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Background: Hypocholesterolemia hallmarks critical illness though the underlying pathophysiology is incompletely understood. As low circulating cholesterol levels could partly be due to an increased conversion to cortisol/corticosterone, we hypothesized that glucocorticoid treatment, via reduced de novo adrenal cortisol/corticosterone synthesis, might improve cholesterol availability and as such affect adrenal gland and skeletal muscle function. Methods: In a matched set of prolonged critically ill patients (n = 324) included in the EPaNIC RCT, a secondary analysis was performed to assess the association between glucocorticoid treatment and plasma cholesterol from ICU admission to day five. Next, in a mouse model of cecal ligation and puncture-induced sepsis, septic mice were randomized to receive either hydrocortisone (1.2 mg/day) (n = 17) or placebo (n = 15) for 5 days, as compared with healthy mice (n = 18). Plasma corticosterone, cholesterol, and adrenocortical and myofiber cholesterol were quantified. Adrenal structure and steroidogenic capacity were evaluated. Muscle force and markers of atrophy, fibrosis and regeneration were quantified. In a consecutive mouse study with identical design (n = 24), whole body composition was assessed by EchoMRI to investigate impact on lean mass, fat mass, total and free water. Results: In human patients, glucocorticoid treatment was associated with higher plasma HDL- and LDL-cholesterol from respectively ICU day two and day three, up to day five (P < 0.05). Plasma corticosterone was no longer elevated in hydrocortisone-treated septic mice compared to placebo, whereas the sepsis-induced reduction in plasma HDL- and LDL-cholesterol and in adrenocortical cholesterol was attenuated (P < 0.05), but without improving the adrenocortical ACTH-induced CORT response and with increased adrenocortical inflammation and apoptosis (P < 0.05). Total body mass was further decreased in hydrocortisone-treated septic mice (P < 0.01) compared to placebo, with no additional effect on muscle mass, force or myofiber size. The sepsis-induced rise in markers of muscle atrophy and fibrosis was unaffected by hydrocortisone treatment, whereas markers of muscle regeneration were suppressed compared to placebo (P < 0.05). An increased loss of lean body mass and total and free water was observed in hydrocortisone-treated septic mice compared to placebo (P < 0.05). Conclusions: Glucocorticoid treatment partially attenuated critical illness-induced hypocholesterolemia, but at a cost of impaired adrenal function, suppressed muscle regeneration and exacerbated loss of body mass. [ABSTRACT FROM AUTHOR]

The diagnosis of adrenal insufficiency (AI) requires a high index of suspicion, detailed clinical assessment including detailed drug history, and appropriate laboratory evaluation. The clinical characteristics of adrenal insufficiency vary according to the cause, and the presentation may be myriad, e.g. insidious onset to a catastrophic adrenal crisis presenting with circulatory shock and coma. Secondary adrenal insufficiency (SAI) often presents with only glucocorticoid deficiency because aldosterone production, which is controlled by the renin angiotensin system, is usually intact, and rarely presents with an adrenal crisis. Measurements of the basal serum cortisol at 8 am (<140 nmol/L or 5 mcg/dL) coupled with adrenocorticotrophin (ACTH) remain the initial tests of choice. The cosyntropin stimulation (short synacthen) test is used for the confirmation of the diagnosis. Newer highly specific cortisol assays have reduced the cut-off points for cortisol in the diagnosis of AI. The salivary cortisol test is increasingly being used in conditions associated with abnormal cortisol binding globulin (CBG) levels such as pregnancy. Children and infants require lower doses of cosyntropin for testing. 21-hydoxylase antibodies are routinely evaluated to rule out autoimmunity, the absence of which would require secondary causes of adrenal insufficiency to be ruled out. Testing the hypothalamic–pituitary–adrenal (HPA) axis, imaging, and ruling out systemic causes are necessary for the diagnosis of AI. Cancer treatment with immune checkpoint inhibitors (ICI) is an emerging cause of both primary AI and SAI and requires close follow up. Several antibodies are being implicated, but more clarity is required. We update the diagnostic evaluation of AI in this evidence-based review. [ABSTRACT FROM AUTHOR]

