OBJECTIVE: To evaluate the health-related quality of life and associated risk factors for Multiple Osteochondromas patients.
METHODS: A cross-sectional, observational study was conducted from May to December 2022 during the routine visit to the referral center for rare skeletal disorders. All patients with Multiple Osteochondromas aged ≥ 3 years were included. EuroQol 5-dimension questionnaires, and demographic, clinical, and surgical history data were collected. Descriptive statistics, Fisher\'s exact test, One-sample t-test, Spearman\'s correlation, and multiple linear and logistic regression were performed to analyze the data. Results are reported following STROBE guidelines.
RESULTS: A total of 128 patients were included in the study, with a mean age of 14 [SD, 10] years. The mean EQ-5D Index Value was 0.863 [SD, 0.200] and the EQ-VAS was 84 [SD, 19] with a positive correlation between two scores [r = 0.541, p < 0.001]. Patients frequently referred problems in pain/discomfort [78.8%], anxiety/depression [50%], and usual activities [38.8%] dimensions. Increasing age was the common risk factor for health-related quality of life [p < 0.000], as well as Index Value and VAS scores were significantly lower in surgical patients [p = 0.001 and p < 0.001, respectively].
CONCLUSIONS: Increasing age and surgical procedures were found highly associated with reduced health-related quality of life in Multiple Osteochondromas patients. Our findings provide relevant information to support the establishment of patient-centered healthcare pathways and pave the way for further research into medical and non-medical therapeutic strategies for these patients.

OBJECTIVE: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes.
METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed.
RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013).
CONCLUSIONS: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.

Skeletal dysplasias are a diverse group of rare disorders in the chondro-osseous tissue that can have a significant impact on patient\'s functionality. The worldwide prevalence of skeletal dysplasias at birth is approximately 1:5000 births. To date, disease burden and trends of skeletal dysplasias in the Sri Lankan population have not been described in any epidemiological study. Our aim was to evaluate the burden and the current trends in hospital admissions for skeletal dysplasias in the Sri Lankan population. A retrospective evaluation of hospital admissions for skeletal dysplasia during 2017-2020 was performed using population-based data from the eIMMR database which covers government hospitals in the entire country. The trends in hospital admissions for skeletal dysplasias by calendar year, age, and types of skeletal dysplasia were described using appropriate summary statistics.
Respective crude admission rates of skeletal dysplasias in the years 2017, 2018, 2019 and 2020 were 5.2, 8.1, 8.0, and 6.5 per million population. A female predominance (1.4:1) was noted during the studied period. Of all reported cases the majority (n = 268; 44.2%) were children less than 4 years. Each year, 0-4 years age group represented 40-47% of the total hospital admissions. More than half of the cases were reported from Colombo (28.1%) and Kandy (25.4%) districts combined. 60% of cases were diagnosed as osteogenesis imperfecta (OI). Rising trends were observed in the hospital admissions for osteogenesis imperfecta, achondroplasia and osteopetrosis, while other skeletal dysplasia types collectively showed a relatively stable trend.
This preliminary study revealed a female predominance of skeletal dysplasias and a relatively high admission rate of osteogenesis imperfecta in the Sri Lankan population. A distinct trend was not visible in the studied years probably due to the impact on hospital services due to COVID- Pandemic. Future research on the healthcare burden on families affected by skeletal dysplasia is required to better understand the overall cost of care and identify therapies that reduce admission rates. This study highlights the value of analysing population-based data on rare diseases to improve healthcare in low-resource countries.

