Friday, June 12, 2009

Collagenopathies and Marfan's Syndrome.




 

Here you can found some one-line material concerning my letter to New England about the Dietz's article on Marfan's sindrome and losartan therapy, published on the June 26, 2008 issue of The Journal. As usually all writed material is based on personal reading of scientific articles and possible are apparently unrelated each other. However they represent the course of my scientific actual knowledge concerning collagenopathies and TGFbeta related disease starting from Marfan's syndrome study.

Since more than a century ago the first professor in pediatrics in Paris, Antoine Marfan, described a young girl with long, spider-like fingers and other curious skeletal anomalies, understanding of the syndrome that now bears his name.

The Marfan syndrome is an inherited disorder of connective tissue characterized by pleiotropic manifestations of many organs, including the eyes, heart, aorta, skeleton, skin, and lung.

The cardinal ocular manifestation, ectopia lentis, was not recognized as being associated with the skeletal changes for some decades.

The cardiovascular system was found to be involved at about the same time, when severe mitral regurgitation was observed; until 1943 was identified the involvement of aortic root, and it was remained for McKusick to show in 1955 that the disease of the aorta accounted for most deaths. Life expectancy is reduced by one thrid, on average because of emergent cardiovascular complications.

By the 1930s, it was recognized that the disease was transmitted by mendelian dominant phenotype; not until 1949 the study of large pedigrees convinced skeptics that the condition was due to a single mutant gene, which needed to be present in only one copy (heterozygosity) to cause the disease.

Half a century was required to to identify the effect of the mutation of the classic triad of Marfan disease:

  1. ectopia lentis
  2. cardiovascular disease: aortic aneurism and mitral valve prolapse
  3. skeletal disease: joint laxity and bone overgrowth

Microfibrillar fibers make up a discrete, widely distributed, and pleiomorphic fiber system in human tissues. When visualized by electron microscopy, the fibers apper as linear bundles containing many individual microfibrils with a tubular cross-section and an average diameter of 10 to 12 nm, showing characteristic like collagen fibers type 3.

Microfibrillar fibers are considered integral components of elastic elements, but such fibers are much more widely distributed than elastin. They have been visualized by immunolocalization studies in skin, tendon, cartilage, muscle, kidney, perichondrium, periosteum, blood vessels, pleura, dura mater, and ciliary zonules of the ocular lens.

In particular McKusick has suggested that understanding the common factor in aortic media lamellar structure and the ciliary zonules causing “ectopia lentis” often present in Marfan syndrome may reveal the basic defect of this disease.

The consistent finding of stretched and occasionally broken zonular fibers in the ectopia lentis of patients with Marfan syndrome argues that these microfibrillar fibers are functionally incompetent to resist to normal stress and elongate progressively over time.

The progressive dilatation of aortic root with the fragmentation of elastic lamellae of the tunica media, the striae atrophicae in the skin, pulmonary bullae, dural ectasia as well’s seletal overgrowth can be linked to functional alteration of the lamellar structure. In particual skeltal overgrowth may be linked to diminished forces generated by periosteal and perochondrial membranes that oppose bone growth.

The absence of reticular meshworks on epidermal sections and in dermal fibroblasts culture of patients affected by Marfan syndrome shows that an alterations is present in these extracellular structures.

However other common clinical pictures can present the same alterations in fiber disposition such as in patients affected by:

- Homocystinuria: due to cystationina beta synthse defect

- Ectodermal dysplasia

- Epidermolysis bullosa-like syndrome

- Coronary artery dissection

- Paudoxantoma elasticum

- Cutis laxa: due to elastin gene mutation

The first major advance came in 1991 when missense mutations in the fibrillin-1 gene (FBN1) were discovered in two unrelated patients with the syndrome by Dietz HC et collegues. Three works on the same issue of Nature outlined the presence of such a mutation as a cause of syndromic complex. These findings were the culminations of biochemical studies that identified “fibrillin” as an extracellular matrix component and specifically such as the principal component of microfibrils associated with elastin fibers.

