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Langer-Giedion syndrome (LGS) is caused by a contiguous deletion at 8q23q24, characterized by exostoses, facial, ectodermal, and skeletal anomalies, and, occasionally, intellectual disability. LGS patients have been diagnosed clinically or by routine cytogenetic techniques, hampering the definition of an accurate genotype-phenotype correlation for the syndrome. We report two unrelated patients with 8q23q24 deletions, characterized by cytogenomic techniques, with one of them, to our knowledge, carrying the smallest deletion reported in classic LGS cases. We assessed the pathogenicity of the deletion of genes within the 8q23q24 region and reviewed other molecularly confirmed cases from the literature. Our findings suggest a 3.2-Mb critical region for a typical presentation of the syndrome, emphasizing the contribution of the TRPS1, RAD21, and EXT1 genes' haploinsufficiency, and facial dysmorphisms as well as bone anomalies as the most frequent features among patients with LGS. We also suggest a possible role for the CSMD3 gene, whose deletion seems to contribute to central nervous system anomalies. Since studies performing such correlation for LGS patients are limited, our data contribute to improving the ge-notype-phenotype characterization for LGS patients. [ABSTRACT FROM AUTHOR]

GATA3 is the most used marker to determine tumors' breast origin, but its diagnostic value in triple-negative breast cancer (TNBC) is limited. The newly identified TRPS1 is highly sensitive and specific for breast carcinoma, especially TNBC. Here, we compared the utility of TRPS1 and GATA3 expression in a subset of salivary gland-type breast tumors (including adenoid cystic, acinic cell, and secretory carcinomas [AdCC, ACC, and SC, respectively]), and we compared TRPS1 and GATA3 expression of such tumors with head and neck (H&N) and AdCC of upper respiratory tumors. TRPS1 was strongly expressed in basaloid TNBC and AdCCs with solid components, including 100 % of mixed and solid breast AdCCs. However, TRPS1 was positive in only 50 % cribriform AdCCs. Expression patterns of TRPS1 in H&N and upper respiratory AdCC were similar. TRPS1 was positive in 30 % of H&N cribriform AdCCs but was strongly expressed in mixed AdCC (67 %) and solid AdCC (100 %). In the upper respiratory AdCCs, TRPS1 was positive in 58.4 % of cribriform AdCCs and positive in 100 % of AdCCs with solid components. On the contrary, GATA3 was negative in predominant AdCCs of the breast, H&N, and upper respiratory tract. These data show that GATA3 and TRPS1 expression varies AdCCs. In addition, TRPS1 and GATA3 expression patterns were similar SC and ACC of breast and H&N. Both markers were positive in SC and negative in ACC. Therefore, TRPS1 and GATA3 cannot be used to differentiate salivary gland-type carcinomas of breast origin from those of upper respiratory or H&N origin., (Copyright © 2024 Elsevier Inc. All rights reserved.)

TRPS1 serves as the causative gene for tricho-rhino phalangeal syndrome, known for its craniofacial and skeletal abnormalities. The Trps1 gene encodes a protein that represses Wnt signaling through strong interactions with Wnt signaling inhibitors. The identification of genomic cis-acting regulatory sequences governing Trps1 expression is crucial for understanding its role in embryogenesis. Nevertheless, to date, no investigations have been conducted concerning these aspects of Trps1. To identify deeply conserved noncoding elements (CNEs) within the Trps1 locus, we employed a comparative genomics approach, utilizing slowly evolving fish such as coelacanth and spotted gar. These analyses resulted in the identification of eight CNEs in the intronic region of the Trps1 gene. Functional characterization of these CNEs in zebrafish revealed their regulatory potential in various tissues, including pectoral fins, heart, and pharyngeal arches. RNA in-situ hybridization experiments revealed concordance between the reporter expression pattern induced by the identified set of CNEs and the spatial expression pattern of the trps1 gene in zebrafish. Comparative in vivo data from zebrafish and mice for CNE7/hs919 revealed conserved functions of these enhancers. Each of these eight CNEs was further investigated in cell line-based reporter assays, revealing their repressive potential. Taken together, in vivo and in vitro assays suggest a context-dependent dual functionality for the identified set of Trps1-associated CNE enhancers. This functionally characterized set of CNE-enhancers will contribute to a more comprehensive understanding of the developmental roles of Trps1 and can aid in the identification of noncoding DNA variants associated with human diseases., (© 2024 Wiley Periodicals LLC.)

