Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 167
Filtrar
1.
Nat Genet ; 24(1): 45-8, 2000 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10615125

RESUMEN

Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.


Asunto(s)
Proteínas Portadoras , Glicoproteínas de Membrana , Mutación , Osteólisis/genética , Señales de Clasificación de Proteína/genética , Receptores del Factor de Necrosis Tumoral/química , Receptores del Factor de Necrosis Tumoral/genética , Secuencia de Bases , ADN , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Ligando RANK , Receptor Activador del Factor Nuclear kappa-B
2.
J Clin Invest ; 76(2): 752-6, 1985 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-4031070

RESUMEN

Markedly increased circulating concentrations of pyridoxal-5'-phosphate (PLP) were found in each of 14 patients representing all clinical forms of hypophosphatasia, an inborn error characterized by deficient activity of the tissue nonspecific (bone/liver/kidney) isoenzyme of alkaline phosphatase (AP). The mean PLP concentration in plasma was 1174 nM (range, 214-3839 nM) in the patients and 57 +/- 26 nM (mean +/- SD) in 38 control subjects. In four affected children, urinary excretion of the PLP degradation product, 4-pyridoxic acid, was unremarkable during consumption of normal quantities of dietary vitamin B6. Our findings identify increased circulating PLP concentration as a marker for hypophosphatasia and provide further evidence that tissue nonspecific AP acts in vitamin B6 metabolism. Tissue nonspecific AP appears to function as an ectoenzyme to regulate extracellular but not intracellular levels of PLP substrate. Performing assays of circulating PLP concentration alone to assess vitamin B6 nutrition may be misleading in disorders associated with altered AP activity.


Asunto(s)
Fosfatasa Alcalina/metabolismo , Hipofosfatasia/sangre , Fosfato de Piridoxal/sangre , Piridoxina/metabolismo , Adulto , Anciano , Niño , Preescolar , Dieta , Femenino , Humanos , Lactante , Isoenzimas/metabolismo , Masculino , Persona de Mediana Edad , Ácido Piridóxico/orina , Ultrafiltración
3.
J Clin Invest ; 81(4): 1234-9, 1988 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-3350970

RESUMEN

"Perinatal" hypophosphatasia is the most severe form of this inborn error of metabolism, which is characterized by deficient activity of the tissue-nonspecific (liver/bone/kidney) isoenzyme of alkaline phosphatase (ALP) (TNSALP). We report that autopsy tissue from three affected subjects, which was profoundly low in ALP activity, had essentially unremarkable levels of pyridoxal-5'-phosphate (PLP), pyridoxal, and total vitamin B6 content despite markedly elevated plasma PLP levels (5,800, 14,500, and 98,500 nM; adult norm, 5-109 nM). Our findings help to explain the general absence of symptoms of vitamin B6 excess or deficiency in hypophosphatasia, and provide evidence that TNSALP acts as an ectoenzyme to regulate extracellular rather than intracellular concentrations of PLP (the cofactor form of vitamin B6) and perhaps other phosphate compounds.


Asunto(s)
Fosfatasa Alcalina/deficiencia , Hipofosfatasia/metabolismo , Fosfato de Piridoxal/sangre , Piridoxina/metabolismo , Fosfatasa Alcalina/fisiología , Femenino , Muerte Fetal , Humanos , Recién Nacido , Masculino , Embarazo , Piridoxal/metabolismo , Distribución Tisular
4.
J Clin Invest ; 86(1): 40-5, 1990 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-1973175

RESUMEN

Idiopathic hypoparathyroidism has been reported to occur as an X-linked recessive disorder in two multigeneration kindreds. Affected individuals, who are males, suffer from infantile onset of epilepsy and hypocalcemia, which appears to be due to an isolated congenital defect of parathyroid gland development; females are not affected and are normocalcemic. We have performed linkage studies in these two kindreds (5 affected males, 11 obligate carrier females, and 44 unaffected members) and have used cloned human X chromosome sequences identifying restriction fragment length polymorphisms to localize the mutant gene causing this disorder. Our studies established linkage between the X-linked recessive idiopathic hypoparathyroid gene (HPT) and the DXS98 (4D.8) locus, peak LOD score = 3.82 (theta = 0.05), thereby mapping HPT to the distal long arm of the X chromosome (Xq26-Xq27). Multilocus analysis indicated that HPT is proximal to the DXS98 (4D.8) locus but distal to the F9 (Factor IX) locus, thereby revealing bridging markers for the disease. The results of this study will improve genetic counseling of affected families, and further characterization of this gene locus will open the way for elucidating the factors controlling the development and activity of the parathyroid glands.


