Diagnosis Of Malignant Hyperthermia Research Articles

Malignant hyperthermia in a paediatric patient; managed successfully without dantrolene: a case report

Introduction: Malignant hyperthermia (MH) is a potentially life-threatening pharmacogenetic syndrome triggered by volatile anaesthetics, succinylcholine, and stress such as vigorous exercise. Case presentation: The authors describe a case of an 8-year-old male who presented with classical symptoms of MH after induction of general anaesthesia and symptomatic treatment was done successfully due to the unavailability of Dantrolene. Discussion: Definitive diagnosis of MH can be done based on a contracture test in fresh muscle biopsy in the presence of halothane and caffeine. In the absence of muscle biopsy and genetic testing, diagnosis for MH can be done based on MH scoring. Conclusion: Anesthesiologists should be made aware that proper symptomatic management can also save the life of a patient. Also, strong advocacy should be done to ensure the availability of Dantrolene and further strengthen lab facilities to confirm diagnosis to facilitate diagnosis and management in the future.

Remimazolam-based total intravenous anesthesia in a patient with a confirmed diagnosis of malignant hyperthermia: a case report

BackgroundMalignant hyperthermia (MH) is a rare, life-threatening disorder of calcium homeostasis in skeletal muscle cells that is triggered by volatile anesthetics and succinylcholine, leading to a hypermetabolic reaction. The pathogenic ryanodine receptor 1 (RYR1) gene variant is critical. Patients susceptible to MH should avoid triggering agents, and total intravenous anesthesia (TIVA) is preferred. Remimazolam is safe in patients with suspected MH.Case presentationWe present the first case of remimazolam treatment in a genetically confirmed patient with MH without MH development. A 72-year-old man with a family history of MH underwent remimazolam-based TIVA. After informed consent was obtained, a muscle biopsy and genetic testing were performed. Intraoperatively and postoperatively, the patient exhibited no signs of MH. An enhanced function of the RYR1 channel into releasing calcium was indicated, and the genetic testing revealed a pathogenic variant of RYR1.ConclusionsRemimazolam-based TIVA is safe in patients confirming the diagnosis of MH.

Malignant Hyperthermia in Belgium: 35 years of practice-led research

As of 1986 a laboratory for the diagnosis of Malignant Hyperthermia (MH) was established at the University of Antwerp which since then served as the national reference laboratory for this rare anesthetic complication. Our unit is an accredited lab within the network of the European Malignant Hyperthermia Group and thus has had the chance to attain a solid practical expertise in this disorder, as well as to collaborate in several multicentre studies on MH. The present review summarizes what collaborative international research has taught us about MH over the last 3,5 decades, and covers evolving insights in such topics as pathophysiology, clinical presentation, treatment, anesthesia for patients with an increased risk of developing MH, molecular genetics, diagnostic work-up and relationship to other myopathies.

Clinical Features of Suspected Malignant Hyperthermia in China from 2015 to 2020: A Retrospective Study from China Malignant Hyperthermia Emergency Assistance Group.

Malignant hyperthermia (MH) is a rare but fatal pharmacogenetic disorder, triggered by inhalational anesthetics or succinylcholine. Since the first nonprofit academic organization China Malignant Hyperthermia Emergency Assistance WeChat-based Group (CMHEA Group) was established in 2015, they have actively participated in the diagnosis and treatment of MH patients. Based on the CMHEA Group, the aim of the study was to retrospectively analyze the characteristics of suspected MH in China from 2015 to 2020. We conducted a retrospective analysis of the suspected MH patients from 2015 to 2020, for analyzing the current clinical diagnosis, treatment and prognosis of MH in China. A total of 58 suspected MH cases occurred from 2015 to 2020, of these, 36 cases were collected with detailed data. The MH clinical grading score of 36 patients ranged from 33 to 73, with a median of 55. Abnormal hyperthermia and hypercarbia were the most common early signs of MH. Four patients were confirmed carrying six different potential MH-causative mutations. Of the total 58 cases, 14 patients (24.1%) received dantrolene and the whole mortality rate was 53.4%. Compared to the patients not receiving dantrolene treatment, the survival rate of patients receiving dantrolene treatment was significantly higher than that of patients not receiving dantrolene (78.6% vs 36.4%, p = 0.007). The current main diagnostic methods of suspected MH in China are still clinical diagnosis. Hence, it is critical to keep dantrolene for immediate accessibility with the introduction of domestic dantrolene to China. The WeChat group model has played an important but limited role in quick diagnosis and treatment of MH.