The "fight or flight" response to critical illness relies on increased cortisol availability, traditionally attributed to several-fold-increased cortisol production via hypothalamus–pituitary–adrenal-axis activation. Recent studies provided evidence against this concept with clinical implications. First, high cortisol availability during critical illness is driven by suppressed cortisol binding and reduced cortisol breakdown rather than increased cortisol production. This implies reduction of hydrocortisone doses when prescribed in ICU. Second, plasma ACTH is low, explained by feedback inhibition by peripherally driven high free cortisol and/or other central glucocorticoid-receptor ligands. Third, ICU patients have elevated plasma concentrations of the ACTH-precursor hormone, pro-opiomelanocortin, because of impaired pituitary processing into ACTH, and pro-opiomelanocortin could drive some adrenocortical cortisol production in face of low ACTH. Fourth, in prolonged critically ill patients, endogenously suppressed ACTH, aggravated by exogenous corticosteroids, associates with poor outcome. In long-stay ICU patients, central adrenal insufficiency may occur due to lack of trophic ACTH signaling. Finally, the Cosyntropin test is not suitable to assess adrenocortical reserve in ICU patients as the test is confounded by increased cortisol distribution volume. These insights necessitate further research focusing on the need, if any, of treating ICU patients with corticosteroids, and timing thereof, outside indications for pharmacological anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

Myrto Eleni Flokas, Michael Tomani, Levon Agdere, Brande BrownDepartment of Pediatrics, NewYork-Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, USACorrespondence: Brande BrownDepartment of Pediatrics, NewYork-Presbyterian Brooklyn Methodist Hospital, 506, 6th Street, Brooklyn, NY 11215, USATel +1 718 780 5260Fax +1 718 780 3266Email bmb9005@nyp.orgAbstract: Allgrove syndrome or triple A (3A) syndrome is a multisystem disorder which classically involves the triad of esophageal achalasia, alacrima, and adrenal insufficiency due to adrenocorticotropin hormone insensitivity. It follows an autosomal recessive pattern of inheritance and is associated with mutations in the AAAS (achalasia–addisonianism–alacrima syndrome) gene. Since its first description in 1978, the knowledge on clinical and genetic characteristics has been expanding; however, the current literature is limited to case reports and case reviews. Early recognition of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of kin. The coordination of care for these patients requires a multidisciplinary team of specialists, including endocrinologists, neurologists, gastroenterologists, ophthalmologists, developmental specialists, dentists, geneticists, and surgeons. In this review, we aim to summarize the current recommendations for the diagnosis, management, and follow-up of patients with 3A syndrome.Keywords: AAA, guidelines, alacrima, achalasia, adrenal failure

Context: Prednisolone has been recommended rather than hydrocortisone for glucocorticoid replacement in adrenal insufficiency due its longer duration of action and lower cost.Objective: To determine mortality rates with prednisolone versus hydrocortisone.Methods: In this observational study, we used data extracted from a UK primary care database (Clinical Practice Research Datalink) to measure the relative mortality of patients with primary and secondary adrenal insufficiency, who were treated with either prednisolone or hydrocortisone, and control individuals who were individually matched for age, sex, period, and place of follow-up.Results: As expected, mortality in adrenal insufficiency irrespective of cause was increased, based on 5478 patients (4228 on hydrocortisone; 1250 on prednisolone) and 54 314 controls (41 934 and 12 380, respectively). Overall, the adjusted hazard ratio (HR) was similar with the 2 treatments (prednisolone, 1.76 [95% CI, 1.54-2.01] vs hydrocortisone 1.69 [1.57-1.82]; P = 0.65). This was also the case for secondary adrenal insufficiency. In primary disease (1405 on hydrocortisone vs 137 on prednisolone; 13 965 and 1347 controls, respectively), prednisolone users were older, more likely to have another autoimmune disease and malignancy, and less likely to have mineralocorticoid replacement. Nevertheless, after adjustment, the HR for prednisolone-treated patients remained higher than for those taking hydrocortisone (2.92 [2.19-3.91] vs 1.90 [1.66-2.16]; P = 0.0020).Conclusion: In primary but not in secondary adrenal insufficiency, mortality was higher with prednisolone. The study was large, but the number of prednisolone-treated patients was small, and they had greater risk factors. Nonetheless, the increased mortality associated with prednisolone persisted despite statistical adjustment. Further evidence is needed regarding the long-term safety of prednisolone as routine replacement. [ABSTRACT FROM AUTHOR]

