The search for a unifying diagnosis involving neurological, endocrine and immune dysfunction: a case report of a novel presentation of DAVID syndrome.

BACKGROUND: We report a novel presentation of deficit in anterior pituitary function with variable immune deficiency (DAVID) syndrome in a healthy young girl presenting in Addisonian crisis with raised intracranial pressure. Nearly all cases of DAVID syndrome described in the literature have presented with recurrent infections and variable immunodeficiency. Pseudotumour cerebri has not been reported in DAVID syndrome to date. CASE PRESENTATION: A four-year-old girl represented to hospital with vomiting, confusion and diplopia after ten days of tiredness, neck and abdominal pain, and headache. Her cranial nerve examination demonstrated a right abducens nerve palsy and papilloedema, and she was found to have ketotic hypoglycaemia and hypocortisolaemia secondary to adrenocorticotrophic hormone (ACTH) deficiency. Her neuroimaging was consistent with pseudotumour cerebri, and her lumbar puncture opening pressure confirmed raised intracranial pressure (30-40 cmH2O). Cerebrospinal fluid analysis was normal. The patient's symptoms improved with hydrocortisone replacement and acetazolamide, but the raised intracranial pressure recurred after acetazolamide was discontinued. She was subsequently found to have panhypogammaglobulinaemia, and DAVID syndrome was diagnosed. Genetic testing demonstrated a truncating mutation in the NFKB2 gene c.2557C > T, p.(Arg853*). CONCLUSIONS: This case demonstrates pseudotumour cerebri as a novel neurological presentation of DAVID syndrome, highlights the rare association between adrenal insufficiency and intracranial hypertension, and shows the challenges in diagnosing isolated ACTH deficiency. We emphasise that cortisol should be checked in pre-pubertal children with pseudotumour cerebri and a diagnosis of DAVID syndrome considered in those presenting with low cortisol and neurological symptoms.

The longitudinal impact of probiotic and peanut oral immunotherapy on health-related quality of life.

BACKGROUND: We previously reported that probiotic and peanut oral immunotherapy (PPOIT) was effective at inducing sustained unresponsiveness compared with placebo in a double-blind, placebo-controlled randomized trial. This study evaluated the impact of PPOIT on health-related quality of life (HRQL). METHOD: Fifty-one participants (PPOIT 24; placebo 27) from the PPOIT trial completed Food Allergy Quality of Life Questionnaire (FAQLQ-PF) and Food Allergy Independent Measure (FAIM) at pre-treatment, end-of-treatment and 3 months after end-of-treatment. A total of 42 participants (20 PPOIT; 22 placebo) completed measures at 12 months post-treatment. Changes over time in PPOIT and placebo groups were examined by repeated-measures analysis of variance and paired t tests. RESULTS: Probiotic and peanut oral immunotherapy was associated with significant improvement in FAQLQ-PF (F = 3.63, P = .02), with mean difference 0.8 at 3 months post-treatment (P = .05) and 1.3 at 12 months post-treatment (P = .005), exceeding the 0.5 minimal clinically important difference for FAQLQ-PF. For FAIM, mean difference was 0.5 (P = .03) at 3 months and 0.4 (P = .04) at 12 months post-treatment. In placebo group, post-treatment FAQLQ and FAIM remained unchanged from pretreatment. Improvement in FAQLQ-PF and FAIM scores related specifically to acquisition of sustained unresponsiveness rather than to receiving PPOIT treatment or participation in the trial. CONCLUSIONS: Probiotic and peanut oral immunotherapy has a sustained beneficial effect on psychosocial impact of food allergy at 3 and 12 months after end-of-treatment. Treatment was not associated with reduced HRQL relative to baseline in either PPOIT or placebo groups, indicating that PPOIT was well tolerated and psychological well-being was not negatively impacted. Improved HRQL was specifically associated with acquisition of sustained unresponsiveness.

Design of a novel, one-sided, pedal-activated wheelchair.

The present paper proposes the design of a novel, one-sided, pedal-activated wheelchair for patients with hemiplegia or hemiparesis. The design comprises a planetary hub transmission, which is embedded in the hub of the wheelchair, with drive, neutral, and reverse modes. The paper first discusses the structural characteristics and motion transmission of the wheelchair, and then presents the motion design of the hub transmission, followed by assembly and testing of the prototype. The results confirm that the proposed wheelchair and hub transmission can meet users' demands, thus improving comfort and independence.