Age-Specific Clinical Features of Pediatric Malignant Hyperthermia: A Review of 187 Cases Over 60 Years in Japan.

Malignant hyperthermia (MH) is an inherited muscle disorder induced by volatile anesthetics and depolarizing muscle relaxants. While the incidence of MH is high in young, there are few reports on the clinical features of pediatric MH. In this study, we selected pediatric cases from an MH database and analyzed the clinical findings by age group. We hypothesized that there would be age-related differences in the clinical characteristics. A retrospective analysis of MH data collected in our database during 1960 to 2020 was performed to identify pediatric subjects (≤18 years) with a Clinical Grading Scale of ≥35, indicating "very likely" or "almost certain" MH. We compared clinical characteristics among the 0 to 24 month, 2 to 12 year, and 13 to 18 year (youngest, middle, and oldest, respectively) age groups. Data were available for 187 patients: 15 in the youngest age group, 123 in the middle-aged group, and 49 in the oldest age group. Of these, 55 patients (29.4%) had undergone muscle biopsy and muscle contracture test. The mortality rates during the study period were 13.3%, 13.8%, 20.4%, and 15.5% in the youngest, middle, and oldest cohorts and overall, respectively. In contrast, the overall mortality rate from 2000 to 2020 was 8.8%. The most frequent initial symptoms of MH were elevated temperature (46.7%) and generalized muscular rigidity (26.7%) in the youngest cohort, masseter spasm (35.0%) and generalized muscular rigidity (19.5%) in the middle cohort, and elevated end-tidal carbon dioxide (26.5%) and tachycardia (22.4%) in the oldest cohort. Physical examination revealed that elevated temperature, sinus tachycardia, and respiratory acidosis occurred frequently in all groups. The middle cohort had high frequencies of masseter spasm (58.4%; P = .02) and dark urine (75.5%; P = .01) compared to those in the oldest groups, and had a higher peak creatine kinase level compared to those in the 3 groups. Skeletal muscle symptoms tended to be more common in patients administered succinylcholine (generalized muscular rigidity, P = .053; masseter spasm, P < .0001; dark urine, P < .0001). In particular, masseter spasm and dark urine were more common in the middle cohort when succinylcholine was administered (masseter spasm: versus youngest cohort, P = .06, versus oldest cohort, P = .027; dark urine: versus youngest cohort, P = .0072, versus oldest cohort, P = .0015). The clinical characteristics of pediatric patients with MH vary according to age group. The difference in initial symptoms of MH depending on age group is noteworthy information for the early diagnosis of MH.

Postoperative Hyperthermia and Hemodynamic Instability in a Suspected Malignant Hyperthermia–Susceptible Patient: A Case Report

Malignant hyperthermia (MH) is a rare but potentially fatal complication of exposure to certain anesthetic drugs. However, stress-induced MH, initially observed in pigs undergoing intense physical or emotional strain, has been reported in the absence of anesthetic exposure. In this case report, we describe a case of postoperative hyperthermia and cardiac dysfunction suspicious for stress-induced MH occurring after an endobronchial biopsy in a patient with recurrent undiagnosed fevers. We also examine our diagnosis of stress-induced MH and possible preventive measures to avoid this complication.

Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists.

