esternón en el 99%. Sin embargo, otros fenotipos, como el de forma de platillo y el de trinchera larga, constituyeron una tercera parte del total. La definición de la deformidad es más fiable mediante la TC (AU)

Background/Purpose: More than forty percent of patients with pectus excavatum have a family history of chest deformity. However, no studies of the frequency of the different phenotypes of pectus excavatum have been published. Methods: A random sample of 300 non-syndromic pectus excavatum patients, from the chest wall deformities clinic at Children's Hospital of The King's Daughters in Norfolk, VA, was studied and classified according to a previously described classification system. Photographs and computed tomography (CT) scans were utilized. Results: Typical pectus excavatum. Photo data: localized deep depression (cup-shaped) deformity occurred in 67%; diffuse (saucer-shaped) 21%, trench-like (furrow-shaped) 10%, and Currarino-Silverman (mixed pectus excavatum/chondromanubrial carinatum) 1%. The deepest point was to the right of midline in 80%, left in 10% and central in 10%. As per the photograph, the deepest point was in the lower sternum in 75%. When asymmetric, the deepest point of the deformity was to the right of midline in 90%. CT data: the average Haller index was 4.9. Severe sternal torsion (>30°) was associated with greater Haller index (6.3) than mild torsion (4.5). The deepest point of the depression was at the mid- or lower sternum in more than 99%. It proved impossible to estimate width or length of the depression because of poorly defined borders. Conclusions: Typical PE is cup-shaped in 67% of cases, to the right of the midline in 80%, and involving the mid-to-lower sternum in 99%. However, other phenotypes, like the saucer and long trench, comprised one-third. Definition of the deformity is more reliable by CT scan (AU)