GATA3 mutation in a family with hypoparathyroidism,deafness and renal dysplasia syndrome

Background

The hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by GATA3 gene mutation. We report here a case that both of a Chinese boy and his father had HDR syndrome which caused by a novel mutation of GATA3.

Methods

Polymerase chain reaction and DNA sequencing was performed to detect the exons of the GATA3 gene for mutation analysis.

Results

Sequence analysis of GATA3 revealed a heterozygous nonsense mutation in this family: a mutation of GATA3 at exon 2 (c.515C >A) that resulted in a premature stop at codon 172 (p.S172X) with a loss of two zinc finger domains.

Conclusion

We identified a novel nonsense mutation which will expand the spectrum of HDR-associated GATA3 mutations.     

Simultaneous mutations in the CLCNKB and SLC12A3 genes in two siblings with phenotypic heterogeneity in classic Bartter syndrome

Two siblings (brother and sister) with renal tubular hypokalemic alkalosis underwent clinical, biochemical and molecular investigations. Although the biochemical findings were similar (including hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism and normal blood pressure), the clinical findings were different: the boy, who also presented syndromic signs, developed glomerular proteinuria and renal biopsy revealed focal segmental glomerular sclerosis; the girl showed the typical signs of classic Bartter syndrome. As described in a previous paper, a heterozygous mutation (frameshift 2534delT) was demonstrated in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) of the distal convoluted tubule; the second molecular analysis revealed a compound heterozygous mutation (A61D/V149E) in the CLCNKB chloride channel gene in both subjects, inherited in trans from the parents. The children were finally diagnosed as having classic Bartter syndrome. These cases represent the first report of the simultaneous presence of heterozygous and compound heterozygous mutations in the SLC12A3 and CLCNKB genes, both of which are involved in renal salt losing tubulopathies, and confirm previous observations regarding classic Bartter syndrome phenotype variability in the same kindred.     

Mitochondrial DNA depletion syndrome causing liver failure

Background

Mitochondrial DNA depletion syndromes are disorders of Mitochondrial DNA maintenance causing varied manifestations, including fulminant liver failure.

Case characteristics

Two infants, presenting with severe fatal hepatopathy.

Observation

Raised serum lactate, positive family history (in first case), and absence of other causes of acute liver failure.

Outcome

Case 1 with homozygous mutation, c.3286C>T (p.Arg1096Cys) in POLG gene and case 2 with compound heterozygous mutations, novel c.408T>G (p.Tyr136X) and previously reported c.293C>T (p.Pro98Leu), in MPV17 gene.

Message

Mitochondrial DNA depletion syndrome is a rare cause of severe acute liver failure in children.     

RenalTube: a network tool for clinical and genetic diagnosis of primary tubulopathies

The main purpose was to build a database while facilitating access to genotyping in order to improve the clinical and molecular knowledge of primary tubulopathies. Three tertiary referral centers of Spain collect clinical data through the site http://www.renaltube.com, while offering the analysis of 22 genes corresponding to 23 primary tubulopathies. There are three ways of collaboration: option 1 consists of adding patients to the database with clinical and biochemical information and requesting for genetic study, option 2 requires the payment of a fee for genetic analysis exclusively, and option 3 allows the enrollment of patients with a previously confirmed mutation. After 2 years of activity, RenalTube has collected data from 222 patients, the majority from Spain and Latin America (85.3 %). The most common tubulopathies are distal renal tubular acidosis (22.5 %) and classical Bartter syndrome (19.3 %) followed by familial hypomagnesemia with hypercalciuria and nephrocalcinosis (15.7 %) and Gitelman syndrome (15 %). Option 1 is the collaborating method preferred by doctors (62.3 %) followed by option 3 (36.3 %). Conclusion: RenalTube is a network-based registry that can be easily reached and filled out worldwide. A web-based approach with a multilateral collaboration scheme enhances the recruitment of data and promotes the understanding of underlying mechanisms of rare inherited diseases, defines more accurate diagnostic and follow-up criteria, develops new molecular techniques and will improve the overall care of the patients.     

Molecular Characterisation and Prenatal Diagnosis of Asparto-acylase Deficiency (Canavan Disease)—Report of Two Novel and Two Known Mutations from the Indian Subcontinent

Objectives

To establish a technique for mutation identification and prenatal screening in confirmed cases of Canavan disease.

