Fraccaro syndrome: report of two Iranian casesþ:þ an infant and an adult in a family

49,XXXXY is rare chromosomal pattern and these patients have mental retardation, small penis,cryptorchidism and skeletal anomalies. We reported a 10 month-old boy who has hypotonia, microcephaly, hypertelorism, depressed nasal bridge, epicanthic folds and bilateral multiple ear tags, high arched palate, down set ears, micrognathia and congenital heart disease such as patent ductus arteriosus [PDA], Atrial septaldefect [ASD], mild pulmonary stenosis. Among the skeletal anomalies, he has kyphoscoliosis, clinodactyly of the fourth and fifth fingers of both hands, and bilateral club foot and unilateral dysplasia of the hip. Karyotype was found as 49,XXXXY[44]/48,XXXY[6] and this cytogenetic analysis was help to establish clinical diagnosis Fraccaro syndrome

[ maternally inherited balanced reciprocal translocation in a mentally retarded dysmorphic girl]

A 29 years old girl with various dimorphic features including short stature and webbed neck with mild to moderate mental retardation was referred to our center for chromosome investigation. Her parents were first cousins. The mother has had two previous miscarriages, one deceased son [12 years old] with apparently similar abnormal features to the proband with congenital heart problems, and one normal son [27 years old]. The patient, her mother and the brother, all were found to have an apparently balanced reciprocal translocation between the long arms of chromosomes 4 and 10. The breakpoint on chromosome 4 is at the distal end [4q35], while for chromosome 10, it is proximal to the centromere [10q11.2]. FISH studies using multiprobe subtelomeric specific probes as well as whole chromosome paints for chromosomes 4 and 10 were carried out in search of a genetic imbalance. The FISH results revealed no telomeric rearrangements and confirmed the balanced reciprocal translocation between chromosomes 4 and 10. To date, this is the first reported case of t[410][q35q11.2]

[Tay-sachs disease report of two affected Iranian cases and review of literature]

Tay-Sachs disease is a rare autosomal recessive disorder of sphingolipid metabolism, caused by deficiency of enzyme beta hexosaminidase A, that leads to accumulation of GM2 ganglioside in cellular lysosomes. Clinical findings are progressive weakness, gradual loss of aquired neuromotor skills, and deterioration of intelligence from about 3 to 6 months of age, as well as seizure attacks and blindness. There is also evidence on progressive neurodegeneration. In most of the patients bilateral cherry red spot were reported on funduscopy. In this report, we present two patients with Tay-Sachs disease, which are confirmed by enzyme assay. In both of them beta hexosaminidase A activity were strongly decreased

Cranio-spondylo-tubular dysostosis A unique historic Iranian giant " Siah Khan syndrome": report of an extremely rare or perhaps a unique case in the world from Iran

Severe overgrowth and tallness is very rare in human beings. The most common cause is gigantism due to the excessive secretion of the growth hormone, especially, before the closure of long bones' epiphyseal growth plates. There are other rare disorders that are categorized on overgrowth syndromes. Herein, we report an extremely rare, or even perhaps a unique, patient from Iran. The clinical and skeletal findings were very unusual, with extensive clavarial, tubular, vertebral, ribs, and scapular overgrowth and synostosis. Indeed, the results of these abnormalities made a monstrous giant with a very tall stature. This is a unique case, which was living during 1912-1940 in Shiraz. The report's information and photos, kindly supplied by Prof. Sheikholeslami. We evaluated thoroughly the findings together. Now we think; this is a very unusual case of its type, perhaps a Craniotubular Dysostosis Syndrome. We searched medical and clinical genetics literature, but did not find any similar case, having been reported before. So, to our knowledge, this is a unique case in the history of world medicine. We suggest to call this entity; "Siah-Khan syndrome" [after the patient's name], or " Ghorban-Sheikholeslami-Shafeghati syndrome" [in honour of Prof. Ghorban who was recently has died, or " Cranio-Spondylo-Tubular Syndrome"

[Cockayne syndrome: reporting a case from Iran with a novel mutation]

