A case of Allgrove (Triple A) syndrome associated with renal ectopia

Allgrove syndrome (triple-A syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone-resistant adrenal insufficiency, achalasia and alacrima. Aside from the classic features of the syndrome, several abnormalities including mainly neurological abnormalities have been reported in the syndrome. Herein, we presented a case of Allgrove syndrome associated with left renal ectopla. To the best of our knowledge renal abnormality in Allgrove syndrome has not been reported in the literature until now. We think that ectopic kidney diagnosed in our patient is coincidental because the incidence of renal ectopia is high, approximately 1 in 900 in population.     

Heterogeneity of the triple A syndrome and assessment of a case

Allgrove syndrome (triple A syndrome) is a rare autosomal recessive disorder characterized by achalasia, alacrima, adrenal insufficiency, and--occasionally--autonomic instability. Disease causing mutations have been found in the AAAS gene on 12q13, but no strong phenotype-genotype correlation could be found. We present a 28 year-old woman with classical systemic features of triple A syndrome with prominent neurological dysfunctions/deficits, including distal muscular atrophy, progressive muscle weakness and wasting of both legs, sensibility dysfunction, hyperreflexia and autonomic dysfunction presented with excessive sweating. DNA sequencing of the AAAS gene revealed compound heterozygosity for previously reported mutations. A similar genotype was previously reported, but with a remarkably different phenotype.     

Familial occurrence of adrenocortical insufficiency in two brothers with Allgrove syndrome. A case report of 4A (Allgrove) syndrome with epilepsy and a new AAAS gene mutation

Allgrove syndrome is a rare autosomal recessive disease with achalasia, alacrima, adrenocortical insufficiency, autonomic neuropathy and other neurological disturbances. A case of two brothers with Addison s disease from early childhood is presented. The younger brother with Addison disease died at the age of 5. The older brother was treated for adrenocortical insufficiency from the age 3, and then treated for achalasia and epilepsy from the age of 5. The patient is currently 26 years old and suffers from achalasia and adrenocortical insufficiency. He also suffers from alacrima, autonomic neuropathy, epilepsy and other damages of the central and peripheral nervous system. The clinical picture is typical for Allgrove or 4A syndrome, and the diagnosis was confirmed by means of molecular analysis of a new AAAS gene mutation.     

Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Much initial molecular analysis supported that Triple-A syndrome was caused by mutations in AAAS, a WD-repeat protein gene. Here we report cloning and characterization of a novel splice variant of human AAAS, which we named AAAS-v2, which is located on the human chromosome 12p13. The cDNA is 1703bp, encoding a 513-amino acid polypeptide, which contains three WD40 domains, one less than the original which we called AAAS-v1 (Gen Bank: NM_015665.3). RT-PCR analysis in our work revealed that AAAS-v2 and AAAS-v1 were ubiquitously detected in human multiple tissue cDNA (MTC) panels (CLONTECH).The nucleotide sequence reported in this paper has been submitted to GenBank under accession number AY237818.Xin Li: These two authors contributed equally to this paper.Chaoneng Ji: These two authors contributed equally to this paper.     

A second locus for Rieger syndrome maps to chromosome 13q14.

Rieger syndrome is a genetically and phenotypically heterogeneous disorder typically characterized by malformations of the eyes, teeth, and umbilicus. The syndrome is inherited as an autosomal dominant trait and exhibits significant variable expressivity. One locus associated with this disorder has been mapped to 4q25. Using a large four-generation pedigree, we have identified a second locus for Rieger syndrome located on chromosome 13q14.     

A novel heterozygous deletion in the EVC2 gene causes Weyers acrofacial dysostosis

Weyers acrofacial dysostosis (MIM 193530) is an autosomal dominant disorder clinically characterized by mild short stature, postaxial polydactyly, nail dystrophy and dysplastic teeth. Ellis–van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive disorder with a similar, but more severe phenotype. Mutations in the EVC have been identified in both syndromes. However, the EVC mutations only occur in a small proportion of EvC patients. Recently, mutations in a new gene, EVC2, were found to be associated with other EvC cases. The EVC and EVC2 are located close to each other in a head-to-head configuration and may be functionally related. In this study, we report identification of a novel heterozygous deletion in the EVC2 that is responsible for autosomal dominant Weyers acrofacial dysostosis in a large Chinese family. This constitutes the first report of Weyers acrofacial dysostosis caused by this gene. Hence, the spectrum of malformation syndromes due to EVC2 mutations is further extended. Our data provides conclusive evidence that Weyers acrofacial dysostosis and EvC syndrome are allelic and genetically heterogeneous conditions. X. Ye and G. Song contributed equally to this work     

Marshall syndrome associated with a splicing defect at the COL11A1 locus.

