Steroid 17α-hydroxylase deficiency: First Australian case report

Abstract: 17α-hyroxylase deficiency is a rare form of congenital adrenal hyperplasia (CAM) that affects both glucocorticoid and sex hormone biosynthesis. We report a case of an unambiguous female with testes and hypertension. She was found to have deficient 17α-hydroxylase activity. The diagnosis was not made easily, the condition being unexpected due to its rarity. The discriminating feature of this form of sex-reversal is the presence of hypertension due to the elevated serum deoxycorticosterone levels. A failure to detect this will inappropriately focus attention on other, more common causes of sex reversal such as androgen insensitivity and gonadal dysgenesis, and expose the patient to the long-term sequelae of uncontrolled arterial hypertension.     

Urinary 17α-hydroxyprogesterone in management of 21 -hydroxylase deficiency

Objectives: The study was designed to assess the reliability of measurement of 24-hour urinary 17α-hydroxyprogesterone (17-OHP) by radio-immunoassay (RIA) as an alternative biochemical assessment for monitoring the treatment of congenital adrenal hyperplasia (CAH) due to 21 -hydroxylase deficiency (21 -OHD) and to assess the need for sample purification by column chromatography to improve assay specificity.
Methodology: Morning serum 17-OHP was measured using RIA and 24-hour urinary pregnanetriol using gas chromatography. Twenty-four-hour urinary 17-OHP was measured in samples from 17 prepubertal patients with CAH due to 21 -OHD, and 20 normal prepubertal children as controls. In 24 urine samples, RIA of 17-OHP was performed with and without column chromatography.
Results: There was a good correlation between 24-hour urinary 17-OHP and 24-hour urinary pregnanetriol (r = 0.962, P <0.01) and between 24-hour urinary 17-OHP and morning serum 17-OHP ( r = 0.955, P <0.01). There was no significant difference in the RIA of the urine samples with and without purification by column chromatography.
Conclusions: The measurement of 24-hour urinary 17-OHP is a reliable alternative for the biochemical monitoring of 21-OHD, and RIA specificity is unaffected by omission of column chromatography.     

Adrenal 21-hydroxylase deficiency in childhood: 25 years' experience

Objective: To review past and present management of congenital adrenal hyperplasia at a single centre, as a guide to best practice.
Methodology The records of 89 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency managed in a children's hospital in Australia over a period of 25 years were reviewed.
Results The diagnosis was made in infancy in 66 patients (37 males and 29 females) and later in 23 (11 males and 12 females). The mean age for genitoplasty in females with ambiguous genitalia was 18 months before 1984 and 3 months thereafter. Significant differences were found between males and females presenting after infancy with regard to virilization, bone age advancement, risk of true precocious puberty and final height. The mean final height standard deviation scores for seven males and seven females treated from infancy were — 1.32 and — 1.26, respectively.
Conclusions The results emphasize the importance of early diagnosis and good control in ensuring a good outcome for patients with 21-hydroxylase deficiency.     

Möbius syndrome in a patient with α 1 antitrypsin deficiency

ABSTRACT. This case report details the coincidence of Möbius syndrome and α antitrypsin deficiency.     

Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision)

Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The “Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)” published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients.     

Non-classical 21-hydroxylase deficiency in children: association of adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk of compound heterozygosity with severe mutations

AIM: To investigate the association between levels of 17-hydroxyprogesterone (17-OHP) and the risk of being compound heterozygous for severe mutations in children with non-classical 21-hydroxylase deficiency (NC21OHD). METHODS: In 86 Spanish NC21OHD children (75 families) an analysis of the 21-hydroxylase (21-OH) gene was performed by CYP21B-specific polymerase chain reaction amplification, allele-specific oligonucleotide hybridization and Southern blotting. Familial analysis established how the alleles segregated, and allowed the selection of 21-OH-genotyped normal and carrier children, which proved useful in determining a more precise definition of the cut-off for diagnosis. Receiver operating characteristics (ROC) curve analyses were performed to determine the potential value of 17-OHP in predicting compound heterozygosity for severe mutations. RESULTS: Thirty-four of the 86 children (39%) were found to carry one severe 21-OH mutation (7.3% deletions or conversions, 2.7% 655G, 2.7% Q318X, 1.3% 1172N, 1.3% R356W, and 3.3% double microconversions or small conversions involving single exons). The predominant mutation was V281L (56.7%). P453S and P30L were less frequent (3.3 and 2%). No patient showed two severe mutations. The degree of enzymic deficiency, as measured by basal or adrenocorticotropic hormone (ACTH)-stimulated 17-OHP levels in fully genotyped patients, but not clinical severity (age and number of symptoms at diagnosis), was found to be significantly greater in children with the severe/mild genotype. ROC curve analyses revealed a strong association between ACTH-17-OHP and genotype (area under the curve 0.908, SE 0.057). CONCLUSION: ACTH-stimulated 17-OHP may predict the risk of severe mutations in compound heterozygosity in children (maximum predictive value 93% sensitivity and 83% specificity for a cut-off at 151 nmol l(-1)), although a certain overlap in individual values is observed and performance of molecular analysis should never be obviated in the genetic counselling of these patients.     