Background: Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study aims to identify the genetic causes for fetal short long bones, and retrospectively evaluate the additional diagnostic yield of exome sequencing (ES) for short long bones following the use of conventional genetic testing. Methods: A cohort of ninety-four fetuses with sonographically identified short long bones was analyzed by trio-exome sequencing between January 2016 and June 2021. Fetuses with abnormal results of karyotype or chromosomal microarray analysis were excluded. Variants were interpreted based on ACMG/AMP guidelines. All diagnostic de novo variants were validated by Sanger sequencing. Results: Of the 94 fetuses, 38 (40.4%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in sixteen genes with 38 variants. Five fetuses (5.3%) had variant(s) of uncertain significance. Thirty-five cases (37.2%) were diagnosed as genetic skeletal dysplasias including 14 different diseases that were classified into 10 groups according to the Nosology and Classification of Genetic Skeletal Disorders. The most common disease in the cohort was achondroplasia (28.9%), followed by osteogenesis imperfecta (18.4%), thanatophoric dysplasia (10.5%), chondrogenesis (7.9%), and 3-M syndrome (5.3%). The diagnostic yield in fetuses with isolated short long bones was lower than the fetuses with non-isolated short long bones, but not reached statistical significance (27.3% vs. 44.4%; p = 0.151). Whereas, the rate in the fetuses with other skeletal abnormalities was significantly higher than those with non-skeletal abnormalities (59.4% vs. 32.5%, p = 0.023), and the diagnostic rate was significantly higher in femur length (FL) below -4SDs group compared with FL 2-4SDs below GA group (72.5% vs. 16.7%; p < 0.001). A long-term follow-up showed that outcomes for fetuses with FL 2-4SDs below GA were significantly better than those with FL below -4SDs. Additionally, fourteen (36.8%) novel short long bones-related variants were identified in the present study. Conclusion: The findings suggest that in fetuses with short long bones routine genetic tests failed to determine the underlying causes, exome sequencing could add clinically relevant information that could assist the clinical management of pregnancies. Novel pathogenic variants identified may broaden the mutation spectrum for the disorders and contributes to clinical consultation and subsequent pregnancy examination.

Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults.
Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes.
Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes.
The findings of this study suggest that, across an individual\'s lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368.

OBJECTIVE: To evaluate the possible outcomes of fetuses diagnosed with short femur length (FL) and to guide diagnosis through a step-wise imaging algorithm.
METHODS: This was a prospective cohort study of 42 pregnancies with fetal femur length (FL) below the 5th centile for gestational age. The cases were divided into two categories of isolated short FL & non-isolated short FL and followed up to determine the etiology.
RESULTS: There were 11 cases of non-isolated short FL with skeletal dysplasia observed in 7 and chromosomal abnormalities in 4 cases. There were 31 cases with isolated short FL in which fetal growth restriction (FGR) occurred in 14/31 (45%) cases; 13 out of 31 (42%) were constitutional (short for gestational age, SGA) whereas 4/31(13%) showed normal interval growth on follow up (false positive).
CONCLUSIONS: Short femur can be isolated or non-isolated. Short femur length can be a good predictor and early sign of FGR. Serial follow up scan of the all cases of isolated short FL is important since a majority of them are normal and not require any further intervention. Cases of non-isolated short FL require step-wise approach to differentiate into dysplasia or aneuploidy.

UNASSIGNED: To determine the frequency of skeletal dysplasia in children with short stature presenting to the endocrine clinic of a tertiary care hospital.
UNASSIGNED: This descriptive cross-sectional study was performed in the Outpatient Department of Endocrinology of National Institute of Child Health, Karachi, for 6 months of duration. A total of 200 children coming to endocrine OPD of NICH of either gender, having the age less than 14 years and height more than -2.5 SD below the mean (<3rd percentile), and growth failure (<4 cm/yr) were enrolled. A complete general physical examination including height, weight, fronto-occipital circumference (FOC), arm span, and U/L (upper/lower) segment ratio (using SI units and SDS) was performed.
UNASSIGNED: Out of 200 children with short stature, skeletal dysplasia was diagnosed in 23 (11.5%) children with the mean age of 4.7 (±3.7) years. Proportion of skeletal dysplasia among short stature was high in females. Out of 75 girls, skeletal dysplasia was diagnosed in 10 (13.3%) girls, while out of 125 boys, skeletal dysplasia was diagnosed in 13 (10.4%) boys, whereas when we see proportion among skeletal dysplasia out of 23 children of skeletal dysplasia, 13 (56.5%) were boys, while 10 (43.5%) were girls.
UNASSIGNED: In this study, skeletal dysplasia was diagnosed in 11.5% children with short stature with the mean age of 4.7 years. It is concluded that the frequency of skeletal dysplasia in this institute is fairly high.