Context: Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations.Objective: To compare mortality risk and causes of death in adrenal insufficiency with an individually matched reference population.Methods: A retrospective cohort study was done using a UK general practitioner database (CPRD). A total of 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) were compared with 67564 individually-matched controls (primary, 20366; secondary, 39134). Main outcomes were all-cause and cause-specific mortality, and hospital admission from adrenal crisis.Results: With follow-up of 40 799 and 406 899 person-years for patients and controls respectively, the hazard ratio (HR [95% CI]) for all-cause mortality was 1.68 [1.58-1.77]. HRs were greater in primary (1.83 [1.66-2.02]) than in secondary (1.52 [1.40-1.64]) disease; primary versus secondary disease (1.16 [1.03-1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15-7.46]). Adrenal crisis contributed to 10% of all deaths. In the first 2 years following diagnosis, the patients' mortality rate and hospitalization from adrenal crisis were higher than in later years.Conclusion: Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality. [ABSTRACT FROM AUTHOR]

Context: Mortality studies have established that cardiovascular disease is the leading cause of death in patients with adrenal insufficiency and the risk is greater than that observed in individually matched controls.Objective: Here we have performed a detailed analysis of cardiovascular morbidity and mortality, taking account of the role of comorbidities.Methods: We performed a retrospective cohort study using the Clinical Practice Research Datalink (CPRD), a UK general practitioner database. The participant population comprised 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) compared with 67 564 individually matched controls, with and without adjustment for comorbidities (diabetes, hypertension, dyslipidemia, previous cardiovascular disease, and smoking). The main outcome measures were composite cardiovascular events recorded in the CPRD and cardiovascular mortality in participants with linked national mortality data.Results: Hazard ratios (95% CI) for composite cardiovascular events in patients with adrenal insufficiency of any cause were 1.28 (1.20-1.36, unadjusted) and 1.07 (1.01-1.14, adjusted). Increased cerebrovascular events in patients with secondary adrenal insufficiency accounted for most of the increased hazard (1.53 [1.34-1.74, adjusted]) and were associated with cranial irradiation therapy. Cardiovascular mortality data were available for 3547 patients and 34 944 controls. The adjusted hazard ratio for ischemic heart disease mortality was 1.86 (1.25-2.78) for primary adrenal insufficiency and 1.39 (1.02-1.89) for secondary.Conclusion: Comorbidities largely accounted for the increased cardiovascular events but in secondary adrenal insufficiency, cerebrovascular events were independently increased and associated with irradiation treatment. However, the risk of cardiovascular mortality remained increased even following adjustment for comorbidities in both primary and secondary adrenal insufficiency. [ABSTRACT FROM AUTHOR]

Abstract Background Triple A syndrome (or Allgrove syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, adrenal insufficiency and autonomic/neurological abnormalities. The majority of cases are caused by mutations in the AAAS gene located on chromosome 12q13. However, the clinical picture as well as genetic testing may be complex since symptomatology is variable and mutations cannot be identified in all clinically diagnosed patients. We present two unrelated patients with triple-A syndrome illustrating the importance of alacrima as an early clinical sign. Case presentation A 3.5 year old girl presented with repeated hypoglycaemic myoclonic events. Adrenal insufficiency was diagnosed. In addition, alacrima, obvious since early infancy, was incidentally reported by the mother and finally lead to the clinical diagnosis of triple A syndrome. This was confirmed by positive mutation analysis of the AAAS gene. The second patient, an 8 months old boy was presented because of anisocoria and unilateral optic atrophy. MRI revealed cerebellar vermis hypotrophy. Psychomotor retardation, failure to thrive, and frequent vomiting lead to further diagnostic work-up. Achalasia was diagnosed radiologically. In addition, the mother mentioned absence of tears since birth leading to the clinical diagnosis of triple A syndrome. In contrast to the first cases genetic testing was negative. Conclusion These two patients illustrate the heterogeneity of triple A syndrome in both terms, clinical expression and genetic testing. We particularly aim to stress the importance of alacrima, which should be considered as a red flag symptom. Further differential diagnosis is required in every child affected by alacrima.

