BackgroundGenetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D3 (1,25(OH)2D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies.MethodsForty three affected individuals from 36 non related families were analyzed. For the genetic analysis, the PHEX gene was sequenced in all of the patients and in 13 cases the study was complemented by mRNA sequencing and Multiple Ligation Probe Assay. For the genotype-phenotype correlation study, the clinical and biochemical phenotype of the patients was compared with the type of mutation, which was grouped into clearly deleterious or likely causative, using the Mann-Whitney and Fisher's exact test.ResultsMutations in the PHEX gene were identified in all the patients thus confirming an XLHR. Thirty four different mutations were found distributed throughout the gene with higher density at the 3' end. The majority of the mutations were novel (69.4%), most of them resulted in a truncated PHEX protein (83.3%) and were family specific (88.9%). Tubular reabsorption of phosphate (TRP) and 1,25(OH)2D serum levels were significantly lower in patients carrying clearly deleterious mutations than in patients carrying likely causative ones (61.39 ± 19.76 vs. 80.14 ± 8.80%, p = 0.028 and 40.93 ± 30.73 vs. 78.46 ± 36.27 pg/ml, p = 0.013).ConclusionsPHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity.
Background: Hypochondroplasia (HCH) is a skeletal dysplasia inherited in an autosomal dominant manner due, in most cases, to mutations in the fibroblast growth factor receptor 3 (FGFR3). Acanthosis nigricans (AN) is a velvety and papillomatous pigmented hyperkeratosis of the skin, which has been recognized in some genetic disorders more severe than HCH involving the FGFR3 gene. Objective and design: After initial study of the proband, who had been consulted for short stature and who also presented AN, the study was extended to the patient's mother and to 12 additional family members. Methods: Clinical, biochemical and radiological studies were performed on the family. In addition, exons 11 and 13 of FGFR3 were analyzed. Results: The proband and ten relatives presented HCH plus AN and the analysis of FGFR3 showed the p.Lys650Thr mutation. The members with normal phenotypes were non-carriers of the mutation. Conclusion: This is the first report of a large pedigree with the clinical phenotype of HCH plus AN due to a FGFR3 mutation, p.Lys650Thr. This finding demonstrates the coexistence of both conditions due to the same mutation and it might represent a true complex, which should be further established by searching for AN in mild HCH patients or for HCH in patients with AN.
Turner syndrome (TS) has been included for several years among the indications for GH treatment, generally with satisfactory outcomes. Nevertheless, the long-term effects of this treatment in non-GH deficient patients are not fully known. The incidence of thyroid carcinoma is rare in patients during childhood, it is unusual to find this neoplasia in children under sixteen years old. This article reports the cases of two Spanish patients with papillary thyroid carcinoma after GH treatment for TS. Recent studies have indicated a possible relationship between the GH -IGF axis and the pathogenesis of neoplasias, questioning the chance association of these two pathologies. In line with this, we detected GH receptor expression in the papillary carcinoma cells. Long-term prospective studies are required to clarify the possible effects of GH treatment on the risk of neoplasia.European Journal of Endocrinology 153 499-502
BackgroundThere are several known autosomal genes responsible for
Ras/MAPK pathway syndromes, including
Noonan syndrome (NS) and related disorders (such as LEOPARD,
neurofibromatosis type 1), although mutations of these genes do not explain
all cases. Due to the important role played by the mitochondrion in the
energetic metabolism of cardiac muscle, it was recently proposed that
variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in
the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a
common clinical feature in Ras/MAPK pathway syndromes. In order to test
these hypotheses, we sequenced entire mtDNA genomes in the largest series of
patients suffering from Ras/MAPK pathway
syndromes analyzed to date (n = 45),
most of them classified as NS patients
(n = 42).Methods/Principal FindingsThe results indicate that the observed mtDNA lineages were mostly of European
ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of
a typical Iberian dataset (including hgs H, T, J, and U). Three new branches
of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first
time, but none of these are likely to be related to NS or
Ras/MAPK pathway syndromes when
observed under an evolutionary perspective. Patterns of variation in tRNA
and protein genes, as well as redundant, private and heteroplasmic variants,
in the mtDNA genomes of patients were as expected when compared with the
patterns inferred from a worldwide mtDNA phylogeny based on more than 8700
entire genomes. Moreover, most of the mtDNA variants found in patients had
already been reported in healthy individuals and constitute common
polymorphisms in human population groups.Conclusions/SignificanceAs a whole, the observed mtDNA genome variation in the NS patients was
difficult to reconcile with previous findings that indicated a pathogenic
role of mtDNA variants in NS.
We report a case of congenital hypothyroidism (CH) with neurological and respiratory alterations due to a heterozygotic c.374-1G > A mutation of TITF1/NKX2-1. The hypothyroidism was detected using a neonatal screening protocol in which the thyroid stimulating hormone (TSH) threshold is re-set each day on the basis of within-day variability and between-day variation. In this case, the threshold on the day of the initial analysis was 8.2 mIU/L, and the measured TSH level in heel-prick blood was 8.3 mIU/L.Conflict of interest:None declared.
Kallmann's syndrome (KS) refers to the association of hypogonadic hypogonadism and anosmia or hyposmia. The X-linked form of the disease is due to mutations in the KAL1 gene that encodes for the protein anosmin-1. We studied the KAL1 gene in a patient with KS and his family by PCR amplification and direct sequencing. A novel missense mutation (V263G) that modifies the major cell adhesion site of the anosmin-1 protein was identified. Our results suggest that this reported mutation is responsible for KS and might help to elucidate the function of an important area of the anosmin-1 protein.
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