Common genetic variants in the repressive GATA-family transcription factor (TF) TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over 80 percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes estrogen receptor alpha (ER) to redistribute in the genome. ER redistribution leads to both repression and activation of dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the genomic distribution of ER, both activating and repressing transcription of genes related to cancer cell fitness., Competing Interests: The authors declare no competing interests., (Copyright: © 2024 Scott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Diagnosing urothelial cancer (UCa) via invasive cystoscopy is painful, specifically in men, and can cause infection and bleeding. Because the UCa risk is higher for male patients, urinary non-invasive UCa biomarkers are highly desired to stratify men for invasive cystoscopy. We previously identified multiple DNA methylation sites in urine samples that detect UCa with a high sensitivity and specificity in men. Here, we identified the most relevant markers by employing multiple statistical approaches and machine learning (random forest, boosted trees, LASSO) using a dataset of 251 male UCa patients and 111 controls. Three CpG sites located in ALOX5 , TRPS1 and an intergenic region on chromosome 16 have been concordantly selected by all approaches, and their combination in a single decision matrix for clinical use was tested based on their respective thresholds of the individual CpGs. The combination of ALOX5 and TRPS1 yielded the best overall sensitivity (61%) at a pre-set specificity of 95%. This combination exceeded both the diagnostic performance of the most sensitive bioinformatic approach and that of the best single CpG. In summary, we showed that overlap analysis of multiple statistical approaches identifies the most reliable biomarkers for UCa in a male collective. The results may assist in stratifying men for cystoscopy.

Objective: The aim of this research was to present prenatal diagnosis of Langer-Giedion syndrome (LGS/TRPS type II) and Cornelia de Lange syndrome-4 (CDLS4). Materials and methods: A 36-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Conventional cytogenetic analysis of amniocentesis revealed an interstitial deletion of chromosome 8q or del(8)(q23.3q24.13). Level II prenatal ultrasound examination revealed craniofacial dysmorphism. The pregnancy was terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism of LGS/TRPS type II and CDLS4. Whole-genome array comparative genomic hybridization (aCGH) on the DNA extracted from cultured amniocytes was performed. Results: The analysis by aCGH revealed a result of arr 8q23.3q24.11 (116,087,006–118,969,399)×1, 8q24.13 (123,086,851–124,470,847)×1 (NCBI build 37) with a 2.88-Mb deletion of 8q23.3–q24.11 encompassing six OMIM genes, TRPS1, EIF3H, RAD21, SLC30A8, MED30, and EXT1, and a 1.383-Mb deletion of 8q24.13 encompassing four OMIM genes, ZHX2, DERL1, ZHX1, and ATAD2. Conclusion: In the present case, the conventional cytogenetic analysis of cultured amniocytes revealed del(8)(q23.3q24.13), whereas aCGH analysis of cultured amniocytes showed the deletions of 8q23.3–q24.11 and 8q24.13 with the presence of the segment 8q24.12. Therefore, aCGH provides the advantage of better understanding of the nature of interstitial deletion and genotype–phenotype correlation in this case.

Currently, there is a paucity of highly specific and sensitive markers to identify breast carcinoma in male patients. Immunohistochemical stains commonly used for unmasking primary breast carcinomas include estrogen receptor (ER) and GATA3. However, these markers are commonly expressed in carcinomas originating from other organ systems and can be reduced in breast carcinomas with higher histologic grades. Androgen receptor (AR) may be used to highlight primary male breast cancer, but this marker can also be expressed in other carcinomas. We evaluated TRPS1, a highly sensitive and specific marker for female breast carcinoma, in cases of male breast carcinoma. Through an institutional database search, we identified 72 cases of primary invasive breast carcinoma in male patients. Among ER/progesterone receptor (PR)-positive cancers, 97% showed intermediate or high positivity for both TRPS1 and GATA3. Among HER2-positive cancers, 100% showed intermediate or high positivity for TRPS1 and GATA3. One case of triple-negative breast cancer was collected, showing high positivity for TRPS1 and negativity for GATA3. AR staining was non-specific and heterogeneous: 76% showed high positivity, but the remaining 24% showed low or intermediate positivity. Additionally, among 29 cases of metastatic carcinoma to male breast tissue, 93% were negative for TRPS1, and the remaining 2 cases (7%), which were carcinomas from salivary gland primary tumors, were intermediate positive. TRPS1 is a sensitive and specific marker in the unmasking of male primary invasive breast carcinoma across different subtypes. Additionally, TRPS1 is not expressed in metastatic carcinomas of multiple primaries, with the exception of salivary gland primaries., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Trichorhinophalangeal syndrome type II is a rare genetic disorder with the few published case reports mainly reporting the radiographic skeletal manifestations. There are no published imaging reports of long bone cysts involving multiple bones in this condition. We report a unique case of bone cysts involving multiple long bones detected with MRI in a patient with trichorhinophalangeal syndrome type II complicated by a subsequent pathological fracture. It is possible that the bone cysts are a previously undescribed feature of this syndrome; however, the evidence is insufficient to establish a definite association. Chromosomal abnormality identified in this patient is consistent with trichorhinophalangeal syndrome type II with no unusual features. Although the nature of these bone cysts is unclear, they are one of the causes of the known increased fracture risk observed in this syndrome. [ABSTRACT FROM AUTHOR]

