Search

Background. Tricho-rhino-phalangeal syndrome (TRPS) is a rare, autosomal dominant disorder characterized by typical craniofacial features, ectodermal and skeletal findings. TRPS type 1 (TRPS1) is caused by pathogenic variations in the TRPS1 gene, which relates to the vast majority of cases. TRPS type 2 (TRPS2) is a contiguous gene deletion syndrome involving loss of functional copies of the TRPS1, RAD21, and EXT1. Herein, we reported the clinical and genetic spectrum of seven TRPS patients with a novel variant. We also reviewed the musculoskeletal and radiological findings in the literature.Methods. Seven Turkish patients (three female, four male) from five unrelated families aged between 7 to 48 years were evaluated. The clinical diagnosis was confirmed by either molecular karyotyping or TRPS1 sequencing analysis via next-generation sequencing.Results. Both TRPS1 and TRPS2 patients had some common distinctive facial features and skeletal findings. All patients had a bulbous nose with hypoplastic alae nasi, brachydactyly, short metacarpals and phalanges in variable stages. Low bone mineral density (BMD) was identified in two TRPS2 family members presenting with bone fracture, and growth hormone deficiency was detected in two patients. Skeletal X-ray imaging revealed cone-shaped epiphysis of the phalanges in all, and multiple exostoses were present in three patients. Cerebral hamartoma, menometrorrhagia and long bone cysts were among the new/rare conditions. Three pathogenic variants in TRPS1 were identified in four patients from three families, including a frameshift (c.2445dup, p.Ser816GlufsTer28), one missense (c.2762G>A), and a novel splice site variant (c.2700+3A>G). We also reported a familial inheritance in TRPS2 which is known to be very rare.Conclusions. Our study contributes to the clinical and genetic spectrum of patients with TRPS while also providing a review by comparing with previous cohort studies.

Trichorhinophalangeal syndrome is an autosomal dominant disease caused by mutations in TRPS gene, characterized by skeletal, skin appendage, and endocrinological manifestations. Clinical presentation may vary widely, and the syndrome frequently remains undiagnosed. The diagnosis is mainly clinical, supported by radiographic images, and is confirmed by genetic investigation. Familiarity with this genetic disorder is crucial for providing correct and early identification, and for determining adequate supportive management, especially to prevent orthopedic complications.

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.

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.

Trichorhinophalangeal syndrome I (TPRSI) has an autosomal dominant inheritance; the proportion of «de novo» cases is unknown

Trichorhinophalangeal syndrome (TRPS) is rare genetic disorder with autosomal dominant inheritance. The TRPS1 gene is located on the long arm of the eighth chromosome (8q24.12). The phenotype is variable and presents a wide clinical spectrum. Most cases are characterised by thin, sparse scalp hair, distinctive facial dysmorphism, and various skeletal abnormalities, especially of the hands and feet. Characteristic facial features may include a "pear-shaped" nose, micrognathia, dental anomalies, prominent ears, elongated philtrum, and thin upper vermillion border. In most cases, affected individuals exhibit skeletal abnormalities including brachydactyly and clinodac-tyly, short metacarpals phalanges, short feet and metatarsals, and pectus carinatum and hip joint malformations. Additionally, patients may exhibit short stature. This report presents four cases of TRPS (three sporadic and one familial). Clinical presentation included typical facial features and vari-ous skeletal abnormalities. Some TRPS symptoms may mimic growth hormone deficiency and other endocrine disturbances. The aim of this article is to deliver TRPS symptomatology. The treatment of TRPS is symptomatic and supportive and requires the coordination of several specialists, including paediatricians, endocrinologists, orthopaedic surgeons, dermatologists, and medical rehabilitation and den-tal specialists. In some cases, recombinant growth hormone therapy may be necessary. Genetic counselling may be of benefit for affect-ed individuals and their families.Zespół włosowo-nosowo-paliczkowy jest rzadką chorobą uwarunkowaną genetycznie, w większości przypadków o autosomalnie do-minującym sposobie dziedziczenia. Gen TRPS1 jest zlokalizowany na długim ramieniu chromosomu 8 – 8q24(8q24.12). Fenotyp jest zróżnicowany i prezentuje szerokie spektrum objawów klinicznych. Do charakterystycznych cech fenotypowych zalicza się rzadkie włosy, dysmorfię twarzoczaszki oraz zaburzenia kostno-szkieletowe, zwłaszcza w obrębie dłoni i stóp. Do typowych cech dysmorficz-nych twarzy należą: "gruszkowaty nos", mikrognacja, anomalie zębowe, wydatne uszy, wydłużona rynienka nosowa i wąska czerwień wargowa. W większości przypadków występują anomalie szkieletowe, takie jak klino- i brachydaktylia, skrócenie paliczków śródręcza i śródstopia, kurza klatka piersiowa oraz malformacje stawu biodrowego. Część pacjentów ma niedobór wzrostu. Artykuł przygotowano na podstawie serii czterech przypadków klinicznych (trzy sporadyczne i jeden rodzinny). Wszystkie dzieci pre-zentowały typowe dla TRPS cechy dysmorfii twarzoczaszki oraz różne anomalie układu kostno-szkieletowego. Przyczyną skierowania na Oddział Endokrynologii Dziecięcej było podejrzenie różnych endokrynopatii, w tym niedobór hormonu wzrostu, zaburzeń gospo-darki wapniowo-fosforanowej czy zespołu Turnera. Celem pracy jest przybliżenie symptomatologii TRPS. Leczenie jest objawowe i wymaga skoordynowanej współpracy wielu specjalistów, w tym lekarza pediatry, endokrynologa, ortopedy, dermatologa, specjalisty rehabilitacji medycznej czy chirurga szczękowego. Część pacjentów z niskorosłością i niedoborem GH może wymagać terapii substytu-cyjnej rGH. Doradztwo genetyczne może przynieść korzyści dotkniętym TRPS osobom i ich rodzinom.