Method

Mutations in ASPA gene were identified by sequencing. Six exons of ASPA gene were amplified using intronic primers flanking the exons and then sequenced on ABI 3500Dx automated unit. This technique was used to identify mutations in three cases of Canavan disease. Prenatal diagnosis was performed in two families.

Results

Two reported mutations c.162 C?>?A (p.Asn54Lys) and c.859 G?>?A (p.Ala287Thr) were identified in two different cases of Canavan disease. Third case was compound heterozygous for two novel mutations (c.728 T?>?G, p.Ile243Ser; c.902 T?>?C, p.Leu301Pro). Prenatal diagnosis was performed in three pregnancies in two families, two affected fetuses and one unaffected fetus were identified.

Conclusions

Molecular characterization of Canavan disease helps identify the cause at genetic level, thus confirming diagnosis and enabling identification of carriers in the family. Though enzyme assay and NAA measurement allows diagnosis and prenatal diagnosis of Canavan diasease, molecular methods have the advantage of bringing accuracy in prenatal testing with an earlier result. This is the first case report of mutation studies in Canavan disease from Indian subcontinent.     

Maternal Medication Use,Fetal 3435 C>T Polymorphism of the ABCB1 Gene,and Risk of Isolated Septal Defects in a Han Chinese Population

The fundamental etiology of the majority of nonsyndromic congenital heart defects is commonly believed to involve the interaction of multiple environmental and genetic factors. This study aimed to explore the joint effects of fetal 3435 C>T polymorphism in the ABCB1 gene and maternal medication use on the risk of septal defects in a Han Chinese population. An age- and gender-matched case–control study involving 265 pairs was conducted from March 2012 to September 2013. Information on maternal periconceptional medication use was obtained through questionnaires. The genotyping of 3435 C>T polymorphism was performed by sequencing. Logistic regression analysis was performed to assess the joint effects of ABCB1 gene 3435 C>T polymorphism and maternal medication use on the risk of septal defects. Use of maternal medication periconceptionally was significantly associated with an increased risk of septal defects [adjusted odds ratio (OR) 2.133; 95 % confidence interval (CI) 1.361–3.444; P = 0.001)]. The genotype distributions of 3435 C>T polymorphism differed significantly between cases and control subjects (P < 0.001). Meanwhile, more patients were carriers of the ABCB1 CC/CT genotypes, which were significantly associated with an increased risk of septal defects (OR 2.414; 95 % CI 1.418–4.110; P = 0.001). Children who carry the CC/CT genotype and have been exposed periconceptionally to medication have an almost fourfold increased risk of having septal defects than nonexposed children with the TT genotype (adjusted OR 3.932; 95 % CI 1.708–9.051), particularly perimembranous ventricular septal defects (VSD) (adjusted OR 4.070; 95 % CI 1.570–10.552). In conclusion, fetal 3435 C>T polymorphism in the ABCB1 gene increases the risk for isolated septal defects in the presence of maternal medication use periconceptionally, particularly for perimembranous VSD.     

Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype

Gitelman syndrome is an inherited renal disorder characterized by impaired NaCl reabsorption in the distal convoluted tubule and secondary hypokalemic alkalosis. In clinical practice, it is distinguished from other hypokalemic tubulopathies by the presence of both hypomagnesemia and normocalcemic hypocalciuria. To date, only mutations in a single gene encoding the thiazide-sensitive NaCl cotransporter have been found as the molecular basis of GS. We describe three unrelated patients presenting with the typical laboratory findings of GS. Mutational analysis in these patients revealed no abnormality in the SLC12A3 gene. Instead, all patients were found to carry previously described mutations in the CLCNKB gene, which encodes the kidney-specific chloride channel ClC-Kb, raising the possibility of genetic heterogeneity. Review of the medical histories revealed manifestation of the disease within the first year of life in all cases. Clinical presentation included episodes of dehydration, weakness, and failure to thrive, much more suggestive of classic Bartter syndrome than of GS. The coexistence of hypomagnesemia and hypocalciuria was not present from the beginning. In the follow-up, however, a drop of both parameters below normal range was a consistent finding reflecting a transition from cBS to GS phenotype. The phenotypic overlap may indicate a physiologic cooperation of the apical thiazide-sensitive NaCl cotransporter and the basolateral chloride channel for salt reabsorption in the distal convoluted tubule.     

