The Molecular Basis of Calcium and Phosphorus Inherited Metabolic Disorders.

Calcium (Ca) and Phosphorus (P) hold a leading part in many skeletal and extra-skeletal biological processes. Their tight normal range in serum mirrors their critical role in human well-being. The signalling "voyage" starts at Calcium Sensing Receptor (CaSR) localized on the surface of the parathyroid glands, which captures the "oscillations" of extracellular ionized Ca and transfers the signal downstream. Parathyroid hormone (PTH), Vitamin D, Fibroblast Growth Factor (FGF23) and other receptors or ion-transporters, work synergistically and establish a highly regulated signalling circuit between the bone, kidneys, and intestine to ensure the maintenance of Ca and P homeostasis. Any deviation from this well-orchestrated scheme may result in mild or severe pathologies expressed by biochemical and/or clinical features. Inherited disorders of Ca and P metabolism are rare. However, delayed diagnosis or misdiagnosis may cost patient's quality of life or even life expectancy. Unravelling the thread of the molecular pathways involving Ca and P signaling, we can better understand the link between genetic alterations and biochemical and/or clinical phenotypes and help in diagnosis and early therapeutic intervention.

Parietal aplasia and hypophosphatasia in a child harboring a novel mutation in RUNX2 and a likely pathogenic variant in TNSALP.

Cleidocranial dysplasia is a dominantly inherited skeletal dysplasia resulting from inherited or spontaneous mutations of Runt-related transcription factor 2 gene (RUNX2). It represents a clinical continuum typically characterized by wide calvarial sutures, clavicular hypoplasia and dental abnormalities. CDD has been rarely associated with skeletal and biochemical features that mimic hypophosphatasia. We report clinical, biochemical and molecular profile of a 3-year-old female with CCD, presented in utero with large cranial defects. She displayed severe parietal dysplasia, wide cranial sutures, clavicular abnormalities and biochemical features of hypophospatasia (HHP). She was preliminary diagnosed with benign perinatal HHP, harboring a likely pathogenic heterozygous TNSALP variant (p.Ser181Leu) inherited by the mother, who also displayed low levels of ALP. Asfotase alfa was introduced for a six-month-period with rather positive impact on cranial ossification. Nevertheless, focal skeletal disease (cranium and clavicles) and absence of clinical symptoms in the mother, carrier of the same genetic variant, posed diagnosis into question and further genetic analysis detected the novel spontaneous frameshift mutation c.1191delC (p.Phe398Leufs*86) in RUNX2 gene, establishing the CCD diagnosis. Although genotype-phenotype correlations are difficult, p.Phe398Leufs*86 appears to be associated with a severe cranial phenotype and absence of parietal bones, similarly to other adjacent frameshift/splicing mutations. The TNSALP variant (p.Ser181Leu) may contributed to patient's final phenotype, as well as to maternal low ALP levels. However, since low ALP levels have been also reported in few CCD patients with no alterations in TNSALP gene, studies to elucidate RUNX2 and TNSALP interactions could shed more light on differential diagnosis between CCD and HHP, CCD appropriate therapy and genetic counselling. ACCESSION NUMBER: (SUB8185506).

Ectopic Intrathyroidal Thymus in Childhood: A Sonographic Finding Leading to Misdiagnosis.

BACKGROUND: During gestation, the primordial thymus migrates from the pharynx to the anterior mediastinum, thus thymic tissue can remain at any point along this path. Intrathyroidal thymic remnants are rare, and their sonographic patterns have only recently been described. This retrospective study presents the sonographic appearance of ectopic intrathyroidal thymus and emphasizes the role of sonography in order to avoid misdiagnosis. METHODS: The population consisted of 42 children, 3.5-14 years old, who had a thyroid sonogram performed due to a positive family history or symptoms indicative of thyroid disease, and ectopic intrathyroidal thymus was recognized. RESULTS: In all patients, the same pattern was revealed: a fusiform intrathyroidal lesion, with no mass effect, homogeneously hypoechoic, with diffuse bright internal echoes. The similarity to the characteristic sonographic pattern of the normal mediastinal thymus was crucial for the diagnosis of ectopic intrathyroidal thymic tissue. In 8 cases, a normal elongated thymus was found connected to the thyroid with an accessory lobe embedded in the lower thyroid pole. The above sonographic appearances mimicked a thyroid nodule. CONCLUSIONS: Awareness of the sonographic patterns of the ectopic intrathyroidal thymus is mandatory to avoid misdiagnosis. In most cases, further investigation is unnecessary, but sonographic follow-up should be recommended.