Asunto(s)
Hipoparatiroidismo/genética , Cromosoma X , Mapeo Cromosómico , Genes Recesivos , Ligamiento Genético , Humanos , Linaje , Polimorfismo de Longitud del Fragmento de Restricción
5.
J Clin Invest ; 96(6): 2683-92, 1995 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8675635

RESUMEN

Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.


Asunto(s)
Hipercalcemia/genética , Hipercalcemia/metabolismo , Hiperparatiroidismo/genética , Hiperparatiroidismo/metabolismo , Mutación , Polimorfismo Conformacional Retorcido-Simple , Receptores de Superficie Celular/genética , Secuencia de Aminoácidos , Secuencia de Bases , Calcio/sangre , Niño , Cartilla de ADN , Femenino , Genes Supresores de Tumor , Tamización de Portadores Genéticos , Humanos , Recién Nacido , Masculino , Datos de Secuencia Molecular , Glándulas Paratiroides/metabolismo , Linaje , Mutación Puntual , Reacción en Cadena de la Polimerasa , Receptores Sensibles al Calcio , Valores de Referencia , Mapeo Restrictivo
6.
J Clin Invest ; 95(4): 1440-5, 1995 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-7706447

RESUMEN

Hypophosphatasia features selective deficiency of activity of the tissue-nonspecific (liver/bone/kidney) alkaline phosphatase (ALP) isoenzyme (TNSALP); placental and intestinal ALP isoenzyme (PALP and IALP, respectively) activity is not reduced. Three phosphocompounds (phosphoethanolamine [PEA], inorganic pyrophosphate [PPi], and pyridoxal 5'-phosphate [PLP]) accumulate endogenously and appear, therefore, to be natural substrates for TNSALP. Carriers for hypophosphatasia may have decreased serum ALP activity and elevated substrate levels. To test whether human PALP and TNSALP are physiologically active toward the same substrates, we studied PEA, PPi, and PLP levels during and after pregnancy in three women who are carriers for hypophosphatasia. Hypophosphatasemia corrected during the third trimester because of PALP in maternal blood. Blood or urine concentrations of PEA, PPi, and PLP diminished substantially during that time. After childbirth, maternal circulating levels of PALP decreased, and PEA, PPi, and PLP levels abruptly increased. In serum, unremarkable concentrations of IALP and low levels of TNSALP did not change during the study period. We conclude that PALP, like TNSALP, is physiologically active toward PEA, PPi, and PLP in humans. We speculate from molecular/crystallographic information, indicating significant similarity of structure of the substrate-binding site of ALPs throughout nature, that all ALP isoenzymes recognize these same three phosphocompound substrates.


Asunto(s)
Fosfatasa Alcalina/metabolismo , Hipofosfatasia/enzimología , Isoenzimas/metabolismo , Embarazo/fisiología , Difosfatos/metabolismo , Etanolaminas/metabolismo , Femenino , Heterocigoto , Humanos , Hipofosfatasia/genética , Placenta/enzimología , Estudios Prospectivos , Fosfato de Piridoxal/metabolismo , Especificidad por Sustrato
7.
J Clin Invest ; 101(10): 2165-73, 1998 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-9593772

