A New de novo Mosaic Mutation of PHEX Gene: A Case Report of a Boy with Hypophosphatemic Rickets.

BACKGROUND: X-linked hypophosphatemia is the most prevalent form of heritable rickets, characterized by an X-linked dominant inheritance pattern. The genetic basis of X-linked hypophosphatemia is a loss-of-function mutation in the PHEX gene (Phosphate regulating gene with Homology to Endopeptidases on the X chromosome), which leads to an enhanced production of phosphaturic hormone FGF23. X-linked hypophosphatemia causes rickets in children and osteomalacia in adults. Clinical manifestations are numerous and variable, including slowdown in growth, swing-through gait and progressive tibial bowing, related to skeletal and extraskeletal actions of FGF23. PHEX gene spans over 220 kb and consists of 22 exons. To date, hereditary and sporadic mutations are known (missense, nonsense, deletions and splice site mutations). CASE PRESENTATION: Herein, we describe a male patient carrying a novel de novo mosaic nonsense mutation c.2176G>T (p.Glu726Ter) located in exon 22 of PHEX gene. CONCLUSION: We highlight this new mutation among possible causative of X-linked hypophosphatemia and suggest that mosaicism of PHEX mutations is not so uncommon and should be excluded in diagnostic workflow of heritable rickets both in male and female patients.

Flavor perception test: evaluation in patients with Kallmann syndrome.

In Kallmann syndrome (KS), congenital hypogonadism is associated with olfactory impairment. To evaluate flavor perception-related disability in KS patients, 30 patients with KS, 12 with normosmic hypogonadism (nIHH), 24 with acquired anosmia (AA), and 58 healthy controls entered the study. All participants completed questionnaires concerning dietary habits, olfaction-related quality of life (QoL), and self-determined olfactory, flavor, and taste abilities prior to undergoing standardized olfactometry and gustometry. Each subject underwent flavor testing, using orally administered aqueous aromatic solutions, identifying 21 different compounds by choosing each out of 5 alternative items. Flavor score (FS) was calculated as the sum of correct answers (range 0-21). Flavor perception by self-assessment was similar between KS, nIHH, and controls, and was mostly reduced only in AA. FS was similar between KS (5.4 ± 1.4) and AA (6.4 ± 1.9), and lower than in nIHH (16.2 ± 2.4, p < 0.001) and controls (16.8 ± 1.7, p < 0.0001). FS showed strong reproducibility, and correlated with olfactory scores in the overall population. KS and AA patients identified aromatics eliciting trigeminal stimulation better than pure odorants. Olfaction-related QoL was more impaired in AA than in KS. We report significant flavor impairment in KS. This contrasts with routine clinic evidence; KS patients, in contrast with AA, do not complain of flavor perception impairment, perhaps owing to the congenital nature of the dysfunction. Flavor perception impairment should be considered a specific KS disability, because of important detrimental effects on physical and mental health and on QoL. KS patients should also be advised of this impairment in order to prevent accidental and life-threatening events.

20 novel point mutations and one large deletion in EXT1 and EXT2 genes: report of diagnostic screening in a large Italian cohort of patients affected by hereditary multiple exostosis.

BACKGROUND: Hereditary multiple exostosis represents the most frequent bone tumor disease in humans. It consists of cartilage deformities affecting the juxta-ephyseal region of long bones. Usually benign, exostosis could degenerate in malignant chondrosarcoma form in less than 5% of the cases. Being caused by mutations in the predicted tumor suppressor genes, EXT1 (chr 8q23-q24) and EXT2 (chr 11p11-p12) genes, HMEs are usually inherited with an autosomal dominant pattern, although "de novo" cases are not infrequent. AIM: Here we present our genetic diagnostic report on the largest Southern Italy cohort of HME patients consisting of 90 subjects recruited over the last 5years. RESULTS: Molecular screening performed by direct sequencing of both EXT1 and EXT2 genes, by MLPA and Array CGH analyses led to the identification of 66 mutations (56 different occurrences) and one large EXT2 deletion out of 90 patients (74.4%). The total of 21 mutations (20 different occurrences, 33.3%) and the EXT2 gene deletion were novel. In agreement with literature data, EXT1 gene mutations were scattered along all the protein sequence, while EXT2 lesions fell in the first part of the protein. Conservation, damaging prediction and 3-D modeling, in-silico, analyses, performed on three novel missense variants, confirmed that at least in two cases the novel aminoacidic changes could alter the structure stability causing a strong protein misfolding. CONCLUSIONS: Here we present 20 novel EXT1/EXT2 mutations and one large EXT2 deletion identified in the largest Southern Italy cohort of patients affected by hereditary multiple exostosis.

Molecular characterization of 11 Italian patients with Darier disease.

Darier disease (DD) is an autosomal dominant genodermatosis characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Heterozygous mutations in ATP2A2, encoding the sarco-endoplasmic reticulum calcium pumping ATPase type 2, are identified as the molecular basis of DD. In this study, molecular features in a large cohort of Italian patients are reported. Molecular data were collected along with the main clinical features. Genomic DNA was used for direct sequencing of ATP2A2. The effect of selected mutations was predicted by in silico analysis or investigated by gene expression studies. 10 different ATP2A2 mutations were identified. Three mutations (c.2300A>G, c.2794G>A, c.569delAins34) have been previously described, while 7, including 2 missense (c.545G>A and c.2116G>A), 2 nonsense (c.1372G>T and c.1675C>T), 1 small deletion (c.142delA), 1 duplication (c.2935_2949dup15) and 1 splice-site mutation (c.2742-1G>A), were novel. Collected data added new variants to the ATP2A2 repertoire and confirmed that ATP2A2 mutations are scattered over the entire gene and, in most cases, private.

KBG syndrome in a cohort of Italian patients.

KBG syndrome comprises a distinct facial phenotype, macrodontia, short stature, and skeletal anomalies. So far, it has been reported in 29 individuals. Recently, diagnostic criteria were outlined. Here, we describe eight new patients whose clinical and radiological findings fit the diagnostic criteria of KBG syndrome. While most patients were sporadic in occurrence, in two families the disorder was transmitted from mildly affected mothers to their affected children. The phenotype of KBG syndrome has been reviewed based on published and present patients. EEG anomalies with or without seizures, mixed hearing loss, palatal anomalies with secondary speech disorder, distinct age-related behavior, and cryptorchidism are possible additional characteristics. Less common manisfestations were posterior fossa malformations, eye defects, and congenital heart defects.