Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or hypochondroplasia

We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.     

Development of body proportions in achondroplasia: Sitting height,leg length,arm span,and foot length

The aims of this study was to construct references for sitting height, leg length, arm span, relative sitting height (sitting height/height), and foot length and to discuss the development for these anthropometric variables in achondroplasia. Sex‐specific references covering ±2 SD are presented for ages 2–20 years. Legs and arms in achondroplasia are already at 2 years of age considerably shorter than in the general population and this deviation increases with age. At adult ages, legs are almost 50% shorter than in the general population and arm span roughly 35% shorter. As sitting height is only mildly affected, relative sitting height position develops far beyond normal ranges. Foot length is also not as affected as limbs.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Metacarpophalangeal pattern profile analysis in Leri-Weill dyschondrosteosis

PURPOSE: To analyze the metacarpophalangeal profile (MCPP) in individuals with Leri-Weill dyschondrosteosis (LWD) and to assess its value as a possible contributor to early diagnosis. MATERIAL AND METHODS: Hand profiles of 39 individuals with a diagnosis of LWD were calculated and analyzed. Discriminant analysis was applied to differentiate between LWD and normal individuals. RESULTS: There was a distinct pattern profile in LWD. Mean pattern profile showed two bone-shortening gradients, with increasing shortening from distal to proximal and from medial to lateral. Distal phalanx 2 was disproportionately long and second metacarpal was disproportionately short. Discriminant analysis yielded correct classification in 72% of analyzed cases. CONCLUSION: MCPP is not age-related and the analysis can be applied at any age, facilitating early diagnosis of LWD. In view of its availability, low costs, and diagnostic value, MCPP analysis should be considered as a routine method in the patients of short stature where LWD is suspected.     

Failures and complications in patients with birth defects restored with fixed dental prostheses and single crowns on teeth and/or implants

Objectives: To assess retrospectively, over at least 5 years, the incidences of technical and biological complications and failures in young adult patients with birth defects affecting the formation of teeth. Material and methods: All insurance cases with a birth defect that had crowns and fixed dental prostheses (FDPs) inserted more than 5 years ago were contacted and asked to participate in a reexamination. Results: The median age of the patients was 19.3 years (range 16.6–24.7 years) when prosthetic treatment was initiated. Over the median observation period of 15.7 years (range 7.4–24.9 years) and considering the treatment needs at the reexamination, 19 out of 33 patients (58%) with reconstructions on teeth remained free from all failures or complications. From the patients with FDPs and single unit crowns (SCs) on implants followed over a median observation period of 8 years (range 4.6–15.3 years), eight out of 17% or 47% needed a retreatment or repair at some point due to a failure or a complication. From the three groups of patients, the cases with amelogenesis/dentinogenesis imperfecta demonstrated the highest failure and complication rates. In the cases with cleft lip, alveolus and palate (CLAP) or hypodontia/oligodontia, 71% of the SCs and 73% of the FDPs on teeth (FDP T) remained complication free over a median observation period of about 16 years. Sixty‐two percent of the SCs and 64% of the FDPs on implants remained complication free over 8 years. Complications occurred earlier with implant‐supported reconstructions. Conclusions: Because healthy, pristine teeth can be left unprepared, implant‐supported SCs and FDPs are the treatment choice in young adults with birth defects resulting in tooth agenesis and in whom the edentulous spaces cannot be closed by means of orthodontic therapy. However, the trend for earlier and more frequent complications with implant‐supported reconstructions in young adults, expecting many years of function with the reconstructions, has to be weighed against the benefits of keeping teeth unprepared. In cases with CLAP in which anatomical conditions render implant placement difficult and in which teeth adjacent to the cleft require esthetic corrections, the conventional FDP T still remains the treatment of choice.     

Survival of patients with head and neck squamous cell carcinoma in association with human papillomavirus and p53 polymorphism

Abstract

Survival of patients with head and neck squamous cell carcinoma (HNSCC) is dependent on many factors — stage of the disease, treatment regimen, operation technique etc. Many authors discuss on association of survival with various biomarkers as HPV infection, p53 mutation and polymorphism or p16 expression. The objective of our study was to analyze the survival of HNSCC patients in association with HPV infection and p53 polymorphism.

Methods

39 patients with primary diagnosed HNSCC were investigated. HPV DNA was detected using PCR with general primers MY09/11; p53 polymorphism was analyzed using single nucleotide polymorphism assay by PCR.

Results

Of the 39 patients, 12 (30.8%) had detectable HPV. After p53 polymorphism analysis heterozygous Prol/Arg type was found in 34 cases (87.2%). Survival was higher in laryngeal cancer patients and in patients when tumour was classified as T_1–2. Somewhat higher survival was in the HPV positive patients, however difference was not statistically significant (P = 0.7). Only significant factor influencing survival in our study group was site of primary tumour (P < 0.05).

Conclusion

HNSCC patients’ survival in our study depend on primary tumour site; HPV infection and p53 SNP was not associated with better survival.

     

Primary malignant peripheral nerve sheath tumour of the heart

A malignant peripheral nerve sheath tumour (MPNST) is a rare variety of soft-tissue sarcoma of ectomesenchymal origin. The World Health Organisation created the term MPNST to replace previous terminology such as malignant schwannoma, malignant neurilemmoma, neurogenic sarcoma, and myxofibrosarcoma for tumours of neurogenic origin with similar biological behavior.[1–3] The vast majority of these tumours develop in extremities. They also tend to be located in unusual sites of the body, such as the pelvic retroperitoneum, infratemporal fossa, intrapericardium, and mediastinum.[1,3,4] This case study presents a patient with an extremely rare primary cardiac MPNST..     

Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery

BackgroundImmunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αβTCR T cells.MethodsWe profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of 5 CAR targets (B7-H3, GD2, IL-13Rα2, EphA2, and HER2), and HLA class I. In addition, we generated B7-H3-CAR T cells and evaluated their antitumor activity in vitro and in vivo.ResultsWe established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL-13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage.ConclusionsOur study highlights the importance of studying target antigen and HLA class I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.