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Laboratory evaluation of parathyroid gland function
Published in Pallavi Iyer, Herbert Chen, Thyroid and Parathyroid Disorders in Children, 2020
After careful historical review and physical examinations, the evaluation of disorders of calcium homeostasis begins with measurements of serum concentrations of total calcium and Ca2+, phosphate, creatinine, and intact PTH1-84 (7). Depending upon whether the problem one is attempting to solve is associated with hypocalcemia, hypercalcemia, or eucalcemia, further evaluation is undertaken. Thus, in the absence of intestinal malabsorption or severe compromise of renal function, the hypocalcemic, hyperphosphatemic child with reproducibly low or unmeasurable serum PTH concentrations most likely has hypoparathyroidism—prompting a search for the cause of parathyroid gland dysfunction such as congenital aplasia or hypoplasia of the parathyroid glands (e.g., the DiGeorge syndrome due to aberrant differentiation of structures derived from the third and fourth branchial pouches; variants of GATA3, NEBL, TBCE, and CHD7 may also be associated with abnormal differentiation of the parathyroid glands, while variants of PTH may result in abnormal synthesis of its product), a destructive autoimmune process affecting the parathyroid glands (isolated or associated with autoimmune polyendocrine syndrome type 1 related to a variant of AIRE), or a post-cervical surgical insult. Gain-of-function variants of CASR, the gene encoding the calcium-sensing receptor, are also associated with suppressed synthesis/secretion of PTH and resultant hypocalcemia. If serum PTH concentrations are elevated in the hypocalcemic, hyperphosphatemic patient, then abnormalities of PTH function (pseudohypoparathyroidism) should be evaluated including those due to variants of GNAS1 encoding the alpha subunit of the guanine nucleotide binding protein. In the hypocalcemic subject with elevated serum concentrations of PTH but normal or low serum levels of phosphate, intestinal absorption of calcium may be extremely low due to decreased intake of this cation or its impaired intestinal absorption due to vitamin D deficiency (identified by subnormal serum concentrations of calcidiol) or an abnormality of vitamin D metabolism and the production of calcitriol. Severe renal impairment may also hinder the synthesis of calcitriol. In the presence of high serum levels of calcitriol, an abnormality of the vitamin D receptor should be considered. Deficiency of magnesium stores may be associated with subnormal secretion of PTH and consequent hypocalcemia. Please see Table 9.1 for an evaluation of a hypocalcemic child, correlating laboratory findings with clinical conditions.
Genetic syndromes and autoimmunity: what do we know? Focus on Down and Turner syndrome
Published in Expert Review of Clinical Immunology, 2023
Alessandra Li Pomi, Malgorzata Wasniewska
The most important genetic locus associated with increased susceptibility to autoimmunity is the HLA locus, which contains genes involved in presenting antigens to immune cells. In the minority of cases, ADs are monogenic, deriving from defects in a single gene with highly penetrant mutations that disrupt essential mechanisms of central and peripheral immune tolerance. For example, Autoimmune Polyendocrine Syndrome Type 1 (APS-1) is defined by the presence of at least two of three clinical features: muco-cutaneous candidiasis, Addison disease and hypoparathyroidism. These conditions can be associated with other organ-specific autoimmune diseases (such as thyroiditis, type 1 diabetes, vitiligo, autoimmune gastritis, etc.). APS-1 is caused by AIRE gene deficiency, which plays a key role in establishing tolerance to self-antigens [2]. Studies to date have concluded that autoimmune diseases are probably caused by an inflammatory response by self-antigen-specific T cells, but the exact pathogenetic mechanisms are still unknown.
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
The main cause of prolidase deficiency is related to the PEPD gene and patients with this defect typically present recurrent infections, hepatomegaly and splenomegaly, which may cause thrombocytopenia [261]. Other defects in regulatory T cells due to mutations in DEF6 and IL2RG have been reported to cause autoimmune thrombocytopenia [237, 245]. DEF6/IBP/SLAT has been considered as a unique guanine nucleotide exchange factor for the Rho GTPase Cdc42 and Rac. DEF6 has contribute to TCR signaling and is phosphorylated by the tyrosine-protein kinases LCK21 and ITK [237]. Defects in T-cell helper differentiation, T-cell expansion and germinal center formation are some consequences of this deficiency [262]. So, the immune response may accompany thrombocytopenia in this disorder [14, 15, 19, 20]. Disrupt normal AIRE activity manifests autoimmune polyendocrine syndrome type 1 (APECED) lead to impaired AIRE protein. AIRE expression is activated in the thymus and known as a critical need to induce T-cell tolerance [263].
Clinical, immunological, and genetic features in 938 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a systematic review
Published in Expert Review of Clinical Immunology, 2021
Niusha Sharifinejad, Majid Zaki-Dizaji, Shafi Tebyanian, Hamed Zainaldain, Mahnaz Jamee, Fatema Sadaat Rizvi, Soheila Hosseinzadeh, Farimah Fayyaz, Haleh Hamedifar, Araz Sabzevari, Mojdeh Matloubi, Edyta Heropolitańska-Pliszka, Fatemeh Aghamahdi, Hassan Abolhassani, Gholamreza Azizi
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) also known as autoimmune polyendocrine syndrome type 1 (APS-1), is an inborn immune error associated with autosomal recessive or dominant mutations in the autoimmune regulator (AIRE) gene [1,2]. The AIRE protein is a transcriptional regulator that plays an important role in self-tolerance by promoting the expression of tissue-specific antigens (TSAs) in the thymus [3]. The human AIRE gene (OMIM: *607,358) is located on chromosome position 21q22.3 and consists of 14 coding exons that encode a transcription regulator of 545 amino acids with a molecular weight of 58 kDa. The most prominent domains in the AIRE protein are the caspase recruitment domain/homogeneously staining (CARD/HSR) region, a conserved nuclear localization signal (NLS), a SAND (SP100, AIRE, Nuc p41/75, DEAF) domain, four LXXLL (L is leucine and X is any amino acid) motifs, and two plant homeodomain (PHD) zinc fingers [4].