A Thai mother and her two daughters were affected with tricho-rhino-phalangeal syndrome type I. The daughters had 15 and 18 supernumerary teeth, respectively. The mother had normal dentition. Mutation analysis of TRPS1 showed a novel heterozygous c.3809_3811delACTinsCATGTTGTG mutation in all. This mutation is predicted to cause amino acid changes in the Ikaros-like zinc finger domain near the C-terminal end of TRPS1, which is important for repressive protein function. The results of our study and the comprehensive review of the literature show that pathways of forming supernumerary teeth appear to involve APC and RUNX2, the genes responsible for familial adenomatous polyposis syndrome and cleidocranial dysplasia, respectively. The final pathway resulting in supernumerary teeth seems to involve Wnt, a morphogen active during many stages of development. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The trichorhinophalangeal syndrome is a rare genetic disorder with a classical clinical triad of sparse hair, bulbous nose, and short digits. There are three known phenotypes, and the type II with exostoses in long bones is known as Langer–Giedion syndrome. Here, we describe a 28-year-old Sri Lankan male with Langer–Giedion syndrome and high-functioning autism. The karyotype found a microdeletion of the long arm of chromosome 8 with mosaicism [46,XY/46,XY,del(8)(q24.1q24.3)]. This is probably the first report of Langer–Giedion Syndrome with autism and the first report of the genetic syndrome from Sri Lanka. Furthermore, we could only access one previous report of the same microdeletion, which was from an autopsy of a 36-week-old infant. [ABSTRACT FROM AUTHOR]

Langer-Giedion syndrome (LGS) is a rare disease caused by deletion of chromosome 8q23.3-q24.11. Clinical manifestations include among others multiple exostoses, short stature, intellectual disability, and typical facial dysmorphism. Dural arterio-venous shunts (DAVS) in the pediatric age are rare lesions, which have been classified into three types: dural sinus malformations (DSM), infantile type DAVS (IDAVS), and adult type DAVS (ADAVS). We report a case of a patient with a known LGS who was diagnosed with complex intracranial dural AV fistula at the age of 20. An association between LGS and intracranial dural AV fistulas has to our knowledge never been reported before. [ABSTRACT FROM AUTHOR]

Lange-Giedion syndrome, or trichorhinophalangeal syndrome type 2 (TRPSII), is a clinical syndrome characterized by mild growth restriction, mental retardation, microcephaly and dysmorphic face. Bulbous nose, large protruding ears and loose redundant skin are distinguishing features, as well as lax joints and phalangeal abnormalities of the hands and multiple exostoses. TRPS1 and EXT1 gene deletion are responsible for this. Diagnosis is mainly based on clinical and radiographic features. In Korea, no cases of this disease have been reported thus far. Along with a review of the literature, we report a case of TRPSII in a neonate who had peculiar face representing TRPSII, polydactyly, Müllerian duct cyst, and ptosis and was found to have an interstitial deletion of 8q23-24.1. [ABSTRACT FROM AUTHOR]

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1 , and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1 . We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype–phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1 . Other mutations are located anywhere in exons 4–7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1 , but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1 , but numbers are too small to allow firm conclusions. [ABSTRACT FROM AUTHOR]

We report a 4.5 year old Egyptian male child, fourth in the order of birth of healthy remote consanguineous parents. He has typical facial as well as skeletal features of Trichorhinophalangeal syndrome (TRPS) II. The facial features included bilateral downward slanting palpebral fissures, bulbous nose, long filtrum, retromicrognathia, sparse hair in the scalp and thick eyebrows. The skeletal features included retarded bone age, cone shaped epiphyses of the phalanges and multiple exostoses. The patient has also growth retardation, moderate mental retardation and hyperlaxity of the right knee joint. However our patient has some features not reported in TRPS II patients. These included bilateral partial ptosis, long eye lashes, preauricular skin tag, short 2nd right finger, short metacarpals of both thumbs. So we have to expand the clinical spectrum. Karyotype demonstrated 46,XY,del 8(q23.3-q24.1). [ABSTRACT FROM AUTHOR]

