scholarly journals SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency

2018 ◽  
Vol 104 (5) ◽  
pp. 1484-1490 ◽  
Author(s):  
Nikolaos Settas ◽  
Rebecca Persky ◽  
Fabio R Faucz ◽  
Nicole Sheanon ◽  
Antonis Voutetakis ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Adrenal Insufficiency ◽  
Brain Mri ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Primary Adrenal Insufficiency ◽  
Sphingosine 1 Phosphate ◽  
Recessive Genes ◽  
Initiation Of Therapy ◽  
Glucocorticoid Deficiency

Abstract Context Multiple autosomal recessive genes have been etiologically linked to primary adrenal insufficiency (PAI). Recently, sphingosine-1-phosphate lyase 1 (SGPL1) gene mutations were recognized as a cause of steroid-resistant nephrotic syndrome type 14 (NPHS14), a sphingolipidosis with multisystemic manifestations, including PAI. Objective To check if SGPL1 mutations are involved in the pathogenesis of PAI in patients who do not exhibit nephrotic syndrome. Methods Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome. Results We identified two missense SGPL1 variants in four patients, two of whom were first cousins. We describe in detail the proband, a boy born to Saudi Arabian consanguineous parents with a homozygous c.665G>A, p.R222Q SGPL1 variant. The patient presented with hypoglycemia and seizures at age 2 years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency). Brain MRI showed abnormalities in the basal ganglia consistent with a degenerative process albeit the patient had no neurologic symptoms. Conclusions New genetic causes of PAI continue to be identified. We suggest that screening for SGPL1 mutations should not be reserved only for patients with nephrotic syndrome but may also include patients with PAI who lack other clinical manifestations of NPHS14 because, in certain cases, kidney disease and accompanying features might develop. Timely diagnosis of this specific sphingolipidosis while the kidneys still function normally can lead to prompt initiation of therapy and improve outcome.

scholarly journals Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome

2017 ◽  
Vol 127 (3) ◽  
pp. 942-953 ◽  
Author(s):  
Rathi Prasad ◽  
Irene Hadjidemetriou ◽  
Avinaash Maharaj ◽  
Eirini Meimaridou ◽  
Federica Buonocore ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Adrenal Insufficiency ◽  
Primary Adrenal Insufficiency ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Sphingosine 1 Phosphate

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Update on pathogenesis of primary adrenal insufficiency: beyond steroid enzyme deficiency and autoimmune adrenal destruction

2017 ◽  
Vol 177 (3) ◽  
pp. R99-R111 ◽  
Author(s):  
Christa E Flück
Keyword(s):  
Adrenal Insufficiency ◽  
Regulatory Protein ◽  
Thioredoxin Reductase ◽  
Complex Form ◽  
Genetic Defects ◽  
Primary Adrenal Insufficiency ◽  
Adrenal Steroidogenesis ◽  
Sphingosine 1 Phosphate ◽  
Glucocorticoid Deficiency ◽  
Steroidogenic Acute Regulatory

Primary adrenal insufficiency (PAI) is potentially life threatening, but rare. In children, genetic defects prevail whereas adults suffer more often from acquired forms of PAI. The spectrum of genetic defects has increased in recent years with the use of next-generation sequencing methods and now has reached far beyond genetic defects in all known enzymes of adrenal steroidogenesis. Cofactor disorders such as P450 oxidoreductase (POR) deficiency manifesting as a complex form of congenital adrenal hyperplasia with a broad clinical phenotype have come to the fore. In patients with isolated familial glucocorticoid deficiency (FGD), in which no mutations in the genes for the ACTH receptor (MC2R) or its accessory protein MRAP have been found, non-classic steroidogenic acute regulatory protein (StAR) and CYP11A1 mutations have been described; and more recently novel mutations in genes such as nicotinamide nucleotide transhydrogenase (NNT) and thioredoxin reductase 2 (TRXR2) involved in the maintenance of the mitochondrial redox potential and generation of NADPH important for steroidogenesis and ROS detoxication have been discovered. In addition, whole exome sequencing approach also solved the genetics of some syndromic forms of PAI including IMAGe syndrome (CDKN1C), Irish traveler syndrome (MCM4), MIRAGE syndrome (SAMD9); and most recently a syndrome combining FGD with steroid-resistant nephrotic syndrome and ichthyosis caused by mutations in the gene for sphingosine-1-phosphate lyase 1 (SGPL1). This review intends do give an update on novel genetic forms of PAI and their suggested mechanism of disease. It also advocates for advanced genetic work-up of PAI (especially in children) to reach a specific diagnosis for better counseling and treatment.