Whereas the work of Hollister DW in 1990 demonstrated the fibrillin deficiency in patients affected by Marfan syndrome by immunohystochemical studies, on 1994 Shores demonstrated with genetic investigations that the region of chromosome 15 was linked to marfanoid syndrome and it was shown to contain the gene coding for fibrillin.

The gene FBN1 is located on chromosome 15 q21.1, codes for fibrillin, the 350 kd protein that is the main component of extracellular microfibrils. The gene was demonstrated to be affected by mutations that resulted in a spectrum of connective tissue disorders, including but not limited to Marfan syndrome, involving structural fibrillin protein domains distributed uniformly over 10 kb FBN1 DNA sequence. So that such as in neurofibromatosis type 1 we have a relatively common dominant disorder with a high rate of new mutations, so that no easy screening test is possible. So that the demonstration of FBN1 mutation or abnormal fibrillin metabolism don’t permit or confirm the diagnosis of Marfan syndrome.

It has been estimated that the frequecy of fibrillin disorders is considerably greater than the estimated incidence of Marfan syndrome of 1 in 10.000 subjects.

Concerning Marfan syndrome four distinct phenotypically groups have been defined:

- alterations of FBN1 gene disrupting the second disulphidrile bridge in 1 of the 44 domains containing six cysteine residues shown to be related to reduced secretion of fibrillin

- nonsense mutations leading to premature termination of polypeptide synthesis shown to be related to a sinthesis of half the normal amount of fibrillin

- rapidly progressive with aortic dilatation, severe scoliosis, ectopia lentis, variable skeletal abnormalities and negligible cardiac involvement or with mitral valve prolapse with skeltal features (with absent fibrillin)

- adult type with dominant form of slowly progressive aortic aneurism without typical ocular and skeletal findings (with locally absent fibrillin)


The basic paradigm of Marfanoid habitus is that fibrillin gene mutations resulted in the production of abnormal fibrillin protein that, when incorporated into microfibrils along with normal fibrillin, resulted in structurally inferior connective tissue. This adverse effect of mutant proteins on normal ones, which genetists term “dominant negative”, appeared to explain many of the cardianal feaures of Marfan syndrome.

This explanantion was reinforced by the contemporaneous discovery of a second fibrillin gene, FNB2 located on chromososme 5, which is associated with a related connective tissue disorder:

. congenital contractural arachnodactyly (Beals’ syndrome)

On late ’90 some researchers developed imbred animal models for Marfan syndrome study; the introduction of mutations into the mouse fibrillin-1 gene, FBN1, recapitulated the disorder. Interestingly lungs were more affected in mice bearing the fibrillin gene mutations showing emphysematous changes in alveolar tissue.

However Dietz HC showed that, instead of damages due to increasing breakdown due to repeated stretching of connective tissue, affected lungs presented an abnormal septation of the distal alveoli in newborn mice pups; a finding more consistent with a developmental defects than a decreased elasticyty.

On the same year, on 2003, it was demonstrated that fibrillin has an homologous structure with Latent TGF beta binding-protein (LTBPs), which serve to hold TGF beta in an inactive complex in various tissues in extracellular matrix. It was showed tha fibrillin can bind TGF beta and LTBP. Dietz HC group hypothesized that abnormal fibrillin, or reduced levels of fibrillin, in connective tissue might result in an excess of active TGF beta. They demonstrated that blocking TGF beta with neutralizing antibodies, inbred mice strains showed a normalization of lung development.

In 2005 Loeys and Dietz showed that some patients can be classified such a separated clinical entity overlapping marfan syndrome, presenting:

- aortic aneurysm

- arachnodactyly

- dural ectasia

this syndromic complex is now called Loeys-Dietz syndrome and it was due to mutations affecting genes coding for TGF beta receptor type 1 and TGF beta receptor type 2 (TGFBR1 and FGFBR2); one affected patient was found to have an increase TGF beta activity in the aortic tissue.