Marshall syndrome is a rare, autosomal dominant skeletal dysplasia that is phenotypically similar to the more common disorder Stickler syndrome. For a large kindred with Marshall syndrome, we demonstrate a splice-donor-site mutation in the COL11A1 gene that cosegregates with the phenotype. The G+1-->A transition causes in-frame skipping of a 54-bp exon and deletes amino acids 726-743 from the major triple-helical domain of the alpha1(XI) collagen polypeptide. The data support the hypothesis that the alpha1(XI) collagen polypeptide has an important role in skeletal morphogenesis that extends beyond its contribution to structural integrity of the cartilage extracellular matrix. Our results also demonstrate allelism of Marshall syndrome with the subset of Stickler syndrome families associated with COL11A1 mutations.     

Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22.

Multiple synostoses syndrome is an autosomal dominant disorder characterized by premature onset of joint fusions, which initially affect the interphalangeal joints, by characteristic facies, and by deafness. We performed linkage analysis on a large Hawaiian family with multiple synostoses syndrome. Because another autosomal dominant disorder, proximal symphalangism, shares some clinical symptoms with multiple synostoses syndrome and has been linked to markers at loci at chromosome 17q21-22, we tested the hypothesis that multiple synostoses syndrome is linked to the same chromosomal region. Using polymorphic markers from the proximal symphalangism interval, we conducted linkage analysis and showed that the multiple synostoses-syndrome phenotype is linked to the same chromosomal region. A maximum LOD score of 3.98 at recombination fraction of .00 was achieved for the marker at locus D17S787. Further genetic analysis identified individuals with recombinant genotypes, allowing localization of the disease gene within the interval D17S931-D17S792, a 16-cM region. These data provide evidence that multiple synostoses syndrome and proximal symphalangism may be allelic disorders.     

Notch signaling in human development and disease

Mutations in Notch signaling pathway members cause developmental phenotypes that affect the liver, skeleton, heart, eye, face, kidney, and vasculature. Notch associated disorders include the autosomal dominant, multi-system, Alagille syndrome caused by mutations in both a ligand (Jagged1 (JAG1)) and receptor (NOTCH2) and autosomal recessive spondylocostal dysostosis, caused by mutations in a ligand (Delta-like-3 (DLL3)), as well as several other members of the Notch signaling pathway. Mutations in NOTCH2 have also recently been connected to Hajdu-Cheney syndrome, a dominant disorder causing focal bone destruction, osteoporosis, craniofacial morphology and renal cysts. Mutations in the NOTCH1 receptor are associated with several types of cardiac disease and mutations in NOTCH3 cause the dominant adult onset disorder CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a vascular disorder with onset in the 4th or 5th decades. Studies of these human disorders and their inheritance patterns and types of mutations reveal insights into the mechanisms of Notch signaling.     

Germinal mosaicism in Crouzon syndrome

Summary Two sibs with classic Crouzon syndrome of the same mother but different fathers are presented as an example of germinal mosaicism in a known autosomal dominant disorder. The mother and both fathers were completely normal.     

Mutations in GMPPA Cause a Glycosylation Disorder Characterized by Intellectual Disability and Autonomic Dysfunction

In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.     

Progress in the search for genetic linkage with Tourette syndrome: An exclusion map covering more than 50% of the autosomal genome

Gilles de la Tourette syndrome is a neuropsychiatric disorder with an autosomal dominant mode of inheritance and reduced penetrance at a single genetic locus. Several research groups have genetic linkage studies underway to detect the chromosomal location of the gene that predisposes for this disorder. Strong and clear evidence of linkage has not yet been produced for Tourette syndrome. This paper presents an overview of the methods and progress of the groups centered at Yale University and Erasmus University in excluding linkage from a large portion of the genome. Our labs have screened 228 genetic marker loci for linkage with a gene for this disorder in a series of affected families in the United States, Canada, The Netherlands, and Norway. More than 50% (and perhaps as much as 66%) of the autosomal genome has now been excluded on the assumption that genetic heterogeneity is not an important factor in the Tourette syndrome pedigrees pooled for this summary.     

Familial transmission of a dysmorphic syndrome: a variant example of Kabuki syndrome?

Familial transmission of a dysmorphic syndrome: a variant example of Kabuki syndrome?: We report a Romanian family with a dysmorphic syndrome in three generations: a boy, his mother and maternal grandfather, who all presented with the typical facial appearance, characteristic skeletal and dermatoglyphic findings of Kabuki syndrome, but no mental retardation, short stature and visceral abnormalities. The phenotype observed in this family may represent the mild end of a spectrum of clinical manifestations described in this condition. This report provides a further evidence for autosomal dominant transmission of the disorder.     

Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.

EEC syndrome is an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts. We have mapped the genetic defect in several EEC syndrome families to a region of chromosome 3q27 previously implicated in the EEC-like disorder, limb mammary syndrome (LMS). Analysis of the p63 gene, a homolog of p53 located in the critical LMS/EEC interval, revealed heterozygous mutations in nine unrelated EEC families. Eight mutations result in amino acid substitutions that are predicted to abolish the DNA binding capacity of p63. The ninth is a frameshift mutation that affects the p63alpha, but not p63beta and p63gamma isotypes. Transactivation studies with these mutant p63 isotypes provide a molecular explanation for the dominant character of p63 mutations in EEC syndrome.     