A 31-year-old lady, diagnosed to have premature ovarian failure in the gynecology clinic, was referred for endocrine assessment because of an abnormal thyroid function test. Clinical examination revealed hypotension, and fungal skin infection under her atrophic breasts. Thyroid stimulating hormone (TSH) level was very high. Assessment of the suprarenal function revealed evidence of Addison’s disease. Polyglandular autoimmune dysfunction was diagnosed. She was treated with prednisone, fludrocortisone, and levothyroxine with significant improvement of her general condition and blood pressure.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and progressive myelopathy in adulthood, although the age of onset and rate of progression are highly variable. In addition, 40% of male patients develop a leukodystrophy (cerebral ALD) before the age of 18 years. Women with ALD also develop myelopathy, but generally at a later age than men and with slower progression. Adrenal failure and leukodystrophy are exceedingly rare in women. Allogeneic hematopoietic cell transplantation (HCT), or more recently autologous HCT with ex vivo lentivirally transfected bone marrow, halts the leukodystrophy. Unfortunately, there is no curative treatment for the myelopathy. In this chapter, clinical spectrum of ALD is discussed in detail., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Allgrove syndrome is a very rare seen disorder with an autosomal recessive trait. The three characteristics of disease are alacrima, achalasia and adrenal failure. Alacrimia is the first manifestation in most cases. Achalasia and adrenal failure are seen later. Neurological involvement is rare and usually occurs in older age. A women 22 years old admitted to our hospital with adrenal failure crisis. She had alacrimia and used teardrop for many years. Achalasia was diagnosed after evaluation of her dysphagia. Thus, diagnosis of Allgrove syndrome, was done. Autonomic cardiac dysfunction and peripheral motor neuropathy were detected. In conclusion, Allgrove syndrome is rare and has life threatening potential due to adrenal failure. Early diagnosis and appropriate treatment may improve life quality and expectancy. Patients with relevant symptoms should be evaluated for autonomic neuropathy. [Med-Science 2015; 4(3.000): 2570-4]

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE , encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins. [ABSTRACT FROM AUTHOR]

Background: Triple A syndrome (or Allgrove syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, adrenal insufficiency and autonomic/neurological abnormalities. The majority of cases are caused by mutations in the AAAS gene located on chromosome 12q13. However, the clinical picture as well as genetic testing may be complex since symptomatology is variable and mutations cannot be identified in all clinically diagnosed patients. We present two unrelated patients with triple-A syndrome illustrating the importance of alacrima as an early clinical sign.Case Presentation: A 3.5 year old girl presented with repeated hypoglycaemic myoclonic events. Adrenal insufficiency was diagnosed. In addition, alacrima, obvious since early infancy, was incidentally reported by the mother and finally lead to the clinical diagnosis of triple A syndrome. This was confirmed by positive mutation analysis of the AAAS gene. The second patient, an 8 months old boy was presented because of anisocoria and unilateral optic atrophy. MRI revealed cerebellar vermis hypotrophy. Psychomotor retardation, failure to thrive, and frequent vomiting lead to further diagnostic work-up. Achalasia was diagnosed radiologically. In addition, the mother mentioned absence of tears since birth leading to the clinical diagnosis of triple A syndrome. In contrast to the first cases genetic testing was negative.Conclusion: These two patients illustrate the heterogeneity of triple A syndrome in both terms, clinical expression and genetic testing. We particularly aim to stress the importance of alacrima, which should be considered as a red flag symptom. Further differential diagnosis is required in every child affected by alacrima. [ABSTRACT FROM AUTHOR]