Background Tricho‐rhino‐phalangeal syndrome (TRPS) is a rare autosomal dominant disorder characterized by craniofacial and skeletal malformations including short stature, thin scalp hair, sparse lateral eyebrows, a pear‐shaped nose, and cone‐shaped epiphyses. This condition is caused by haploinsufficiency or dominant‐negative effect of the TRPS1 gene. Methods In this study, we analyzed the clinical and genetic data of five unrelated TRPS patients. They were suspected of having TRPS on the basis of clinical and radiological features including typical hair and facial features, as well as varying degrees of skeletal abnormalities. Next‐generation sequencing was performed to identify variants of the TRPS1 gene in the five patients. Results In patient 1, we found a novel mutation at c.1338C>A (p.Tyr446*) (de novo). Patient 2 had a novel phenotype of hydrocephaly and Arnold–Chiari syndrome and we also found a maternally inherited novel mutation at c.2657C>A (p.Ser886*). Patient 3 had a de novo novel mutation at c.2726G>C (p.Cys909Ser) leading to more severe phenotypes. Patient 4 had a paternally inherited known mutation at c.2762G>A (p.Arg921Gln). Patient 5 with a novel phenotype of hepatopathy had a novel deletion at [GRCh37] del(8)(q23.3‐q24.11) chr8:g.116,420,724‐119,124,058 (over 2,700 kb). In addition, the patient 3 who harboring missense variants in the GATA binding domain of TRPS1 showed more severe craniofacial and skeletal phenotypes. Conclusions We describe four novel mutations and two novel phenotypes in five patients. The mutational and phenotypic spectrum of TRPS is broadened by our study on TRPS mutations. Our results reveal the significance of molecular analysis of TRPS1 for improving the clinical diagnosis of TRPS., In this study, we described five Chinese patients of TRPS, including the clinical presentation and molecular features of each patient. We found four novel mutations and two novel phenotypes in five patients. And we believe that our study makes a significant contribution to the literature because it adds to a growing body of studies that characterize the nature of conditions arising from mutations in the TRPS1 gene.

Serine protease inhibitor SerpinB2 is one of the most upregulated proteins following cellular stress. This multifunctional serpin has been attributed a number of pleiotropic activities, including roles in cell survival, proliferation, differentiation, immunity and extracellular matrix (ECM) remodeling. Studies of cancer cells demonstrated that expression of SerpinB2 is directly repressed by the Trps1 transcription factor, which is a regulator of skeletal and dental tissues mineralization. In our previous studies, we identified SerpinB2 as one of the novel genes highly upregulated by phosphate (P(i)) at the initiation of the mineralization process, however SerpinB2 has never been implicated in formation nor homeostasis of mineralized tissues. The aim of this study was to establish, if SerpinB2 is involved in function of cells producing mineralized ECM and to determine the interplay between P(i) signaling and Trps1 in the regulation of SerpinB2 expression specifically in cells producing mineralized ECM. Analyses of the SerpinB2 expression pattern in mouse skeletal and dental tissues detected high SerpinB2 protein levels specifically in cells producing mineralized ECM. qRT-PCR and Western blot analyses demonstrated that SerpinB2 expression is activated by elevated P(i) specifically in osteogenic cells. However, the P(i)-induced SerpinB2 expression was diminished by overexpression of Trps1. Decreased SerpinB2 levels were also detected in osteoblasts and odontoblasts of 2.3Col1a1-Trps1 transgenic mice. Chromatin immunoprecipitation assay (ChIP) revealed that the occupancy of Trps1 on regulatory elements in the SerpinB2 gene changes in response to P(i). In vitro functional assessment of the consequences of SerpinB2 deficiency in cells producing mineralized ECM detected impaired mineralization in SerpinB2-deficient cells in comparison with controls. In conclusion, high and specific expression of SerpinB2 in cells producing mineralized ECM, the impaired mineralization of SerpinB2-deficient cells and regulation of SerpinB2 expression by two molecules regulating formation of mineralized tissues suggest involvement of SerpinB2 in physiological mineralization.

Chromothripsis is a type of chaotic complex genomic rearrangement caused by a single event of chromosomal shattering and repair processes. Chromothripsis is known to cause rare congenital diseases when it occurs in germline cells, however, current genome analysis technologies have difficulty in detecting and deciphering chromothripsis. It is possible that this type of complex rearrangement may be overlooked in rare-disease patients whose genetic diagnosis is unsolved. We applied long read nanopore sequencing and our recently developed analysis pipeline dnarrange to a patient who has a reciprocal chromosomal translocation t(8;18)(q22;q21) as a result of chromothripsis between the two chromosomes, and fully characterize the complex rearrangements at the translocation site. The patient genome was evidently shattered into 19 fragments, and rejoined into derivative chromosomes in a random order and orientation. The reconstructed patient genome indicates loss of five genomic regions, which all overlap with microarray-detected copy number losses. We found that two disease-related genes RAD21 and EXT1 were lost by chromothripsis. These two genes could fully explain the disease phenotype with facial dysmorphisms and bone abnormality, which is likely a contiguous gene syndrome, Cornelia de Lange syndrome type IV (CdLs-4) and atypical Langer–Giedion syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPSII). This provides evidence that our approach based on long read sequencing can fully characterize chromothripsis in a patient’s genome, which is important for understanding the phenotype of disease caused by complex genomic rearrangement.