scholarly journals Adrenal Crisis in Long Term Use of Exogenous Steroid With Inappropriate Tapering off Process

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A108-A109
Author(s):  
Nani Oktavia ◽  
Chici Pratiwi ◽  
Jerry Nasaruddin ◽  
Muhammad Ikhsan Mokoagow ◽  
Marina Epriliawati ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Blood Glucose ◽  
Adrenal Insufficiency ◽  
Clinical Manifestations ◽  
Adrenal Crisis ◽  
High Dose ◽  
Symptomatic Therapy ◽  
Bowel Sound ◽  
Primary Adrenal Insufficiency

Abstract Background: Adrenal crisis is an emergency condition in endocrinology that commonly found in primary adrenal insufficiency but also occur in chronic adrenal insufficiency triggered by various conditions such as sepsis, infection, trauma, burns, surgery, and myocardial infarction. In chronic adrenal insufficiency, adrenal crisis can be induced by excessive reductions or inadequate discontinuation of steroid treatment. Case Illustration: A 40-year old-man admitted with chief complaint abdominal pain since seven days before admission. He felt pain in the umbilical area and slowly radiated to all the part of abdomen. Other than that, he also felt nausea, had vomitus, fever, and constipation for five days. He was immobilized for four months, with muscles weakness and atrophy. He was diagnosed with Focal Segmented Glomerulosclerosis and had a high dose of methylprednisolone (48 mg) for 6 months, 40 mg for the next 2 months and methylprednisolone 12 mg for the last 2 months. The last two month, he began to have severe general weakness and hypotension. On physical examination we found hypotension, fever (38.1o C), pale conjunctiva, moon face, buffalo hump, slightly distended and tenderness of abdomen, normal bowel sound, and purple striae all over the abdomen and extremities. On laboratory examination, Hb was 8.2 (n 11.7 – 15.5 g/dl), leukocytes 10,400 (5.00 – 10.00 x 103/μL), Na 123 (n 135 – 147 mmol/L), random blood glucose 74 (n 70 – 140 mg/dL). On abdominal X ray, there was prominent faecal material and no signs of ileus. No sign of infection found in urinalysis. He had sodium correction, packed red cell transfusion, symptomatic therapy including laxative, methylprednisolone 12 mg, but no improvement of signs and symptoms beside be able to defecate. The abdominal ultrasound gave a normal result. The morning cortisol level was then examined, with the result 14.4 (n 3.7–19.4). The patient was then diagnosed with adrenal crisis based on the clinical manifestations and had hydrocortisone therapy 100 mg a day for 2 consecutive days. After hydrocortisone administration, the symptoms improved, no fever and abdominal pain, he had normotension, increased sodium level 132 (n 135 – 147 mmol/L) and blood glucose level 118 (n 70 – 140 mg/dL). On the third day the patient discharged with oral hydrocortisone 15 mg in the morning and 10 mg in the afternoon. Conclusion: Adrenal crisis was generally found in primary adrenal insufficiency but could also occur in secondary adrenal insufficiency due to inappropriate tapering off process of long term glucocorticoid use.

scholarly journals Identification of scavenger receptor BI as a potential screening candidate for congenital primary adrenal insufficiency in humans

2020 ◽  
Vol 319 (1) ◽  
pp. E102-E104
Author(s):  
Menno Hoekstra
Keyword(s):  
Adrenal Insufficiency ◽  
Scavenger Receptor ◽  
Failure To Thrive ◽  
Type I ◽  
Concomitant Treatment ◽  
Treatment Optimization ◽  
Primary Adrenal Insufficiency ◽  
Hormone Synthesis ◽  
Relative Contribution ◽  
Glucocorticoid Deficiency

