Hypoparathyroidism in Complex Disorders (APS1, APS2)


Autoimmune hypoparathyroidism polyendocrine syndrome type 1 (APS1, OMIM phenotype number #240300)

Autoimmune hypoparathyroidism polyendocrine syndrome type 2 (APS2, OMIM phenotype number #269200)

Autoimmune polyendocrinopathy syndrome type 1 (APS1, also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, APECED, OMIM phenotype number #240300) is a complex disorder usually inherited as an autosomal recessive trait, although an autosomal pattern of inheritance has been described in one kindred. The prevalence of APS1, usually referred to as a rare disease, can be relatively high in genetically isolated population because of a founder effect, i.e. 1:9000 in Iranian Jewish, 1:12000 in Sardinians and 1:2500 in Finnish.  The clinical phenotype is characterized by the presence of the Whitaker’s triad, encompassing chronic mucoutaneous candidiasis, hypoparathyroidism and autoimmune adrenal insufficiency (i.e. Addison’s disease). Diagnosis of APS1 is made when at least two of these signs are present. Oral trush, representing a sing of T-cell deficiency, is generally present at birth, while hypoparathyroidism and Addison’s disease manifest later, usually in the first and third decades, respectively. Penetrance of hypoparathyroidism is high (60% in females and 100% in males). Other autoimmune and non-autoimmune diseases (such as autoimmune thyroid disease, vitiligo, insulin-dependent diabetes mellitus, primary gonadal failure, pernicious anemia, celiac disease, chronic active hepatitis, alopecia and other ectodermal anomalies) can be associated to the main manifestations, characterizing a various phenotype.

APS1 is cause by mutations in the autoimmune regulator type 1 gene (AIRE1, OMIM locus number #607358 on chromosome 21q22.3). More than 200 mutations have been identified, so far, including deletions, missense, non-sense and alternative splicing mutations. AIRE1 is expressed early in thymus, fetal spleen, liver, lymph nodes and peripheral hamtopoietic tissue. It is essential to initiate proper central and peripheral tolerogenic mechanisms, leading to multiorgan autoimmune alterations when altered or missing. A chronic inflammation with infiltration of autoreactive T-lymphocytes is present in involved glands/organs. Several non–specific autoantibodies can be detected in the serum, such as antibodies against T-helper type 17 cell-related cytokines type I interferon (IFN). Antibodies against parathyroid autoantigens, such as the ones against CaSR or NALP5, may be present but they cannot be used as a specific and sensitive marker of the diagnosis of hypoparathyroidism in APS1 or disease progression.

A specific APS1 bone phenotype has not been described, although features of long-standing hypoparathyroidism, such as increased trabecular and cortical thickness, in adult subjects can be present. In two cases heterosygous and homozygous for an AIRE1 13-bp deletion, a reversible metaphyseal dysplasia due to altered endochondral ossification has been described, characterized by skeletal deformities developing in childhood leading to short stature in childhood. Histologically, islands of calcified cartilagine within bone have been found. This abnormalities usually resolve at puberty.


Activating mutations of AIRE1 (OMIM locus number #607358 on chromosome 21q22.3).


Mucocutaneous candidiasis, and signs related to hypoparathyroidism and Addison’s disease.

Main biochemical alterations 

APS1: hypocalcemia, low serum PTH levels, hyperphosphatemia, low serum 1,25(OH)2 vitamin D, hypocortisolism, high ACTH, defective response to ACTH in terms of cortisol; non-specific autoantibodies, anti-IFN1 antibodies, 21-Oh hydroxylase antibodies.


Figure: features of metaphyseal dysplasia in two subjects with AIRE1 mutation and APS1

Reproduced from Am J Hum Genet, Vol 96, Rauch F, Fahiminiya S, Majewski J, et al. Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB, Pages 425-31, Copyright 2015, with permission from Elsevier.

Other resource

Hypoparthyroidism  Association Inc.



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