Interestingly studying a large cohort of patients with TGFBR1 and TGFBR2 mutations, it was demonstrated that some had the classic Loeys-Dietz syndrome with better outcome after aortic surgery, whereas others resembling patients with Ehlers-Danlos syndrome known to be linked to defects in collagen type III gene.

Taken together, the genetic findings from these studies help us to describe a group of connective tissue diseases due to inhborn error of extracellular matrix proteins with a larger incidence on populations than previously known, we can call “fibrillinopathies”.

Inhborn error of genes coding for different types of collagens give rise to “collagenopaties”:

- Osteogenesis Imperfecta: due to collagen type 1 defect

- Spondyloepyphiseo dysplasia: due to collagen type 2 defect

- Ehlers-Danlos disease: due to collagen type 3 or type 5 defect

- Mutiple Epiphyseal Dysplasia: due to collagen 9 defect

- Methapyseal Dysplasia Schmid type: due to collagen type 10 defect

- Marshall syndrome: due to collagen type 11 defect

Its’ becoming clear that collagenopathies and fibrillinopathies show sometimes the same clinical picture in affected patients; and the more common manifestation of more subtle biochemical pathways involved into signal transduction share same proteins present on extracellular matrix space for their final actions.

It’s also likely that understanding the role of these proteins present in large amount on extracellular space may explain the physical properties of tissues such as the skin and bone where connective tissue components play a relevant role.

In particular in view of recent result on marphanoid habits, involving elastin associated microfibrils in TGF beta signal transmission, it is easy to imagine a role of Bone Morphogenetic Proteins action also on mechanical transduction of physical forces applied on bone and on regulation of bone stiffness.

References

Peyritz RE, McKusick VA. The Marfan syndrome: diagnosis and management. N Engl J Med 1979;300:772-7.

Pyeritz RE, McKusick VA. Basic defects in the Marfan syndrome. N Engl J Med 1981;305:1011-2.

Boucek RJ, Noble NL, Gunja-Smith Z et al. The Marfan syndrome: a deficiency in chemically stable collagen-cross-links. N Engl J Med 1981;305:988-91.

Gott VL, Pyeritz RE, Magovern GJ Jr et al. Surgical treatment of aneurysms of the ascending aorta in the Marfan syndrome: results of composite-graft repair in 50 patients. N Engl J Med 1986;314:1070-4.

Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350 kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 1986;103:2499-509.

Hollister DW, Godfrey M, Sakai LY et al. Immunologic abnormalities of the microfibrillar-fiber system in the Marfan Syndrome. N Engl J Med 1990;323:152-9.

Kainulainen K, Pulkkinen L, Savolainen A et al. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990;323:935-9.

Pyeritz RE. Marfan syndrome. N Engl J Med 1990;323:987-9.

Lee B, Godfrey M, Vitale E et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991;352:330-4.

Maslen CL, Corson GM, Maddox BK et al. Partial sequence of a candidate gene for the Marfan syndrome. Nature 1991;352:334-7.

Dietz HC, Cutting GR, Pyeritz RE et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337-9.

Tsipouras P, Del Mastro R, Sarfarazi M et al. Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. N Engl J Med 1992;326:905-9.

Shores J, Berger KR, Murphy EA et al. Progression of aortic dilatation and the benefit of long term beta adrenergic blockade in Marfan syndrome. N Engl J Med 1994;330:1335-41.

Francke U, Furthmayr H. Marfan’s syndrome and other disorders of fibrillin. N Engl J Med 1994;330:1384-5.

Loeys BL, Chen J, Neptune ER et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275-81.

Habashi JP, Judge DP, Holm TM et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-21.

Loeys BL, Schwarze U, Holm T et al. Aneurysm syndromes caused by mutations in the TGF beta receptor. N Engl J Med 2006;355:788-98.