Introduction It is rare for a patient to present with adrenal insufficiency secondary to bilateral adrenal metastases from a malignant colorectal tumor. Case presentation An 82-year-old Japanese man presented to our hospital with high fever and malaise. He was receiving oral chemotherapy for the treatment of rectal cancer with multiple metastases. Computed tomography showed new bilateral adrenal gland metastases. A rapid adrenocorticotropic hormone (ACTH) test showed adrenal insufficiency. Treatment with hydrocortisone provided immediate symptom improvement. Discussion Adrenal insufficiency secondary to bilateral adrenal metastases from rectal cancer is rare. A rapid ACTH test is useful to diagnose adrenal insufficiency. Conclusion The incidence of adrenal insufficiency may be underestimated in patients with multiple metastasis. Appropriate therapy with adrenal corticosteroid hormone supplementation may lead to a significant improvement in the patient’s symptoms and quality of life. [ABSTRACT FROM AUTHOR]

Steroidogenic acute regulatory protein (StAR) mutations are the most frequent aetiologies of congenital lipoid adrenal hyperplasia (CLAH). Phenotypes may vary, and puberty may be absent in affected individuals. To date, only two pregnancies have been described in 46,XX CLAH patients with StAR mutations; these patients exhibited ovarian steroidogenesis along with spontaneous puberty and menarche and normal menses. The patient described here presented with CLAH caused by the homozygous (unreported, 1 bp) deletion c.719del in the StAR gene, which was diagnosed after acute adrenal insufficiency when the patient was 10 days old. The patient did not undergo spontaneous puberty, so puberty was induced by HRT when the patient was 13 years old. At the age of 25 years, the patient was referred to our reproductive unit because she desired to conceive. An initial cycle of clomiphene, stimulation produced follicular growth with two mature follicles measuring 18 and 15 mm, respectively, but the plasma oestradiol levels remained low (18 pg/ml) and the endometrium was thin (3 mm). Pregnancy was finally achieved after ovarian stimulation, IVF and transfer of frozen-thawed embryos after endometrial preparation with HRT. A normal female child was delivered following a 40 weeks' uneventful pregnancy. We therefore report the first IVF pregnancy achieved in a 46,XX CLAH patient homozygous for a StAR mutation, with inadequate ovarian steroidogenesis and no spontaneous puberty. [ABSTRACT FROM AUTHOR]

Skeletal dysplasias are complex group of diseases with different clinical and radiologic findings involving bone, and/or cartilage. Although skeletal dysplasias are rarely seen when considered individually, general incidence in the population is 1/3000-5000. Skeletal dysplasias are classified in 40 main groups on the basis of clinical, laboratory, radiological and molecular evaluations, and congenital malformations, spinal abnormalities, short extremities, and disproportionate short stature are seen in sekondereletal dysplasias. In addition to bone abnormalities, endocrine problems including hyperglycemia, hypo/hypercalcemia, adrenal failure, pubertal alterations, and disorders of sexual development which are mostly due to genetic disorders may accompany skeletal dysplasias. Differential diagnosis of skeletal dysplasias requires detailed history and physical examination, skeletal X-rays, genetic analysis, some advanced laboratory methods, and multidisciplinary aproach. hi this review, it is aimed to present a general approach to skeletal dysplasias, endocrine abnormalities that may accompany, and the most recent classification published in 2010. [ABSTRACT FROM AUTHOR]

Sepsis is defined as "systemic signs and symptoms of infection in the presence of infection". Nearly one fourth of sepsis cases eventually die. Therefore, rapid and correct management of sepsis is important. There is no reliable test to evaluate adrenal insufficiency in sepsis due to the changes in the hypothalamic-pituitary-adrenal axis and intracellular effects of cortisol during the critical illness. Clinical studies reported conflicting results regarding the effects of steroid therapy on mortality and morbidity in sepsis. Contemporary sepsis management guidelines - although not based on strong evidence - suggest consideration of steroid use in septic patients who do not respond to intravenous fluids and vasopressors. Stronger evidence obtained from randomized controlled trials is needed for this suggestion to be certain. [ABSTRACT FROM AUTHOR]