Glucocorticoids belong to the superfamily of steroid hormones that are synthesized from the common precursor cholesterol. Adrenal gland-derived glucocorticoids, e.g., cortisol in humans and corticosterone in rodents, contribute to various processes essential for normal daily life. Glucocorticoid deficiency, also referred to as primary adrenal insufficiency, therefore, often becomes evident early in life and can be present with hypoglycemia, a failure to thrive, recurrent development of infections, and neurological problems, such as seizures and coma. The majority of congenital primary adrenal insufficiency cases are caused by deleterious mutations in genes involved in the intracellular mobilization of cholesterol and the subsequent conversion of cholesterol into glucocorticoids. A significant number of glucocorticoid deficiency cases, however, cannot be explained by known genetic variations. This perspective highlights existing literature regarding the importance of lipoprotein-derived cholesterol acquisition through scavenger receptor class B, type I (SR-BI/SCARB1) for the maintenance of an optimal adrenal glucocorticoid function in mice and humans. On the basis of the reviewed findings, it is suggested that the SCARB1 gene should be included in the standard glucocorticoid deficiency genetic screening panel to 1) facilitate knowledge development on the relative contribution of SR-BI-mediated cholesterol acquisition to steroid hormone synthesis in humans and 2) open up the possibility to reclassify glucocorticoid deficiency patients without a currently known genetic cause for concomitant treatment optimization.

Increase in T3 levels during hypocorticism in patients with chronic secondary adrenocortical insufficiency

1992 ◽  
Vol 126 (4) ◽  
pp. 319-324 ◽  
Author(s):  
Ronald Comtois ◽  
Josée Hébert ◽  
Jean-Paul Soucy
Keyword(s):  
Adrenal Insufficiency ◽  
Medical Literature ◽  
Clinical Manifestations ◽  
Adrenocortical Insufficiency ◽  
Primary Adrenal Insufficiency ◽  
Sodium Potassium ◽  
Acth Deficiency ◽  
Differential White Blood Cell ◽  
Peripheral Conversion ◽  
Cortisol Deficiency

The clinical and biochemical manifestations of secondary adrenocortical insufficiency are not well defined in the medical literature. This study was designed to determine the clinical and laboratory features suggesting the diagnosis of adrenal insufficiency in 15 chronic ACTH deficiency patients during low and normal cortisol states. Except for fatigue and weakness, the characteristic clinical manifestations of primary adrenal insufficiency occurred rarely. ACTH deficiency did not significantly modify blood glucose, serum calcium, sodium, potassium and differential white blood cell count. However, serum T4 was lower (65±19 vs 95±21 nmol/l, p< 0.001) during cortisol deficiency, while T3 was higher (2.4±0.67 vs 2.0±0.60 nmol/l, p<0.001). Furthermore, rT3 decreased significantly during hypocorticism (0.27±0.07 vs 0.18±0.07 nmol/l, p<0.001). TheT4/T3 ratio was significantly lower than the normal in 15 out of the 17 episodes of ACTH deficiency (29±12.5 vs 57±9.4, p<0.0001). We conclude that the increase in T3 and decrease in T4 levels are associated with chronic secondary adrenocortical insufficiency. This laboratory feature could be due, at least in part, to the increased peripheral conversion of T4 to T3 during cortisol deficiency.

scholarly journals Presentation of Primary Adrenal Insufficiency in Childhood

2011 ◽  
Vol 96 (6) ◽  
pp. E925-E928 ◽  
Author(s):  
Susan Hsieh ◽  
Perrin C. White
Keyword(s):  
Adrenal Insufficiency ◽  
Chart Review ◽  
Clinical Symptoms ◽  
Tertiary Care ◽  
Retrospective Chart Review ◽  
Signs And Symptoms ◽  
Primary Adrenal Insufficiency ◽  
Adrenal Hypoplasia ◽  
Glucocorticoid Deficiency ◽  
Rule Out