To explore the genetic etiology of a pedigree affected with tricho-rhino-phalangeal syndrome.Next-generation sequencing (NGS) using a gene panel for hereditary osteopathies was carried out for the proband. Suspected mutation was validated in the proband and her parents by Sanger sequencing.A heterozygous frameshift variation c.1995dupA (p.Gly666Argfs*20) of the TRPS1 gene was detected in the proband but not in her parents.The novel c.1995dupA (p.Gly666Argfs*20) mutation of the TRPS1 gene probably underlies the disease in the proband.

The TRPS1 protein is a potent regulator of proliferation, differentiation, and apoptosis. The TRPS1 gene aberrations are strongly associated with rare trichorhinophalangeal syndrome (TRPS) development. We have conducted MLPA analysis to capture deletion within the crucial 8q24.1 chromosomal region in combination with mutation analysis of TRPS1 gene including core promoter, 5'UTR, and 3'UTR sequences in nine TRPS patients. Low complexity or extent of untranslated regulatory sequences avoided them from analysis in previous studies. Amplicon based next generation sequencing used in our study bridge over these technical limitations. Finally, we have made extended in silico analysis of TRPS1 gene regulatory sequences organization. Single contiguous deletion and an intragenic deletion intervening several exons were detected. Mutation analysis revealed five TRPS1 gene aberrations (two structural rearrangements, two nonsense mutations, and one missense substitution) reaching the overall detection rate of 78%. Several polymorphic variants were detected within the analysed regulatory sequences but without proposed pathogenic effect. In silico analysis suggested alternative promoter usage and diverse expression effectivity for different TRPS1 transcripts. Haploinsufficiency of TRPS1 gene was responsible for most of the TRPS phenotype. Structure of TRPS1 gene regulatory sequences is indicative of generally low single allele expression and its tight control.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal malformations including short stature, cone-shaped phalangeal epiphyses and Perthes-like changes of the hip. We describe the response to growth hormone (GH) treatment in a boy with TRPS. The patient presented at age 3.5 years for evaluation of short stature (-3.2SD). On physical examination, the characteristic facial phenotype of TRPS was noted. Radiographs showed cone-shaped phalangeal epiphyses and bilateral small and fragmented femoral heads. The diagnosis was confirmed by Sanger sequencing of the TRPS1 gene. Two GH stimulation tests revealed GH deficiency, and GH treatment was initiated. Subsequently, growth velocity improved, as did the radiographic appearance of the femoral epiphyses, as seen on sequential pelvis radiographs. This observation suggests the possibility of a beneficial effect of GH treatment on both height and epiphyses status in TRPS patient with GH deficiency. Further studies are needed to support the observation.

Background Tricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterized by distinctive craniofacial and skeletal abnormalities, while non-ossifying fibroma (NOF) is a common benign bone tumour in children and adolescents. To date, no case of TRPS coexisting with NOF has been reported. This report presents a 12-year-old girl who had the characteristic features of tricho-rhino-phalangeal syndrome and non-ossifying fibroma with a fibula fracture. Case presentation A 12-year-old girl was admitted to the Department of Endocrinology and Diabetes for evaluation of brachydactyly and a right fibula fracture. Clinical examination revealed sparse scalp hair, a characteristic bulbous pear-shaped nose, and brachydactyly with significant shortening of the fourth metatarsal. Neither intellectual disability nor multiple exostoses were observed. Radiography of both hands showed brachydactyly and cone-shaped epiphyses of the middle phalanges of the digits of both hands with deviation of the phalangeal axis. Genetic analysis of TRPS1 identified a heterozygous germline sequence variant (p.Ala932Thr) in exon 6 in the girl and her father. Approximately 1 month before being admitted to our department, the girl experienced a minor fall and suffered a fracture of the proximal fibula in the right lower limb. The pathological cytological diagnosis of the osteolytic lesion was NOF. Ten months following the surgery, the lesion on the proximal fibula of the girl disappeared. Conclusions In conclusion, the present study is the first to report a rare case of NOF with a pathologic fracture in the fibula of a girl with TRPS. The identification of a missense mutation, (p.Ala932Thr), in exon 6 of TRPS1 in this kindred further suggested that the patient had type I TRPS and indicated that mutations in this exon may be correlated with more pronounced features of the syndrome. Radiological techniques and genetic analysis played key roles in the definitive diagnosis. Electronic supplementary material The online version of this article (10.1186/s12881-018-0732-4) contains supplementary material, which is available to authorized users.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare congenital disorder that is characterized by abnormal hair growth and skeletal deformities. These result in sparse hair, short stature, and early onset of joint problems. Recent reports have shown that a relatively high proportion of patients with TRPS exhibit a broad range of congenital heart defects. To determine the regulation of Trps1 transcription in vivo, we generated novel transgenic mice, which expressed Cre recombinase under the murine Trps1 proximal promoter sequence (Trps1-Cre). We crossed these mice with Cre reporter mice to identify Trps1 daughter cells. Labeled cells were observed in the appendicular joint tissue, dermal papilla of the hair follicles, cardiac valves, aortic sinus, atrial walls, and the interventricular septum. In situ analysis showed restricted Trps1 expression, which was observed in endocardial cushions of the outflow tract, and in leaflets of all mature cardiac valves. These results suggest that the Trps1 proximal promoter sequence contains some of the tissue-specific Trps1 regulatory region. Further, our findings partially explain why patients with TRPS show a broad range of congenital cardiac defects, although Trps1 expression is observed in a more restricted fashion. genesis 54:379-388, 2016. © 2016 Wiley Periodicals, Inc.

Trichorhinophalangeal syndrome (TRPS) is an extremely rare complex genetic disorder with autosomal dominant inheritance. This case report discusses the management of a 4-year-old child with TRPS II (previously known as Langer–Giedion syndrome), who presented with right-sided hemiparesis and a limping gait secondary to spinal cord compression at the level of C1. Here, we document a child who underwent a successful decompressive laminectomy, highlighting the importance of a multidisciplinary team approach in managing rare and complex cases.