Molecular epidemiology and antigenic analyses of influenza A viruses H3N2 in Taiwan.

The severity of an influenza epidemic season may be influenced not only by variability in the surface glycoproteins, but also by differences in the internal proteins of circulating influenza viruses. To better understand viral antigenic evolution, all eight gene segments from 44 human H3N2 epidemic strains isolated during 2004-2008 in Taiwan were analyzed to provide a profile of protein variability. Comparison of the evolutionary profiles of the HA, NA and PB2 genes of influenza A (H3N2) viruses indicated that they were derived from a group of H3N2 isolates first seen in 2004. However, the PA, M and PB1 genes were derived from a different group of H3N2 isolates from 2004. Tree topology revealed the NP and NS genes could each be segregated into two groups similar to those for the polymerase genes. In addition, new genetic variants occurred during the non-epidemic period and become the dominant strain after one or two seasons. Comparison of evolutionary patterns in consecutive years is necessary to correlate viral genetic changes with antigenic changes as multiple lineages co-circulate.

Novel mutation affecting the pterin-binding site of PTS gene and review of PTS mutations in Thai patients with 6-pyruvoyltetrahydropterin synthase deficiency.

Tetrahydrobiopterin (BH(4)) deficiency comprises heterogeneous disorders resulting in hyperphenylalaninaemia (HPA) and lack of monoamine neurotransmitters. Among these, 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is the most common disorder. We report a female Thai patient with PTPS deficiency who was initially detected by newborn screening for HPA, and later treated by supplements of BH(4), L-dopa/carbidopa, and 5-hydroxytryptophan. Monitoring of serum prolactin representing dopamine sufficiency is used for optimizing the dosage of L-dopa. She showed a remarkable progress of development despite delayed treatment at 5 months of age. Mutation analysis revealed two heterozygous missense mutations of the PTS gene: c.259C>T (p.P87S) inherited from the father; and c.147T>G (p.H49Q) inherited from the mother. The latter is a novel mutation that affects the pterin-binding site of the PTPS enzyme. This novel mutation expands the mutation spectrum of PTPS deficiency. Notably, some PTS mutations have been reported in both Thai and Chinese patients. Whether these common mutations are the result of a founder effect with common ancestors of Thai and Chinese people or intermarriage between Thai and Chinese descents in Thailand remain unclear. In conclusion, severe neurological impairment from BH(4) deficiency could be prevented by newborn screening for HPA and proper metabolic management. However, pterin analysis for early diagnosis of BH(4) deficiency is still not available in most developing countries.

Factors predicting mortality in victims of blunt trauma brain injury in emergency department settings.

OBJECTIVE: The aim of the study was to identify risk factors for mortality in patients brought to the emergency department (ED) after blunt traumatic brain injury (TBI). METHODS: The medical records of such patients who visited the ED from June 2004 to May 2005 were retrospectively reviewed. Data (age, gender, initial Glasgow coma scale (GCS) scores, initial vital signs, brain computed tomography scan findings and cause of trauma) were collected from the records of 204 TBI patients, who were treated at the ED and needed intensive care. Among these patients, 48 died in the intensive care unit (ICU) of the hospital. Logistic regression was used to assess factors affecting mortality after trauma. RESULTS: Age (odds ratio (OR) 1.04; 95% CI 1.01 to approximately 1.07), GCS score less than 9 (OR 19.29; 95% CI 5.04 to approximately 73.82) and skull bone fracture (OR 10.44; 95% CI 3.59 to approximately 30.38) were identified as possible risk factors of mortality in TBI patients. CONCLUSION: These predictors appear to be clinically relevant and may help improve ED triage of TBI patients in need of ICU care.

Miniaturized GPCR signaling studies in 1536-well format.

