FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets

Autosomal dominant hypophosphatemic rickets (ADHR; MIM 193100) is a hereditary disorder characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D₃ levels. Recent studies have shown that the fibroblast growth factor 23 (FGF23) gene is responsible for this disease. FGF23 protein is a phosphaturic factor that is elevated in several diseases associated with hypophosphatemia and rickets but varies with disease status in ADHR. In the present study we observed a Chinese family of Han ethnic origin diagnosed with ADHR. The proband is a 30-year-old woman with no history of rickets but with multiple tooth abscesses as a young adult. She presented with progressive painful swelling of the left ankle after a blunt trauma at 26 years of age. She developed back pain, generalized weakness, and fatigue, and she could barely walk at age 27. She was found to have severe hypophosphatemia, low ratio of phosphorus tubule maximum (TmP) to glomerular filtration rate (GFR) (TmP/GFR), and elevated alkaline phosphatase at age 28. Her brother, 26 years old, presented with fatigue at 24 years of age and is normophosphatemic. The parents of this family had no history of rickets or hypophosphatemia. Direct sequence analysis of genomic DNA demonstrated a single heterozygous c.527G>A (p.R176Q) mutation in the FGF23 gene in three family members, including the proband, her brother, and their mother. Intact FGF23 assay of seven time points during the oral phosphate loading test showed no significant relationship between intact FGF23 and serum phosphorus levels of the subject with ADHR and a control. It is probably the first report of a Chinese family with ADHR.     

The enigma of hyperparathyroidism in hypophosphatemic rickets

Familial hypophosphatemic rickets (XLH) is caused by inactivating mutations of the cell surface metalloproteinase PHEX. It is characterized by low-normal serum levels of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], normocalcemia, and hypophosphatemia. Hyperparathyroidism is regularly seen in patients treated with phosphate supplements, although circulating serum phosphate levels do not reach the normal range. The mechanism is unknown. Decreased serum concentrations of ionized calcium following phosphate supplements might contribute to the development of hyperparathyroidism. Secondary and even tertiary hyperparathyroidism can, however, be observed in patients who have never received phosphate treatment. This points to an abnormal regulation of production and/or degradation of parathyroid hormone (PTH). Recently, the expression of the PHEX gene in hypertrophied parathyroid glands of a patient with XLH has been reported. It is unclear whether the mutant PHEX gene can induce hyperparathyroidism by abnormal regulation of peptidases.     

Hereditary breast cancer and family cancer syndromes

Hereditary breast cancer (HBC) shows extant clinical and genetic heterogeneity. Clinically one finds the onset of breast cancer at an early age, an excess of bilaterality, and patterns of multiple primary cancer such as combinations of breast and ovarian carcinoma in the hereditary breast-ovarian cancer (HBOC) syndrome. In addition to HBOC, one sees a variety of putative breast cancer-prone genotypes inclusive of hereditary site-specific breast cancer, and the Li-Frameni (SBLA) syndrome that is characterized by cancers involving all three germinal layers including sarcomas, brain tumors, leukemia, lymphoma, and adrenal cortical carcinoma in addition to often markedly early-onset breast cancer. Breast cancer is also associated with autosomal dominantly inherited Cowden's disease and autosomal recessively inherited ataxia-telangiectasia. Examples of pedigrees depicting clincal examples of these several HBC syndromes are presented in order to describe HBC's heterogeneity. The recent identification of the BRCA1 gene in early-onset hereditary sitespecific breast cancer and the HBOC syndrome has led to new challenges for the genetic counselor. We review genetic counseling, which embraces surveillance and management recommendations that are responsive to the natural history of HBC and address the concept for future development of centers of expertise for HBC in the interest of improving cancer control.

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Resumen El cáncer mamario hereditario (CMH) exhibe una gran heterogeneidad clínica y genética. Desde el punto de vista clínico, se observa el comienzo del cáncer mamario en una edad temprana, una tasa considerable de bilateralidad, y patrones de múltiples cánceres primarios, tal como la combinación de carcinomas mamario y ovárico en el síndrome del cáncer de seno-ovario hereditarios (CSOH). Además del CSOH, se puede observar una variedad de genotipos putativos propensos al cáncer, incluyendo el cáncer mamario hereditario de ubicación específica y el síndrome de Li-Fraumeni, que se caracteriza por cánceres que afectan a todas las tres capas germinales, incluyendo sarcomas, tumores cerebrales, leucemia, linfoma y carcinoma adrenocortical, además de un notorio comienzo precoz del cáncer mamario. El cáncer mamario también se asocia con la enfermedad de Cowden hereditaria y autosómica dominante y con la ataxia-telangiectasia autosómicamente recesiva. Se presentan ejemplos de pedigríes que ilustran diversos síndromes de CMH, con el objeto de demostrar la heterogeneidad del CMH. La reciente identificación del gen BRCA1 en el cáncer mamario hereditario, de ubicación específica y de comienzo temprano, y el sindrome CSOH, ha significado nuevos desafíos para el consejero genético. En este artículo hacemos una revisión de la consejería genética que se refiere a la vigilancia y a las recomendaciones sobre manejo que corresponda a la historia natural del CMH, y enfocamos el concepto en cuanto al desarrollo de centros de especializados en CMH, con el propósito de mejorar el control del cáncer.

