Novel phenotype of achondroplasia due to biallelic FGFR3 pathogenic variants.

Pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) gene are responsible for a broad spectrum of skeletal dysplasias, including achondroplasia (ACH). The classic phenotype of ACH is caused by two highly prevalent mutations, c.1138G > A and c.1138G > C (p.Gly380Arg). In the homozygous state, these variant results in a severe skeletal dysplasia, neurologic deficits, and early demise from respiratory insufficiency. Although homozygous biallelic mutations have been reported in patients with ACH in combination with hypochondroplasia or other dominant skeletal dysplasias, thus far, no cases of heterozygous biallelic pathogenic ACH-related variants in FGFR3 have been reported. We describe a novel phenotype of an infant with two ACH-related mutations in FGFR3, p.Gly380Arg and p.Ser344Cys. Discordant features from classic ACH include atypical radiographic findings, severe obstructive sleep apnea, and focal, migrating seizures. We also report the long-term clinical course of her father, who harbors the p.Ser344Cys mutation that has only been reported once previously in a Japanese patient. The phenotype of heterozygous biallelic mutations in FGFR3 associated with ACH is variable, underscoring the importance of recognition and accurate diagnosis to ensure appropriate management.

Pregnancy in patients with mucopolysaccharidosis: a case series.

The mucopolysaccharidoses (MPS disorders) are rare inherited diseases associated with multi-organ accumulation of glycosaminoglycans, leading to musculoskeletal, respiratory, cardiac, neurological, ophthalmological, otolaryngological, and gastrointestinal abnormalities. As a result of improvements in diagnosis, multi-disciplinary care, and therapies such as enzyme replacement therapy and hematopoietic stem cell transplantation, an increasing number of patients with MPS are reaching adulthood and are involved in family planning. Data on fertility and pregnancy outcome in MPS is sparse and comprises primarily isolated case reports. To address this evidence gap, we present a case series on fertility and pregnancy in eight mothers and five fathers with MPS. This case series demonstrates that women with MPS have high-risk pregnancies and deliveries secondary to their underlying disease. However, with appropriate pre-conceptual multi-disciplinary evaluation, optimization and discussion regarding potential risks, combined with regular multi-disciplinary maternal and fetal surveillance in a tertiary center, the outcome of most pregnancies in this case series seems to be favorable with all babies developing normally. Partners of fathers with MPS had uncomplicated pregnancies and deliveries. All children were healthy, with normal growth and development.

Expert Opinions on Managing Fertility and Pregnancy in Patients With Mucopolysaccharidosis

Abstract The mucopolysaccharidosis (MPS) disorders are rare genetic diseases caused by deficiencies in lysosomal enzymes involved in the degradation of glycosaminoglycans, leading to pulmonary, cardiac and neurological dysfunctions, skeletal anomalies, impaired vision, and/or hearing and shortened life spans. Whereas in the past, few individuals with MPS reached adulthood, better diagnosis, multidisciplinary care, and new therapies have led to an increasing number of adult patients with MPS. Therefore, fertility and pregnancy questions in this patient population are becoming more important. Management of fertility issues and pregnancy in patients with MPS is challenging due to the lack of documented cases and a dearth in the literature on this topic. This review presents multidisciplinary expert opinions on managing fertility and pregnancy based on case studies and clinical experience presented at a meeting of MPS specialists held in Berlin, Germany, in April 2015. An overview of the existing literature on this subject is also included.

Musculoskeletal function in patients with mucopolysaccharidosis using the pediatric outcomes data collection instrument.