Urinary excretion of 17-hydroxypregnanolones in patients with different forms of congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency

To improve diagnostic criteria in different (classical salt-wasting (SW), classical simple virilizing (SV) and non classical late onset (LO)) forms of congential adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency, we investigated the urinary excretion of 17-hydroxypregnanolones (17OH-PO(5) and (5), 15-hydroxypregnanolone(15OH-PO), pregnanetriol(PT) and 11-oxo-pregnanetriol (11-O-PT) compared to hydrocortisone metabolities During the 1st month of life newborn infants with CAH-SW excreted from barely detectable to very large amounts of 17OH-PO(5), 15OH-PO and PT, and, in 12 of 14 cases, also 11-O-PT in their urines. From the 1st to the 28th day of life, cortisol metabolites were virtually absent in urines of CAH-SW infants. This was in contrast of 36 healthy newborn infants. We measured the excretion of 17OH-PO(5) in children with CAH of whom 19 patients with CAH-SV had a median 17OH-PO(5) excretion of 1110 g/day (range: 152–5515). In 21patients with CAH-LO, median excretion of 17OH-PO(5) was 294g/day (range: 66–1273). Besides the conventional metabolites of 17-hydroxyprogesterone (17OH-PO(5), PT and 11-O-PT),no 17OH-PO(5) was detected in the urines of 14 patients with precocious pubarche, in 14 patients with virilization of unknown origin and in 94 healthy children of comparable age. The ratio of 17OH-PO(5) to tetrahydrocortisone (THE) discriminated between CAH-SV and CAH-LO from the 1st to the 18th year of age. The determination of urinary 17OH-PO(5) is an excellent diagnostic method in CAH-SV as well as CAH-LO.     

Young adults with α1antitrypsin deficiency identified neonatally: their health, knowledge about and adaptation to the high-risk condition

The psychological and psychosocial consequences of screening for α₁-antitrypsin deficiency (α₁ ATD) were investigated when the subjects were 5–7 years old. The present study was conducted when the subjects were 18–20 years old, the foci of interest being their health, psychosomatic problems, knowledge about α₁ATD and the potential effect of that knowledge on their lives and future family planning. Samples of 61 PiZ and 61 demographically matched control subjects, 18–20 years old, were asked to participate. Written, structured questionnaires covered the following items: basic familial characteristics, psychosomatic symptoms, opinions on medical check-ups, information and views on future α₁ATD screening, whether the knowledge about α₁ATD had affected the life and family planning of α₁ATD individuals. Items concerning the “α₁ATD matter” were excluded in the questionnaires given to the controls. Questionnaire data were obtained from 50 α₁ ATD and 48 control individuals, 41 of each being matched α₁ATD-control pairs. No significant differences were found in demographic or educational backgrounds, psychosomatic complaints such as headache, sleep difficulties, stomach ache, tiredness or anxiety. Lung symptoms occurred more frequently in α₁ATD subjects (p= 0.05). Six per cent of the α₁ATD individuals planned working careers with a high risk of air pollution. The majority (86%) of the α₁ATD subjects perceived the contact with the medical services as positive; 14% as both positive and negative. The information concerning α₁ATD was assessed as satisfactory by 73%, as both good and bad by 17% and as unsatisfactory by 10%. All α₁ATD subjects advocated general screening for α₁ATD, the neonatal period being chosen as optimal by 94%. Half of the α₁ATD individuals thought that the knowledge of their high-risk condition had affected their lives, particularly their awareness of the dangers of smoking and environmental pollution. The majority, 88%, knew that they should avoid smoking to protect their lungs. In conclusion, no negative psychosocial consequences of the neonatal α₁AT-screening were found in early adulthood. The α₁ATD individuals were aware of the dangers of smoking and were of the opinion that α₁ AT-screening should be recommended.     