Gelb BD. Marfan’s syndrome and related disorders – more than tightly connected than we thought. N Engl J Med 2006;355;841-4.

Brooke BS, Habashi JP, Judge DP et al. Angiotensin II blockade and aortic-root dilatation in Marfan's syndrome. N Engl J Med 2008;358:2787-95.

Pyeritz RE. A small molecule for a large disease. N Engl J Med 2008;358:2829-31.

Hypoparathyroidism and Hypercalciuria

 

           

Calcium homeostasis


The present discussion is about the recent articles published on NEJM, concerning Hypoparathyroidism and Hypercalciuria. They represent on line material of my studies on these topics, as I’ve done a summary on my recent letter to the Editor on Brief Report on NHERF1 gene mutations and parathyroid hormone by PriĆ© Dominique working in Paris, France at Hopithal Necker – Enfants Malades.

Calcium crystallization process

Excessively high concentration of calcium ions in the urine is one identifiable and correctable factor in stone formation. Calcium stone formation is a process of mineral crystallization in body tissue or fluid.

Inorganic crystal are shaped to become an integral part of organic tissue to provide strength and hardness. Thsese inorganic substances are capable of reversible interactions with biomolecules so that the crystalline structures can be remodeled for physiological needs.

Calcium salts have an highly adaptable coordination geometry, that greatly facilitates the protein binding, in its solid state or solution, adapting theirself to irregular geometry of proteins.

The physical properties of bone and teeth result from the activities of proteins that functions as the organic-inorganic interface.

Proteins share specific domains that specifically are able to interact with calcium crystals. The sequence below seems to be specific in these extracellular matrix proteins:

Aspartate-phosphoserine-phosphoserine-glutamate-glutamate

(DpSpSEE)

The motif described in the saliva protein “statherin” is also found in other calcium crystal-interacting proteins, such as osteopontin.

Interestingly unlike EF domain hand that binds ionic calcium, this structure specifically binds to solid phase calcium phosphate crystals and it is conserved in all phylogenetically evolved forms of life in the heart from invertebrates, such as crustaceans, to higher vertebrates, such as humans.

Physiologic crystallization includes formation of exoskeleton, pearl, endoskeleton, and dentition, whereas pathophysiologic crystallization includes pyroposphate arhtropathy, pigmented gallstones, vascular calcifications, and urolithiasis.

Serum calcium concentration is tightly regulated in humans, so that also small decrement in its concentration can led to clinical manifestations of “tetania”, as we have in hypoparathyroidism where Trousseau and Kwostek signs are present as clinical maifestations of altered muscle cells contraction regulations.

On other side increments of calcium levels can lead to increased urinary calcium secretions with kidney function alterations, hypergastrinemia with gastric ulcer formation, hypertension, bone reabsorption with osteoporomalacia and bone fractures, parodontopathies with alterations in theet adherence to bone stucture in particular of mandible (inferior dental arc), as mention the more important clinical manifestations.

The calcium homeostasis is under control of four main organs, bowel and intestinal system, parathyroid glands, bone tissues, and kidneys. Interestingly small changes in calcium levels can be evident such as alterations in acid-base equilibrium (i.e blood PH), due to important action exerted on these physicochemical equilibrium by renal cells activity of secretion and reabsorption. So that small changes in blood PH have to be resetted by intervention of kidney system ( metabolic acidosis or alkalosis) and only after by lung gas exchanges ( respiratory acidosis or alkalosis).

The secretion and reabsorption of calcium ions by kidney, in that view, is essential to human life. When these equilibrium is altered the first alteration we see is an excessive excretion or loss of calcium ions in urine, so that we call hypercalciuria.

Isolated hypercalciuria per se is not detrimental, but clinician interest in hypercalciuria concerns the complications that include mainly nephrolithiasis and nephrocalcinosis.