Cockayne syndrome is a very rare genetic disorder with a recessive autosomal inheritance. The disease is characterized by dwarfism, microcephaly, mental retardation, deafness, photosensive dermatitis and a peculiar form of retinal pigmentation. We report here an Iranian family with one affected child who is suffering from Cockayne syndrome. Cardinal features were failure to thrive, short stature, premature aging, microcephaly, dysarthric speech, photosensivity, sunken eyes, and dental caries. There was no blindness or deafness, and the fundus examination showed tapetoretinal degeneration. Direct sequencing of all coding sequences of CSA and CSB genes, showed a novel mutation [c.2382+57G>T] in intron 10 of CSB that was not reported before. This variation might perturb splicing in CSB. However to prove the pathogenicity of this mutation mRNA analysis on fibroblast is planned to be investigated

[Prenatal diagnosis of chromosomal abnormalities by amniocentesis: report of 261 cases]

Amniocentesis is a technique for detection of chromosomal abnormalities in the unborn fetuses. The technique is being applied to the all high risk pregnancies, mostly in advanced maternal ages and abnormal results in the 1st or 2nd trimester pregnancies. In current situation, first trimester screening is being done in the 11 to 13 weeks and 6 days of gestation, and mid-trimester screening [between weeks 15 to 20]. We report the result of our samples in this article. 261 pregnancies were followed and screened by 1st and 2nd trimester screening by Iranian Fetal Foundation protocols in an 18 months period [from January 2007 to July 2008]. Advanced maternal ages [35 years and more], or detected a balanced structural chromosomal abnormalities in one of the parents were indications for amniocentesis in this group. Amniocentesis was performed in the 261 cases during the mentioned period. In all of the culture tubes [100%] cell growth was successful. Mean of the time for screening and reporting the results was 12 days. Twelve affected fetuses [4.6%] were detected. The most common abnormalities were Down's syndrome and balanced translocation. First and second trimester screening is recommended to all pregnancies by international FMF protocol. Whenever the results showed that the pregnancy is prone to the risk then amniocentesis is highly recommended to detect chromosomal abnormalities

[Clinical, epidemiological, and molecular evaluation of SMA type I in Iran [a pilot study]]

Spinal muscular atropies are common [genetically determined] disorders. They are heterogeneous both in genetic and phenotypic characteristics. Prevalence of disease was reported between 1 in 6000 to 1 in 25000 in different populations. So, carrier frequency should be 1 in 40 to 1 in 80 in those people. Deletion of both copies of SMA, gene was detected in more than%90 of SMA patients. According to present data there were not any epidemiological study and data in Iran regarding SMAs. So, we do not have accurate information about prevalence, incidence of disease and its carrier frequency. Because of high rate of consanguinity it should be high. With this background, we decided to carry this pilot study out, to determine prevalence, incidence, carrier rate, along with consanguinity rate, clinical spectrum, and molecular abnormality in the affected cases. In a 2 years period, 30734 live-born babies followed, 4 patient affected to SMA type I were detected. Prevalence of SMA I in this population was 1 in 7683, and carrier frequency was 1 in 43. At least 2 third of the newborn babies were product of consanguineous marriages

Deletions in the survival motor neuron gene in Iranian patients with spinal muscular atrophy

<p><b>INTRODUCTION</b>Spinal muscular atrophy (SMA) is a common neuromuscular disorder with progressive paralysis caused by the loss of alpha-motor neurons in the spinal cord. The survival motor neuron (SMN) protein is encoded by 2 genes, SMN1 and SMN2. The most frequent mutation is the biallelic deletion of exon 7 of the SMN1 gene. In SMA, SMN2 cannot compensate for the loss of SMN1, due to the exclusion of exon 7. The aim of our study was to estimate the frequency of the common SMN1 exon 7 deletion in patients referred to our centre for carrier detection and prenatal diagnosis.</p><p><b>MATERIALS AND METHODS</b>We performed the detection of exon 7 deletion of the SMN1 gene for the affected patients and fetuses suspected to have SMA.</p><p><b>RESULTS</b>Of 243 families, 195 were classified as SMA type I, 30 as type II, and 18 as type III according to their family histories. The analysis of exon 7 deletion among living affected children showed that 94% of the patients with SMA type I, 95% with type II families and 100% with type III had homozygous deletions. Of the prenatal diagnoses, 21 (22.8%) of the 92 fetuses were found to be affected and these pregnancies were terminated.</p><p><b>CONCLUSIONS</b>The homozygosity frequency for the deletion of SMN1 exon 7 for all 3 types was (94%), similar to those of Western Europe, China, Japan and Kuwait.</p>