The tricho-rhino-phalangeal syndrome (TRPS) type I is a rare genetic disorder related to the TRPS1 gene mutation in chromosome 8, characterized by craniofacial abnormalities and disturbances in formation and maturation of bone matrix. The hallmarks are sparse and brittle hair, tendency to premature baldness, bulbous nose called pear-shaped, long and flat filter and low ear implantation. The most noticeable skeletal changes are clinodactyly, phalangeal epiphyses of the hands appearing as cone-shaped, short stature and hip joint malformations. We report a case of a teenager boy diagnosed with TRPS and referred for rheumatologic evaluation due to joint complaints.

Trichorhinophalangeal syndrome type I (TRPSI) is a rare disorder that causes distinctive ectodermal, facial, and skeletal features affecting the hair (tricho-), nose (rhino-), and fingers and toes (phalangeal) and is inherited in an autosomal dominant pattern. TRPSI is caused by loss of function variants in TRPS1, involved in the regulation of chondrocyte and perichondrium development. Pathogenic variants in TRPS1 include missense mutations and deletions with variable breakpoints, with only a single instance of an intragenic duplication reported to date. Here we report an affected individual presenting with a classic TRPSI phenotype who is heterozygous for a de novo intragenic ∼36.3-kbp duplication affecting exons 2–4 of TRPS1. Molecular analysis revealed the duplication to be in direct tandem orientation affecting the splicing of TRPS1. The aberrant transcripts are predicted to produce a truncated TRPS1 missing the nuclear localization signal and the GATA and IKAROS-like zinc-finger domains resulting in functional TRPS1 haploinsufficiency. Our study identifies a novel intragenic tandem duplication of TRPS1 and highlights the importance of molecular characterization of intragenic duplications.

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.

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. (C) 2015 Elsevier Masson SAS. All rights reserved.

A representative phenotype of patients with tricho-rhino-phalangeal syndrome (TRPS) is sparse hair. To understand the developmental defects of these patient's hair follicles, we analyzed the development of hair follicles histologically and biochemically using Trps1 deficient (KO) mice. First, we compared the numbers of primary hair follicles in wild-type (WT) and KO embryos at different developmental stages. No differences were observed in the E14.5 skins of WT and KO mice. However, at later time points, KO fetal skin failed to properly develop secondary hair follicles, and the number of secondary hair follicles present in E18.5 KO skin was approximately half compared to that of WT skin. Sonic hedgehog expression was significantly decreased in E17.5 KO skin, whereas no changes were observed in Eda/Edar expression in E14.5 or E17.5 skins. In addition, Noggin expression was significantly decreased in E14.5 and E17.5 KO skin compared to WT skin. In parallel with the suppression of Noggin expression, BMP signaling was promoted in the epidermal cells of KO skins compared to WT skins as determined by immunohistochemistry for phosphorylated Smad1/5/8. The reduced number of secondary hair follicles was restored in skin graft cultures treated with a Noggin and BMP inhibitor. Furthermore, decreased cell proliferation, and increased apoptosis in KO skin was rescued by Noggin treatment. Taken together, we conclude that hair follicle development in Trps1 KO embryos is impaired directly or indirectly by decreased Noggin expression.

Background Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant disorder characterized by craniofacial and skeletal malformations including short stature, thin scalp hair, sparse lateral eyebrows, pear-shaped nose and cone shaped epiphyses. This condition is caused by haploinsufficiency of the TRPS1 gene. Previous genotype-phenotype studies have correlated exon 6 missense mutations with TRPS type III, a severe form of type I with pronounced, facial characteristics, short stature and brachydactyly and differing from type II by the absence of exostoses and mental retardation. Case presentation We report the first case of a Moroccan family, a father and his three children, in which the diagnosis of type III TRPS was suspected based on severe clinical and radiological features. Molecular analysis of the TRPS1 gene revealed a novel missense mutation in exon 6, (p.Ala932Ser), located in the GATA-type DNA-binding zinc finger domain. Conclusion Our observations in this kindred support the previous genotype-phenotype results suggesting that patients with more pronounced facial characteristics and more severe shortening of hands and feet are more likely to have mutation in exon 6 of TRPS1.

Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright's hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes. The study was supported by funding from a research project grant (PI13/00467) from the Instituto de Salud Carlos III (Carlos III Institute of Health) of the Ministry of Economy and Competitiveness (Spain), co-financed by the European Regional Development Fund, and the Department of Health of the Basque Government (GV2014111017). AP is partly supported by the University of the Basque Country (Ref: 48198). GPN is partly supported by the I3SNS Program of the Spanish Ministry of Health (CP03/0064; SIVI 1395/09).

Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal-dominant disease characterized by sparse and slow-growing scalp hair and craniofacial and skeletal abnormalities. We report here the case of two girls and their father who had TRPS type 1 and received a diagnosis of a new mutation of TRPS1 based on their clinical symptoms. Moreover, histological studies on skin samples obtained from one of the patients showed enhanced signal transducers and activator of transcription (STAT) 3 expression in the outer root sheath. However, TRPS1 protein expression was not reduced in the patient's follicles. These findings indicate that truncated TRPS1 protein from the mutant allele may be stably expressed in the patient's follicles and that enhanced STAT3 expression may be involved in the development of sparse and thin scalp hair in TRPS.