RESUMEN

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in bone mass during adult life. Despite the rarity of HCAO, understanding the mediator(s) of the skeletal disease is of great interest. The IGFs-I and -II have potent anabolic effects on bone, and alterations in the IGFs and/or IGF-binding proteins (IGFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, IGF-II, IGF-IIE (an IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary ( approximately 150 kD) and binary (approximately 50 kD) complexes was also determined to assess IGF bioavailability. HCAO patients had normal serum levels of IGF-I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an increase in IGFBP-2 was unique to these patients and was not found in control hepatitis C or hepatitis B patients. IGF-I and -II in sera from patients with HCAO were carried, as in the case of sera from control subjects, bound to IGFBP-3 in the approximately 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the approximately 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced by over threefold IGFBP-2 binding to extracellular matrix produced by human osteoblasts and that in an extracellular matrix-rich environment, the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF-IIE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possible means to increase bone mass in patients with osteoporosis.


Asunto(s)
Hepatitis C/complicaciones , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Osteosclerosis/virología , Somatomedinas/análisis , Fosfatasa Alcalina/sangre , Aspartato Aminotransferasas/sangre , Disponibilidad Biológica , División Celular/efectos de los fármacos , Matriz Extracelular/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Factor II del Crecimiento Similar a la Insulina/análisis , Osteoblastos/efectos de los fármacos , Osteocalcina/sangre , Osteoporosis/terapia , Unión Proteica/efectos de los fármacos , Proteínas Recombinantes/metabolismo
8.
J Dent Res ; 84(11): 1021-5, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16246934

RESUMEN

Hypophosphatasia (HPP) often leads to premature loss of deciduous teeth, due to disturbed cementum formation. We addressed the question to what extent cementum and dentin are similarly affected. To this end, we compared teeth from children with HPP with those from matched controls and analyzed them microscopically and chemically. It was observed that both acellular and cellular cementum formation was affected. For dentin, however, no differences in mineral content were recorded. To explain the dissimilar effects on cementum and dentin in HPP, we assessed pyrophosphate (an inhibitor of mineralization) and the expression/activity of enzymes related to pyrophosphate metabolism in both the periodontal ligament and the pulp of normal teeth. Expression of nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) in pulp proved to be significantly lower than in the periodontal ligament. Also, the activity of NPP1 was less in pulp, as was the concentration of pyrophosphate. Our findings suggest that mineralization of dentin is less likely to be under the influence of the inhibitory action of pyrophosphate than mineralization of cementum.


Asunto(s)
Cemento Dental/patología , Dentina/patología , Hipofosfatasia/patología , Adolescente , Adulto , Estudios de Casos y Controles , Cementogénesis/fisiología , Niño , Preescolar , Cemento Dental/química , Pulpa Dental/enzimología , Dentina/química , Dentinogénesis/fisiología , Difosfatos/análisis , Humanos , Hipofosfatasia/metabolismo , Hipofosfatasia/fisiopatología , Lactante , Microrradiografía , Minerales/análisis , Ligamento Periodontal/enzimología , Hidrolasas Diéster Fosfóricas/análisis , Pirofosfatasas/análisis , Calcificación de Dientes/fisiología
9.
Arch Intern Med ; 141(6): 727-31, 1981 May.
Artículo en Inglés | MEDLINE | ID: mdl-7235780

RESUMEN

Two cases of women with adult hypophosphatasia illustrate the clinical spectrum and potential difficulties in the diagnosis of this condition. Both patients had subnormal serum alkaline phosphatase activity, absence of leukocyte alkaline phosphatase, increased amounts of urinary phosphoethanolamine, and normal levels of immunoreactive calcitonin and parathyroid hormone. In undecalcified bone biopsy specimens, the number of osteoblasts and the tetracycline-labeled calcification front were similar in the two patients, although the percentage of unmineralized bone matrix and the extent of osteoid-covered bone surface were different. Twenty years of bone pain, severe skeletal deformities, and a generalized increase of osteoid in one patient contrasted with an 18-month history of bone pain and patchy osteoid in the other. These cases suggest that adult hypophosphatasia is a heterogeneous disorder and may be more common than previously realized.