Vitamin D-dependent rickets type II: report of a novel mutation in the vitamin D receptor gene

Hereditary vitamin D-resistant rickets type or vitamin D-dependent rickets type II is a genetically determined and rare autosomal recessive disorder, most often caused by mutations in the vitamin D receptor gene. It usually presents with rachitic changes not responsive to vitamin D treatment and the circulating levels of 1,25 [OH]2 vitamin D-3 are elevated, differentiating it from vitamin D-dependent rickets type I. Alopecia capitis or alopecia totalis is seen in some families with vitamin D-dependent rickets type II. This is usually associated with a more severe phenotype. In this report, we present the clinical findings on a family which exhibited the typical clinical features of hereditary vitamin D-resistant rickets in two siblings. In addition, molecular analysis of the vitamin D receptor gene was performed by sequencing all coding exons. The cardinal findings in the index patient were alopecia totalis, renal tubular acidosis, mild generalized aminoaciduria, refractory rickets, high alkaline phosphatase, and hyperparathyroidism. Other routine biochemical tests were within normal limits, but 1+ glycine was detected in his urine. Skin biopsy results were compatible with alopecia areata. A previous child with similar phenotype was reported to be deceased at the age of 32 months. Mutation analysis of the vitamin D receptor gene by direct sequencing analysis of all coding exons showed a homozygous c.122G A[p.Cys41Tyr] variant in exon 2 with several arguments pointing to a pathogenic effect. We should be aware of this very rare disease whenever we see a patient with refractory rickets and alopecia

[ brief review on clinical classification and pathophysiologic considerations of neurometabolic disorders]

Because of efficient progress in controlling common and lethal environmental, infectious and nutritional disorders, gradually referral for genetic and metabolic disorders are being more common. Currently about 20 to 30% of referral and academic hospital beds are occupied by these patients. Also, about 20% of mortality of patients in the early pediatric age group belongs to these disorders. More than 100 years ago for the first time, Sir Archibald Garrod introduced some metabolic disorders. More than 500 different phenotypes of metabolic disorders identified and categorized in the literature. There are a huge number of very different metabolic pathways inside the cells. In a metabolic pathway, a biochemical molecule in a step by step reaction synthesized or degraded and changed to the new one. If the responsible enzyme was deficient in a specific reaction, a block in that pathway will occur. The end result would be accumulation of the enzyme's substrate or deficiency of its product. Both of them can cause apoptosis or cell death and a specific disabling or serious phenotype. In this article I will try to explain some of the clinical and pathophysiologic characteristics and classification of these rare disorders briefly. Also I will explain available modern technologies that are used for evaluation, diagnosis, treatment, prevention, and screening. I believe that by considering the mentioned issues, we will be able to approach better and more logically confronting these patients. For some of these disorders specific treatment is available. For those that there is no therapy, reaching an accurate diagnosis will help us to offer necessary information in genetic counseling sessions, and prevent the recurrence of the tragedic problem in the next pregnancies

[ review on genetic counseling for miscarriages [spontaneous and recurrent] and stillbirths]

Recurrent miscarriages, intra-uterine fetal death, and still-birth are very common problems in obstetrics and clinical genetics. Frequently, families refer to genetic counseling centers because of these problems. Affected families are eager to know the cause of the problem, how to cope with, and how to prevent the recurrence. It should be mentioned that the level of knowledge and experience of the most of the health care professionals is low in this regard, and should be up-dated. In the past decades a significant rate of information appeared in related medical journals and books, as research papers. Most of the authorities recommend a comprehensive evaluation of these families and the products of the pregnancies. Identification of the genetic and non-genetic causes of the phenomenon and their effects on choosing an appropriate reproduction modality, are very important point that researchers are insistently following. Whenever a catastrophic event, like this, was occurred, it would be the duty of obstetricians, neonatologists, geneticists, and other specialists to counterpart very efficiently on the process of evaluation, diagnosis, management, and also providing an informative genetic counseling for these families