A genetic study of panic disorder pedigrees.

Pedigree analysis is done on 19 kindreds of panic disorder, and the results suggest that this disorder is transmitted as an autosomal dominant trait. Seven of these 19 kindreds were ascertained through a panic disorder proband with mitral valve prolapse. When the analysis is done omitting these seven kindreds, the results also suggest that panic disorder without prolapse is transmitted as an autosomal dominant trait.     

Mice lacking the nuclear pore complex protein ALADIN show female infertility but fail to develop a phenotype resembling human triple A syndrome

Triple A syndrome is a human autosomal recessive disorder characterized by adrenal insufficiency, achalasia, alacrima, and neurological abnormalities affecting the central, peripheral, and autonomic nervous systems. In humans, this disease is caused by mutations in the AAAS gene, which encodes ALADIN, a protein that belongs to the family of WD-repeat proteins and localizes to nuclear pore complexes. To analyze the function of the gene in the context of the whole organism and in an attempt to obtain an animal model for human triple A syndrome, we generated mice lacking a functional Aaas gene. The Aaas-/- animals were found to be externally indistinguishable from their wild-type littermates, although their body weight was on the average lower than that of wild-type mice. Histological analysis of various tissues failed to reveal any differences between Aaas-/- and wild-type mice. Aaas-/- mice exhibit unexpectedly mild abnormal behavior and only minor neurological deficits. Our data show that the lack of ALADIN in mice does not lead to a triple A syndrome-like disease. Thus, in mice either the function of ALADIN differs from that in humans, its loss can be readily compensated for, or additional factors, such as environmental conditions or genetic modifiers, contribute to the disease.     

Genetic aspects of hemifacial microsomia

Summary The majority of patients with hemifacial microsomia (HM) including Goldenhar syndrome are sporadic cases. The sporadic nature of this disorder is emphasized by the discordant occurrence of HM in one of female monozygotic twins reported here. Previous publications, however, also suggest autosomal dominant and autosomal recessive modes of inheritance. Possible formes frustes will also have to be considered when giving genetic counsel.     

Does the rare A172G mutation of PTPN11 gene convey a mild Noonan syndrome phenotype?

BACKGROUND: Noonan syndrome NS (OMIM 163950) is an autosomal dominant developmental disorder characterized mainly by typical facial dysmorphism, growth retardation and variable congenital heart defects. In unrelated individuals with sporadic or familial NS, heterozygous missense point mutations in the gene PTPN11 (OMIM 176876) have been confirmed, with a clustering of mutations in exons 3 and 8, the mutation A922G Asn308Asp accounting for nearly 25% of cases. PATIENT AND METHODS: We report a 7-year-old boy with short stature and some other clinical features of NS, who has been investigated by molecular analysis for the presence of mutations in the PTPN11 gene. Result: The de novo mutation A172G in the exon 3 of the PTPN11 gene, predicting an Asn58Asp substitution, has been found. To the best of our knowledge, this specific mutation has only been described once before, but this is the first report of detailed clinical data suggesting a mild phenotype. CONCLUSION: Detailed clinical phenotype in every patient with major or minor features of NS and molecular identification of PTPN11 gene mutation may contribute to a better phenotype-genotype correlation.     

46,XX ovotesticular disorder in a Mexican patient with Beckwith--Wiedemann syndrome: a case report

ABSTRACT: INTRODUCTION: Beckwith--Wiedemann syndrome is an overgrowth syndrome that is characterized by hypoglycemia at birth, coarse face, hemihypertrophy and an increased risk to develop embryonal tumors. In approximately 15% of patients, the inheritance is autosomal dominant with variable expressivity and incomplete penetrance, whereas the remainder of Beckwith--Wiedemann syndrome cases are sporadic. Beckwith--Wiedemann syndrome molecular etiologies are complex and involve the two imprinting centers 1 (IC1) and 2 (IC2) of 11p15 region. This case report describes, for the first time, the unusual association of ovotesticular disorder in a patient from Morelia, Mexico with Wiedemann-Beckwith syndrome. CASE PRESENTATION: We report the case of a Mexican six-year-old girl with Beckwith--Wiedemann Syndrome, ambiguous genitalia, and bilateral ovotestes. She has a 46,XX karyotype without evidence of Y-chromosome sequences detected by fluorescence in situ hybridization with both SRY and wcp-Y probes. CONCLUSION: Although a random association between these two conditions cannot be excluded, future analysis of this patient with Beckwith--Wiedemann syndrome and 46,XX ovotesticular disorder may lead to new insights into these complex pathologies. We speculate that a possible misregulation in the imprinted genes network has a fundamental role in the coexistence of these two disorders.