BACKGROUND: Musculoskeletal function is often the limiting factor in quality of life in patients with mucopolysaccharidosis (MPS). The Pediatric Outcomes Data Collection Instrument (PODCI) is a validated tool to be used in children aged 2 to 18 years with chronic musculoskeletal disorders and is freely available to any investigator. The goal of this study is to establish normative data for patients with MPS. METHODS: Of our 25 patients with MPS, 16 had PODCI's performed at initial evaluation. This included 4 patients with MPS IH (Hurler), 7 patients with MPS II (Hunter), 4 patients with MPS IV (Morquio), and 1 patient with MPS VI (Maroteaux-Lamy). Differences in PODCI scores among children with MPS IH (Hurler), II (Hunter), and IV were estimated using a Kruskal-Wallis test. RESULTS: With the exception of upper extremity and physical functioning function in MPS IV, all domains for our MPS patients measured below average for typically developing children. We found a statistically significant difference among the groups in the upper extremity and physical function scale [H (2) = 8.16, P = 0.02]. The single MPS VI patient had the highest scores overall. MPS IV patients scored better than the MPS IH patients, and the MPS II patients scored lowest. CONCLUSIONS: This study demonstrates the limited musculoskeletal function in patients with MPS and the differences among different MPS diagnoses. CLINICAL RELEVANCE: The data establishes a basic understanding of musculoskeletal function in patients with MPS and should provide comparative data for future studies in which musculoskeletal function is measured as an objective outcome. It can also serve as a better objective measure for interventions, as previous models have only served as proxies to musculoskeletal function.

Asymptomatic methylmalonic acidemia in a homozygous MUT mutation (p.P86L).

Deficiency in methylmalonyl-coenzyme A mutase (MCM) is associated with accumulation of methylmalonic acid (MMA) and clinical outcomes that include early death and neurological impairment. Reported here are two unrelated patients with a homozygous p.P86L mutation in the MUT gene, which encodes MCM, diagnosed following newborn screening. This is the first description of a homozygous mutation in the N-terminal extended segment of the MCM apoenzyme. Both in vitro and in vivo testing did not find a response to supplemental hydroxocobalamin. After discontinuation of hydroxocobalamin in one patient, serum MMA level remained elevated but stable, while urine MMA increased. Both patients have remained asymptomatic with normal development. The observed homozygous p.P86L mutation in the N-terminal extended segment may yield reduced MCM activity and is refractory to hydroxocobalamin supplementation, while not inducing a metabolically unstable phenotype. These genotype-phenotype associations further enhance the understanding of methylmalonic acidemia, which will continue to improve patient care.

Spondyloepiphyseal dysplasias and bilateral legg-calvé-perthes disease: diagnostic considerations for mucopolysaccharidoses.

Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, MIM 253200 ) is an autosomal recessive lysosomal storage disease (LSD) caused by decreased activity of arylsulfatase B (N-acetylgalactosamine 4-sulfatase) enzyme resulting in dermatan sulfate accumulation; mucopolysaccharidosis type IVA (MPS IVA, Morquio syndrome A, MIM 253000 ) by decreased activity of N-acetylgalactosamine 6-sulfatase enzyme resulting in accumulation of keratan sulfate. Clinical symptoms include coarse facial features, joint stiffness, hepatosplenomegaly, hip osteonecrosis, and dysostosis multiplex. MPS IVA symptoms are similar but with joint hypermobility.With suspicion of MPS disease, clinicians request urine studies for quantitative and qualitative glycosaminoglycans (GAGs). Diagnosis is confirmed by decreased enzyme activity in leukocytes or cultured skin fibroblasts. Further confirmation is obtained with identification of two mutations in the ARSB gene for MPS VI or mutations in the GALNS gene for MPS IVA.We report slowly progressing patients, one with MPS VI and two with MPS IVA, who presented with skeletal changes and hip findings resembling Legg-Calvé-Perthes disease or spondyloepiphyseal dysplasia and normal/near normal urine GAG levels. The urine analysis data presented suggest that present screening techniques for MPS are inadequate in milder patients and result in delayed or missed diagnoses. The patients presented in this paper emphasize the importance of enzymatic and molecular testing.

Musculoskeletal manifestations of Sanfilippo Syndrome (mucopolysaccharidosis type III).

