Despite their rarity, diseases of premature aging, or "progeroid" syndromes, have provided important insights into basic mechanisms that may underlie cancer and normal aging. In this review, we highlight these recent developments in Hutchinson-Gilford progeria syndrome (HGPS), Werner syndrome, Bloom syndrome, Cockayne syndrome, trichothiodystrophy, ataxia-telangiectasia, Rothmund-Thomson syndrome, and xeroderma pigmentosum. ...

Preeclampsia is the development of new-onset hypertension with proteinuria after 20 weeks of gestation. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) is a severe form of preeclampsia with high rates of neonatal and maternal morbidity. In recent years, loss of function of cdkn1c (a tight-binding inhibitor of ...

Akhenaten was one of Egypt's most controversial pharaohs, in part because of his strange appearance in images produced after he had declared Aten, the Sun-disc, his one-and-only god. Whether these were symbolic representations or realistic ones that indicate a deforming genetic disorder is the subject of continuing debate. The authors ...

CHARGE syndrome affects up to 1 in 8500 births, and is most commonly due to de novo truncating mutations in the CHD7 gene. In addition to the 4 major (choanal atresia, coloboma, cranial nerve dysfunction and characteristic ear abnormalities) and 7 minor features (genital hypoplasia, developmental delay, cardiac anomalies, growth ...

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations ...

BACKGROUND: The Smith-Lemli-Opitz (SLO) syndrome is a multiple congenital anomaly with mental retardation due to a decreased or lack of activity of 7-dehydrocholesterol reductase as a consequence of mutations of the DHCR7 gene. This paper describes a special patient with SLO syndrome. Laboratory examination showed low cholesterol (2.77 mmol/L) and ...

Stüve-Wiedemann syndrome (SWS) is an autosomal recessive bone dysplasia (OMIM #601559) characterized by bowing of long bones, camptodactyly, respiratory insufficiency, hyperthermic episodes, and neonatal death from hyperthermia or apnea. We describe two female siblings with SWS born from consanguineous Gypsy parents. For a further delineation of SWS, we report hypothyroidism ...

We report five cases of multiple giant cell lesions in patients with typical Noonan syndrome. Such association has frequently been referred to as Noonan-like/multiple giant cell (NL/MGCL) syndrome before the molecular definition of Noonan syndrome. Two patients show mutations in PTPN11 (p.Tyr62Asp and p.Asn308Asp) and three in SOS1 (p.Arg552Ser and ...

Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder. Here, we assign the IFAP locus to the 5.4 Mb region between DXS989 and DXS8019 on Xp22.11-p22.13 and provide evidence that missense mutations exchanging highly conserved amino acids of membrane-bound transcription factor protease, site 2 ...

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized clinically by the triad of abnormal nails, reticular skin pigmentation, and oral leukoplakia, and is associated with high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors. Patients have very short germline telomeres, and approximately half have ...

It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene, PMS2, play a far more ...

Short stature, with a mean final height almost two standard deviations below the normal mean, is a major feature of Noonan syndrome. The biological basis of the growth failure is not yet clear. The recent detection of mutations in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11) in half ...

Möbius syndrome is a rare disorder primarily characterized by congenital facial palsy, frequently accompanied by ocular abduction anomalies and occasionally associated with orofacial, limb and musculoskeletal malformations. Abnormal development of cranial nerves V through XII underlines the disease pathogenesis. Although a genetic etiology for Möbius syndrome was proposed, molecular genetic ...

Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and ...

INTRODUCTION: Congenital nephrotic syndrome may be caused by mutations in NPHS1 and NPHS2, which encode nephrin and podocin, respectively. Since the identification of the NPHS2 gene, various investigators have demonstrated that its mutation is an important cause of steroid-resistant nephrotic syndrome. We aimed to evaluate frequency and spectrum of podocin ...

Gitelman's syndrome is a hereditary disorder occurring due to loss of functional mutations of the gene encoding the distal convoluted tubule sodium chloride cotransporter (NCCT) and is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. This case reports an adolescent girl presenting with episodes of carpopedal spasms and difficulty in ...

Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes. Both microsatellite instability (MSI) testing and immunohistochemical analyses (IHC) of colon cancers are valuable diagnostic strategies for Lynch syndrome. We sought to determine whether these markers of MMR deficiency were also detectable in pre-cancerous colorectal adenomas. Fifteen ...

Birt-Hogg-Dubé syndrome is a hereditary syndrome characterized by benign disease of skin and lungs and a risk of malignant renal tumors. We describe a clinical and genetic study of a large Dutch family with a novel mutation in the FLCN gene. Renal cancer at very young age occurred in one ...

We describe members of 4 kindreds with a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia). By analysis of linkage we localize the putative causative gene to a 2.5-Mb segment of chromosome 1q23.2-23.3. Direct DNA sequencing of KCNJ10, which ...