Stones formation

It has been suggested that the importance of hypercalciuria versus hyperoxaluria in calcium oxalate stones formers is equal; so that both urinary concentration of calcium and oxalate are important contributing factors in formation of kidney stones.

Kidney stones have a lifetime incidence of up to 13% in USA; in at least 70% of cases the stones are formed by calcium oxalate crystals, often with calcium phosphate or sodium urate.

For a stone to form there must be “supersaturation” a chemical condition dependent from PH, Ionic strength and Ionic concentration; in the presence of a “nidus” the nucleation process occurs, where the “nidus” is formed by extracellular matrix components or cellular debris. The subsequent step is the formation of of a true stone by crystal growth and aggregation.

The molecular mechanisms underlying the stone formation are described as:

. heterogeneous nucleation: in which the initial ion complex is attached to a foreign surface

. homogeneous nucleation: in which stones are formed independently from a nucleating surface

The heterogeneous nucleation occurs more often, requiring less energy and so at low level of supersaturation.

Some “factors” control the nucleation and crystal growth processes such as lowering supersaturation energy required and the presence of chemical inhibitors of crystal growth such as:

. pyrophosphate inorganic

. citrate

. glycoproteins

The majority of stone formers are defined such as affected by ”idiopathic hypercalciuria” . Any analysis of hypercalciuria should take into account a Pak pioneering work of 1975 introducing a tripartite classification of hypercalciuria:

  1. Absorptive hypercalciuria
  2. Reabsorptive hypercalciuria
  3. Renal hypercalciuria

From pathophysiological point of view and also by genetic view, this classification may seem to be very important and today useful.

Accordingly the extracellular fluid compartment can be regulated by the exchanges with three systems:

  1. Intestinal system
  2. Bone system
  3. Kidney system

Where the action of main hormones secreted and regulated by parathyroid glands is exerted : parathormone, 1,25 dihydroxy vitamin D3. Interestingly the physiological action exerted by the third hormone “calcitonin” in humans is not relevant, whereas in fish living in water mabient rich in calcium salts, this hormene is very important.

A possible classification of clinical parameters avaible if we consider renal hypercalciuria is the present:

- Parathyroid hormone and 1,25 vitmian D3 are higher than expected

- Hypercalciuria is inappropriate for the slightly elevated parathyroid homone, normal serum calcium, and normal filtered calcium.

- Persistent hypercalciuria is present even during fasting

- Increased bone resorption markers and/or reduced bone mineral density are present.

Interestingly half of patients labeled as havng idipatic hypercalciuria shown a family history of kidney stones. However the genetic rules observed by hypercalciuric patients don’t follow the Mendelian pattern of inheritance, but it seems likely a variable under the effect of

- Polygenic influence

- Polymorphism if a single gene locus (heterogeneity)

- Secondary and compensatory influences by three systems before described

- Under influece of external non genetic factors in particular dietary and lifestyle factors

So that also calciuria can be considered a continous variable with a polygenic determination and those phennotypic expression is modulated by non genetic environmental factors such as blodd pressure and body mass.

Parathyroid hormone hyposecretion or hypoactivity

Post-surgical

Radiation induced

Metastatic infiltration

Autoimmune (isolated or combined with polyglandular endocrine defects)

Autoimmune Polyglandular Syndrome type 1

It is linked to chromosome 21q22.3 coding for AIRE gene, inherited as autosomal recessive moitety. Loss-of-function mutation in AIRE, a zinc finger transcription factor present in thymus and lymph nodes, it is critical in mediating central tolerance by the thymus. NALP-5 is an intracellular signalling molecule strongly expressed in the parathyroid, and it can be target of specific parathyroid autoantigens in patients affected by APS-1. Autoantibodies to NALP5 were found in 49% of patients with APS-1 and hypoparathyroidism.