Asunto(s)
Fosfatasa Alcalina/sangre , Hipofosfatasia/diagnóstico , Estatura , Huesos/patología , Calcitonina/sangre , Etanolaminas/orina , Femenino , Humanos , Hipofosfatasia/metabolismo , Leucocitos/enzimología , Persona de Mediana Edad , Compuestos Organofosforados/orina , Dolor , Hormona Paratiroidea/sangre , Factores de Tiempo
10.
Arch Intern Med ; 139(10): 1187-9, 1979 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-485758

RESUMEN

A 22-year-old woman had polyostotic fibrous dysplasia (POFD) and idiopathic hypothalamic hypogonadotropic hypogonadism (isolated gonadotropin deficiency). Recurrent fracture of dysplastic bone during childhood was associated with primary amenorrhea, clinical and laboratory evidence of estrogen deficiency, and subnormal circulating and urinary gonadotropin levels during adolescence. Gonadorelin (luteinizing hormone-releasing hormone) stimulation initially showed a luteinizing hormone (LH) response but absent follicle-stimulating hormone (FSH) response. After three months without estrogen and progesterone and after four days of gonadorelin "priming," a subsequent gonadorelin infusion produced an enhanced LH and FSH response. All other tests of peripheral and trophic hormone levels and pituitary trophic hormone reserves were normal. Whereas POFD is known to occur with sexual precocity and other endocrinopathies, to our knowledge this is the first report of its association with isolated gonadotropin deficiency.


Asunto(s)
Displasia Fibrosa Ósea/complicaciones , Displasia Fibrosa Poliostótica/complicaciones , Gonadotropinas Hipofisarias/deficiencia , Hipogonadismo/etiología , Sistema Hipotálamo-Hipofisario/fisiopatología , Adulto , Amenorrea/etiología , Femenino , Displasia Fibrosa Poliostótica/diagnóstico , Humanos , Hipogonadismo/diagnóstico
11.
Exp Hematol ; 27(10): 1528-32, 1999 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-10517494

RESUMEN

Abundant evidence supports a viral etiology for Paget's disease of bone (PD), however, an infectious virus has not been isolated from PD patients. Thus, it is unclear how the virus is maintained for the many years that the disease persists in patients. We considered if a primitive multipotential hematopoietic stem cell (HSC), which is self-renewing, passes the virus to its differentiated progeny and serves as a reservoir for the pathogen. If a primitive stem cell harbored measles virus (MV), then other hematopoietic lineages derived from this stem cell in PD patients should also express MV transcripts. Therefore, because the human hematopoietic stem cell has not been clearly identified or isolated in large numbers, we isolated RNA from highly purified erythroid and multipotential hematopoietic progenitors that are the precursors for erythroid, granulocyte, megakaryocyte and macrophages (CFU-GEMM), and used RT-PCR to determine if MV nucleocapsid transcripts were present. MV transcripts were detected in PD patients in early erythroid (BFU-E) and more primitive multipotential myeloid progenitors (CFU-GEMM). Nonhematopoietic stromal cells from PD patients did not express MV transcripts. The expression of MV transcripts in erythroid progenitors was further confirmed by in situ hybridization using antisense riboprobes to MV nucleocapsid transcripts. Thus, our findings suggest that the pluripotent HSCs may be a potential reservoir for the virus. We propose that when HSCs, which contain MV, divide they produce a second HSC that serves as a reservoir for the virus and also transmit the virus to their more differentiated progeny in the erythroid and myeloid lineages. This mechanism would permit a defective virus to persist in HSCs of PD patients for many years, since HSCs are usually in G0 phase, and then be transmitted to more differentiated cells. This model further suggests that a mature complete virus that affects cell function could only act pathogenetically in the osteoclast lineage, which offers a permissive milieu.