G protein-coupled receptors (GPCRs) are involved in various physiological processes, such as behavior changes, mood alteration, and regulation of immune-system activity. Thus, GPCRs are popular targets in drug screening, and a well-designed assay can speed up the discovery of novel drug candidates. The Promega cAMP-Glo Assay is a homogenous bioluminescent assay to monitor changes in intracellular cyclic adenosine monophosphate (cAMP) concentrations in response to the effect of an agonist, antagonist, or test compound on GPCRs. Together with the Labcyte Echo 555 acoustic liquid handler and the Deerac Fluidics Equator HTS reagent dispenser, this setup can screen compounds in 96-, 384-, and 1536-well formats for their effects on GPCRs. Here, we describe our optimization of the cAMP-Glo assay in 1536-well format, validate the pharmacology, and assess the assay robustness for HTS. We have successfully demonstrated the use of the assay in primary screening applications of known agonist and antagonist compounds, and confirmed the primary hits via secondary screening. Implementing a high-throughput miniaturized GPCR assay as demonstrated here allows effective screening for potential drug candidates.

Pre-medication with intravenous clonidine suppresses fentanyl-induced cough.

BACKGROUND: A reflex cough is often observed after an intravenous bolus of fentanyl. This study was conducted to determine whether pre-treatment with intravenous clonidine could effectively attenuate fentanyl-induced cough. METHODS: Three hundred ASA I-II patients, aged between 18 and 80 years, undergoing various elective surgeries, were enrolled in this study. All patients were randomly assigned to one of two groups treated with intravenous clonidine 2 microg/kg (clonidine group) or the same volume of normal saline (control group). Intravenous fentanyl (2 microg/kg in 2 s) was injected 2 min after the clonidine or normal saline injection. Changes in the hemodynamics, auditory evoked potentials (AEPs) and Observer Assessment of Alertness/Sedation (OAA/S) rating scale were recorded before and 2 min after the clonidine or normal saline injection and 1 min after the fentanyl injection. The number of coughs 1 min after the fentanyl injection was also recorded. RESULTS: Patients in the clonidine group showed a significantly lower incidence of cough than those in the control group (17.3% vs. 38.7%, respectively; P < 0.01). The blood pressure was lower in the clonidine group than in the control group. There were no significant differences in AEP or OAA/S rating scale. CONCLUSIONS: Pre-treatment with intravenous clonidine (2 microg/kg) suppressed the reflex cough induced by fentanyl, with mild hemodynamic changes. Therefore, intravenous clonidine may be a clinically useful method of suppressing fentanyl-induced cough.

Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency.

Tetrahydrobiopterin (BH(4)) deficiency is an autosomal recessive disorder caused by enzyme defects in the biosynthesis or recycling of BH(4). Patients with BH(4) deficiency present with severe neurological signs and symptoms and require a different treatment from classical phenylketonuria. During the last 12 years, 31 cases of BH(4) deficiency were identified in our department. They were all classified as 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. They were diagnosed at the ages of 2.5-48 months and treated with BH(4), L-dopa and 5-hydroxytryptophan immediately after diagnosis. The average development quotients (DQ) at diagnosis and after treatment for more than 3 years were 53+/- 16, and 78+/- 15, respectively. A significant negative correlation was observed between the level of the DQ and the age at which treatment was commenced (r = -0.751, p = 0.002). Developmental profiles were uneven. Language, adaptability and at later age mathematics were particularly weak areas. Only two patients achieved a good performance in mathematics. Eleven patients who were treated with drugs from ages of 2.9-48 months had neuroradiological scanning. Computed tomography disclosed calcification in lentiform nuclei in one patient and magnetic resonance imaging disclosed delayed myelination and abnormal high intensity signal in cerebral white matter in all of them. Even though most of abnormalities were reversible, small patchy or spotted areas were still present on these regions after treatment for 10-46 months. In summary, our study supports the substantial efficacy of the current therapeutic approach in PTPS deficiency of normalizing amine neurotransmitters with three drugs as early as possible. For the first time, calcifications could be detected in patients with PTPS deficiency. Abnormalities in white matter on magnetic resonance imaging were not related to clinical manifestations and most were reversible.

Novel mutations at carboxyl terminus of CIC-1 channel in myotonia congenita.