Introduction Langer-Giedion syndrome (trichorhinophalangeal syndrome type II) is an extremely rare disorder characterized by dysmorphic facial features, multiple exostoses, mental retardation and digit deformities. We report the first case of any maxillofacial pathology in such a syndromic patient. Case presentation A 22-year-old Indian woman with mild intellectual disability presented with malaligned teeth. Routine radiographic screening demonstrated a large multilocular lesion in her right mandible. She had peculiar features such as short stature, short limbs, brachydactyly, and dysmorphic facial characters, which prompted us to evaluate her further. After findings of multiple bony exostoses she was diagnosed with Langer-Giedion syndrome. On surgical exploration of her right mandibular lesion an empty cavity was found suggestive of traumatic bone cyst. The lesion healed completely after 1 year without loss of vitality of any teeth. Conclusions Although diagnosis and management of any maxillofacial pathology can be challenging in syndromic patients, our report suggests a possible correlation between traumatic bone cyst and Langer-Giedion syndrome. Clinicians should routinely screen these patients for any undetected maxillofacial pathology. In future cases of this syndrome, one should consider the possibility of traumatic bone cyst which may not require aggressive surgical management. [ABSTRACT FROM AUTHOR]

Trichorhinophalangeal syndrome (TRPS) is an extremely rare autosomal dominant multisystem disorder characterized by craniofacial and skeletal abnormalities. Three subtypes of TRPS have been described: TRPS type I, TRPS type II, and TRPS type III. Mutations in the TRPS1 gene can cause both TRPS type I and TRPS type III. Therefore, the genotype-phenotype correlation is crucial to determine the subtype. The current family study from Cyprus involves affected patients from 4 generations who presented with alopecia, unoperated umbilical hernia, caput quadratum, long philtrum, depressed nasal bridge, frontal bossing, pes planus, beaked nose, and some deformities in hands and feet. Sequence analysis of the TRPS1 gene revealed a novel c.2854_2858del (p.Asn952ArgfsTer2) frameshift variant leading to a premature stop codon. To the best of our knowledge, we report here the first case of a Turkish Cypriot family of 4 generations with a novel frameshift mutation leading to truncated protein in the TRPS1 gene causing TRPS type I clinical phenotype. Overall, as the genotype and phenotype correlation in TRPSI is still uncertain and complex, the present outcome can enhance our knowledge of this complicated, rare, and severe genetic disorder., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Langer-Giedion syndrome (LGS) is caused by a deletion of chromosome 8q23.3-q24.11. The LGS clinical spectrum includes intellectual disability (ID), short stature, microcephaly, facial dysmorphisms, exostoses. We describe a 4-year-old girl with ID, short stature, microcephaly, distinctive facial phenotype, skeletal signs (exostoses on the left fibula, coccyx agenesis, stubby and dysmorphic sphenoid bone, osteoporosis), central nervous system malformations (hypoplastic and dysmorphic corpus callosum and septum pellucidum), pituitary gland hypoplasia and hyperreninemia. Array-CGH revealed complex chromosomal rearrangements. A diagnosis of LGS was confirmed by the detection of a 8q23.3-q24.1 deletion. Associated chromosomal abnormalities were a 21q22.1 deletion and a balanced reciprocal translocation t(2;11)(p24;p15) de novo, confirmed by FISH analysis. We document the patient's atypical findings, never described in LGS patients, in order to update the genotype-phenotype correlation. We speculate that the disruption of regulatory elements mapping upstream CYP11B2 involved in the deleted region could cause hyperreninemia. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Trichorhinophalangeal syndrome (TRP) is a group of rare genetic disorders with characteristic clinical and radiological features. In this case report we discuss the evolution of imaging features in hands in a Chinese boy diagnosed with TRP II (Langer-Giedion syndrome, LGS). This article ramifies the diagnostic value of serial hand radiograph in clinically suspected cases of TRP. [ABSTRACT FROM AUTHOR]