Trichorhinophalangeal syndrome (TRPS) is a rare, autosomal dominant malformation syndrome characterized by hair, craniofacial and skeletal abnormalities, skin laxity, deformation of phalanges and anomalies of pelvis, femurs, and tibias. Three subtypes have been described: TRPS I, caused by mutations in TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. We present the case of a 7-year-old boy, affected by TRPS with a severe osteoporosis and several spontaneous bone fractures, an association described only once in the literature, successfully treated with biphosphonates. Bone mineral density (BMD) at dual-energy X-ray Absorptiometry (DXA) was of 0.331 g/cm(2) at lumbar spine with. He had four spontaneous femoral fractures in a year, and for this reason he was been operated for positioning intramedullary osteosynthesis and orthopedic supports. Due to the severity of the clinical and radiological pattern it was established, after approval of the Ethical Committee, to begin off-label therapy with infusions of neridronate at a dose of 2 mg/kg IV every 3 months. The treatment was, in this patient, effective both in terms of clinical (absence of new fractures) and mineralomethric (+45% BMD ath the lumbar level). We therefore suggest that treatment with biphosponates can be taken in account as a possible therapeutic option in case of bone fragility in patients with TRPSI.

We present a 19-year-old male with laxity of skin and joints, sparse scalp hair, facial dysmorphism, epilepsy, multiple exostoses, scoliosis, gastroesophageal reflux, cardiovascular defects, and an 8q23.3-q24.22 deletion detected by array comparative genomic hybridization. The patient was previously misdiagnosed as having Ehlers-Danlos syndrome. However, his clinical findings are in fact correlated with trichorhinophalangeal syndrome type II/Langer-Giedion syndrome and Cornelia de Lange syndrome-4. We discuss the genotype-phenotype correlation and the consequence of haploinsufficiency of TRPS1, RAD21, EXT1 and KCNQ3 in this case.

Trichorhinophalangeal syndrome type I is a rare autosomal dominant disorder characterized by cone-shaped epiphysis, sparse fine hair, pear-shaped nose and variable growth retardation. The typical craniofacial features include thin upper lip, elongated philtrum, large outstanding ears, shortened posterior facial height associated with short mandibular ramus and reduced and superiorly deflected posterior cranial base. This report describes a 17-year-old male patient with trichorhinophalangeal syndrome type I and a detailed description of the craniofacial radiographic findings, including the use of cone beam computed tomography images for determination of the airway and temporomandibular joint discrepancies.

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.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare congenital disorder that is characterized by abnormal hair growth and skeletal deformities. These result in sparse hair, short stature, and early onset of joint problems. Recent reports have shown that a relatively high proportion of patients with TRPS exhibit a broad range of congenital heart defects. To determine the regulation of Trps1 transcription in vivo, we generated novel transgenic mice, which expressed Cre recombinase under the murine Trps1 proximal promoter sequence (Trps1-Cre). We crossed these mice with Cre reporter mice to identify Trps1 daughter cells. Labeled cells were observed in the appendicular joint tissue, dermal papilla of the hair follicles, cardiac valves, aortic sinus, atrial walls, and the interventricular septum. In situ analysis showed restricted Trps1 expression, which was observed in endocardial cushions of the outflow tract, and in leaflets of all mature cardiac valves. These results suggest that the Trps1 proximal promoter sequence contains some of the tissue-specific Trps1 regulatory region. Further, our findings partially explain why patients with TRPS show a broad range of congenital cardiac defects, although Trps1 expression is observed in a more restricted fashion. genesis 54:379-388, 2016. © 2016 Wiley Periodicals, Inc.

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.

Background Autosomal dominant tricho-rhino-phalangeal syndrome I (TRPS I) is due to mutations in the TRPS1 gene. Tricho-rhino-phalangeal syndrome I is characterized by peculiar face and skeletal anomalies. Cone-shaped epiphyses are the characteristic radiographic findings. Objective To describe 2 families with TRPS I and 2 novel mutations in the TRPS1 gene. Patients The study included 2 nonrelated families with TRPS I. All exons of the TRPS1 gene were analyzed from genomic DNA. Results The TRPS1 gene mutation analysis showed in family 1 the c.978C>A nonsense mutation within exon 4 and in family 2 the c.164A>C missense mutation within exon 3. Conclusions We found 2 families with TRPS1 caused by 2 novel mutations in the TRPS gene, particularly a missense mutation in exon 3, outside the GATA zinc finger domain, that leads a mild TRPS phenotype. Our data show a higher genotypic spectrum in the TRPS I and demonstrate that mutations in the amino terminus of the transcription factor result in TRPS I syndrome.

In 1987 Fitzsimmons and Guilbert described identical male twins with progressive spastic paraplegia, brachydactyly with cone shaped epiphyses, short stature, dysarthria, and "low-normal" intelligence. In subsequent years, four other patients, including one set of female identical twins, a single female child, and a single male individual were described with the same features, and the eponym Fitzsimmons syndrome was adopted (OMIM #270710). We performed exome analysis of the patient described in 2009, and one of the original twins from 1987, the only patients available from the literature. No single genetic etiology exists that explains Fitzsimmons syndrome; however, multiple different genetic causes were identified. Specifically, the twins described by Fitzsimmons had heterozygous mutations in the SACS gene, the gene responsible for autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), as well as a heterozygous mutation in the TRPS1, the gene responsible in Trichorhinophalangeal syndrome type 1 (TRPS1 type 1) which includes brachydactyly as a feature. A TBL1XR1 mutation was identified in the patient described in 2009 as contributing to his cognitive impairment and autistic features with no genetic cause identified for his spasticity or brachydactyly. The findings show that these individuals have multiple different etiologies giving rise to a similar phenotype, and that "Fitzsimmons syndrome" is in fact not one single syndrome. Over time, we anticipate that continued careful phenotyping with concomitant genome-wide analysis will continue to identify the causes of many rare syndromes, but it will also highlight that previously delineated clinical entities are, in fact, not syndromes at all. © 2016 Wiley Periodicals, Inc.