Clinical picture is variably present in people concentrated in Finnish, Iranian Jewis, and Sardinian populations, presenting more than 58 mutations. Classic triad is represented by:

  1. Mucocutaneous candidiasis
  2. Adrenal insufficiency
  3. Hypoparathyroidism

(any of these two conditions are suffcient to formulate the diagnosis of APS-1). Other different features include hypogonadism, type 1 diabetes, hypothyroidism, vitiligo, alopecia, keratoconjuntivitis, hepatitis, pernicious anemia, and malabsorption. More than 80% of patients with APS-1 have hypoparathyroidism, as sole endocrinopathy. Typically the disease is presented in childhood or adolescence, but patients with only one disease manifestation is folowed long-term for the appearance of other signs of disease.

Deposition of heavy metals

Thalassemia for iron excess

Hemochromathosis

Wilson’s disease

Severe magnesium depletion

alchoolism, malnutrition, malabsorption, diabetes, metabolic acidosis, renal disorders leading to magnesium wasting (pyelonephritis, postostructive nephropathy, renal tubular acidosis, acute tubular necrosis, drugs toxicity ( diuretics, cisplatinum, aminoglycoside antibiotics, amphotericin B, cyclosporin)

Primary renal magnesium wasting or familial hypomagnesiemia with hypercalciuria and nephrocalcinosis (OMIM 248250) due to mutations in genes coding for parcellin-1 and claudin 16

Hypermagnesiemia

On patients receiving tocolytic therapy or in patients with chronic kidney disease receiving magnesium supplements, antiacids or laxatives

Genetic disorders of PTH biosynthesis and parathyroid gland development

PTH gene mutations

Familial Isolated hypoparathyroidism

It is linked to chromosomal alteration of gene coding for pre-pro-PTH located on chromosome 11p15, and it is inherited in an autosomal recessive fashion. Mutations in signal peptides, disrupting PTH secretion, or in a donor splice site of the PTH gene, leading to skipping of PTH exon-2, which contains the initiation codon and signal peptide, are the molecular gene derangements accounting for the clinical picture. Very low or undetectable levels of of PTH and symptomatic hypocalcemia are main features of this syndromic complex.

Instead of mutations in signal peptides, we can have on the same chromosomal locus point mutations in the signal sequence of the pre-pro PTH that prevents processing and translocation of PTH across endoplasmic reticulum and memebrane exocytosis. Mutant PTH is believed to be trapped into endoplasmic reticulum inside cells; resulting stress in endoplasmic reticulum is thought to predispose cells to undergo to apoptosis.

Large deletions in transcription factor for gene coding for PTH called Glial cell Missing B or 2 transcription factor coded on chromosome 6p23-p24 (GCMB or GCM2) are autosomal recessive transmitted gene mutations responsible for forms of familial hypoparathyroidism due to large deletions of these transcription factors with subsequent loss-of-function mutation or point-mutations in the DNA-binding domain of these transcription factors. Leading to loss of transactivating capacity. Interestingly the two transcription factors are highly expressed in parathyroid cells and they controls the embryologic development of parathyroid glands

X-linked Hypoparathyroidism

The X linked recessive mutations affecting the chromosome Xq26-27 involve deletions or insertions of genetic material from chromosome 2p25.3 to chromosome Xq27.1, causing a position effect on regulatory elements controlling SOX3 transcription factor. SOX3 transcription factoris believed to be expressed during developement of parathyroid glands and its mutations cause parahtyroid agenesis of these glands.

Hypoparathyroidism may is a part of complex genetic syndromes:

Familial hypocalcemia with hypercalciuria:

The gene locus responsible is located on chromosome 3q13 and it is coding for calcium sensing receptor, the mutation is transmitted as autosomal dominant form and the phenotypic appearance of affected patients is cause by a gain-of-function mutation in calcium sensing receptor leading to milf hypocaĆ²cemia and hypomagnesemia with hypocalciuria. Mutant receptors caused a left shifted set point for PTH secretion , definied as extracellualr calcium level necessary for half maximal suppression of PTH secretion. Most than 40 mutations have been identified at present, some of them responsible for the Batter’s syndrome type 5 (OMIM 601199 ).