[Survival motor neuron gene deletions among Iranian patients with spinal muscular atrophy]

Spinal muscular atrophy [SMA] is a common neuromuscular disorder with progressive paralysis caused by the loss of alpha-motor neuron in the spinal cord. SMN is encoded by two genes, SMN1 and SMN2, which essentially differ by a single nucleotide in exon 7. The most frequent mutation is biallelic deletion of exon 7 of the SMN1 gene. A small percentage of SMA patients present compound heterozygosity with a point mutation on one allele and deletion on the other. In the remaining cases, the disease is unlikely to be related to SMN1 defects. In spinal muscular atrophy [SMA], SMN2 is not able to compensate for the loss of SMN1 due to exclusion of exon 7. The aim of our study was to estimate the frequency of the common exon 7 SMN1 deletion in the families who referred to our center for carrier detection and prenatal diagnosis. Between March 1999 and March 2006, one hundred sixty seven families with history of at least one affected member were referred to us. We performed detection of deletion exon 7 SMN1 for the patients and carrier detection for their parents, prenatal diagnosis in subsequent pregnancies to couples who previously had an affected child became possible [63 prenatal diagnosis]. From 167 families, 139 categorized in type I of the disease, 21 in type II, and 7 in type III. Carrier detection for the parents indicated that in 96 families with history of affected member with type I SMA both parents carried the deletion in exon 7 and in 20 families, one of the parents was carrier. These rates were 16 to 1 for SMA type II, and 3 to 2 for type III SMA. Sixty-four children affected with SMA were studied, 58 of them were found to be homozygous for the loss of exon 7 of the SMN1 gene, except two patients who were heterozygote for exon 7 deletion [frequency of homozygocity: 90.7%]. Eleven of sixty-three [17.5%] fetal samples were found to be affected and these pregnancies were terminated. The molecular analysis of the biallelic exon 7 of the SMN1 deletion is a standard and reliable test in cases of SMA

[Seventeen years experience in precise diagnosis and prenatal diagnosis of mucopolysaccharidoses [MPS]]

Upon a scientific collaboration, families having affected offspring suspected for MPS disease were enzymaticaly analyzed. In 82 families the deficit enzymes were detected. Seventy prenatal diagnosis for parous at risk were performed, revealing 53 unaffected and 17 affected fetuses. All families with affected fetuses opted for pregnancy termination. The prenatal result of unaffected newborns confirmed the prenatal diagnosis findings. The summary of clinical findings and epidemiological distribution of MPS disorders and PND results are presented in this short report

[Molecular basis of proxysomal disorders in Zellweger syndrome]

Peroxisomes are organelles present in all eukaryotic cells from yeast to human cells. It is now well known that approximately fifty different biochemical reactions occur within the peroxisome, including synthesis of bile acids, cholesterol, ether-phospholipids [plasmalogens], docosahexaenoic acid and catabolism of certain fatty acids, particularly very long chain fatty acids [VLCFAs]. Proteins involved in peroxisomal function are known as peroxins. At least 29 peroxins are required for peroxisome membrane biogenesis, fission, and protein import. So far, mutations in 13 genes that encode peroxins are associated with human disease. Peroxisomal disorders currently falling into one of three groups; peroxisome biogenesis disorders [PBDs], peroxisomal multi-enzyme disorders, and peroxisomal single-enzyme disorders. Infantile Refsum's disease [IRD], neonatal adrenoleukodystrophy [NALD] and Zellweger's syndrome [ZS] are different variants of a group of congenital diseases known as peroxisome biogenesis disorders. These disorders are characterized by the absence of normal peroxisomes in the cells of the body which mostly are fatal. Here we describe molecular events that cause these deficiencies and we introduce current molecular approaches for diagnosis of these disorders like mutation analysis and fibroblasts characterization derived from the patients