BACKGROUND: The most pronounced symptom in mucopolysaccharidosis type III (MPS III, Sanfilippo Syndrome) is the severe neurocognitive deterioration of the central nervous system. The effects of MPS III on the musculoskeletal system are less severe than those caused by other forms of MPS, however, it is our experience that many families seek orthopaedic attention for perceived musculoskeletal discomfort, particularly about the hip and spine. The purpose of this study is to report musculoskeletal findings in a case series of patients with MPS III. METHODS: This study represents a retrospective case series of all records available from 2 institutions on patients with MPS III. Chart and radiographic review was performed and outcomes tabulated. Our hypotheses are: (1) Musculoskeletal abnormalities are prevalent in children with MPS III and (2) Musculoskeletal deformities in children with MPS III may require surgical intervention. RESULTS: Eighteen patients were identified (10 female and 8 male) with an average age of 10.3 years. Three had significant scoliosis (21 to 99 degrees) and 2 others had L1 hypoplasia. Four patients had osteonecrosis of the femoral heads. One patient required a carpal tunnel release, and another a trigger thumb release. There were no cases of cervical instability. CONCLUSIONS: In our study with these patients, we have observed several unreported musculoskeletal manifestations of MPS III. Osteonecrosis of the hips can be a source of severe discomfort for these children. Although uncommon, operative intervention for orthopaedic conditions is sometimes warranted. Operative indications in this cohort include progressive scoliosis of large magnitude, carpal tunnel syndrome, and trigger digits. LEVEL OF EVIDENCE: Level IV; case series.

Association between symptomatic giant sacral meningeal diverticulum and spinal cord tethering with thickened lipomatous filum.

STUDY DESIGN: A review of cases where symptomatic sacral meningeal diverticula, as known as, sacral meningoceles, were treated. OBJECTIVE: To determine whether there is an association between symptomatic sacral meningeal diverticulum and spinal cord tethering with a thickened fatty filum. SUMMARY OF BACKGROUND DATA: In 2008, the primary author reported on the unusual case of a giant sacral meningeal diverticulum containing a tethering fatty filum. This led the author to be alert to the presence of spinal cord tethering in future cases involving symptomatic meningeal diverticula. Since the time of the initial report, 49 patients with meningeal diverticula have subsequently undergone surgical treatment and not infrequently spinal cord tethering was also found. The opportunity, therefore, presented itself to determine to what degree the two pathologies were associated. METHODS: We reviewed the intraoperative findings, preoperative imaging, and basic epidemiologic data from 50 consecutively treated patients with symptomatic sacral meningeal diverticula. RESULTS: Of the 50 patients, 14 (28%) were found to have associated spinal cord tethering with a thickened fatty filum. All 14 had a thickened fatty filum identifiable at surgery. Of these, 14 had evidence of spinal cord tethering on preoperative imaging studies, including 11 with the conus at the level of L2 or below, and 13 with a fatty filum seen on magnetic resonance images. CONCLUSION: The association between symptomatic sacral meningeal diverticula is more than incidental and is probably reflective of a common congenital etiology. Treatment of symptomatic meningeal diverticula should include a careful search for evidence of spinal cord tethering with a thickened fatty filum.

Musculoskeletal health in Hunter disease (MPS II): ERT improves functional outcomes.

Musculoskeletal disease is a significant burden for children with Mucopolysaccharide (MPS) disorders. The Pediatric Outcomes Data Collection Instrument (PODCI) is a validated, functional measure of musculoskeletal health in children with disabilities. The goal of this study is to describe the musculoskeletal manifestations of children with MPS II (Hunter syndrome), and their functional response to intravenous enzyme replacement therapy (ERT). Patients with MPS II were prospectively entered into an IRB approved registry. Chart review of physical findings including, shoulder, elbow, hip, knee and ankle range of motion, and need for carpal tunnel release was performed. Radiographs of the spine and pelvis were evaluated in all patients. Serial PODCI exams were administered to all patients. Seven patients, 5 receiving ERT, were included. Four patients had spinal deformities, seven had modest hip disease, and two required carpal tunnel release. PODCI scores were abnormally low in all domains, but significant improvements in PODCI scores were documented with enzyme replacement therapy. Spine and hip deformity are ubiquitous in MPS II, none of which have required surgical intervention, but require long term monitoring. Patients with MPS II should be monitored for carpal tunnel syndrome. Functional improvements are seen, as documented by the PODCI, in children with MPS II on ERT.