Constitutive active Calcium Sensing Receptors

Most commonly coused by mutations and rarely caused by acquired antibodies that stimulates the calcium sensing receptor; appears to be among the most common causes of hypoparathyroidism.

Syndrome of hypoparathyroidism, deafness, and renal anomalies.

This syndromic complex is linked to mutations on chromosome 10p14-10pter, coding for the transcription factor GATA3. This mutation is inherited through an autosomal dominant form and interfere with the ability of GATA3 to bind to DNA or other transcriptional complexes. GATA3 is a transcription factor known to be highly expressed in in parathyroid glands, kidney and otic-vescicles during organ development precesses. So that clinical alterations characterizing this syndromic complex are hypoparathyroidism, bilateral sensorineural deafness, and renal anomalies or disfunction.

Syndrome of hypoparathyroidism with growth retardation, mental diseases and dysmorphism.

- Kenny-Caffey syndrome

- Sanjad-Sakati syndrome

The syndromic complex is due to mutations affecting chromosome 1q42-q43 coding for transcription factor TBCE and transmitted as autosomal recessive trait. TBCE mutations cause loss of function and alter the assembly of microtubules in affected tissues. Kenny-Caffey syndrome is presented such as hypoparathyroidism probably due to agenesia of the glands, shorth stature, osteosclerosis, cortical bone thickening, calcifications of basal ganglia, ocular abnormalities; whereas Sanjad-Sakati syndrome is characterized by parathyroid aplasia, growth failure, ocular amalformations, microencephaly, and mental retardation.

DiGeorge Syndrome or VeloCardioFacial Syndrome

An heterozygous deletion of chromosome 22q11.2 coding for the transcription factor TBX1 is the known cause of this syndrome. Loss of function mutation of TBX1 is responsible for loss of adjuvating action by TBX1 on other transcription factors known to be involved into the development of thymus and parathyroid glands. Embriological alterations are demonstrated to occurs in these patients in the formation and development of thrid and fourth branchial pouches. Wide spectrum of phenotypc expression, may include conotruncal cardiac defects, parathyroid and thymic hypoplasia, neurocognitive problems, and palatal, renal, ocular, and skeletal abnormalities. Hypocalccemia (in 50% of patients) can be transient or permanent and can develop in adulthood. A screening test si available with confirmed dletion by FISH technique.

Mithocondrial disorders with hypoparathyroidism

- Kearns-Sayre syndrome

- MELAS syndrome

- MTPDS syndrome

Are known syndromic complexes due to deletions, mutations, rearrangments and duplications in the mitochondrial genome. These diseases are inherited uniquely by maternal cells (as all mithocondrial structures) and hypopararhytoidism can be present with various syndromic complexes:

In Kearns-Sayre syndrome with progressive external ophtalmoplegy, pigmentary retinopathy, hearth block or cardiomegaly, diabetes. In MELAS syndrome with diabetes only In MTPDS with fatty acids oxidation alterations, peripheral europathy, retinopathy, acute fatty liver in pregnancy.

Resistance to PTH action

Pseudo-Hypoparathyroisim Type 1a

The disease is due to inactivating mutation in the gene coding for the subunit alfa of G protein coupled with PTH Receptor (GNAS gene on chromosome 20q13.3).

GNAS gene is able to code for the a-subunit of the stimulatory G protein (GSa) and it is located on Chromosome 20q11, where 13 exons are present with differnt promoter regions. It is well demonstrated that this protein is linked to many transmembrane receptors such as Parathyroid hormone receptor, TSH Receptor, FSH and LH Receptors, GH Receptor.