Peroxisomal disorders: our experiments and physician guide

Peroxisomes are responsible for a number of very important metabolic reactions, including synthesis of glycerol ethers, shortening very long chain fatty acids [VLCFAs; C24:O and C26:O], and oxidation of the side chain of cholesterol needed for bile acid production. Peroxisomal biogenesis disorders [PBDs] are genetically and phenotypically related disorders that involve enzymatic activities of peroxisomes. They are rare mostly autosomal recessive diseases characterized by multi-systemic structural and functional abnormalities. A number of biochemical abnormalities have been described in PBD patients including decreased levels of plasmalogens, and increased levels of VLCFAs and cholestanoic acid derivatives. More than 25 different entities have been diagnosed and reported in the last two decades. The most severe condition is the Zellweger syndrome, a condition due to the absence of functional peroxisomes. Affected patients are severely ill, and show multiple congenital anomalies and neurological aberrations. Chondrodysplasia punctata is another example; they are genetically heterogeneous group of dysplasias having stippling of the epiphyses in infancy as a common feature. Peroxisomal abnormalities only found in the rhizomelic type I. There are specific biochemical tests for evaluating peroxisomal functions. The diagnoses on suspected cases can now be confirmed precisely by detailed biochemical evaluation and molecular analysis in some metabolic centers. Accumulation of certain VLCFAs [C24:0, and C26:0]; deficiency of plasmalogens, and elevation of phytanic acid are some of them. Herein we report 10 Iranian families with 15 affected cases of Zellweger syndrome and rhizomelic type I chondrodysplasia punctata [RCDP I]

[Diagnosis and treatment of mucopolysaccharidoses]

Mucopolysaccharidoses are a group of rare mostly autosomal recessive metabolic and genetic disorders. Because of the high rate of consanguinity, they are not uncommon in our population. Clinical diagnosis is not difficult for experienced physicians, but it is not enough for treatment and prevention measures in the future pregnancies. So, it is necessary to detect the type of MPS by measurement of responsible enzyme activity in the leukocytes and skin fibroblasts. Whenever we determined the exact type of the MPS and deficient enzyme, we would be able to treat the patients with the different therapeutic options, like bone marrow transplantation, stem cell transplantation, enzyme replacement therapy, or even gene therapy. At present, wild type or normal enzymes for MPSs type I, II, and III are being produced by recombinant DNA technology. Results from phase I, II, and III extended clinical studies have shown that the enzymes are safe and efficient and alleviate many systemic signs and symptoms of these diseases. There are some difficulties regarding the marketing and high cost of the available enzymes. If public health responsibilities and insurance companies support the families financially there is not any problem to use enzymes in our patients in Iran. In the next step we should consider other therapeutic options like stem cell transplantation, or even gene therapy. Now our best choice is to do prenatal testing and detect affected fetuses by enzyme assay on fetal cells by amniocentesis or CVS

Report of molecular diagnosis in iranian families with spinal muscular atrophy

Spinal muscular atrophies [SMA] are a group of heterogeneous disorders characterized by the degeneration of the lower motor neurons. The inheritance is by autosomal recessive pattern, and because of the high rate of consanguinity in the Iranian population the incidence of these diseases is common in this region, but the precise frequency has not been determined. To establish a clinical and molecular diagnosis for SMA in Iran, we have set up molecular tests for the diagnosis of affected patients, carrier detection, and prenatal diagnosis for high risk pregnancies. We investigated the presence or absence of the [SMN] gene in 47 Iranian families, including 60 patients by PCR amplification of exons 7 and 8 in affected individuals and parents of patients for carrier detection. In addition, prenatal testing was performed on 15 pregnant mothers. Mutation detection in the 22 live patients showed that in 21 cases, both alleles were deleted. In 1 case only one deletion was detected suggesting that the other allele must have a point mutation. In 34 families both of the parents were carriers, and carried only one copy of the normal SMN gene. In 9 couples a mutation was detected in one partner, suggesting that the other one had a point mutation that is not detected by this techniqe. Molecular testing of 15 fetuses showed that 4 of the fetuses were normal, 3 fetuses were affected carrying both mutations, five fetuses were carrier carrying one of the mutations, and of the remaining two were either carrier or healthy and only one was carrier or affected. Due to the high rate of consanguineous marriage, our study showed that this disorder is relating common, in the Iranian population. Preventive measures by genetic counseling, carrier detection, and prenatal diagnosis are now available and very helpful in the prevention of recurrence and in disease control