Male GPs' views on men seeking medical help: a qualitative study.

OBJECTIVE: Analysis of health service statistics reveals that men tend to under-use primary health care services. Previous research has suggested that men view illness as a form of weakness and have negative views about men who seek medical help. It has also indicated that some men believe that male General Practitioner (GP)s hold similar views, a factor which may influence their own tendency to self-refer. This study aims to explore male GPs' experiences of their male patients' patterns of self-referral and to identify factors that may negatively influence doctor-patient relationships. METHOD: Semi-structured interviews were carried out with 10 male GPs (ages=35-53). These were audiotaped and subjected to interpretative phenomenological analysis to identify relevant themes. RESULTS: For all participants, managing service demands were seen as a major challenge. Analysis of these GP's accounts suggested that they see men's self-referral as being primarily influenced by the need to conform to masculine gender roles and a number of ways that men accessed services in a way congruent with this were identified. This study also explored how participants' own adherence to gender roles may itself influence the doctor-patient relationship. CONCLUSION: This study suggests that, like other men, male GPs may have ambivalent attitudes towards male self-referral and that this may influence their interactions with male patients.

Patterns of self-referral in men with symptoms of prostate disease.

OBJECTIVE: Analysis of health statistics reveals that, although men have a shorter life expectancy and a higher mortality rate than women, they have less contact with their GP. This study investigates men's experiences of prostate disease, with a particular focus on how they made the decision to seek medical help. METHOD: Semi-structured interviews were carried out with 20 men aged 51-75 with prostate disease who had recently contacted their GP. These were audiotaped, transcribed and subjected to interpretative phenomenological analysis. RESULTS: Analysis revealed that their referral behaviours were profoundly influenced by a need to live up to traditional images of masculinity. Far from being uncaring, men were extremely anxious about their health and fears about the effects of illness and treatment emerged as major influences on their decision to seek help. Their delay in approaching their GP was due to their beliefs about symptoms as markers of serious disease, their ability to hide symptoms from others and their attitude towards male GPs who were often seen as having negative attitudes towards male patients. CONCLUSIONS: This study identifies some reasons why men with prostate disease may fail to seek medical care and has implications for increasing referral rates for men.

The dilemma of success: percutaneous coronary interventions in patients > or = 75 years of age-successful but associated with higher vascular complications and cardiac mortality.

Elderly patients are increasingly referred to percutaneous coronary interventions (PCIs). Recent reports suggest complications rates are declining in the elderly. We sought to determine whether procedural and in-hospital outcomes are different in patients aged > or = 75 years undergoing nonemergent PCI as compared to patients age < 75 years. The outcome of 266 consecutive patients age > or = 75 years undergoing nonemergent PCI was compared to that of 1,681 consecutive patients age < 75 years. Compared with younger patients, greater proportions of elderly patients were women and had a history of hypertension, peripheral vascular disease, and cerebral vascular events. Elderly patients had more extensive coronary involvement. Procedural success was similar in both groups (94%). The in-hospital cardiac death rate was significantly higher in the elderly patients (2.3% vs. 0.7%; P = 0.03). Aged patients also had a significantly higher incidence of vascular and bleeding complications. Blood transfusion was required more often in the elderly group (4.5% vs. 2.6%; P = 0.07). The hospitalization length was significantly higher in the elderly group (4.1 +/- 6.0 vs. 2.5 +/- 4.3 day; P = 0.0004). By multivariate logistic regression (adjusted for baseline clinical and angiographic variables), age > or = 75 years was found to be an independent predictor of in-hospital cardiac death (odds ratio = 3.9; 95% CI = 1.3-11.5; P = 0.015). Although PCI is technically successful in patients aged > or = 75 years; it is associated with more acute cardiac and vascular complications and higher in-hospital cardiac mortality.