Asunto(s)
Virus del Sarampión/genética , Proteínas de la Nucleocápside/genética , Osteítis Deformante/virología , Antígenos CD34/metabolismo , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Células Precursoras Eritroides/metabolismo , Células Precursoras Eritroides/virología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/virología , Humanos , Hibridación in Situ , Osteítis Deformante/metabolismo , ARN/biosíntesis , ARN/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células del Estroma/metabolismo , Células del Estroma/virología
12.
J Dent Res ; 94(5): 706-14, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25716980

RESUMEN

Mutations in ALPL result in hypophosphatasia (HPP), a disease causing defective skeletal mineralization. ALPL encodes tissue nonspecific alkaline phosphatase (ALP), an enzyme that promotes mineralization by reducing inorganic pyrophosphate, a mineralization inhibitor. In addition to skeletal defects, HPP causes dental defects, and a mild clinical form of HPP, odontohypophosphatasia, features only a dental phenotype. The Alpl knockout (Alpl (-/-)) mouse phenocopies severe infantile HPP, including profound skeletal and dental defects. However, the severity of disease in Alpl (-/-) mice prevents analysis at advanced ages, including studies to target rescue of dental tissues. We aimed to generate a knock-in mouse model of odontohypophosphatasia with a primarily dental phenotype, based on a mutation (c.346G>A) identified in a human kindred with autosomal dominant odontohypophosphatasia. Biochemical, skeletal, and dental analyses were performed on the resulting Alpl(+/A116T) mice to validate this model. Alpl(+/A116T) mice featured 50% reduction in plasma ALP activity compared with wild-type controls. No differences in litter size, survival, or body weight were observed in Alpl(+/A116T) versus wild-type mice. The postcranial skeleton of Alpl(+/A116T) mice was normal by radiography, with no differences in femur length, cortical/trabecular structure or mineral density, or mechanical properties. Parietal bone trabecular compartment was mildly altered. Alpl(+/A116T) mice featured alterations in the alveolar bone, including radiolucencies and resorptive lesions, osteoid accumulation on the alveolar bone crest, and significant differences in several bone properties measured by micro-computed tomography. Nonsignificant changes in acellular cementum did not appear to affect periodontal attachment or function, although circulating ALP activity was correlated significantly with incisor cementum thickness. The Alpl(+/A116T) mouse is the first model of odontohypophosphatasia, providing insights on dentoalveolar development and function under reduced ALP, bringing attention to direct effects of HPP on alveolar bone, and offering a new model for testing potential dental-targeted therapies in future studies.


Asunto(s)
Adenina , Técnicas de Sustitución del Gen/métodos , Hipofosfatasia/genética , Enfermedades Periodontales/genética , Timina , Desmineralización Dental/congénito , Fosfatasa Alcalina/genética , Proceso Alveolar/patología , Animales , Fenómenos Biomecánicos , Densidad Ósea/fisiología , Matriz Ósea/patología , Resorción Ósea/patología , Calcificación Fisiológica/fisiología , Cemento Dental/patología , Modelos Animales de Enfermedad , Fémur/fisiopatología , Humanos , Masculino , Mandíbula/patología , Ratones , Hueso Parietal/patología , Docilidad , Desmineralización Dental/genética , Microtomografía por Rayos X/métodos
13.
J Bone Miner Res ; 3(4): 385-8, 1988 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-3146897

RESUMEN

We explored the effects of transfusion of carbonic anhydrase II (CA-II)-replete erythrocytes on systemic pH, serum electrolytes, and urinary acidification of a patient with CA-II deficiency. Pretransfusion studies documented hyperchloremic acidosis, increased urinary pH with decreased titratable acidity, and profound CA-II deficiency in erythrocytes. During transfusion, CA-II in circulating erythrocytes increased to above the half-normal levels seen in asymptomatic heterozygote carriers of CA-II deficiency. However, no significant change occurred in venous, arterial or urinary pH, serum electrolytes, and urinary acid excretion during the transfusion or during the subsequent 60 hr of observation. These studies argue that the renal acidification defect in CA-II deficiency results from deficiency of CA-II in the renal parenchyma, and is not secondary to deficiency of CA-II in erythrocytes. Bone marrow transplantation is not a promising approach to correct the renal manifestations of CA-II deficiency.