Congenital myasthenic syndromes are a genetically and phenotypically heterogeneous group of hereditary disorders affecting neuromuscular junction. Mutations in the gene encoding choline acetyltransferase cause presynaptic defects. The missense mutation I336T has been identified in Turkish population, and most of the cases carrying this mutation present with exercise-induced fatigability and ptosis. ...

Congenital duplication of the palm is a rare syndrome with the following features: the dorsal aspects of both hands have thick palmar skin with no hair or nails; bilateral ulnar ray deficiency; short hypoplastic upper limbs; and severe lower limb abnormalities. In this paper, we report a new case of ...

Barth Syndrome (BTHS) is a rare X-linked recessive inborn error of metabolism, which is characterized by dilated cardiomyopathy, neutropenia, skeletal myopathy and short stature. Barth Syndrome is associated with mutations in the tafazzin (TAZ) gene at Xq28 that result in cardiolipin deficiency and abnormal mitochondria. Here we report a 5.5-month ...

OBJECTIVE: Evaluation of the IRF6 gene in Van der Woude syndrome cases from an Indian population. SUBJECTS: Nine affected and four unaffected individuals from seven families with Van der Woude syndrome as well as five normal controls (with no history of Van der Woude or any other congenital malformation and ...

Perspectives on craniosynostosis are discussed under the following headings: sutural biology (anatomic and genetic categories of synostosis; sutures, suture systems, and types of craniosynostosis; well-known syndromes (Muenke syndrome and Pfeiffer syndrome); and unusual syndromes (thanatophoric dysplasia, Beare-Stevenson cutis gyrata syndrome, Crouzonodermoskeletal syndrome, Carpenter syndrome, Elejalde syndrome, hypomandibular faciocranial syndrome, and ...

Snyder-Robinson syndrome (SRS, OMIM 309583) is a rare X-linked syndrome characterized by mental retardation, marfanoid habitus, skeletal defects, osteoporosis, and facial asymmetry. Linkage analysis localized the related gene to Xp21.3-p22.12, and a G-to-A transition at point +5 of intron 4 of the spermine synthase gene, which caused truncation of the ...

AIM: To clarify the role of PTCH in patients with NBCCS-related and non-sydromic keratocystic odontogenic tumors. METHODOLOGY: Mutation analysis was undertaken in 8 sporadic and 4 NBCCS-associated KCOTs. RESULTS: Four novel and two known mutations were identified in 2 sporadic and 3 syndromic cases, two of which being germline mutations ...

The aim of the present study was to identify the molecular mechanism behind ventricular tachycardia in a patient with Brugada syndrome. Arrhythmias in patients with Brugada syndrome often occur during sleep. However, a 28-year-old man with no previously documented arrhythmia or syncope who experienced shortness of breath and chest pain ...

Alport syndrome is a progressive hereditary renal disease. Mutations in the genes encoding for three members of the type IV collagen protein family have been found to be the cause of the disease. Alport syndrome is often associated with sensorineural hearing loss and ocular abnormalities, and patients suffering from typical ...

Myosin heavy chain 9 (MYH9)-related platelet disorders belong to the group of inherited thrombocytopenias. The MYH9 gene encodes the nonmuscle myosin heavy chain IIA (NMMHC-IIA), a cytoskeletal contractile protein. Several mutations in the MYH9 gene lead to premature release of platelets from the bone marrow, macrothrombocytopenia, and cytoplasmic inclusion bodies ...

Mutations identified in a cohort of patients with atrioventricular septal defects as a part of Ellis van Creveld syndrome (EvC syndrome) led us to study the role of two non-homologous genes, EVC and LBN, in heart development and disease pathogenesis. To address the cause of locus heterogeneity resulting in an ...

Bergman et al. performed a search for exon copy number alterations in the CHD7 gene using MLPA in CHARGE syndrome patients who did not have a CHD7 mutation. Based on their results they recommended to extend testing using MLPA solely in individuals with a typical CHARGE syndrome phenotype. However, since ...

The use of co-immunoprecipitation (co-IP) to purify multi-protein complexes has contributed greatly to our understanding of the DNA damage response network associated with Fanconi anemia (FA), Bloom syndrome (BS) and breast cancer. Four new FA genes and two new protein partners for the Bloom syndrome gene product have been identified ...

Myeloproliferative disorders and the inherited thrombophilias have been described as the main causes underlying the Budd-Chiari syndrome. Moreover, the presence of the JAK2V617F was associated with a higher frequency of Budd-Chiari syndrome in patients who have overt or even latent myeloproliferative disorder. We herein describe a 28-year-old woman who was ...

Two unrelated young women presented with similar dysmorphic features including severe retrognathia, beaked nose, narrow chest, sloping shoulders, and an acrogeric appearance of the hands and feet. Neither had any evidence of skeletal myopathy, but both developed progressive dilated cardiomyopathy, both experienced premature ovarian failure, and both were found to ...