Context: Primary adrenal insufficiency is usually diagnosed in infancy or adulthood, and cases presenting in childhood have not been systematically reviewed. Objective: Our objective was to determine etiologies, signs, and symptoms of primary adrenal insufficiency presenting in childhood. Design and Setting: We conducted a retrospective chart review at a tertiary-care pediatric hospital. Patients: Patients were children with corticoadrenal insufficiency, glucocorticoid deficiency, or mineralocorticoid deficiency. Results: Seventy-seven cases were identified in 1999–2010. Thirty-five had congenital adrenal hyperplasia (CAH) and were not reviewed further. Forty-two patients (20 diagnosed at our institution) had primary adrenal insufficiency. These had etiologies as follows: autoimmune (18), autoimmune polyendocrinopathy syndrome (an additional five), ACTH resistance (four), adrenoleukodystrophy (three), adrenal hypoplasia congenita (two), adrenal hemorrhage (two), IMAGe syndrome (one), and idiopathic (two). Of 20 patients diagnosed at our institution, two were being monitored when adrenal insufficiency developed and were not included in the analysis of presenting signs and symptoms: 13 of 18 patients were hypotensive; 12 of 18 had documented hyperpigmentation. Hyponatremia (&lt;135 mEq/liter) occurred in 16 of 18. However, hyperkalemia (&gt;5.0 mEq/liter) was noted in only nine. Hypoglycemia and ketosis were documented in four of 15 and four of six patients in whom it was sought, respectively. Fifteen patients underwent cosyntropin stimulation testing with median baseline and stimulated cortisol of 1.1 and 1.2 μg/dl, respectively. ACTH and renin were markedly elevated in all patients. Conclusions: Hyperkalemia is not a consistent presenting sign of primary adrenal insufficiency in childhood, and its absence cannot rule out this condition. A combination of chronic or subacute clinical symptoms, hypotension, and hyponatremia should raise suspicion of adrenal insufficiency.

Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees With X‐linked Adrenoleukodystrophy and Review of the Literatures

2021 ◽  
Author(s):  
Bingzi Dong ◽  
Wenshan Lv ◽  
Lili Xu ◽  
Yuhang Zhao ◽  
Xiaofang Sun ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Brain Mri ◽  
Protein A ◽  
Clinical Manifestations ◽  
Atp Binding ◽  
Loss Of Function ◽  
Novel Mutations ◽  
First Case ◽  
Abcd1 Gene ◽  
Atp Binding Cassette

Abstract BackgroundX-linked adrenoleukodysrophy (ALD) is an inherited peroxisomal metabolism disorder, results from the loss-of-function mutation of ATP-binding cassette protein subfamily D1 ( ABCD1 ) gene. The dysfunction of ALD protein, a peroxisomal ATP-binding cassette transporter, results in the excessive saturated very long chain fatty acids (VLCFAs) accumulation in organs including brain, spine and adrenal cortex. X-ALD is characterized as the childhood, adolescent, adult cerebral ALD, adrenomyeloneuropathy (AMN), adrenal insufficiency, and asymptomatic phenotypes, exhibiting a high variety of clinical neurological manifestations with or without adrenocortical insufficiency. ResultsIn this study, we reported two cases of X-ALD, which were firstly diagnosed as adrenal insufficiency (Addison’s disease) and treated with adrenocortical supplement. However, both of the cases progressed as neurological symptoms and signs after decades. Elevated VLCFAs level, brain MRI scan and genetic analysis confirmed final diagnosis. In addition, we identified two novel mutations of ABCD1 gene, c.874_876delGAG (p.Glu292del) and c.96_97delCT (p.Tyr33Profs*161) in exon 1 of ABCD1 gene. Sanger sequencing confirmed that the proband’s mother of the first case was hemizygous carrying the same variant. Adrenal insufficiency-only type is very rare, however, it may be the starting performance of X-ALD. In addition, we summarized reported mutation sites and clinical manifestations to investigate the correlationship of phenotype-genotype of X-ALD. ConclusionsThe early warning manifestations should be noticed, and the probability of X-ALD should be considered. This report could be beneficial for the early diagnosis and genetic counseling for patients with X-ALD.

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