Type 1 Trichorhinophalangeal syndrome (TRPS) is characterized by typical facial and skeletal abnormalities. These patients frequently exhibit short stature; however, only one case with growth hormone (GH) deficiency can be found in the literature. Our patient is a 10-year-old girl with two novel nonsense pathogenic mutations in the TRPS1 gene, both in heterozygosity: c. 1198CT (p. Gln400X) and c.2086CT (p. Arg696X). She has an additional GH deficiency. The patient is short in stature, with a growth velocity of 1.5 cm per year (SDS - 4.07), a bone age of 4.5 years, and she shows no response to the GH stimulation tests. According to a previous report of an identical case, catch-up growth will occur after beginning GH treatment. We believe that GH stimulation tests should be performed on patients with TRPS1 exhibiting a growth velocity below the normal range expected for their age and sex. If the result is subnormal, then GH therapy should be attempted.

Das Trichorhinophalangeal-Syndrom (TRPS) wurde 1966 von Andres Giedion, einem Schweizer Kinderradiologen, beschrieben 1 , jedoch publizierte Klingmuller bereits 1956 eine Beobachtung uber diese Anomalie 2 . Der Typ 1 ist gekennzeichnet durch kolbenformig aufgetriebene Epiphysen (Phalangeal), sparlich dunnes Haupthaar (Tricho), eine Ausdunnung der seitlichen Augenbrauen, birnenformiger Nase (Rhino) und eine unterschiedliche Wachstumsretradierung 3 . Beim Typ 2 finden sich zusatzlich multiple Exostosen, Mikrozephalgie und geistige Retradierung 4 , dem sogenannten Langer-Giedion-Syndrom. Weiterhin finden sich bei Typ 2 grose Fledermausohren, Hypermobilitat der Gelenke und Perthes-ahnliche Huftkopfveranderungen. Beim Typ 3 sind die Hand- und Fusanomalien starker ausgepragt als bei Typ 1 und 2. An der Hand zeigt sich meist eine generelle Verkurzung der Phalangen und Metakarpalknochen. Grobe Achsenabweichungen treten bei allen 3 Typen hauptsachlich am Zeigefinger auf, gefolgt vom Mittel- und Ringfinger in annahernd gleicher Haufigkeitsverteilung, hingegen am Kleinfinger nur selten 5 . Das TRPS Typ 1 und 3 wird meist autosomal-dominant vererbt, Typ 2 tritt sporadisch durch eine Deletion des langen Arms von Chomosom 8 auf 3 5 6 7 . Typische Merkmale des TRPS kraniofazial sind in Tab. 1 dargestellt.

Homozygous mutation of the short stature homeobox-containing gene, SHOX, results in Langer mesomelic dysplasia (LMD). Our case presented with severe short stature and skeletal deformities with Turner syndrome (TS) and a SHOX gene abnormality due to a downstream allele deletion in her normal X chromosome. Medical literature review did not reveal similar cases that were treated with GH therapy.We present an 11-yr-old with combined TS and LMD with severe short stature and skeletal deformities. She was studied for the effect of GH therapy on stature and skeletal deformities. Karyotype testing showed 45,X/46,X,idic(X). Genetic analysis of SHOX gene testing did not detect any exonic mutations. Interestingly, both alleles of the flanking marker DXYS233, a marker downstream of the 3' end of SHOX coding sequence, were absent with resultant LMD. GH therapy in the mean dose of 0.321 mg/kg/wk was administered for 4 yr (0.287, 0.355, 0.317, and 0.327 mg/kg/week in the first, second, third, and fourth years, respectively). Clinical data were reviewed.The growth rates of 3.46, 3.87, 2.3, and 0.7 cm/yr were observed in the first, second, third, and fourth years of the GH therapy, respectively. There was no clinical deterioration of the skeletal deformities.There was a failure to achieve growth improvements with GH therapy for 4 years, but there was no worsening of the skeletal deformities. We conclude that GH therapy may not be beneficial in severe short stature due to combined TS and LMD resulting from homozygous SHOX deficiency.

The EULAR Executive Committee defined eight overall objectives for EULAR to achieve by 2012. The first of these objectives is to strengthen activities in areas that are currently less prioritized, such as non-inflammatory and orphan diseases. This study aims to increase awareness of rheumatologists towards rare hereditary musculoskeletal disorders, by describing their genetics, pathogenesis, and typical clinical and radiological features. We analyzed patient charts from the recent 5 years from the Rheumatology Outpatient Department of the University Erlangen-Nuremberg and of two rheumatologic practices, all joined in a regional network ("Rheumazentrum Erlangen") retrospectively for hereditary musculoskeletal disorders other than hemochromatosis, autoinflammatory syndromes, lysosomal storage diseases, and hypermobility syndromes. We were able to identify four patients with trichorhinophalangeal syndrome type I, multiple exostoses, Kirner's deformity, and osteopoikilosis. In addition, a PubMed and OMIM ("Online Mendelian Inheritance in Man") database search was carried out using these as key words and all relevant articles were reviewed for each of these diseases. Our findings show that rare hereditary musculoskeletal disorders occur in a routine rheumatological setting and that rheumatologists should know the clinical and radiological features of these diseases in order to adequately counsel the patient.

An 8-year-old boy with the features of Langer-Giedion syndrome except for short stature is described. Chromosome analysis using high resolution G-banding techniques revealed an interstitial deletion of the long arm of chromosome 8:46,XY,del(8)(q24.13-q24.22).