Comparison of treatments of chronic hepatitis B in children with lamivudine and α-interferon combination and α-interferon alone

BACKGROUND: The aim of this study was to compare the efficacy of the alpha-interferon treatment with treatment using alpha-interferon and lamivudine in combination for cases of childhood chronic hepatitis B infection. METHODS: Patients were evaluated in two groups retrospectively. In group 1, 27 patients were simultaneously given alpha-interferon 2b 10 MU/m2, 3 days a week by s.c. injection plus lamivudine 4 mg/kg a day (maximum 100 mg) for 12 months. In group 2, there were 13 patients who only received the same dosage of alpha-interferon and no lamivudine over the same period of time. RESULTS: In group 1 the initial mean value of alanine aminotransferase (ALT) was 121 +/- 66 IU/L and decreased to 27.8 +/- 11.5 IU/L; in group 2, initial mean values of ALT was 129 +/- 46 IU/L and decreased to 60 +/- 6 IU/L at the end of the twelfth month of the therapy (P < 0.05). Hepatitis B virus DNA (HBV-DNA) clearance was obtained in all group 1 patients and six of 13 patients in group 2 at the end of the therapy (P < 0.001). The rates of hepatitis B early (HBe) antigen clearance and anti-HBe seroconversion were 59 and 37% in group 1 and 46 and 30.7% in group 2 (P > 0.05). The number of patients with complete response was found to be 10 out of 27 (37%) in group 1 and four out of 13 cases (30.7%) in group 2, 6 months after the end of the therapy. There was no statistically significant difference between both groups (P > 0.05). CONCLUSION: alpha-Interferon and lamivudine combination therapy had a more beneficial effect than alpha-interferon monotherapy in normalization of ALT and clearance of HBV-DNA; however, the complete response rate at 6 months after the end of the therapy was not statistically significantly different between both groups.     

Plasma levels of granulocyte elastase–α1-proteinase inhibitor complex in children with hemolytic uremic syndrome caused by verotoxin-producing Escherichia coli

BACKGROUND: Activated neutrophils play an important role in the pathogenesis of renal injury in humans and in experimental models of hemolytic uremic syndrome (HUS). To evaluate the clinical significance of the circulating granulocyte elastase-alpha1-proteinase inhibitor complex (GEPIC), which is a marker of neutrophil activation, we investigated the plasma concentrations of GEPIC in children with hemolytic uremic syndrome (HUS) associated with verotoxin-producing Escherichia coli (VTEC), VTEC gastroenteritis without HUS and in normal controls. METHODS: Of 22 children (1-19 years of age; mean age 5.5 years) with VTEC infection, nine were diagnosed with HUS. Plasma GEPIC, soluble thrombomodulin (sTM) and thrombin-antithrombin-III complex (TAT) levels were measured by ELISA. RESULTS: The number of polymorphonuclear leukocytes and the levels of plasma GEPIC in patients with HUS were significantly higher than those in non-HUS (9850+/-5091 vs. 5278+/-3327 /microL, P<0.05; 432.1+/-211.7 vs. 188.3+/-117.0 ng/mL, P<0.01) or control subjects (9850+/-5091 vs. 4728+/-1977 /microL, P<0.05; 432.1+/-211.7 vs. 105.9+/-51.1 ng/mL, P<0.001). Furthermore, plasma GEPIC levels showed a positive correlation with sTM (r = 0.522; P<0.01), a marker of endothelial cell injury, and TAT (r = 0.594; P<0.01), a marker of thrombin activity. CONCLUSIONS: These results suggest that an increase in circulating GEPIC levels in patients with VTEC-associated HUS may be related to endothelial injury, which may possibly lead to a more severe episode of this disease.     

Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with α1-antitrypsin deficiency

Individuals identified in the Swedish neonatal α₁-antitrypsin (AAT) screening study were followed prospectively from their first to their eighteenth year of life. The aim of this study was to analyse the effect of environmental factors, i.e. active and passive smoking, and of clinical factors on lung function and the occurrence of respiratory symptoms in AAT-deficient adolescents. The study group consisted of 88 protease inhibitor (Pi)ZZ and 40 PiSZ adolescents. Medical history including respiratory symptoms, and active and passive smoking were recorded at each follow-up up to the age of 18 y. Lung function tests were performed at the present check-up. At the age of 18 y, both forced expiratory volume in one second (FEV₁) and FEV₁/vital capacity (VC) were significantly lower in the smoking than in the non-smoking subgroup, and significantly more smokers than non-smokers reported the presence of phlegm. The mean FEV₁/VC ratio was lower for those presently exposed to parental smoking. Multiple linear regression analysis indicated that clinical liver disease in early life, active smoking and parental smoking were independent determinants of FEV₁/VC. The results suggest that marginal deviations in lung function and the symptom of phlegm among AAT-deficient adolescents occur characteristically early in the subgroup of smokers. Parental smoking may contribute to decreased lung function     