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Résumé Le cancer du sein héréditaire (CSH) est cliniquement et génétiquement hétérogène. au point de vue clinique, le cancer dbute habituellement à un âge jeune, est souvent bilatéral, et est parfois associé à d'autres cancers primitifs, comme par exemple dans le syndrome de cancer héréditaire du sein et de l'ovaire (SCO). On peut également observer d'autres génotypes présumés susceptibles de donner des cancers du sein héréditaires ainsi que le syndrome Li-Fraumeni (SBLA), caractérisé par l'envahissement des trois couches germinales et comprenant les tumeurs sarcomateuses, les tumeurs du cerveau, les leucémies, les lymphomes, et des cancers des corticosurrénales associées à des cancers du sein à un âge précoce. Le cancer du sein est parfois associé à la maladie de Cowden, une maladie autosomique dominante, et la télangiectasie ataxique, une maladie autosomique récessive. Des exemples de pedigrees de plusieurs types des CSH sont présentés, soulignant l'hétérogénéité de ce syndrome. La plus récente identification du gène BRCA1 et son rôle dans le cancer du sein et le syndrome HBOC est un nouveau challenge pour le généticien d'aujourd'hui. Nous passons en revue nos attitudes de conseil génétique comprenant à la fois les recommandations de surveillance nouveau challenge pour le généticien d'aujourd'hui. Nous passons en revue nos attitudes de conseil génétique comprenant à la fois les recommandations de surveillance et d'attitude thérapeutiques compatibles avec l'histoire naturelle des CSH, et qui ont trait au développement future des Centres spécialisés pour évaluer ces CSH dans le but l'améliorer leur contrôle.

     

The collagen crosslinking in the hypophosphatemic male mouse

Summary In order to evaluate the influence of bone mineralization on collagen metabolism, the bone collagen crosslinks were determined in femur diaphyses of mice with X-linked hypophosphatemia and of control littermates. No quantititative difference could be elicited between the two groups. It was also noted that in the mouse, cortical bone maturation is accompanied by a slight increase in the number of reducible crosslinks.     

Therapeutics of X-linked hypophosphatemic rickets

X-linked hypophosphatemia, the most common form of familial rickets, is conventionally treated with 1,25-dihydroxyvitamin D₃ (5–50 ng/kg per day) plus phosphate supplementation (70–100 mg/kg per day). However, nephrocalcinosis is noted in many children treated with this therapy. Whether to treat or not and whether such treatment should be continued into adulthood or in pregnancy are unsettled questions. This article reviews these controversies and provides current recommendations.     

The effects of bone marrow transplantation on X-linked hypophosphatemic mice.

The genes responsible for X-linked hypophosphatemic (XLH) vitamin D-resistant rickets and the murine homolog, hypophosphatemic mice (Hyp), were identified as PHEX and Phex (phosphate-regulating gene with homology to endopeptidases on the X chromosome), respectively. However, the mechanism by which inactivating mutations of PHEX cause XLH remains unknown. We investigated the mechanisms by syngeneic bone marrow transplantation (BMT) from wild mice to Hyp mice. The expression of the Phex gene was detected in mouse BM cells. BMT introduced a chimerism in recipient Hyp mice and a significant increase in the serum phosphorus level. The renal sodium phosphate cotransporter gene expression was significantly increased. The effect of BMT on the serum phosphorus level depended on engraftment efficiencies, which represent the dosage of normal gene. Similarly, the serum alkaline phosphatase (ALP) activity was decreased and bone mineral density was increased. Furthermore, the renal expression of 25-hydroxyvitamin D3 24-hydroxylase, which is a key enzyme in the catabolic pathway and is increased in XLH/Hyp, was improved. From these results, we conclude that transplantation of normal BM cells improved abnormal bone mineral metabolism and deranged vitamin D metabolism in Hyp by replacing defective gene product(s) with normal gene product(s). This result may provide strong evidence for clinical application of BMT in metabolic bone disorders.     

An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare disease, characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D₃ (calcitriol) levels. This syndrome involves rickets with bone deformities in childhood and osteomalacia, osteoporosis, articular and para-articular pain, and fatigue in adulthood. It is caused by mutations in a consensus sequence for proteolytic cleavage of the FGF23 protein. Normally, this protein actively regulates phosphate homeostasis. Here we report a Tunisian family in which one parent and three children show clinical and biological features of ADHR. Mutation analysis of the FGF23 gene finds a heterozygous substitution of the C at position 526 by a T (526 C → T), leading to an amino acid replacement of the FGF23 protein (R176W) at position 176. This causative new mutation is located in the consensus sequence for the proteolytic cleavage domain. These results confirm the importance of this site in FGF23 function and its essential role in ADHR physiopathology.     