Long-term observations of individuals with the so-called Langer-Giedion (LGS) or tricho-rhino-phalangeal type II (TRPS2) are scarce. We report here a on follow-up of four LGS individuals, including one first described by Andres Giedion in 1969, and review the sparse publications on adults with this syndrome which comprises ectodermal dysplasia, multiple cone-shaped epiphyses prior to puberty, multiple cartilaginous exostoses, and mostly mild intellectual impairment. LGS is caused by deletion of the chromosomal segment 8q24.11-q24.13 containing among others the genes EXT1 and TRPS1. Most patients with TRPS2 are only borderline or mildly cognitively delayed, and few are of normal intelligence. Their practical skills are better than their intellectual capability, and, for this reason and because of their low self-esteem, they are often underestimated. Some patients develop seizures at variable age. Osteomas on processes of cervical vertebrae may cause pressure on cervical nerves or dissection of cerebral arteries. Joint stiffness is observed during childhood and changes later to joint laxity causing instability and proneness to trauma. Perthes disease is not rare. Almost all males become bald at or soon after puberty, and some develop (pseudo) gynecomastia. Growth hormone deficiency was found in a few patients, TSH deficiency so far only in one. Puberty and fertility are diminished, and no instance of transmission of the deletion from a non-mosaic parent to a child has been observed so far. Several affected females had vaginal atresia with consequent hydrometrocolpos. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We describe the anesthetic and perioperative management of a child with Langer-Giedion syndrome (trichorhinophalangeal syndrome type II). This is a very rare genetic syndrome caused by 8q chromosome deletion. The clinical features of this syndrome include craniofacial and urogenital abnormities, variable postnatal growth deficiency with mental retardation, multiple exostoses, hyperflexible joints, and recurrent respiratory tract infections. Potential perioperative problems are highlighted. [ABSTRACT FROM AUTHOR]

STUDY DESIGN::Case report of a severe upper cervical cord compression and tetraparesis by a massive cervical exostotic osteochondroma in a patient with multiple exostoses-mental retardation syndrome (Langer-Giedion syndrome; LGS). OBJECTIVE::To describe this very rare pathological condition and the results of surgical intervention. SETTING::Gifu, Japan. METHODS::A 23-year-old man was referred to our clinic because of progressing tetraparesis. He had previously been diagnosed with hereditary multiple exostoses and mental retardation. As he had not complained of any symptoms, his family only noticed the tetraparesis after advanced deterioration. His face possessed the pathognomic features of LGS. A postmyelogram CT scan demonstrated an exostotic mass arising from the left-side C2 pedicle with associated severe spinal cord compression. He was diagnosed with LGS. Hemilaminectomy on the left side and resection of the osteochondroma were performed. RESULTS::At 5 years postoperatively, a neurological examination showed the full return of all motor functions. The CT scan revealed no intracanalar recurrence of the tumor. CONCLUSION::In this case of severe tetraparesis due to cervical osteochondroma, decompression by hemilaminectomy provided excellent results. In patients with LGS and intracanalar osteochondroma, the neurological deficit may be masked by mental retardation. Hence, awareness of this pathological condition will help clinicians diagnose it at an early stage.Spinal Cord (2005) 43, 190-194. doi:10.1038/sj.sc.3101690 Published online 7 December 2004 [ABSTRACT FROM AUTHOR]

When a sarcomatous neoplasm is identified in the breast, distinguishing metaplastic carcinoma, malignant phyllodes tumor (MPT), and primary sarcoma is a diagnostic challenge, especially on small biopsies, as all these tumors may have overlapping morphological features, thoroughly grossing with histological examination and immunohistochemical staining being the standard approach to aid in classifying these lesions. Recently, we identified a highly sensitive and specific breast carcinoma marker TRPS1 with high expression in metaplastic breast carcinoma. In the current study, we tested TRPS1 in MPTs and primary sarcoma of the breast. We found TRPS1 was highly expressed (95%) within spindle cell, chondro-osseous, and/or liposarcomatous components of MPTs, in all breast primary chondrosarcomas and extraskeletal osteosarcomas, but not in other sarcomas of the breast. In extramammary sarcomas, TRPS1 was expressed in 28% of conventional chondrosarcomas and 56% of osteosarcomas of bone, but rarely in undifferentiated pleomorphic sarcomas (UPSs), liposarcomas, and angiosarcomas. In summary, MPTs may share similar genetic background with metaplastic carcinoma exhibiting TRPS1 expression, and TRPS1 may play a role in chondro-osseous differentiation because of its expression in chondro-osseous sarcomas from both breast and extramammary sites. Our findings suggest TRPS1 may be clinically useful in distinguishing MPT and metaplastic carcinoma from primary breast sarcoma except for tumors with chondro-osseous differentiation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth-plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone-related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)-like skeletal malformations without a clear clinical diagnosis were analyzed by whole-exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho-rhino-phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)-binding zinc-containing domain) and Ikaros-like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO-like features, and the need for a close interdisciplinary workout in these rare patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)