Three children with triple A syndrome due to a mutation (R478X) in the AAAS gene

OBJECTIVE: To investigate the phenotype and genotype of 3 unrelated children with triple A syndrome from southern Turkey. METHODS: The coding sequence of the AAAS gene was sequenced including exon-intron boundaries. Haplotype analysis using markers from AAAS region was performed in order to assess potential founder effects. RESULTS: In all 3 patients, the identical nonsense mutation (R478X) in exon 16 of the AAAS gene was identified. The patients who may be distantly related appeared phenotypically similar with the classical triad of the triple A syndrome (adrenal insufficiency, alacrima and achalasia) with dermatological manifestations while lacking neurological features except for mild mental retardation. CONCLUSION: The R478X mutation tends to result in a rather severe phenotype although genotype-phenotype relationships cannot be drawn due to the small number of patients.     

A novel AAAS gene mutation (p.R194X) in a patient with triple A syndrome

OBJECTIVE: The clinical and molecular data of a patient with triple A syndrome are reported. PATIENT: A 21-year-old male who was diagnosed for adrenal insufficiency at the age of 2 years after a severe attack of adrenal crisis. At the age of 4 years, achalasia and alacrima were diagnosed. Puberty started at the age of 17 years. At the same time, symptoms of central, peripheral, and autonomic nervous system dysfunction were noted. Later on, at the age of 20 years, a bone age delay of 6 years and severe osteoporosis was diagnosed. RESULTS: A compound heterozygous AAAS mutation consisting of two mutations was found: a C > T transition in exon 7 resulting in a change of arginine at amino acid position 194 into a stop codon (Arg194X) at one allele, and a C > T transition in exon 12 resulting in a change of glutamine at amino acid position 387 into a stop codon (Gln387X) on the other allele. CONCLUSION: The mutation in exon 7 (p.R194X) of the AAAS gene is a novel mutation which has not been found in any other family so far, whereas the second was already found in some other families. This case adds to the clinical and molecular spectrum of triple A syndrome and may provide a new insight into the functions of AAAS gene.     

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.     

Recurrent achalasia in a child with Williams-Beuren syndrome

Williams-Beuren syndrome is a multysistem genetic disorder caused by the 1.6Mb hemizygous deletion involving the elastin gene in the region q11.23 of chromosome 7. The phenotype of Williams-Beuren syndrome is extremelly variable but the most common findings include cardiovascular disease, distinctive facies, mental retardation, a specific congitive profile, endocrine abnormalities, growth retardation and connective tissue abnormalities. Although gastrointestinal difficulties are one of the most constant and prominent finding of the syndrome, including gastro-esophageal reflux (GER), poor suckling, vomiting, constipation, prolonged colic, rectal prolapse, inguinal, umbilical and hiatal hernia, there have been no reports of achalasia in association with Williams-Beuren syndrome in the literature. We present the case of a boy with Williams-Beuren syndrome, achalasia and recurrent postoperative stenosis of the cardia. After Heller myotomy, the boy developed severe restenosis of the cardia with abundant adhesions which repeated after every treatment, five times in periods shorter than one month. Eventually, he developed GER, errosive gastritis and hiatal hernia which led to severe malnutrition and failure to thrive. Although the genetic defect causing Williams-Beuren syndrome might not be the direct cause of achalasia we suggest that the frequent development of severe restenosis of cardia due to tight adhesions could be the consequence of elastin gene haploinsufficiency and altered structure and function of elastic fibers in esophageal connective tissue. This case highlights the importance of early diagnosis of esophageal motor disorders in childhood which should be included in the differential diagnosis when a child with Williams-Beuren syndrome presents with dysphagia and/or regurgitation.     

Ullrich-Feichtiger syndrome in a 3-year-old boy]

A case of a 3 year old boy with Ullrich-Feichtiger syndrome is presented, because of the rarity of this syndrome. Ullrich-Feichtiger syndrome diagnosis was based on the following clinical signs and symptoms: a) micrognathia with several teeth developmental abnormalities; b) polydactyly (six toes); c) varied genital malformations; d) multiple ocular abnormalities. Cause of these multiple malformations remains unclear.     

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.     

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.     