Asunto(s)
Acidosis Tubular Renal/terapia , Encefalopatías/terapia , Calcinosis/terapia , Anhidrasas Carbónicas/deficiencia , Transfusión de Eritrocitos , Isoenzimas/deficiencia , Osteopetrosis/terapia , Acidosis Tubular Renal/sangre , Adulto , Encefalopatías/sangre , Calcinosis/sangre , Anhidrasas Carbónicas/sangre , Eritrocitos/enzimología , Femenino , Hemoglobinas/análisis , Humanos , Isoenzimas/sangre , Osteopetrosis/sangre , Valores de Referencia , Síndrome
14.
J Bone Miner Res ; 4(6): 863-75, 1989 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-2692405

RESUMEN

IBIDS is a syndrome characterized by ichthyosis, brittle hair, impaired intelligence, decreased fertility, and short stature, but unassociated with skeletal lesions. This condition is considered a form of trichothiodystrophy because hair from several cases has been found to have a low sulfur content. We describe a 9-year and 10-month-old white boy whose clinical features resemble the IBIDS syndrome (ichthyosis, brittle hair, cataracts, and short stature), but who also has marked axial osteosclerosis and peripheral osteopenia. No abnormalities of mineral homeostasis were noted. Histopathologic assessment of nondecalcified bone specimens excluded osteopetrosis, but suggested slow skeletal remodeling. When subjected to polarized light microscopy, his hair exhibited the band-like pattern of birefringence described in trichothiodystrophy. Literature review disclosed 8 patients, 2 of whom had been diagnosed as trichothiodystrophy, with like clinical features including osteosclerosis. These skeletal abnormalities together with clinical features of the IBIDS/trichiodystrophy syndrome, we believe, reflect the prototype of a disorder that seems best described as central osteosclerosis with ectodermal dysplasia.


Asunto(s)
Displasia Ectodérmica/complicaciones , Osteosclerosis/complicaciones , Huesos/patología , Niño , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/patología , Cabello/patología , Humanos , Masculino , Osteosclerosis/diagnóstico por imagen , Osteosclerosis/metabolismo , Osteosclerosis/patología , Radiografía
15.
J Bone Miner Res ; 16(9): 1724-7, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11547844

RESUMEN

In 1948, Dr. John Campbell Rathbun characterized the disorder "hypophosphatasia" when he reported paradoxically low levels of alkaline phosphatase (ALP) activity in blood and in several tissues from an infant who died with rickets and epilepsy, which seemed to reflect "a new developmental anomaly." Hypophosphatasia is now recognized to be an inborn error of metabolism featuring deficient activity of the tissue-nonspecific isoenzyme of ALP (TNSALP) caused by deactivating mutations in TNSALP. Here, we show, more than 50 years after Rathbun's case report, that analysis of the parental DNA indicates compound heterozygosity involving two missense mutations (G340A and A881C) in TNSALP caused the death of Rathbun's patient.


Asunto(s)
Fosfatasa Alcalina/genética , Hipofosfatasia/historia , Mutación Missense , Fosfatasa Alcalina/sangre , Alelos , Femenino , Impresión Genómica , Heterocigoto , Historia del Siglo XX , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/enzimología , Hipofosfatasia/genética , Masculino , Mutación Puntual
16.
J Bone Miner Res ; 15(12): 2521-3, 2000 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11127218

RESUMEN

Café-au-lait spots, fibrous dysplasia of bone, and endocrine gland hyperactivity are the principal features of McCune-Albright syndrome (MAS). Café-au-lait spots appear at, or soon after, birth. We illustrate "café-au-lait spots" acquired during middle age in a patient with MAS that are an illusion caused by vitiligo. This 64-year-old woman is the oldest patient reported with this disorder.


Asunto(s)
Manchas Café con Leche/etiología , Displasia Fibrosa Poliostótica/complicaciones , Vitíligo/complicaciones , Femenino , Displasia Fibrosa Poliostótica/diagnóstico por imagen , Humanos , Persona de Mediana Edad , Radiografía
17.
J Bone Miner Res ; 11(4): 554-8, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8992887

RESUMEN

A former intravenous substance abuser, seropositive for hepatitis C virus infection, was referred for diffuse osteosclerosis. There was no history of fracture or skeletal deformity. Cortical and trabecular bone density was approximately twice the mean value for controls. Skeletal histology revealed dense lamellar bone. Recognized causes of acquired generalized osteosclerosis or hyperostosis were excluded. This patient verifies the syndrome of painful diffuse osteosclerosis after intravenous drug abuse and shows that skeletal mass can be markedly increased with histologically normal, structurally sound bone during adult life. Elucidation of the etiology and pathogenesis could offer an effective treatment for osteoporosis.