Effect of ketorolac on renal function after donor nephrectomy.

OBJECTIVES: To evaluate the safety of ketorolac, a nonsteroidal anti-inflammatory drug, that is being used more frequently for postoperative analgesia, we performed a detailed analysis of healthy patients undergoing open donor nephrectomy. METHODS: We conducted a retrospective review of 198 consecutive patients who underwent open living donor nephrectomy between January 1998 and July 2000. We compared patients who were and were not given ketorolac. Regression analysis was used to determine whether any significant interactions were present between ketorolac and donor age, sex, weight, estimated surgical blood loss, or operative time in terms of its effect on renal function. Creatinine clearance was calculated by the Gault-Cockcroft equation. RESULTS: Among the 83 patients given ketorolac, the mean amount received was 200 mg (range 30 to 360, median 210). No differences were found in the preoperative creatinine clearance between patients who did (118 +/- 29 mL/min) or did not (118 +/- 27 mL/min, P = 0.89) receive ketorolac. Patients who received ketorolac had a slightly lower creatinine clearance on the second postoperative day relative to patients who did not receive ketorolac (66% versus 72% of preoperative calculated creatinine clearance, P = 0.05). However, at a minimum of 3 months postoperatively, the creatinine clearance did not differ between the two groups (70% versus 73%, P = 0.92). Among patients who received ketorolac, no significant association was found between the amount received and renal function at any point tested. In the regression analysis, no significant interactions were found between ketorolac and the clinical variables of age, sex, weight, estimated surgical blood loss, or operative time. Moreover, in an analysis of only the patients who received ketorolac, no significant interactions were found between the amount of ketorolac received and the clinical variables of age, sex, weight, estimated surgical blood loss, or operative time. CONCLUSIONS: Ketorolac use was not associated with any long-term impairment in renal function when used during the first 2 postoperative days in healthy patients undergoing open donor nephrectomy. Moreover, in the range administered, no subset of patients or maximal ketorolac dose was identified at which ketorolac use was not safe.

Ketorolac-based analgesia improves outcomes for living kidney donors.

BACKGROUND: To reduce the morbidity of living kidney donors we introduced ketorolac-based analgesia for patients undergoing open donor nephrectomy in August 1999. There are no prior reports on the use of ketorolac for patients undergoing donor nephrectomy. METHODS: We conducted a retrospective review of all 198 consecutive patients who underwent open living donor nephrectomy between January 1998 and July 2000 at our institution. We compared patients who underwent surgery before and after introduction of ketorolac-based analgesia. RESULTS: The introduction of ketorolac-based analgesia resulted in a reduction in length of postoperative stay from 3.7+/-0.1 to 3.1+/-0.1 days (P<0.001). Patients who underwent surgery after ketorolac introduction required 58% less narcotics (P<0.001), recalled having less postoperative pain, and stopped taking pain medications sooner than patients before routine ketorolac use. Moreover, these patients drank 38% more liquids on the first postoperative day (P<0.001) and were able to resume a regular diet sooner than patients who were not managed with ketorolac. Patients who received ketorolac had a slightly lower creatinine clearance on the second postoperative day relative to patients who did not (66 vs. 72% of preoperative calculated creatinine clearance, P=0.05). However at a minimum of 3 months postoperatively, creatinine clearance did not differ between the two groups (70 vs. 73%, P=0.92). There were no differences in the rates of complications between the two groups. CONCLUSIONS: The use of ketorolac to control postoperative pain for patients undergoing open donor nephrectomy reduced morbidity and was not associated with any effect on long-term renal function or increased risk of complications. This is the first study to demonstrate the safety of using ketorolac at the time of donor nephrectomy.