The genetic basis of triple A (Allgrove) syndrome in a Greek family

Triple A (or Allgrove) syndrome is an autosomal recessive genetic disorder. Patients typically suffer from chronic adrenal insufficiency due to resistance to ACTH (Addison's disease), achalasia of the cardia, and defective tear formation (alacrima). The syndrome is caused by mutations in the AAAS gene which encodes the protein ALADIN, a constituent of eukaryotic nuclear pore complexes. The multi-systemic nature and variable manifestations of the triple A syndrome often confound its diagnosis and limit our understanding of its exact pathogenesis. We performed mutational screening of the AAAS gene in a Greek family of four individuals, including an affected propositus with typical symptoms of late-onset triple A syndrome. Our results are consistent with an autosomal recessive pattern of inheritance within the family, caused by a functional c.43C > A mutation in exon 1 of the AAAS gene. All members of the family were also homozygous for a silent c.855C > T nucleotide change within exon 9 of the AAAS gene, representing a common single nucleotide polymorphism. The compromising c.43C > A mutation is predicted to cause a p.Gln15Lys amino acid substitution in the ALADIN protein. However, it has been suggested that the functional impact of this mutation may be more severe, causing a shift in the reading frame of AAAS gene via formation of an aberrant premature donor splice site within exon 1. We propose that mutational analysis of the AAAS gene should be considered in adult patients with one or more clinical signs of the disease, as diagnosis of late-onset cases can be ambiguous.     

Mosaic triple X syndrome in a female with primary amenorrhea

BACKGROUND:

Turner''s syndrome is the most common chromosomal abnormality in females, affecting 1 in 2,500 live female births. It is a result of absence of an X chromosome or the presence of a structurally abnormal X chromosome. Its most consistent clinical features are short stature and ovarian failure.

AIM:

The aim of the study was to report a rare case of mosaic triple X syndrome in a female with primary amenorrhea.

MATERIALS AND METHODS:

The chromosomal analysis using GTG banding was carried out, which revealed a mosaicism with 45,XO/47,XXX chromosomal constitution. Fluorescent in situ hybridization was also carried out to further confirm the observation made in the study.

CONCLUSION:

The physical features presented by the female could be due to the 45,XO/47,XXX mosaicism and the karyotype analysis was consistent with the diagnosis and clinical symptoms. Triple X mosaicism was confirmed with conventional and molecular cytogenetic analysis.     

The ICF syndrome: new case and update

The ICF syndrome: New case and update: We report the clinical progress in a 5-year-old boy with the (ICF) syndrome. Early diagnosis and intervention has led to a good outcome. DNMT3B mutation analysis was negative, supporting genetic heterogeneity in this condition.     

Progeroide Variante eines Marfan-Syndroms

Severe congenital lipodystrophy, progeroid facies and additional variable features of Marfan syndrome represent a unique entity: a Marfan syndrome variant caused by a truncating mutation at the 3?? end of the fibrillin 1 gene in the penultimate and final coding exons. It is highly likely that the mutant protein avoids nonsense mediated decay (NMD) and thus gives rise to this special phenotype. Only five cases of this pattern of symptoms have been published to date; in three instances the diagnosis was confirmed by molecular genetics. The following clinical features require that this diagnosis be considered and clarified: retarded intrauterine growth, progeroid facies at birth, reduced levels of subcutaneous fat and other variable features of Marfan syndrome.     

Baller-Gerold syndrome associated with dextrocardia

Baller-Gerold Syndrome (BGS) is a rare autosomal recessive disorder that is apparent at birth. The disorder is characterized by distinctive malformations of the skull and facial area and bones of the forearms and hands. We report a 4 year old boy in whom the clinical features of craniosynostosis and bilateral absent thumbs and radii led to a diagnosis of Baller-Gerold syndrome. Physical examination revealed that the heart was localized to the right side. Echocardiography confirmed dextrocardia. Dextrocardia has not previously been reported with Baller-Gerold syndrome. To the best of our knowledge, this is the first reported case of Baller-Gerold syndrome associated with dextrocardia.     

Partial 4q duplication due to inherited der(20), t(4;20)(q25;q13)mat.

A boy with mental and growth retardation associated with congenital anomalies has a partial duplication of the distal 4q chromosome region as a result of inheritance of a t(4:20) from his mother. Comparison with twelve other patients from the literature indicates that similar clinical features may be associated with this chromosome change suggesting a partial 4q duplication syndrome.     