Malignant hyperthermia is defined in the International Classification of Diseases as a progressive life-threatening hyperthermic reaction occurring during general anaesthesia. Malignant hyperthermia has an underlying genetic basis, and genetically susceptible individuals are at risk of developing malignant hyperthermia if they are exposed to any of the potent inhalational anaesthetics or suxamethonium. It can also be described as a malignant hypermetabolic syndrome. There are no specific clinical features of malignant hyperthermia and the condition may prove fatal unless it is recognised in its early stages and treatment is promptly and aggressively implemented. The Association of Anaesthetists has previously produced crisis management guidelines intended to be displayed in all anaesthetic rooms as an aide memoire should a malignant hyperthermia reaction occur. The last iteration was produced in 2011 and since then there have been some developments requiring an update. In these guidelines we will provide background information that has been used in updating the crisis management recommendations but will also provide more detailed guidance on the clinical diagnosis of malignant hyperthermia. The scope of these guidelines is extended to include practical guidance for anaesthetists dealing with a case of suspected malignant hyperthermia once the acute reaction has been reversed. This includes information on care and monitoring during and after the event; appropriate equipment and resuscitative measures within the operating theatre and ICU; the importance of communication and teamwork; guidance on counselling of the patient and their family; and how to make a referral of the patient for confirmation of the diagnosis. We also review which patients presenting for surgery may be at increased risk of developing malignant hyperthermia under anaesthesia and what precautions should be taken during the peri-operative management of the patients.

Malignant hyperthermia: a case report with good outcome.

Malignant hyperthermia: a case report with good outcome.

Rapid screening for mutations associated with malignant hyperthermia using high-resolution melting curve analysis.

Objectives:The diagnosis of malignant hyperthermia (MH) is based on clinical signs or laboratory testing. The gold standard laboratory test is the in vitro contracture test, although it is invasive, expensive, and only performed at specialized centers. Genetic diagnosis is another option, although direct mutation screening is a laborious task. Therefore, we evaluated whether high-resolution melting (HRM) curve analysis could be used as a rapid screening tool to target MH-associated mutations.Materials and Methods:The feasibility of HRM analysis was evaluated using plasmids that were constructed by cloning wild-type or mutated versions of the ryanodine receptor 1 (RYR1) gene into the pCR2.1 plasmid. We obtained engineered plasmids and patient DNA extracted from blood samples with known wild-type or mutated sequences that are associated with MH. Amplicon lengths were kept relatively short (<250 bp) to improve discrimination between the engineered and patient plasmids. Real-time polymerase chain reaction (PCR) cycling and HRM analysis of the engineered plasmids and patient DNA were performed using the LightCycler 480 System (Roche).Results:The HRM results were clearly different from those obtained using real-time PCR. Furthermore, the HRM analysis provided sufficient resolution to identify two single-nucleotide variants in the tested RYR1 exons.Conclusion:We conclude that HRM analysis can provide high resolution for identifying single-nucleotide variants in RYR1, which might be useful for predicting the risk of MH in the preanesthesia setting.

Next-generation sequencing and bioinformatics to identify genetic causes of malignant hyperthermia

Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disease with only two known causative genes, RYR1 and CACNA1S. Both are huge genes containing numerous exons, and they reportedly only account for 50-70% of known MH patients. Next-generation sequencing (NGS) technology and bioinformatics could help delineate the genetic diagnosis of MH and several MH-like clinical presentations. We established a capture-based targeted NGS sequencing framework to examine the whole genomic regions of RYR1, CACNA1S and the 16.6 Kb mitochondrial genome, as well as 12 other genes related to excitation-contraction coupling and/or skeletal muscle calcium homeostasis. We applied bioinformatics analyses to the variants identified in this study and also to the 48 documented RYR1 pathogenic variants. The causative variants were identified in seven of the eight (87.5%) MH families, but in none of the 10 individuals classified as either normal controls (N = 2) or patients displaying MH-like clinical features later found to be caused by other etiologies (N = 8). We showed that RYR1 c.1565A>G (p.Tyr522Cys)(rs118192162) could be a genetic hot spot in the Taiwanese population. Bioinformatics analyses demonstrated low population frequencies and predicted damaging effects from all known pathogenic RYR1 variants. We estimated that more than one in 1149 individuals worldwide carry MH pathogenic variants at RYR1. NGS and bioinformatics are sensitive and specific tools to examine RYR1 and CACNA1S for the genetic diagnosis of MH. Pathogenic variants in RYR1 can be found in the majority of MH patients in Taiwan.