Three autosomal recessive disorders are associated with mutations in the RECQL4 gene: Rothmund-Thomson syndrome (RTS), Baller-Gerold syndrome (BGS), and RAPADILINO syndrome. BGS is characterized by two major clinical abnormalities: craniosynostosis and preaxial limb anomalies but not cancer development. We performed RECQL4 mutation detection in a patient with BGS and several ...

We have earlier described a syndrome characterized by microcephaly, cutis verticis gyrata, retinitis pigmentosa, cataracts, hearing loss and mental retardation (Mendelian inheritance in man (MIM) no: 605685) in two brothers from a non-consanguineous Lebanese family. In view of the rarity of the disorder and the high rate of inbreeding in ...

Muenke syndrome, defined by heterozygosity for a Pro250Arg substitution in fibroblast growth factor receptor 3 (FGFR3), is the most common genetic cause of craniosynostosis in humans. We have used gene targeting to introduce the Muenke syndrome mutation (equivalent to P244R) into the murine Fgfr3 gene. A rounded skull and shortened ...

Börjeson-Forssman-Lehmann syndrome is an X-linked condition caused by PHF6 mutations. The classical description of males with this disorder includes severe intellectual disability with epilepsy, microcephaly, short stature, obesity, hypogonadism, and gynecomastia. We present three males with PHF6 mutations whose features included deep-set eyes, large ears, coarse face, tapering fingers, and ...

Aicardi syndrome ( OMIM 304050) is defined by the clinical triad of early-onset infantile spasms, agenesis of the corpus callosum and chorioretinal lacunae. Almost all patients are females showing severe cognitive and physical disabilities, and early onset seizures. Astrocytic inclusions containing filamin have been found, but the molecular defect in ...

Blau syndrome is a rare, autosomal-dominant, autoinflammatory disorder characterized by granulomatous arthritis, uveitis, and dermatitis. Genetics studies have shown that the disease is caused by single nonsynonymous substitutions in NOD-2, a member of the NOD-like receptor or NACHT-leucine-rich repeat (NLR) family of intracellular proteins. Several NLRs function in the innate ...

We describe the long-term clinical outcome of a patient with Leigh-like syndrome presenting as an early onset encephalopathy and peripheral neuropathy caused by the T8993G mutation in the mitochondrial DNA (mtDNA). Clinical follow-up for 20 years revealed a peculiar pattern of slow disease progression, characterized by the addition of new ...

Germline mutations in LKB1 cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder with a predisposition to gastrointestinal polyposis and cancer. Hyperactivation of mTOR-signaling has been associated with PJS. We previously reported that rapamycin treatment of Lkb1(+/-) mice after the onset of polyposis reduced the polyp burden. Here we evaluated the ...

During the last 25 years, there have been revolutionary advances in the treatment of Familial Adenomatous Polyposis (FAP). The purpose of this article is to describe the pathophysiology, genetic testing, surveillance, surgical interventions, and psychosocial issues. The genetic defect in FAP is germline mutation in the adenomatous polyposis coli (APC) ...

The knowledge of the genetic bases of hypertension has improved over the last decade; this area of research has high priority due to the high incidence of hypertension and its impact on public health. Monogenetic mineralocorticoid hypertension syndromes are associated with suppressed plasma renin activity due to excessive activation of ...

Craniosynostosis represents a defection of the skull caused by early fusion of one or more cranial sutures. The shape alteration of the cranial vault varies, depending on the fused sutures, so that compensatory growth occurs in dimensions not restricted by sutures. Craniosynostosis can be divided into two main groups: syndromic ...

OBJECTIVE: Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in ...

Adrenocorticotrophin resistance syndromes comprise familial glucocorticoid deficiency (FGD) and triple A syndrome, which are rare autosomal recessive diseases with distinct clinical features and molecular etiologies. Mutations of melanocortin-2 receptor (MC2R) have been described in segregation with FGD in 25% of patients. More recently melanocortin-2 receptor accessory protein (MRAP), a small ...

Several congenital syndromes caused by germline mutations in tumor suppressor genes predispose to the development of glial tumors. In the last few decades our knowledge about the molecular functions of these genes and the pathogenesis of hereditary tumor syndromes has greatly increased. The most common syndromes are the neurofibromatoses (type ...

The hereditary autoinflammatory diseases arise from mutations of genes regulating the innate immune system. These rare disorders are well characterized, both clinically and in terms of their molecular pathogenesis. The recurrent attacks of febrile polyserositis of Familial Mediterranean Fever (FMF) are due to defective pyrin, a protein that down-regulates inflammation. ...

Noonan syndrome (NS) is one of the most common syndromes transmitted by a mendelian mode. In recent years, germline mutations that affect components of the RAS-MAPK (mitogen-activated protein kinase) pathway were shown to be involved in the pathogenesis of NS and four rare syndromes with clinical features overlapping with NS: ...