Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.

INTRODUCTION: Hypophosphatemic rickets (HR) comprises a rare group of inherited diseases. Very recently, mutations in the dentin matrix protein 1 (DMP1) gene were identified in patients with an extremely rare autosomal recessive form of HR (ARHR). To date, very few cases of these mutations were reported. MATERIALS AND METHODS: A Lebanese consanguineous family with 2 affected sisters was studied. Patients aged 45 and 47years old presented with short stature, severe genu varum, cranial hyperostosis and a very high bone density that led to a diagnosis of a familial sclerosing bone dysplasia. Molecular analysis of known genes involved in osteopetrosis showed normal results. A combination of genotyping and exome sequencing was performed in order to elucidate the genetic basis of this pathology. RESULTS: Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum phosphorus and elevated PTH values. Serum c-terminal FGF-23 was elevated in one of the two patients. A homozygous mutation disrupting the initiation codon of the DMP1 gene (OMIM 600980), NM_001079911.2: c.1A>G, p.Met1Val, was identified by exome sequencing and confirmed by Sanger sequencing. CONCLUSION: We report here a family of ARHR secondary to a DMP1 mutation located in the first coding exon of the gene. Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth.

Peptide bound hypohydroxyprolinuria in Handigodu Disease: a familial syndrome of spondylo epi(meta)physeal dysplasia.

Handigodu Disease (HD) is disorder of the osteoarticular system prevalent in few villages of two districts of the state Karnataka in southern India. 24 hrs urinary excretions of proline (Pro) and 4-hydroxyproline (Hyp) were analyzed by HPLC. Decreased peptide bound Hyp excretions (mumole/24 hrs) were found in patient group when compared with controls (Nonaffected; 113.02 +/- 67.96, Type-I; 36.22 +/- 20.76, Type-II; 45.74 +/- 14.95, Type-III; 40.46 +/- 22.68) and without significant difference in Pro excretions. Significant increased peptide bound Pro to Hyp ratio were found in patient group compared to control (Nonaffected n=63: 2.02 +/- 1.65, Type-I n=18: 3.144 +/- 1.42, Type-II n=28: 4.21 +/- 1.95, Type-III n=8: 8.60 +/- 6.55). 24 hrs urinary excretions of deoxypyridinoline (DPD) crosslinks were found without significant difference among affected and control, hence HD ruled out from general bone reduction. These results suggest hypohydroxyprolinuria may be because of reduced bone turnover or defective hydroxylation of prolyl residues during post translational modification of collagen biosynthesis.

Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome.

Wolcott-Rallison syndrome (WRS) (OMIM 226980) is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3. We report a female patient who developed insulin-requiring diabetes at 2.5 months of age. Multiple epiphyseal dysplasia was diagnosed at age 2 years. At age 5.5 years she developed a Reye-like syndrome with hypoketotic hypoglycaemia and renal and hepatic insufficiency and died. A partial autopsy showed fat infiltration in the liver and kidneys. Examination of urine by gas chromatography and mass spectrometry showed large amounts of C(6)-dicarboxylic acid (adipic acid), 3-hydroxy-C(8)-dicarboxylic acid, 3-hydroxy-C(10)-dicarboxylic acid, and 3-hydroxydecenedioic acid. Acetoacetate and 3-hydroxybutyrate were absent. The findings suggested a metabolic block in mitochondrial fatty acid oxidation, but lack of material precluded enzyme analyses. The clinical diagnosis of WRS was suggested in retrospect, and confirmed by sequencing of DNA extracted from stored autopsy material. The patient was compound heterozygous for the novel EIF2AK3 mutations c.1694_1695delAT (Y565X) and c.3044T > C (F1015S). Our data suggest that disruption of the EIF2AK3 gene may lead to defective mitochondrial fatty acid oxidation and hypoglycaemia, thus adding to the heterogeneous phenotype of WRS.

[Qualitative and quantitative determination of urinary glycosaminoglycans in patients with osteochondrodysplasias]. / Determinación cualitativa y cuantitativa de glucosaminoglucanos urinarios en pacientes con osteocondrodisplasias.

A quantitative and qualitative assay of urinary glycosaminoglycans (GAGs) was performed, by means of spectrophotometry and electrophoresis in 37 patients with a suspected diagnosis of osteo-chondrodysplasia. Levels were increased in 70.2% of the cases. One patient showed an electrophoretic pattern which was different and could not be identified in accord with the standard used.

Alaskan malamute chondrodysplasia. II. Urinary excretion of hydroxyproline, uronic acid and acid mucopolysaccharides.

The urinary excretion of free, total and non-dialyzable hydroxyproline appeared to be similar in both chondrodysplastic and non-chondrodysplastic Alaskan Malamutes of ages six and twenty-six weeks suggesting the metabolic defect was probably not related to a gross disturbance in collagen metabolism. Urinary hexuronic acids also appeared to be similar in levels for both populations. A four-fold increase in urinary mucopolysaccharide levels observed at age twenty-six weeks in the chondrodysplastic Alaskan Malamute suggested a deviation from normal. The magnitude and variability of deviation were not sufficient to indicate that this condition could serve as a model for the mucopolysaccharidosis of man but probably indicated a delayed maturation process.