Berardinelli-Seip syndrome type 1 in an Egyptian child

Berardinelli-Seip syndrome type 1 or Berardinelli-Seip congenital lipodystrophy 1 (BSCL1) is a very rare genetic disorder characterized by lipoatrophy, hypertriglyceridemia, hepatomegaly and acromegaloid features. Its prevalence in Egypt is not known. Here, we report case of a 12-year-old Egyptian boy with the clinical, metabolic and molecular genetics manifestations of BSCL1 including overt diabetes mellitus.     

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.     

Chylothorax as a possible diagnostic pitfall: a report of 2 cases with cytologic findings

BACKGROUND: Chyothorax is an uncommon medical condition. To the best of our knowledge, there have been no detailed English-language report dealing with its cytopathologic findings and diagnostic pitfalls CASES: A 12-year-old boy, hemodialysis dependent, with congenital nephrotic syndrome due to focal segmental glomerular sclerosis and a failed renal transplant, developed shortness of breath. Physical and radiologic examinations revealed a left pleural effusion. A 7-year-old boy developed shortness of breath, with a subsequent finding of a left pleural effusion. Multiple osteolytic skeletal lesions were found in this patient. Both patients underwent thoracocentesis. Cytologically, both fluids contained many relatively uniform, large lymphoid cells with high nuclear/cytoplasmic (N/C) ratio, condensed chromatin and occasional nucleoli, resembling blasts. Some nuclei were convoluted. Mitotic figures were present. Foamy macrophages were present in both cases. The differential diagnosis of these populations of cells included a lymphoproliferative disorder. However, the mature T-lymphocytic nature of the cells was confirmed by immunohistochemistry performed on cell block preparations, confirming the clinical impression of chylothorax in both cases. The first patient had chylothorax as a result of trauma due to therapeutic interventions (subclavian vein cannulation), in the second patient the chylothorax was a part of Gorham-Stout syndrome. CONCLUSION: The large T-lymphocytes that are the major cellular component of chylothorax may arouse suspicion of a lymphoproliferative disorder. Attention to the clinical history and immunophenotyping confirm the benign nature of the pleural space fluid. Also, abundant foamy macrophages can be considered a low-power clue to this diagnosis.     

Trisomy 20p due to a paternal reciprocal translocation

A mentally retarded boy with multiple malformations was found to have trisomy for the distal two-thirds of the short arm of chromosome 20 (trisomy 20p), resulting from a paternal translocation (5;20)(p15;p11). The patient had a cleft palate, a feature not present in other trisomy 20p patients. A review of the reported trisomy 20p patients indicates that their varied features do no constitute a readily recognizable clinical syndrome.     

Mitochondrial diseases mimicking neurotransmitter defects

OBJECTIVES: Mitochondrial disorders are clinically heterogeneous. We aimed to describe 5 patients who presented with a clinical picture suggestive of primary neurotransmitter defects but who finally fulfilled diagnostic criteria for mitochondrial disease. METHODS: We report detailed clinical features, brain magnetic resonance findings and biochemical studies, including cerebrospinal fluid (CSF) biogenic amine and pterin measurements, respiratory chain enzyme activity, and molecular studies. RESULTS: The 5 patients had a very early onset age (from 1 day to 3 months) and a severe clinical course. They all showed a clinical picture suggestive of infantile hypokinetic-rigid syndrome (hypokinesia, hypomimia, slowness of reactions, tremor), other abnormal movements (myoclonus, dystonia), axial hypotonia, limb hypertonia, feeding difficulties, and psychomotor delay. Abnormal CSF findings among the 4 patients without treatment included low levels of homovanillic acid (HVA) in 3 patients, with associated low 5-hydroxyindoleacetic acid (5-HIAA) concentrations in two of them. Absent or mild and transitory improvement was observed after treatment with L-dopa. A diagnosis of mitochondrial disorder was finally made due to the appearance of hyperlactacidemia, diverse respiratory chain defects, and multisystemic involvement. CONCLUSIONS: Secondary neurotransmitter disturbances may occur in mitochondrial diseases. Differential diagnosis of hypokinetic-rigid syndrome presenting in infancy could also include paediatric mitochondrial disorders.