OBJECTIVES: Myotonia congenita (MC), caused by mutations in the muscle chloride channel (CLCN1) gene, can be inherited dominantly or recessively. The mutations at the carboxyl terminus of the CLCN1 gene have been identified in MC patients, but the functional implication of these mutations is unknown. MATERIAL AND METHODS: Direct sequencing of polymerase chain reaction products covering the whole coding region of the CLCN1 gene was performed in a MC family. This study was designed to investigate the clinical manifestations and genetic analysis of the CLCN1 gene. RESULTS: We identified two novel mutations, 2330delG and 1892C>T, from a genetic screening of the CLCN1 gene in the MC family. The 2330delG mutant allele producing a fs793X truncated protein was identified in a heterozygous state in all the patients. The 1892C>T nucleotide change induced a missense mutation (T631I) found in several asymptomatic individuals, indicating that it may not be associated with MC. Intriguingly, the 2330delG mutation was also found in an asymptomatic subject who also carried the 1892C>T mutation. CONCLUSION: The data indicate that the fs793X mutant protein causes dominantly inherited MC. Because the mutation has been found in a recessive pedigree, the fs793X mutation may have a dual inheritance pattern.

Karyotypic evolution of a novel cervid satellite DNA family isolated by microdissection from the Indian muntjac Y-chromosome.

A minilibrary was constructed from DOP-PCR products using microdissected Y-chromosomes of Indian muntjac as DNA templates. Two microclones designated as IM-Y4-52 and IM-Y5-7 were obtained from negative screening of all three cervid satellite DNAs (satellites I, II, and IV). These two microclones were 295 and 382 bp in size, respectively, and shared approximately 70% sequence homology. Southern blot analysis showed that the IM-Y4-52 clone was repetitive in nature with an approximately 0.32-kb register in HaeIII digest. Sequence comparison revealed no similarities to DNA sequences deposited in the GenBank database, suggesting that the microclone sequences were from a novel satellite DNA family designated as cervid satellite V. A subclone of an Indian muntjac BAC clone which screened positive for IM-Y4-52 had a 3,325-bp insert containing six intact monomers, four deleted monomers, and two partial monomers. The consensus sequence of the monomer was 328 bp in length and shared more than 80% sequence homology with every intact monomer. A zoo blot study using IM-Y4-52 as a probe showed that the strong hybridization with EcoRI digested male genomic DNA of Indian muntjac, Formosan muntjac, Chinese muntjac, sambar deer, and Chinese water deer. Female genomic DNA of Indian muntjac, Chinese water deer, and Formosan muntjac also showed positive hybridization patterns. Satellite V was found to specifically localize to the Y heterochromatin region of the muntjacs, sambar deer, and Chinese water deer and to chromosome 3 of Indian muntjac and the X-chromosome of Chinese water deer.

Suggestive linkage of familial primary cutaneous amyloidosis to a locus on chromosome 1q23.

BACKGROUND: There is a high incidence of primary cutaneous amyloidosis (PCA) in South America, South-east Asia and Taiwan. To date, the aetiology of PCA remains unknown, but it is believed to be multifactorial. Although most cases are sporadic, some patients have a family history. Familial aggregation and different susceptibility to PCA among ethnic groups suggest that genetic factors may play an important role in its pathogenesis. However, no genetic loci for familial PCA (FPCA) have been identified so far. OBJECTIVES: In order to identify the susceptibility gene of FPCA, we took a candidate gene approach and performed linkage analysis on chromosome 1q21.3-24.2, including the 1q23.2 region where the gene encoding serum amyloid P component (APCS) is located. PATIENTS AND METHODS: Nine FPCA families including 29 individuals affected with PCA were recruited for this linkage study. Initially, 11 highly polymorphic microsatellite markers spanning the region from 1q21.3 to 1q24.2 were genotyped and revealed a suggestive linkage region. This region was further fine-mapped with seven additional markers. We also re-sequenced the 2.5-kb genomic region of the APCS gene in 29 affected and 42 control individuals. Two-point and multipoint linkage analyses were performed using the LINKAGE program. Nonparametric linkage (NPL) analysis and reconstruction of haplotypes were performed with the GENEHUNTER program. RESULTS: Both two-point and multipoint linkage analysis for all 11 markers generated negative or small positive total lod scores for all nine families. However, when we considered only three families, a maximum two-point total lod score of 2.09 was obtained for the marker D1S2844 at theta = 0.01. A plateau of multipoint total lod score between D1S2768 and D1S2878 with a maximum of 2.48 at the marker D1S2844 was observed. A maximum NPL score of 3.11 (P = 0.008) was also obtained for the marker D1S2878. However, re-sequencing of the APCS gene identified no functional mutation. CONCLUSIONS: Both parametric and nonparametric linkage evidence suggested that a possible susceptibility locus for a subset of FPCA might exist on chromosome 1q23. This is the first report demonstrating suggestive evidence of linkage of FPCA to a locus in this candidate region. No functional sequence variations of the APCS gene were found to be associated with this disease among the study families. Our data imply the existence of at least one additional locus responsible for FPCA in these families, confirming genetic heterogeneity of this skin disorder.