Analysis of Blood Spot 17α-Hydroxyprogesterone Concentration in Premature Infants—Proposal for Cut-Off Limits in Screening for Congenital Adrenal Hyperplasia—

Blood Spot 17α-hydroxyprogesterone (17-OHP) concentrations in neonates, especially in premature babies, were determined in relation to 1) the gestational age at birth, 2) the equivalent age of gestation at blood sampling and 3) the birth weight. The 17-OHP concentrations were found to be higher with prematurity. Accordingly, the cut-off limit in screening for congenital adrenal hyperplasia (CAH) in premature infants is proposed as 20 ng/ml. Ideal cut-off limits were set by the equivalent age of gestation at blood sampling. Cut-off limits on the basis of gestational age at birth and birth weight are also suggested, where the sampling age is not so advanced. The rate of false positivity in premature infants can be reduced by this method.     

Generation and Function of αδ T Cells after Allogeneic Bone Marrow Transplantation in Humans: Comparison in Absence or Presence of HLA-Matched or Mismatched Thymus

We have observed two patients who exhibited an exclusive increase of δ TCS1₊ subset of αδ T cells in the peripheral blood after bone marrow transplantation (BMT). In one case with severe combined immunodeficiency (SCID) who received haploidentical BMT from his father, αδ T cells appeared only after thymus transplantation. However, his T cell-mediated immunity remained severely defective despite the generation of T cells of donor origin. In the other case with aplastic anemia, δ T CS1_-αδ T cells began to increase in the peripheral blood later. This indicates that the thymus is necessary for the generation of αδ T cells and that the δ TCS1₊ subset is dominant in the early stages of their ontogeny. δ TCS1₊ T cell lines were established from both patients, and allo-reactivity was investigated. The cell line from the latter case reacted to recipient cells in a mixed lymphocyte reaction, but did not show cytotoxity to the allogeneic cells including recipient cells. The other cell line, from the former case, did not react to either donor or recipient cells. This indicates that an intact thymus is needed for αδ T cells to acquire allo-reactivity. Both cell lines showed MHC non-restricted cytotoxity against NK-sensitive target cells.     

A Case of a Preterm Infant with 21-Hydroxylase Deficiency: Implications of the Biochemical Diagnosis with Urinary Pregnanetriolone by Gas Chromatography/Mass Spectrometry in Selected Ion Monitoring (GCMS-SIM)

The biochemical diagnosis of 21-hydroxylase deficiency (21-OHD) is difficult in preterm infants. To date, no marker for the biochemical diagnosis of 21-OHD has been found. Seventeen α-hydroxyprogesterone (17-OHP), is not useful because of interference by delta 5 steroids from the fetal adrenal cortex. A 5-d-old female infant, born at 31 wk of gestation, was suspected of having 21-OHD based on physical findings (mild clitoromegaly, pigmentation of the tongue and gingiva) as well as laboratory data (17-OHP >93.5 ng/ml by ELISA 7 prime extractive method in filter paper-dried blood spot and 718.3 ng/ml by RIA after high performance liquid chromatography extraction in serum; plasma ACTH 690 pg/ml; and serum testosterone 3,169 ng/dl). We examined her urinary steroid profiles by gas chromatography/mass spectrometry in selected ion monitoring (GCMS-SIM) at 8 d of age. The pregnanetriolone (Ptl) level was noticeably high (0.80 mg/g creatinine), which was strongly suggestive of 21-OHD. Gene analysis of CYP21A2 showed compound heterozygosity, one allele having a cluster mutation in exon 6 and the other having a large deletion including CYP21A2, confirming the diagnosis of 21-OHD. This case suggested that, in preterm infants, urinary Ptl by GCMS-SIM can be useful for the biochemical diagnosis of 21-OHD.     