Prevalence of malignant hyperthermia diagnosis in obstetric patients in the United States, 2003 to 2014

BackgroundThe cost-benefit of stocking dantrolene in maternity units for treating malignant hyperthermia (MH) has been recently questioned because of the low incidence of MH crisis in the general population and the low utilization of general anesthesia in obstetrics. However, no study has examined the prevalence of MH susceptibility in obstetrics. This study aimed to assess the prevalence of MH diagnosis and associated factors in obstetric patients.MethodsData for this study came from the National Inpatient Sample from 2003 to 2014, a 20% nationally representative sample of discharge records from community hospitals. A diagnosis of MH due to anesthesia was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification code 995.86. MH prevalence was estimated according to the delivery mode and patient and hospital characteristics.ResultsDuring the 12-year study period, 47,178,322 delivery-related discharges [including 15,175,127 (32.2%) cesarean deliveries] were identified. Of them, 215 recorded a diagnosis of MH, yielding a prevalence of 0.46 per 100,000 [95% confidence interval (CI), 0.40 to 0.52]. The prevalence of MH diagnosis in cesarean deliveries was 0.81 per 100,000 (95% CI, 0.67 to 0.97), compared with 0.29 per 100,000 (95% CI, 0.23 to 0.35) in vaginal deliveries (P < 0.001). Multivariable logistic regression revealed that cesarean delivery was associated with a significantly increased risk of MH diagnosis [adjusted rate ratio (aOR) 2.88; 95% CI, 2.19 to 3.80]. Prevalence of MH diagnosis was lower in Hispanics than in non-Hispanic whites (aOR 0.47; 95% CI, 0.29 to 0.76) and higher in the South than in the Northeast census regions (aOR 2.44; 95% CI, 1.50 to 3.96).ConclusionThe prevalence of MH-susceptibility is about 1 in 125,000 in cesarean deliveries, similar to the prevalence reported in non-obstetrical surgery inpatients. The findings of this study suggest that stocking dantrolene in maternity units is justified.

The current status of malignant hyperthermia.

Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 ( RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.

悪性高熱症の遺伝子診断を目指したリアノジン受容体の簡単で迅速な変異体作製法

悪性高熱症の遺伝子診断を目指したリアノジン受容体の簡単で迅速な変異体作製法

Administration of anaesthetic triggering agents to patients tested malignant hyperthermia normal and their relatives in New Zealand: an update.

Testing for malignant hyperthermia in New Zealand involves two tests-in vitro contracture testing of excised lateral quadriceps muscle and DNA analysis. In vitro contracture testing is regarded as the gold standard in malignant hyperthermia diagnosis but several publications have questioned the reliability of a normal result. Analysis of 479 anaesthetic records in 280 patients or their descendants throughout New Zealand who had tested negative for malignant hyperthermia, demonstrated there was no evidence of malignant hyperthermia episodes in this group who had been administered anaesthetic triggering agents. A wide range of anaesthetics were used over the study period. Analysis of each anaesthetic record was undertaken using the malignant hyperthermia grading scale which determines the likelihood that an anaesthetic event represents a malignant hyperthermia episode. Confirmation of the negative results was further supported by normal DNA analysis of patients in 48% of anaesthetics. There are advantages to using inhalational agents in certain situations and although demonstrating a zero risk of a malignant hyperthermia episode is not statistically possible, evidence in this large series suggests that the risk of an episode in these patients is extremely low and may be negligible. We suggest that anaesthetic triggering agents can be used safely in patients with normal in vitro contracture tests, and in their descendants.

Prevalence of malignant hyperthermia diagnosis in hospital discharge records in California, Florida, New York, and Wisconsin

Study objectiveMalignant hyperthermia (MH) is a rare yet potentially fatal pharmacogenetic disorder triggered by exposure to inhalational anesthetics and the depolarizing neuromuscular blocking agent succinylcholine. Epidemiologic data on the geographic variation in MH prevalence is scant. The objective of this study is to examine the prevalence of recorded MH diagnosis in patients discharged from hospitals in four states in the United States. DesignObservational study. SettingHealthcare Cost and Utilization Project (HCUP) State Inpatient Database (SID) for California (2011), Florida (2011), New York (2012) and Wisconsin (2012). PatientsA total of 164 hospital discharges that had a recorded diagnosis of MH using the International Classification of Disease, 9th Revision, Clinical Modification code 995.86. MethodsMH prevalence was assessed by patient demographic and clinical characteristics. Main resultsThe prevalence of MH per 100,000 hospital discharges ranged from 1.23 (95% Confidence Interval [CI], 0.80–1.66) in New York to 1.91 (95% CI, 1.48–2.34) in California, and the prevalence of MH per 100,000 surgical discharges ranged from 1.47 (95% CI, 0.93–2.02) in New York to 2.86 (95% CI, 2.00–3.71) in Florida. The prevalence of MH in male patients was more than twice the prevalence in female patients. Of the 164 patients with MH diagnosis, 11% were dead on discharge. ConclusionsThere exists a modest variation in the prevalence of recorded MH diagnosis in hospital discharges in California, Florida, New York and Wisconsin. Epidemiologic patterns of MH diagnosis in hospital discharges appear to be similar across the four states. Further research is needed to better understand the geographic variation and contributing factors of MH in different populations.

Suspected Malignant Hyperthermia in the Setting of Hypothermic Circulatory Arrest for Type A Aortic Dissection Repair

Malignant Hyperthermia (MH) is a life-threatening biochemical process of hypermetabolism brought about in susceptible individuals by a triggering drug or event. Type A aortic dissections are surgical emergencies requiring cardiopulmonary bypass and frequently deep hypothermic circulatory arrest. We present a case of suspected MH in a patient undergoing emergent repair of a type A aortic dissection. Upon arrival at our institution, the patient had multiple signs of MH. However, no known triggering agent had been administered. Eventually, the unique physiologic changes of cardiopulmonary bypass provided strong support for the diagnosis of MH and dantrolene was administered, effectively treating the episode.

An automated real-time method for the detection of patients at risk for malignant hyperthermia.

Malignant hyperthermia (MH) is a rare anesthetic pharmacogenetic disorder that can be difficult to detect in its earliest phases. Prompt treatment is known to improve outcomes. The modern anesthesia information management systems (AIMS) collect enormous amounts of data. However, data lack context and are not able to provide real-time guidance. Utilizing our AIMS, we developed the capacity to incorporate decision support. We describe the creation and evaluation of a real-time detection tool for MH. Cases of MH from 2003 to 2013 were retrospectively reviewed to confirm the diagnosis of MH and to calculate a MH clinical grading scale score. The index cases were utilized to develop four electronic data Rules, based on endtidal CO2 (ETCO2 ) and temperature criteria. The Rules were then applied retrospectively to the index cases and to a full cohort of general operating room (OR) patients from January 2012 to June 2012. If criteria for possible MH was met, the detection tool generated an alert on the monitor at the patient's bedside. We identified seven patients with confirmed MH with MH Scores ranging from 28 to 70. Using four data Rules, all of our seven index cases were captured and generated an appropriate alert. Median time from MH computer alert time to dantrolene administration time among our index cases was 23 min (IQR 17-77). There were 938 false-positive alerts for possible MH (1.8%) when the Rules were applied to a general OR cohort of 51 579 total cases from January 2012 to June 2012. We demonstrated a real-time MH detection tool based on established physiologic criteria that is sensitive enough to capture cases suspicious for MH, while limiting false positives to prevent alarm fatigue. This has the potential to notify the provider of possible MH such that treatment may be rapidly initiated.

Neuromuscular conditions associated with malignant hyperthermia in paediatric patients: A 25-year retrospective study

Malignant Hyperthermia (MH) is a rare pharmacogenetic syndrome that can be fatal and the risk of MH in non RYR1-related disorders is unknown. We conducted a retrospective study to determine the prevalence of neuromuscular disorders among patients with MH at our centre. Patients who were admitted to the Hospital for Sick Children during the study period of January 1, 1990 to April 1, 2015 with a CK level > 8000 IU/L, or who received dantrolene, or who had a clinical diagnosis of MH were included. Medical records of 166 patients who met the inclusion criteria were reviewed and 13 patients were identified with MH-like reactions. Nine patients were classified as having true MH after review of the anaesthesia record and genetic testing results were available for 7 patients, 5 of whom had mutations in RYR1. Of the four patients who had severe reactions to anaesthesia but did not meet the criteria for true MH, two had Duchenne muscular dystrophy (DMD). In this retrospective study over 25 years, RYR1 mutations were the most common cause of MH in our cohort, and of these, one third had an underlying neuromuscular diagnosis. Genetic testing of RYR1 is indicated for all patients with MH, and anaesthetic precautions should be considered for any child with symptoms of neuromuscular disease.

Prevalence of Malignant Hyperthermia Diagnosis in New York State Ambulatory Surgery Center Discharge Records 2002 to 2011.

Malignant hyperthermia (MH) is a rare yet potentially fatal pharmacogenetic disorder triggered by exposure to inhaled anesthetics and the depolarizing neuromuscular blocking drug succinylcholine. Epidemiologic research on MH is largely limited to inpatients. In this study, we examined the prevalence of recorded MH diagnosis in patients discharged from ambulatory surgery centers (ASCs). We analyzed the New York State Ambulatory Surgery Dataset for the years 2002 to 2011 and identified patients with a discharge diagnosis of MH due to anesthesia by using the International Classification of Disease, Ninth Revision, Clinical Modification code 995.86. MH prevalence was assessed by demographic, clinical, and ASC characteristics. During the study period, 31 of 17,092,765 discharges from ASCs had a recorded diagnosis of MH, yielding a prevalence of 0.18 per 100,000 discharges (95% confidence interval, 0.12-0.25). The prevalence of recorded MH diagnosis per discharge differed significantly across age groups and surgical procedure categories. All patients with a recorded diagnosis of MH were from hospital-based ASCs and were discharged alive from ASCs. The prevalence of recorded MH diagnosis in ASC patients is approximately 1 per 500,000 and varies considerably with surgical procedures.

Cellular Pathophysiology of “MHH”, A Large Group of Patients with Equivocal Diagnosis of Malignant Hyperthermia

Is Malignant Hyperthermia a disease? Experts call it a “condition” and define it as a susceptibility (MHS), diagnosed by tests (CHCT or IVCT) that measure the response of a muscle biopsy to set concentrations of caffeine and halothane. Of 40 patients who tested positive recently at the Malignant Hyperthermia Investigation Unit, MHIU, of the Canadian University Health Network, 10 (25%, here called MHS) were positive to both agonists and 30 (75%, here denominated MHH) were positive to halothane but not caffeine. None of the MHH had mutations in known MH-linked locations (hot spots) of RyR1. These patients were compared with the normally reacting subjects (MHN, 25 patients) using a “clinical index”, built from the collection of clinical symptoms, including pain, weakness and creatine kinase levels, and a “calcium index”, cobbled from measures of Ca2+ signals, spontaneous and evoked, and steady [Ca2+] in cytosol, of myotubes derived from patient biopsies. The average clinical index was significantly greater in the MHH than the MHN; it was also greater in the MHH than in the MHS, but not significantly so. The difference between MHS and MHN was not significant. The calcium index was elevated approximately equally in MHH and MHS, in comparison with MHN. Additional cellular-level measurements, in progress, may reveal greater differences between groups with positive MH diagnosis. Conclusions from the initial sample: (1) most MHH are clinically sick, while MHS have only a susceptibility; (2) the cellular studies allow detection of defects in calcium management that apply to most of the susceptible individuals, whether they are abnormally reactive to one or both agonists in conventional MH tests. We are currently testing the hypotheses that MHH and MHS have mechanistically different pathogenesis and genetically different etiologies.