The Langer-Giedion syndrome, also known as trichorhinophalangeal syndrome type II, is a hereditary multisystemic disease part of the group of contiguous gene deletion syndromes. The cause of this syndrome is a heterozygous deletion that involves the chromosomal region 8q23.3-q24.11 and mainly affects genes TRPS1, RAD21, and EXT1. This syndrome is characterized by the presence of multiple osteochondromas in limbs, hypertrichosis, and facial phenotype that includes sparse scalp hair, large laterally protruding ears, a long nose with a bulbous tip. We report the case of a Colombian patient with finding of an 8q23.1-q24.12 deletion by comparative genomic hybridization array technique and classical clinical findings, being the first case reported in Colombia.El síndrome de Langer-Giedion, también conocido como síndrome tricorrinofalángico tipo II, es una enfermedad hereditaria multisistémica que pertenece al grupo de síndromes por deleción de genes contiguos. La causa de este síndrome es una deleción heterocigota que compromete, por lo general, la región 8q23.3-q24.11 y afecta, principalmente, los genes TRPS1, RAD21 y EXT1. Este síndrome se caracteriza por osteocondromatosis múltiple en las extremidades, hipertricosis y fenotipo facial, que incluye pelo escaso en el cuero cabelludo, orejas grandes sobresalientes y nariz larga con una punta bulbosa. Se reporta el caso de un paciente colombiano con hallazgo de deleción en la región cromosómica 8q23.1-q24.12 mediante técnicas de hibridación genómica comparativa y hallazgos clínicos clásicos. Este es el primer caso reportado en Colombia.

A comprehensive differential gene expression screen on a panel of 54 breast tumors and >200 normal tissue samples using DNA microarrays revealed 15 genes specifically overexpressed in breast cancer. One of the most prevalent genes found was trichorhinophalangeal syndrome type 1 (TRPS-1), a gene previously shown to be associated with three rare autosomal dominant genetic disorders known as the trichorhinophalangeal syndromes. A number of corroborating methodologies, includingin situhybridization, e-Northern analysis using ORF EST (ORESTES) and Unigene EST abundance analysis, immunoblot and immunofluorescence analysis of breast tumor cell lines, and immunohistochemistry, confirmed the microarray findings. Immunohistochemistry analysis found TRPS-1 protein expressed in >90% of early- and late-stage breast cancer, including ductal carcinomain situand invasive ductal, lobular, and papillary carcinomas. The TRPS-1 gene is also immunogenic with processed and presented peptides activating T cells found after vaccination of HLA-A2.1 transgenic mouse. Human T cell lines from HLA-A*0201+female donors exhibiting TRPS-1-specific cytotoxic T lymphocyte activity could also be generated.

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). To describe this very rare pathological condition and the results of surgical intervention. Gifu, Japan. 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. 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. 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.

We report on a 10-year-old girl with tricho-rhino-phalangeal syndrome type II (TRPS II) and pronounced short stature (−4.8 SD). The patient has an interstitial chromosome 8q24.1 deletion of 12–15 Mb. The deletion spans all genes from CSMD3 to at least ANXA13 including the TRPS1 and EXT1 genes, which are responsible for the TRPS II phenotype. In addition to the features of TRPS II, the patient had growth hormone (GH) deficiency with diminished response in three stimulation tests. Therapy with 0.2 mg GH/kg/week led to an increase of growth velocity from 2.5 to 6.6 cm/year. To our knowledge, such a combination of TRPS II and GH deficiency has not yet been described. © 2004 Wiley-Liss, Inc.

Multiple exostoses represent a genetically heterogeneous disorder that may occur isolated or as part of a complex contiguous gene syndrome such as Langer-Giedion syndrome on chromosome 8 and the proximal 11p deletion syndrome on chromosome 11. Here we describe a boy with multiple exostoses, hypertrichosis, mental retardation, and epilepsy due to a de novo deletion on chromosome 8q24. Molecular analysis revealed that the deletion interval overlaps with the Langer-Giedion syndrome and involves the EXT1 gene and additional genes located distal to EXT1, but probably not encompassing the TRPS1 gene located proximal to EXT1.

The tricho-rhino-phalangeal syndromes (TRPS type I, II, and III) are autosomal dominant disorders sharing the following characteristics: slowly growing and sparse scalp hair, medially thick and laterally thin eyebrows, bulbous tip of the nose, long flat philtrum, thin upper lip with vermilion border, and protruding ears. In addition, individuals with TRPS generally share skeletal and bone anomalies, including shortening of the phalanges and metacarpals (mild to severe brachydactyly), cone-shaped epiphyses, hip dysplasia, and short stature. The etiology of the different types of TRPS can result from either single base pair mutations, or the complete deletion of the TRPS1 gene, which encodes a zinc-finger transcription factor located on chromosomal band 8q24.1. We have identified nine heterozygous mutations, five novel and four recurrent, in unrelated families diagnosed with TRPS. The five novel mutations identified show 1- or 2-bp deletions and a single base substitution, whereas all of the recurrent mutations are single base substitutions. Seven of the nine mutations result in a premature stop codon, leading to a truncated, nonfunctional TRPS1 protein. The final two mutations are missense mutations in the GATA DNA binding zinc finger, which is believed to be important for the protein's normal function.

We report a new Japanese family with tricho-rhino-phalangeal syndrome type III (TRPS III) who have a missense mutation (Arg908Gln) of theTRPS1 gene (TRPS1) in affected individuals of the family. This study supports the notion that TRPS III results from missense mutations in exon 6 of TRPS1. © 2001 Wiley-Liss, Inc.