Asunto(s)
Densidad Ósea/fisiología , Osteosclerosis/etiología , Abuso de Sustancias por Vía Intravenosa/complicaciones , Absorciometría de Fotón , Adulto , Biopsia , Fémur/patología , Cuello Femoral/patología , Hepatitis C/complicaciones , Hepatitis C/fisiopatología , Humanos , Ilion/patología , Vértebras Lumbares/patología , Osteosclerosis/fisiopatología , Abuso de Sustancias por Vía Intravenosa/fisiopatología , Síndrome , Vértebras Torácicas/patología
18.
J Bone Miner Res ; 5(5): 469-74, 1990 May.
Artículo en Inglés | MEDLINE | ID: mdl-2368628

RESUMEN

To determine if chronic hypophosphatemia causes myocardial dysfunction, we explored one model for this metabolic derangement by prospectively investigating 11 patients (aged 5-18 years) with X-linked hypophosphatemic rickets (XLH) by M-mode, two-dimensional, and Doppler echocardiography. Inorganic phosphate and calcitriol (1,25-dihydroxyvitamin D3) treatment was withheld 72 h prior to study. None of the patients had cardiovascular symptoms. Fasting serum inorganic phosphate concentrations were subnormal in all: 2.6 +/- 0.5 mg/dl (SD). Serum total and ionized calcium, magnesium, sodium, potassium, and creatine kinase myocardial fraction (CK-MB) levels were unremarkable. Electrocardiograms revealed early repolarization abnormalities in 3 of the 11 patients: 1 had significant QT prolongation (corrected for heart rate), and 2 had T wave abnormalities. Exaggerated U waves occurred in 4 subjects. Resting echocardiograms were normal in 9 patients. In 1 subject there was mitral valve prolapse, and 1 patient possibly had an atrial septal defect (these findings were considered unrelated to hypophosphatemia). All M-mode measurements were normal. The two-dimensionally derived end-diastolic and end-systolic left ventricular volumes were 60.3 +/- 18.0 and 20.5 +/- 6.9 ml, respectively. Left ventricular ejection fraction was 66.1 +/- 4.7%, and the cardiac index by Doppler study was 4.1 +/- 0.8 liters/min per m2 (both values were within normal limits). Although the precise pathogenesis of XLH is unknown and our findings suggest that some electrocardiographic abnormalities may be common in this disorder, we found no evidence for left ventricular dysfunction in this human model of clinically significant long-standing hypophosphatemia.


Asunto(s)
Corazón/fisiopatología , Hipofosfatemia Familiar/fisiopatología , Raquitismo/fisiopatología , Adolescente , Gasto Cardíaco , Niño , Preescolar , Ecocardiografía , Electrocardiografía , Femenino , Ligamiento Genético , Humanos , Hipofosfatemia Familiar/complicaciones , Hipofosfatemia Familiar/genética , Masculino , Raquitismo/complicaciones , Raquitismo/genética , Volumen Sistólico , Cromosoma X
19.
J Bone Miner Res ; 16(8): 1564-71, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11499880