A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets

Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting. Dentin matrix protein 1 (DMP1), a noncollagenous extracellular protein, plays critical roles in bone mineralization and phosphate homeostasis. Recently, loss-of-function mutations in DMP1 gene have been identified as the molecular cause of ARHR. Here, we describe a Japanese family that includes two ARHR-affected siblings carrying a novel mutation of the DMP1 gene. The patients were a 53-year-old woman and a 50-year-old man with short stature and skeletal deformities who were the offspring of a first-cousin marriage. Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)₂D. Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR. Sequence analysis of peripheral leukocytes from the patients revealed that they carried a novel homozygous nonsense mutation in the DMP1 gene (98G>A, W33X), which leads to a truncated DMP protein with no putative biological function. Unaffected family members were heterozygous for the mutation. This is the first report of a Japanese family with ARHR carrying a novel mutation of the DMP1 gene.     

Concomitant occurrence of Gitelman and Bartter syndromes in the same family?

The molecular defects responsible for the two most-common forms of inherited normotensive hypokalemic metabolic alkalosis have recently been defined. Most patients with Bartter syndrome have defects in transporters in the thick ascending limb of the loop of Henle, such as the Na-K-2Cl cotransporter, NKCC2, or the ATP-sensitive potassium channel, ROMK. Patients with Gitelman syndrome usually have mutations in the thiazide-sensitive Na-Cl cotransporter in the distal convoluted tubule. The location of the affected transporters correlates well with the typical presentation of these syndromes. Patients with Bartter syndrome typically present with normal or increased calcium excretion. Hypomagnesemia is present in only one-third of affected individuals. In contrast, hypomagnesemia and hypocalciuria are considered hallmarks of Gitelman syndrome. This report describes siblings presenting as young adults with mild symptoms associated with normotensive hypokalemic metabolic alkalosis. One sibling has hypocalciuria and hypomagnesemia, consistent with Gitelman syndrome. Surprisingly, the other sibling has normal serum magnesium and urinary calcium excretion. These siblings demonstrate the biochemical heterogeneity that can exist in patients with normotensive hypokalemic metabolic alkalosis. This report indicates that hypocalciuria does not always distinguish Gitelman and Bartter syndromes. Received May 29, 1997; received in revised form and accepted June 26, 1997     

Hypokalaemic, hypophosphatemic thyrotoxic periodic paralysis

Thyrotoxic periodic paralysis is an uncommon neuromuscular disorder frequently associated with severe hypokalemia. We describe a patient with hypophosphatemia occurring in the setting of hypokalemic thyrotoxic periodic paralysis, an association reported only once previously. A review of the literature indicates that this combined biochemical derangement may not be uncommon and that thyrotoxic periodic paralysis should be recognized as a potential cause of hypophosphatemia. The correction of both hypokalemia and hypophosphatemia may lead to a more rapid resolution of the associated acute neurologic syndrome.     

Renal failure in adult onset hypophosphatemic osteomalacia with Fanconi syndrome: a family study and review of the literature.

Follow-up of a previously reported family with dominantly inherited adult onset hypophosphatemic osteomalacia with Fanconi syndrome and diabetes mellitus has shown that both the proposita and her affected sister have developed renal glomerular failure. We describe the evolution of renal failure in this family and discuss the possible mechanisms involved. The development of renal tubular acidosis in this condition further impairs renal function and we suggest that correction of systemic acidosis might improve renal function and prevent further decline in these patients.     

The phenotypic overlap of syndromes associated with hereditary gingival fibromatosis: follow-up of a family for five years.

Hereditary gingival fibromatosis (HGF) is characterized by the slowly progressive fibrous enlargement of gingival tissue. It usually develops as an isolated disorder but can also be one feature of various syndromes. The currently preferred terminology of these syndromes mainly describes the clinical features of the disorder without identifying the cause. In this report, we present the 5-year follow up of a family with HGF and features of 3 previously described syndromes: Jones syndrome, Zimmerman-Laband syndrome, and HGF-hypertrichosis syndrome. The 45-year-old father had HGF, hypertrichosis, hearing loss, and short stubby fingers and toes with hypoplasia of the terminal phalanges and hypoplasia of the nails on the thumbs. The features of 13-year-old son were almost identical to those of his father except for hypertrichosis, but in addition he was mentally retarded. Although the 10-day-old son had HGF and defective fingers, the mother and 7-year-old daughter were unaffected. Owing to the overlap of these syndromes, we argue that the identification of the genetic pathways and mechanisms will be the most important factor in classifying these disorders, with the phenotype playing a minor role.