Gait deviations, lower limb pain and joint stiffness represent key symptoms in patients with X-linked hypophosphatemia (XLH, OMIM 307800), a rare disorder of mineral homeostasis. While the pathomechanism for rickets is well understood, the direct role of PHEX (Phosphate-regulating neutral endopeptidase) deficiency in non-rachitic features including complex deformities, skull and dental affections remains unclear. FGF23-inhibiting antibody treatment can normalize serum phosphate levels and to improve rickets in XLH patients. However, linear growth remains impaired and effects on lower limb deformity and gait are insufficiently studied.
To characterize and evaluate the course of lower limb deformity in a case series of pediatric XLH patients receiving Burosumab therapy.
Comparative assessment of planar radiographs, gait analysis, biochemical and clinical features of pediatric patients before and ≥12 months after initiation of FGF23-inhibiting was performed prospectively. Lower limb maltorsion was quantified by torsional MRI and gait analysis. Standardized deformity analysis of lower limb anteroposterior radiographs was conducted.
Seven patients (age 9.0 +/-3.6 years) were eligible for this study. All patients received conventional treatment before onset of antibody treatment. Maltorsion of the femur was observed in 8/14 legs using torsional MRI (mean antetorsion 8.79°). Maltorsion of the tibia was observed in 9/14 legs (mean external torsion 2.8°). Gait analysis confirmed MRI findings with femoral external malrotation prior to and one year after onset of Burosumab therapy. Internal foot progression (intoeing gait) remained pathological in all cases (mean 2.2°). Knee rotation was pathologically internal 10/14 legs. Mean mechanical axis deviation (MAD) of 16.1mm prior to Burosumab changed in average by 3.9mm. Three children underwent guided growth procedures within the observation period. Mild postprocedural rebound of frontal axis deviation was observed under Burosumab treatment in one patient.
This is the first study to investigate lower limb deformity parameters quantitatively in children with XLH receiving Burosumab. One year of Burosumab therapy was associated with persistent maltorsion and frontal axis deviation (varus/valgus) despite improved rickets in this small, prospective uncontrolled study.

BACKGROUND: Frontometaphyseal dysplasia 1 (FMD1) is a rare X-linked craniofacial syndrome belonging in the otopalatodigital spectrum of disorders. Here we present a case with severe FMD1 that was caused by a mutation in the FLNA gene located on Xq28.
METHODS: A diagnosis for FMD1 was clinically set for a 22-year-old male who presented with cranial hyperostosis with marked supraorbital ridge, hypertelorism, progressive mixed hearing loss, partial anodontia, scoliosis, generalized skeletal dysplasia, and muscle atrophy. The patient\'s two older brothers had also severe FMD1 manifestations with generalized skeletal dysplasia, cranial hyperostosis, progressive hearing loss, and scoliosis, while their mother and maternal grandmother had some less prominent FMD1 signs. Total DNA was extracted from blood samples of the patient, his brothers, and his parents.
RESULTS: DNA sequencing of all 48 exons of the FLNA gene revealed a single-point mutation (3476A>C) in exon 22. The missense mutation changes an Asp codon into an Ala codon in amino acid position 1159. The patient\'s two brothers had the same mutation, while their mother was a heterozygous carrier having both the mutant allele and the normal allele.
CONCLUSIONS: The clinical diagnosis for FMD1 was confirmed by genetic analysis. It is evident that the FLNA gene product filamin A plays a critical developmental role in morphogenesis of several tissues being a cytoskeleton component, since mutations in its gene cause multiple manifestations and diverse disorders of the otopalatodigital spectrum.

OBJECTIVE: To quantify otolaryngologic surgery utilization in patients with achondroplasia, and to identify any changes in utilization over the past four decades.
METHODS: Retrospective cohort study.
METHODS: A retrospective cohort study of 1,374 patients with achondroplasia enrolled in the CLARITY retrospective cohort study at four centers of multi-specialty care for patients with achondroplasia. Otolaryngologic surgeries are presented by birth cohort decade. The main outcomes were number of primary and additional otolaryngologic procedures; age at surgery; likelihood of repeated surgery; temporal trends in surgical utilization.
RESULTS: In this cohort of 1,374 patients with achondroplasia, 620 (45.1%) had pharyngeal surgery at least once, 150 (10.9%) had pharyngeal surgery on more than one occasion, and patients who had adenoidectomy first were 2.68 times more likely to require a second pharyngeal surgery than those who had adenotonsillectomy. Seven hundred and seventy-nine (56.7%) had tympanostomy tubes placed at least once, and 447 (32.5%) had tympanostomy tubes placed more than one time. Age at first pharyngeal surgery decreased by 1.2 years per birth cohort decade, and age at tympanostomy tube placement decreased by 1.1 years per decade.
CONCLUSIONS: Patients with achondroplasia often require otolaryngologic surgery, particularly adenoidectomy and/or tonsillectomy as well as tympanostomy tube placement. Such surgery is performed now more frequently and at younger ages than in earlier decades. While otolaryngologic disease associated with achondroplasia is now recognized earlier and treated more frequently, long-term outcome studies are needed.
METHODS: 3 Laryngoscope, 2021.