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Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children.

ABSTRACT: BACKGROUND:Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children's Hospital Wuerzburg, Germany over the last 25?years. RESULTS:The cohort comprises 4 (8%) perinatal, 17 (34%) infantile and 29 (58%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88%), low alkaline phosphatase (AP) activity (in 96%), accumulating substrates of AP (in 58%) and X-ray findings (in 48%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5?months (min. 0, max. 107), while median time to diagnosis was 13?months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78%), impairment of mineralization (72%), premature loss of teeth (64%), musculoskeletal pain and craniosynostosis (each 64%) and failure to thrive (62%). Up to now 20 patients started medical treatment with Asfotase alfa. CONCLUSIONS:Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.

SUBMITTER: Vogt M

PROVIDER: S-EPMC7436954 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children.

Vogt Marius M Girschick Hermann H Schweitzer Tilmann T Benoit Clemens C Holl-Wieden Annette A Seefried Lothar L Jakob Franz F Hofmann Christine C

Orphanet journal of rare diseases 20200818 1

<h4>Background</h4>Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HP ...[more]

PMID: 32811521

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Project description:BackgroundHypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The severity of HPP is widely diverse from the perinatal form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to pneumonia which was caused by severe hypomineralization of the bones-such as chest deformity and fractured ribs-and muscle weakness. Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6-12.5] years; 60% male). This is a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan.ResultsOne case of perinatal form of HPP, two cases of benign prenatal form, and seven cases of childhood form were observed. The most common symptom at onset was pain. All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA. All HPP patients seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity.ConclusionsAA may be effective in patients with mild to severe pediatric-onset forms of HPP.

Project description:BackgroundWith the continuation of the COVID-19 pandemic, shifting active COVID-19 care from short-term acute care hospitals (STACHs) to long-term acute care hospitals (LTACHs) could decrease STACH census during critical stages of the pandemic and maximize limited resources.ObjectiveThis study aimed to describe the characteristics, clinical management, and patient outcomes during and after the acute COVID-19 phase in an LTACH in the Northeastern United States.MethodsThis was a single-center group comparative retrospective analysis of the electronic medical records of patients treated for COVID-19-related impairments from March 19, 2020, through August 14, 2020, and a reference population of medically complex patients discharged between December 1, 2019, and February 29, 2020. This study was conducted to evaluate patient outcomes in response to the holistic treatment approach of the facility.ResultsOf the 127 total COVID-19 admissions, 118 patients were discharged by the data cutoff. At admission, 29.9% (38/127) of patients tested positive for SARS-CoV-2 infection. The mean age of the COVID-19 cohort was lower than that of the reference cohort (63.3, 95% CI 61.1-65.4 vs 65.5, 95% CI 63.2-67.8 years; P=.04). There were similar proportions of males and females between cohorts (P=.38); however, the proportion of non-White/non-Caucasian patients was higher in the COVID-19 cohort than in the reference cohort (odds ratio 2.79, 95% CI 1.5-5.2; P=.001). The mean length of stay in the COVID-19 cohort was similar to that in the reference cohort (25.5, 95% CI 23.2-27.9 vs 29.9, 95% CI 24.7-35.2 days; P=.84). Interestingly, a positive correlation between patient age and length of stay was observed in the COVID-19 cohort (r2=0.05; P=.02), but not in the reference cohort. Ambulation assistance scores improved in both the reference and COVID-19 cohorts from admission to discharge (P<.001). However, the mean assistance score was greater in the COVID-19 cohort than in the reference cohort at discharge (4.9, 95% CI 4.6-5.3 vs 4.1, 95% CI 3.7-4.7; P=.001). Similarly, the mean change in gait distance was greater in the COVID-19 cohort than in the reference cohort (221.1, 95% CI 163.2-279.2 vs 146.4, 95% CI 85.6-207.3 feet; P<.001). Of the 16 patients mechanically ventilated at admission, 94% (15/16) were weaned before discharge (mean 11.3 days). Of the 75 patients admitted with a restricted diet, 75% (56/75) were discharged on a regular diet.ConclusionsThe majority of patients treated at the LTACH for severe COVID-19 and related complications benefited from coordinated care and rehabilitation. In comparison to the reference cohort, patients treated for COVID-19 were discharged with greater improvements in ambulation distance and assistance needs during a similar length of stay. These findings indicate that other patients with COVID-19 would benefit from care in an LTACH.

Dataset Information

Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children.

Publications

Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children.

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