During the past few years it became apparent that GNAS gene enchodes not only for for GSa but also for several splice variants:

1. XLas (paternal allele)

2. NESP55 neurosecretory protein (maternal allele)

3. A/B (1A) (paternal allele)

4. Antisense transcript

Later it was demosntrated that the alternative exons and their promoter regions are “methylated” on one parental allele, giving rise only to “non-methylated” allele transcription.

Moreover, in most tissues the transcripts encoding GSa are derived from both alleles; whereas in a few tissues such as

. proximal renal tubular cells

. adipocytes

. pituitary cells

GSa appears to be expressed only from maternal allele.

In the type 1a the mutation is an heterozygous inactivating mutation transmitted with autosomal dominant pattern with maternal transmission of the biochemical phenotype. Clinical features include those described first as Albright’s Hereditary Osteodystrophy such as round facies, mental retardation, frontal bossing, shorth stature, obesity, brachydactyly, ectopic ossification, hypocalcemia, hyperphopshatemia, evelated PTH levels, hypothyroidism, hypogonadism.

Pseudohypoparathyroidism Type 1b

The disease is due to a partenally imprinted defect in G protein due to methylation defect in exon A and exon B, this alterations lead to a selective resistance only to parathyroid hormone and not to other G coupled receptors linking other hormones. So the features are not those present in classic Albright Hereditary Osteodystrophy but hypoparathyroidism with elevalted PTH values, hypocacemia, hyperphosphatemia and elevated levels of urinary cAMP after administration of PTH.

Pseudohypoparathyroidism Type 2 or Pseudo-pseudo-hypoparathyroidism

It is due to GNAS inactivating mutation paternally inherited; however a resistance to PTH is present so that patients secrete normal urinary cAMP levels but not phosphaturic responses to PTH. It can have inheried or sporadic occurrence.

References

Calcium homeostasis

Starnes CW, Welsh JD. Intestinal sucrase-isomaltase deficiency and renal calculi. N Engl J Med 1970;282:1023-4.

Pak CY, Kaplan R, Bone H et al. A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. N Engl J med 1975;292:497-500.

Coe FL, Parks JH, Moore ES. Familial idiopathic hypercalciuria. N Engl J Med 1979;300:337-40.

Tieder M, Modai D, Samuel R et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 1985;312:611-7.

Charnas LR, Bernardini I, Rader D et al. Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N Engl J Med 1991;324:1318-25.

Coe FL, Parks JH, Asplin JR. The pathogenesis and treatment of kidney stones. N Engl J Med 1992;327:1141-52.

Curhan GC, Willet WC, Rimm EB et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993;328:833-8.

Lemann J Jr. Composition of diet and calcium kidney stones. N Engl J Med 1993;328:880-2.

Pearce SH, Williamson C, Kifor O et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor gene. N Engl J Med 1996;335:1115-22.

Simon DB, Lu Y, Choate KA et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 1999;285:103-6.

Borghi L, Schianchi T, Meschi T et al. Comparison of two diets for the prevention of recurrent stones in idiopatic hypercalciuria. N Engl J Med 2002;346:77-84.

Bushinsky DA. Recurrent hypercalciuric nephrolithiasis – Does diet help? N Engl J Med 2002;346:124-5.

Bushinsky DA. Genetic hypercalciuric stone forming rats. Curr Opin Nephrol Hypertens 1999;8:479-488.

Lemann J Jr, Pleuss JA, Worcester EM et al. Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults. Kidney Int 1996;49:200-8 [Erratum Kidney Int 1996;50:341]

Phillips MJ, Cooke JNC. Relation between urinary calcium and sodium in patients with idiopathic hypercalciuria. Lancet 1967;1:1354-7.

Silver J, Rubinger D, Friedlander MM et al. Sodium-dependent idiopatic hypercalciuria in renal-stone formers. Lancet 1983;2:484-6.

Parathyroid hormone hyposecretion or hypoactivity

Ahonen P, Myllamierni S, Sipila I et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322:1829-36.

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