Analysis of Transferrin and α1-Fetoprotein in Amniotic Fluid and Neonatal Serum: a Possible Means for Indirect Prenatal Diagnosis of the Carbohydrate-deficient Glycoprotein Syndrome

A new type of inborn error of glycoprotein metabolism has recently been identified (CDG syndrome). The disease has systemic manifestations but mainly involves the nervous system. The most striking biochemical abnormality is the presence of secretory glycoproteins that are partially deficient in their carbohydrate moieties, the most pronounced of which is seen in serum transferrin. The basic genetic defect of the syndrome has not yet been identified. This study was carried out in order to provide a basis for indirect prenatal diagnosis by qualitative and quantitative analyses of a corresponding carbohydrate-deficiency in transferrin and also in α¹-fetoprotein in amniotic fluid. On isoelectric focusing both glycoproteins normally showed a carbohydrate (sialic acid (-dependent microheterogeneity in amniotic fluid as well as in neonatal serum which in transferrin differed from adult serum. Reference values of total transferrin (TT) and carbohydrate-deficient isotransferrins (CDT) during gestation were determined. Analysis of the microheterogenity of these glycoproteins by isoelectric focusing or determination of the CDT/TT ratio in amniotic fluid might provide a possibility for prenatal diagnosis of this syndrome. It was also shown that neonatal diagnosis is possible by analysis of serum transferrin.     

A Case of Mixed-type Dysgerminoma with a High Serum Concentration of both Human Chorionic Gonadotropin and α-Fetoprotein in a Child

Dysgerminoma is divided into two types: pure and mixed. The mixed type is related to other various elements of germ cell tumors. We experienced a case of mixed type dysgerminoma with a high serum concentration of both human chorionic gonadotropin and a-fetoprotein. The patient was a 6 year old girl who was admitted to the Hamamatsu University School of Medicine with an abdominal mass. Laboratory investigations revealed elevated serum a-fetoprotein and high concentration of serum β-human chorionic gonadotropin. The tumor originated from the left ovary. The histopathological diagnosis was dysgerminoma. Serum human chorionic gonadotropin and α-fetoprotein levels were useful markers in monitoring the response to treatment in this patient.     

Three siblings with triple A syndrome with a novel frameshift mutation in the <Emphasis Type="Italic">AAAS</Emphasis> gene and a review of 17 independent patients with the frequent p.Ser263Pro mutation

The triple A syndrome is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and impairment of the central, peripheral, and autonomic nervous system functions. The disease is caused by mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. In the present study, we report three siblings with triple A syndrome caused by a compound heterozygous mutation consisting of a novel Val421 frameshift mutation in exon 14 and a previously described Ser236Pro (T>C transition) missense mutation in exon 8. The second mutation is one of the most frequent mutations in the AAAS gene, occurring in 17 independent patients from different countries. With haplotype analysis, we demonstrate a founder effect for at least 13 of the 17 patients. We conclude that, although very helpful in establishing the final diagnosis of triple A syndrome, DNA analysis is not useful for the prediction of the clinical expression and outcome of the disorder. Further investigations are necessary to evaluate the correlation between genotype and clinical phenotype in the triple A syndrome.     

Age-related changes in adrenal size during the first year of life in normal newborns,infants and patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: comparison of ultrasound and hormonal parameters

An adrenal size index (ASI) was specifically designed to improve ultrasound evaluation of adrenal size in the 1st year of life. In 84 newborns and infants, ASI and plasma dehydroepiandrosterone sulphate (DHEA-S) concentrations were determined to study in vivo changes in adrenal size and cortical zonal composition. ASI was higher (P<0.0001) in the first 2 postnatal weeks (median 60.5 mm²) than in the rest of the first year (median 39.6 mm²) and showed a negative correlation with chronological age (r=-0.41). A positive correlation existed between DHEA-S concentrations and ASI (r=0.29) as well as ASI relative to body weight (r=0.57). These data and changes in gland echogenicity are consistent with histopathological observations that the early decrease in adrenal size is due to involution of the fetal zone. In four patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OHase) deficiency, ASI and plasma concentrations of pre-defect steroid were determined. Two patients with severe salt loss had markedly elevated ASI, which returned to normal during treatment. Two patients without severe salt loss had pretreatment ASI in the upper normal range, which decreased with treatment. Our findings indicate that ASI is useful in assessing physiological changes in adrenal size and, in conjunction with DHEA-S determinations, in adrenal cortex composition. ASI may aid in the early diagnosis of the salt-losing variety of 21-OHase deficiency. ASI is an instantaneously available tool which, in addition to biochemical and clinical data, can be used to monitor treatment of 21-OHase deficiency.Abbreviations ACTH adrenocorticotrophic hormone - ASI adrenal size index - CAH congenital adrenal hyperplasia - DHEA-S dehydroepiandrosterone sulphate - 21-OHase 21-hydroxylase     

Evaluation of long-term safety,tolerability, and behavioral outcomes with adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with Lennox-Gastaut syndrome: Final results from randomized study 303

Objective

Evaluate the long-term safety, tolerability, and behavioral effects of adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with inadequately controlled seizures associated with Lennox-Gastaut syndrome (LGS).