Objective: To report a case of Adrenal hypoplasia congenita (AHC) in an Indian boy presenting with adrenal failure in the neonatal period. Molecular diagnosis demonstrated absence of the entire DAX1 gene sequence region. Methods: Real-time SYBR Green Polymerase Chain Reaction (PCR) amplification followed by melt curve analysis was the molecular analytical method used. Analysis of the PCR products by Agarose gel electrophoresis was also performed. Results: Real-time SYBR Green PCR amplification carried out on a 240 bp region of Exon 1 and 320 bp region of Exon 2 of DAX1 gene did not result in any amplification for two independent DNA extractions of the patient sample. The melt curve analysis also failed to show the characteristic melt peaks. Additional analysis of the PCR products performed by Agarose gel electrophoresis of the patient samples did not reveal any DNA bands. Conclusions: Inability to amplify two distinct regions located on two distinct exons of the DAX1 gene of the patient sample point to the possible absence of the entire DAX1 gene sequence region in the index patient. Such molecular diagnostic techniques may prove very useful in making a diagnosis as well as for genetic counseling. [ABSTRACT FROM AUTHOR]

Triple A (Allgrove) syndrome was first described by Allgrove in 1978 in two pairs of siblings. Since then, about 100 cases have been reported, all of them displaying an autosomal recessive pattern of inheritance. Clinical picture is characterized by achalasia, alacrimia and ACTH-resistant adrenal failure. A progressive neurological syndrome including central, peripheral and autonomic nervous system impairment, and mild mental retardation is often associated. The triple A syndrome gene, designated AAAS, is localized on chromosome 12q13. It consists of 16 exons, encoding for a 546 aminoacid protein called ALADIN (Alacrimia-Achalasia-aDrenal Insufficiency Neurologic disorder). We report on a 13 year-old boy presenting with Addison's disease, dysphagia, muscle weakness, excessive fatigue and recent onset gait ataxia. The analysis of the AAAS gene revealed a homozygous missense mutation in exon 12. It was a T > G transversion at nucleotide position 1224, resulting in a change of leucine at amino acid position 381 into arginine (Leu381Arg or L381R). Brain appearance was found normal at magnetic resonance imaging (MRI) and functional spectroscopy analysis showed normal levels of the main metabolites. Spine MRI showed a cystic cavity within the spinal cord (syringomyelia), localized between the sixth cervical vertebra and the first thoracic vertebra. Cerebellar tonsils descended 7 mm caudal to foramen magnum, consistently with a mild type 1 Chiari malformation. Mild posterior inter-vertebral disk protrusions were evident between T9 and T10 and between L4 and L5. To our knowledge, this is the first report describing type 1 Chiari malformation and multiple spinal cord abnormalities in a patient with Allgrove syndrome. [ABSTRACT FROM AUTHOR]

Steroidogenic factor-1 (SF-1) (Ad4BP, NR5A1) is a nuclear receptor that plays a key role in adrenal and reproductive development and function. Deletion of the gene encoding Sf-1 (Nr5a1) in mice results in severe developmental defects of the adrenal gland and gonad. Consequently, initial work on the potential effects of SF-1 disruption in humans focused on individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis, and Müllerian structures. This is a rare phenotype, but has been reported on two occasions, because of alterations that affect key DNA-binding domains of SF-1. Attention then turned to a potential wider role of SF-1 in human adrenal and reproductive disorders. Although changes in SF-1 only very rarely cause isolated adrenal failure, it is emerging that variations in SF-1 are a surprisingly frequent cause of reproductive dysfunction in humans. In 46,XY disorders of sex development, a spectrum of phenotypes has been reported including severe and partial forms of gonadal (testicular) dysgenesis, hypospadias, anorchia with microphallus, and even male factor infertility. In 46,XX females, alterations in SF-1 are associated with primary ovarian insufficiency. Thus, SF-1 seems be a more significant factor in human reproductive health than was first envisioned, with implications for adults as well as children. [ABSTRACT FROM AUTHOR]