RESUMEN

An athletic 8-year-old boy developed severe muscle weakness over 2 years. At the age of 10 years, investigation for possible neuromuscular disease disclosed hypophosphatemia (1.8 mg/dl) and rickets. There was selective renal tubular wasting of inorganic phosphate (Pi) but no history of toxin exposure, familial bone or kidney disease, or biochemical evidence of vitamin D deficiency. Urine amino acid quantitation was unremarkable. Serum 1,25-dihydroxyvitamin D [1,25(OH)2D] concentration was in the lower half of the reference range. Our presumptive diagnosis was tumor-induced rickets; however, physical examination and bone scanning in search of a neoplasm were unrevealing. Soon after 1,25(OH)2D3 and Pi treatment began, muscle strength improved considerably. After 6 months of therapy, radiographic abnormalities were substantially better. During the next 6 years, physical examinations, a second bone scan, whole-body and nasal sinus magnetic resonance imaging, and octreotide scintigraphy were unremarkable. When his physes fused at the age of 16 years, assessment of his course showed excellent control of his rickets requiring decreasing doses of medication. Furthermore, fasting serum Pi levels and tubular maximum phosphorus/glomerular filtration (TmP/ GFR) values had increased steadily and normalized after 3 years of treatment. Accordingly, therapy was stopped. Seven months after stopping medication, he continues to feel completely well. Fasting serum Pi levels, TmP/GFR, other biochemical parameters of bone and mineral homeostasis, creatinine clearance, and renal sonography are normal. Neither spontaneous or pharmacologic cure of tumor-induced rickets or osteomalacia nor a patient matching ours has been reported. His disorder, which we call pseudo-(tumor-induced) rickets, should be considered when investigation for oncogenic rickets or osteomalacia discloses no causal lesion. Consequently, prolonged medical therapy and futile searches for a neoplasm may be avoided.


Asunto(s)
Hipofosfatemia/fisiopatología , Raquitismo/fisiopatología , Calcitriol/uso terapéutico , Niño , Estudios de Seguimiento , Humanos , Hipofosfatemia/complicaciones , Hipofosfatemia/tratamiento farmacológico , Rodilla/diagnóstico por imagen , Masculino , Neoplasias , Fosfatos/uso terapéutico , Radiografía , Raquitismo/complicaciones , Raquitismo/tratamiento farmacológico , Resultado del Tratamiento
20.
J Bone Miner Res ; 16(12): 2245-50, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11760838

RESUMEN

Spondyloepiphyseal dysplasia tarda (SEDT), an X-linked recessive skeletal disorder, presents with disproportionate short stature and "barrel-chest" deformity in affected (hemizygous) adolescent boys. In four reported families to date, mutations in a gene designated SEDL (spondyloepiphyseal dysplasia late) cosegregate with SEDT. We diagnosed SEDT in a short-stature, kyphotic 15-year-old boy because of his characteristic vertebral malformations. Clinical manifestations of SEDT were evident in at least four previous generations. A novel 2-base pair (bp) deletion in exon 5 of SEDL was found in the propositus by polymerase chain reaction (PCR) amplification and sequencing of all four coding exons. The mutation ATdel241-242 cosegregated with the kindred's skeletal disease. The deletion is adjacent to a noncanonical splice site for exon 5 but does not alter splicing. Instead, it deletes 2 bp from the coding sequence, causing a frameshift. A maternal aunt and her three young sons were investigated subsequently. Radiographs showed subtle shaping abnormalities of her pelvis and knees, suggesting heterozygosity. X-rays of the spine and pelvis of her 8-year-old son revealed characteristic changes of SEDT, but her younger sons (aged 6 years and 3 years) showed no abnormalities. SEDL analysis confirmed that she and only her eldest boy had the 2-bp deletion. Molecular testing of SEDL enables carrier detection and definitive diagnosis before clinical or radiographic expression of SEDT. Although there is no specific treatment for SEDT, preexpression molecular testing of SEDL could be helpful if avoiding physical activities potentially injurious to the spine and the joints proves beneficial.


Asunto(s)
Emparejamiento Base , Proteínas Portadoras/genética , Proteínas de Transporte de Membrana , Osteocondrodisplasias/genética , Eliminación de Secuencia , Osteofitosis Vertebral/genética , Adolescente , Adulto , Niño , Preescolar , Exones , Femenino , Humanos , Vértebras Lumbares/anomalías , Vértebras Lumbares/diagnóstico por imagen , Masculino , Osteocondrodisplasias/fisiopatología , Linaje , ARN Mensajero , Radiografía , Osteofitosis Vertebral/fisiopatología , Factores de Transcripción
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA