Syndrome of Congenital Adrenocortical Unresponsiveness to ACTH. Report of Six Patients

AbstractFamilial glucocorticoid deficiency (FGD) or unresponsiveness to ACTH at the receptor level is a rare autosomal recessive hereditary syndrome characterized by a low cortisol level despite high serum ACTH concentration. Aldosterone levels are normal. The clinical entity generally presents in the first year of life with skin hyperpigmentation and hypoglycemic convulsions. Cortisol response to exogenous ACTH is also absent. Unresponsiveness to ACTH may be due to a mutation in the ACTH receptor; sometimes no mutation is found. We discuss the clinical and laboratory findings and genetic studies in six patients with a diagnosis of FGD. A homozygous V142L mutation was detected in three of the patients and a homozygous D103N mutation was detected in two patients.

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Heterogeneity in the molecular basis of ACTH resistance syndrome.

Acta Endocrinologica ◽

10.1530/eje-08-0079 ◽

2008 ◽

Vol 159 (1) ◽

pp. 61-68 ◽

Cited By ~ 15

Author(s):

Cristhianna Viesti Advincula Collares ◽

Jose Antunes-Rodrigues ◽

Ayrton Custodio Moreira ◽

Suzana Nesi Franca ◽

Luiz Alberto Pereira ◽

...

Keyword(s):

Molecular Analysis ◽

Molecular Basis ◽

Clinical Findings ◽

Triple A Syndrome ◽

Allgrove Syndrome ◽

Gene Coding ◽

Acth Receptor ◽

Glucocorticoid Deficiency ◽

Low Cortisol ◽

Design And Methods

ObjectiveACTH resistance syndromes are rare, autosomal, and genetically heterogeneous diseases that include familial glucocorticoid deficiency (FGD) and triple A syndrome. FGD has been shown to segregate with mutations in the gene coding for ACTH receptor (MC2R) or melanocortin 2 receptor accessory protein (MRAP), whereas mutations in the triple A syndrome (AAAS, Allgrove syndrome) gene have been found in segregation with triple A syndrome. We describe the clinical findings and molecular analysis ofMC2R,MRAP, andAAASgenes in five Brazilian patients with ACTH resistance syndrome.Design and methodsGenomic DNA from patients and their unaffected relatives was extracted from peripheral blood leucocytes and amplified by PCR, followed by automated sequencing. Functional analysis was carried out using Y6 cells expressing wild-type and mutant MC2R.ResultsAll five patients showed low cortisol and elevated plasma ACTH levels. One patient had achalasia and alacrima, besides the symptoms of adrenal insufficiency. The molecular analysis of FGD patients revealed a novel p.Gly116Val mutation in theMC2Rgene in one patient and p.Met1Ile mutation in theMRAPgene in another patient. Expression of p.Gly116Val MC2R mutant in Y6 cells revealed that this variant failed to stimulate cAMP production. The analysis of theAAASgene in the patient with triple A syndrome showed a novel g.782_783delTG deletion. The molecular analysis of DNA from other two patients showed no mutation inMC2R,MRAP, orAAASgene.ConclusionsIn conclusion, the molecular basis of ACTH resistance syndrome is heterogeneous, segregating with genes coding for proteins involved with ACTH receptor signaling/expression or adrenal gland development and other unknown genes.

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Transcobalamin II deficiency in twins with a novel variant in the TCN2 gene: case report and review of literature

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0096 ◽

2020 ◽

Vol 33 (11) ◽

pp. 1487-1499

Author(s):

Engin Kose ◽

Ozge Besci ◽

Elif Gudeloglu ◽

Suzan Suncak ◽

Yesim Oymak ◽

...

Keyword(s):

Bone Marrow ◽

Failure To Thrive ◽

First Year ◽

Laboratory Findings ◽

Case Presentation ◽

Optimal Outcomes ◽

Novel Variant ◽

First Year Of Life ◽

Cobalamin Metabolism ◽

Transcobalamin Ii

AbstractObjectivesTranscobalamin II (TC) is an essential plasma protein for the absorption, transportation, and cellular uptake of cobalamin. TC deficiency presents in the first year of life with failure to thrive, hypotonia, lethargy, diarrhea, pallor, mucosal ulceration, anemia, pancytopenia, and agammaglobulinemia. Herein, we present TC deficiency diagnosed in two cases (twin siblings) with a novel variant in the TCN2 gene.Case presentation4-month-old twins were admitted with fever, respiratory distress, vomiting, diarrhea, and failure to thrive. Physical examination findings revealed developmental delay and hypotonia with no head control, and laboratory findings were severe anemia, neutropenia, and hypogammaglobulinemia. Despite normal vitamin B12 and folate levels, homocysteine and urine methylmalonic acid levels were elevated in both patients. Bone marrow examinations revealed hypocellular bone marrow in both cases. The patients had novel pathogenic homozygous c.241C>T (p.Gln81Ter) variant in the TCN2 gene. In both cases, with intramuscular hydroxycobalamin therapy, laboratory parameters improved, and a successful clinical response was achieved.ConclusionsIn infants with pancytopenia, growth retardation, gastrointestinal manifestations, and immunodeficiency, the inborn error of cobalamin metabolism should be kept in mind. Early diagnosis and treatment are crucial for better clinical outcomes. What is new? In literature, to date, less than 50 cases with TC deficiency were identified. In this report, we presented twins with TCN2 gene mutation. Both patients emphasized that early and aggressive treatment is crucial for achieving optimal outcomes. In this report, we identified a novel variation in TCN2 gene.

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The Development of Swallowing Respiratory Coordination

Perspectives on Swallowing and Swallowing Disorders (Dysphagia) ◽

10.1044/sasd18.1.19 ◽

2009 ◽

Vol 18 (1) ◽

pp. 19-24

Author(s):

Maggie-Lee Huckabee

Keyword(s):

Cortical Activation ◽

First Year ◽

Healthy Children ◽

Nasal Airflow ◽

Single Session ◽

Primary Finding ◽

Patterns Of Behavior ◽

Cortical Modulation ◽

First Year Of Life ◽

Swallowing Apnea

Abstract Research exists that evaluates the mechanics of swallowing respiratory coordination in healthy children and adults as well and individuals with swallowing impairment. The research program summarized in this article represents a systematic examination of swallowing respiratory coordination across the lifespan as a means of behaviorally investigating mechanisms of cortical modulation. Using time-locked recordings of submental surface electromyography, nasal airflow, and thyroid acoustics, three conditions of swallowing were evaluated in 20 adults in a single session and 10 infants in 10 sessions across the first year of life. The three swallowing conditions were selected to represent a continuum of volitional through nonvolitional swallowing control on the basis of a decreasing level of cortical activation. Our primary finding is that, across the lifespan, brainstem control strongly dictates the duration of swallowing apnea and is heavily involved in organizing the integration of swallowing and respiration, even in very early infancy. However, there is evidence that cortical modulation increases across the first 12 months of life to approximate more adult-like patterns of behavior. This modulation influences primarily conditions of volitional swallowing; sleep and naïve swallows appear to not be easily adapted by cortical regulation. Thus, it is attention, not arousal that engages cortical mechanisms.

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