Paediatric home ventilatory support: the Auckland experience.

OBJECTIVES: To examine the trend over time, describe the disease categories treated, intervention success and outcomes of the children treated at home with continuous positive airway pressure (CPAP), non-invasive ventilation (NIV) and ventilation via tracheostomy (invasive ventilatory support, IVS) by the Respiratory Service at the Starship Children's Hospital in Auckland. METHODS: A retrospective review was undertaken of the Respiratory Service records from November 1991 to February 2004. RESULTS: Home CPAP, NIV or IVS was initiated in 160 children (89 boys, median age 6 years) in the study period. Sixty-nine (46 boys) remain on support and are still actively managed by the Starship Respiratory Service, of whom 46% live outside the Greater Auckland Region. Despite 42% of children being less than 5 years of age at initiation of therapy, institution of support failed in only 11%. The majority received treatment by non-invasive mask interface (68% (n = 108) CPAP, 29% (n = 47) NIV), with only 3% (n = 5) supported via tracheostomy. The numbers and complexity of support rose over the 12 years. Respiratory support was discontinued in 57% of cases, after a median of 12.5 months (range 3-52 months); in two-thirds, support was no longer required due to an improvement in the medical condition. The most common indication for support in current patients is respiratory parenchymal or airway disease followed by neuromuscular disease. Obesity is not a common indication. CONCLUSION: This review documents the increasing trend in children receiving respiratory support at home. Future planning and resources are needed to address this growing need.

DNA sequence and comparative analysis of chimpanzee chromosome 22.

Human-chimpanzee comparative genome research is essential for narrowing down genetic changes involved in the acquisition of unique human features, such as highly developed cognitive functions, bipedalism or the use of complex language. Here, we report the high-quality DNA sequence of 33.3 megabases of chimpanzee chromosome 22. By comparing the whole sequence with the human counterpart, chromosome 21, we found that 1.44% of the chromosome consists of single-base substitutions in addition to nearly 68,000 insertions or deletions. These differences are sufficient to generate changes in most of the proteins. Indeed, 83% of the 231 coding sequences, including functionally important genes, show differences at the amino acid sequence level. Furthermore, we demonstrate different expansion of particular subfamilies of retrotransposons between the lineages, suggesting different impacts of retrotranspositions on human and chimpanzee evolution. The genomic changes after speciation and their biological consequences seem more complex than originally hypothesized.

Epidemiological and genetic studies of myotonic dystrophy type 1 in Taiwan.

To investigate the prevalence and genetic characteristics of myotonic dystrophy type 1 (DM1) in Taiwan, DM-suspected patients and their families identified during the period of 1990-2001 had their clinical records reevaluated and the CTG repeat sizes at the DM1 locus examined. A total of 96 subjects belonging to 26 families were identified as DM1 patients, which gave a minimal disease prevalence of 0.46/100,000 inhabitants. Clinical anticipation was frequently observed in affected families, even in some parent-child pairs with transmission contraction of the CTG repeat size. The inverse correlation between age at onset and CTG repeat length was significant only in patients with small expansions. In addition, a DM1 carrier with a childhood-onset son was found to have CTG length heterogeneity in the range of 40-50, indicating that premutation alleles could be unstable during gametogenesis as well as in somatic tissues. Our data demonstrated that DM1 is a rare disease in Taiwan and showed that transmission contraction of repeat size is more likely to occur in alleles with large repeats.

Three-dimensional power Doppler imaging of ovarian stromal blood flow in women with endometriosis undergoing in vitro fertilization.