Trichorhinophalangeal syndrome type I (TRPS I) is an autosomal dominant malformation syndrome characterized by a triad of hair alteration, craniofacial and skeletal abnormalities. TRPS1 gene was first identified in 2000 and mapped on chromosome 8q23.3. A 39-year-old female patient with short stature (149 cm) visited for fine sparse and slow-growing hair with receded medio-occipital hairline of roughly triangular shape since infancy. A typical pear-shaped nose and elongated philtrum were noticeable. In addition, she reported deviation of middle phalanges, bilateral coxa varus in both hips and brachydactyly on bilateral fourth digits. Mutation analysis identified a transition of cytosine to thymine at position 1630 (exon 4), which results in amino acid change R544X and a premature stop of translation. There is no established treatment. But through careful evaluation of suspicious cases to identify potential mutation carriers, the patient can receive information about the disease and genetic counseling.

Langer-Giedion Syndrome (LGS), with characteristic phenotypic features including craniofacial dysmorphic signs, postnatal growth retardation and skeletal abnormalities, mental impairment, urogenital malformations and heart defects, is caused by partial deletions of the long arm of chromosome 8. We present a case of a female fetus with LGS. The diagnosis was molecularly proven with the BACs on Beads™ method at 32 weeks of gestation. To the best of our knowledge, prenatal recognition of that genetic defect had previously been made in only one case. Also, it has never been described before.

Hintergrund: Das Trichorhinophalangeale Syndrom (TRPS II) oder Langer-Giedion-Syndrom gilt als sehr seltenes Krankheitsbild, welches durch eine Vielzahl klinischer Merkmale in unterschiedlicher Ausbildung gepragt wird. Ergebnisse: Im Falle eines nun 14-jahrigen Patienten findet sich die in der Literatur haufig beschriebene Deviation der Finger im Rahmen des Trichorhinophalangealen Syndroms Typ II nicht. Jedoch war der Verlauf bislang kompliziert durch syndrombedingte konsekutive Achsenfehler zweier groser Gelenke der unteren Extremitat. Aufgrund ausgepragter Exostosen im Bereich der Epiphysenfugen des linken Kniegelenks entwickelte sich dort ein Genu valgum, welches mittels einer temporaren Epiphyseodese korrigiert wurde. Ebenso erfolgte bei zunehmender Valgusfehlstellung im rechten oberen Sprunggelenk die Exostosenabtragung am rechten Malleolus lateralis und eine korrigierende temporare Epiphyseodese der rechten distalen medialen Tibia. Bereits in fruhester Kindheit fielen bei dem Jungen rezidivierende kartilaginare Exostosen sowohl an den Extremitaten als auch stammnah auf. Ausgepragt sind weiterhin die fazialen Stigmata, welche die syndromtypische Gesichtsform bestimmen. Schlussfolgerung: Anhand der Falldarstellung eines nun 14-jahrigen Jungen mit besonders ausgepragten orthopadischen Problemen werden die therapeutischen Prinzipien des Trichorhinophalangealen Syndromes (TRPS II) erlautert. Introduction: The trichorhinophalangeal syndrome type II or Langer-Giedion syndrome is regarded as a rare abnormity that is marked by a number of clinical characteristics beside multiple cartilaginous exostoses. Results: The deviation of the fingers within the scope of the TRPS II that is often reported in literature can not be found in the case at issue of a now 14 year old boy. The course of disease was complicated due to consecutive axis deviation of two large joints of the lower extremities being determined by the syndrome. Due to the marked exostoses in the area of the growth plate of the left knee joint a valgus deformity developed there. It was corrected with means of a temporary clamping of the growth plate. With the increasing valgus deformity of the right ankle causing a calcaneovalgus foot deformity the osteochondroma located at the distal fibula was also removed and a temporary clamping of the growth plate was carried out at the right medial malleolus. From earliest childhood repeating cartilaginous exostoses both at the extremities and the trunk attracted attention. Also strongly developed are the facial distinguishing marks which determine the typical shape of the face. Conclusion: By the case of a now 14 year old boy with severe orthopedic complications considerations are made concerning therapeutic principles due to the TRPS II.

In 1956 Klingmuller first described the trichorhinophalangeal syndrome (TRPS), which was named by Giedion ten years later. The syndrome includes a combination of typical hair, facial and bone abnormalities with variable expression allowing the further distinction of three subtypes. In a 37-year old patient with TRPS type I who reportedly had reduced hair growth length, clinically fine and brittle hair were found. Scanning electron microscopy revealed widely spaced cuticular scales. Quantitative measurement of the biomechanical properties of the hair showed a significant increase in the viscous parameter. This could be a result of decreased disulfide bridges and increased halogen bonds in the keratin matrix of the hair. In dermatological practice patients with TRPS often present because of hair abnormalities. Because of premature arthrosis due to skeletal abnormalities, occupational counseling is advised.Congenital heart problems, kidney abnormalities and endocrinological problems are rare, but should be sought in the symptomatic individual. Apart from mild hair care and avoidance of additional physical or chemical injuries due to hair cosmetic procedures,there is no treatment for the hair defects.

We have developed an integrated map for a 35-cM area of human chromosome 8 surrounding the Langer-Giedion syndrome deletion region. This map spans from approximately 8q22 to 8q24 and includes 10 hybrid cell intervals, 89 polymorphic STSs, 118 ESTs, and 37 known genes or inferred gene homologies. The map locations of 25 genes including osteoprotegerin, syndecan-2, and autotaxin have been refined from the general locations previously reported. In addition, the map has been used to indicate the location of nine deletions in patients with Langer-Giedion syndrome and trichorhinophalangeal syndrome type I to demonstrate the potential usefulness of the map in the analysis of these complex syndromes. The map will also be of interest to anyone trying to clone positionally disease genes in this region, such as Cohen syndrome (8q22-q23), Klip-Feil syndrome (8q22.2), hereditary spastic paraplegia (8q24), and benign adult familial myoclonic epilepsy (8q23.3-q24.1).