OBJECTIVE: The aims of this retrospective study were to investigate whether the quantification of ovarian stromal blood flow and/or leptin concentration are predictive of in vitro fertilization (IVF) outcomes in women after laparoscopic ovarian cystectomy for large endometriomas. METHODS: Twenty-two women undergoing IVF after laparoscopic surgery for ovarian endometriomas (> 6 cm) comprised the study group. Twenty-six women with tubal factor infertility constituted the control group. Ovarian stromal blood flow was evaluated by three-dimensional (3D) power Doppler ultrasound imaging using virtual organ computer-aided analysis (VOCAL( trade mark )). Serum and follicular fluid (FF) leptin concentrations were quantified using an enzyme-linked immunosorbent assay kit. RESULTS: There were significantly decreased ovarian stromal blood flow parameters (including vascularization index, flow index (FI), and vascularization flow index) in the endometriosis group without an evident difference in total ovarian volume on the day of human chorionic gonadotropin. The value of FF leptin demonstrated a negative correlation with ovarian stromal FI in the control group, but there was a loss of this effect in the endometriosis group. CONCLUSIONS: Quantification of ovarian stromal blood flow by 3D power Doppler ultrasound in women with endometriosis may provide an important prognostic indicator in those undergoing IVF.

Phagocytosis of apoptotic cells by macrophages induces novel signaling events leading to cytokine-independent survival and inhibition of proliferation: activation of Akt and inhibition of extracellular signal-regulated kinases 1 and 2.

Recent evidence indicates that phagocytic clearance of apoptotic cells, initially thought to be a silent event, can modulate macrophage (M phi) function. We show in this work that phagocytic uptake of apoptotic cells or bodies, in the absence of serum or soluble survival factors, inhibits apoptosis and maintains viability of primary cultures of murine peritoneal and bone marrow M phi with a potency approaching that of serum-supplemented medium. Apoptotic uptake also profoundly inhibits the proliferation of bone marrow M phi stimulated to proliferate by M-CSF. While inhibition of proliferation is an unusual property for survival factors, the combination of increased survival and decreased proliferation may aid the M phi in its role as a scavenger during resolution of inflammation. The ability of apoptotic cells to promote survival and inhibit proliferation appears to be the result of simultaneous activation of Akt and inhibition of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and ERK2 (ERK1/2). While several activators of the innate immune system, or danger signals, also inhibit apoptosis and proliferation, danger signals and necrotic cells differ from apoptotic cells in that they activate, rather than inhibit, ERK1/2. These signaling differences may underlie the opposing tendencies of apoptotic cells and danger signals in promoting tolerance vs immunity.

Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese.

BACKGROUND: Hyperphenylalaninemia (HPA) may be caused by either a deficiency in phenylalanine-4-hydroxylase or in tetrahydrobiopterin (BH4), the essential cofactor required for the hydroxylation of aromatic amino acids. The most common forms of BH4 deficiency are 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency (MIM 261640) and dihydropteridine reductase (DHPR) deficiency (MIM 261630), which require a different treatment from classical HPA. RESULTS: Approximately 86% of BH4-deficient HPA in the Chinese population was found to be caused by PTPS deficiency. Eleven missense (73C-->G, 120T-->G, 155A-->G, 166G-->A, 200C-->T, 209T-->A, 226C-->T, 259C-->T, 286G-->A, 317C-->T, 430G-->C), one splicing (IVS3+1G-->A) and two deletion mutations (116-119delTGTT, 169-171delGTG) were identified in 37 unrelated PTPS-deficient Chinese families. Among these, 155A-->G, 259C-->T and 286G-->A mutation accounted for about 80% of the mutant alleles. The 155A-->G and 286G-->A mutations were found to be the common mutation in southern and northern Chinese, respectively. Only two Chinese DHPR-deficient families were detected among about 300 Chinese hyperphenylalaninemia cases. A single base transition 508G-->A on the DHPR cDNA was identified in two consanguineous DHPR-deficient siblings. A reduced level of DHPR mRNA expression was found in the other DHPR-deficient patient, which suggested that the mutation might lie in the regulatory region of the DHPR gene. CONCLUSIONS: The BH4-deficient HPA was estimated to make up around 30% of the Chinese population in Taiwan suffering from HPA, which is much higher than in Caucasian populations (1.5-2% of HPA).