Eight novel mutations of <Emphasis Type="Italic">CBS</Emphasis> gene in nine Chinese patients with classical homocystinuria

Background

Classical homocystinuria (homocysteinemia type 1, MIM# 236200) is a rare inherited disorder in Mainland China. This study aimed to identify mutations in the cystathionine β-synthase (CBS) gene which are associated with classical homocystinuria in nine Chinese patients.

Methods

Nine Chinese patients were diagnosed at the age of 5 years 4 months to 18 years by plasma total homocysteine and blood methionine determination. CBS gene analysis was performed for the patients and their families.

Results

All nine patients had significantly increased plasma total homocysteine (142–500 μmol/L vs. the normal range of 0–15 μmol/L) and blood methionine (144.3–500 μmol/L vs. the normal range of 0–50 μmol/L). None of the patients was pyridoxine responsive. Eleven mutations in CBS gene were identified in the nine patients. Eight mutations (IVS3+1G>A, p.Thr493fsX46, p.Thr236Asn, p.Leu230Gln, p.Lys72Ile, p.Ser201ProfsX36, p.Met337IlefsX115, and IVS14-1G>C) were novel. Three mutations (p.Arg125Gln, p.Thr257Met and p.Gly116Arg) had been previously reported.

Conclusions

In this study, eight novel mutations in CBS were identified in nine Chinese patients with classical homocystinuria. None of the hotspot mutations reported in other regions previously was found. These data indicated that Chinese maybe had different CBS mutation spectrum from other population. The identification of mutations not only confirms the diagnosis but also enables accurate genetic counselling and prenatal diagnosis for the fetuses of the families.

     

Cystic Leucoencephalopathy in <Emphasis Type="Italic">NDUFV1</Emphasis> Mutation

Complex I deficiency is one of the most common mitochondrial respiratory chain defect. This deficiency of oxidative phosphorylation results from mutation in nuclear and mitochondrial DNA. Mutations in NDUFV1 (Flavin binding subunit of Respiratory complex 1) results in neurological manifestations including Leigh syndrome and leucoencephalopathy. The authors report a one-year-old boy with history of regression of motor milestones following a trivial fall from the bed. His magnetic resonance imaging revealed diffuse, cystic leucoencephalopathy involving corpus callosum and periventricular white matter. Clinical features and radiological findings may resemble those of vanishing white matter disease. Next generation sequencing revealed likely compound heterozygous missense pathogenic variant in exon 8 of NDUFV1 gene [c.1156C?>?C/T (p.Arg386Cys)] and possibly novel splice site variation in intron 2 of NDUFV1 gene (c.155?+?1G?>?G/A). NDUFV1 related leucoencephalopathy must be considered among those presenting with sudden onset of motor regression with neuroimaging correlate of diffuse cystic leucodystrophy.     

Don’t miss patients with atypical FMR1 mutations: dysmorphism and clinical features in a boy with a partially methylated FMR1 full mutation

Fragile X syndrome characterized by intellectual disability (ID), facial dysmorphism, and postpubertal macroorchidism is the most common monogenic cause of ID. It is typically induced by an expansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene on Xq27 to more than 200 repeats. Only rarely patients have atypical mutations in the FMR1 gene such as point mutations, deletions, or unmethylated/partially methylated full mutations. Most of these patients show a minor phenotype or even appear clinically healthy. Here, we report the dysmorphism and clinical features of a 17-year-old boy with a partially methylated full mutation of approximately 250 repeats. Diagnosis was made subsequently to the evaluation of a FMR1 premutation as the cause for maternal premature ovarian failure. Dysmorphic evaluation revealed no strikingly long face, no prominent forehead/frontal bossing, no prominent mandible, no macroorchidism, and a head circumference in the lower normal range. Acquisition of a driving license for mopeds and unaccompanied rides by public transport in his home province indicate rather mild ID (IQ?=?58). Conclusion: This adolescent demonstrates that apart from only minor ID, patients with a partially methylated FMR1 full mutation present less to absent pathognomonic facial dysmorphism, thus emphasizing the impact of family history for a straightforward clinical diagnosis.     

Primary Carnitine Deficiency – A Rare Treatable Cause of Cardiomyopathy and Massive Hepatomegaly

Systemic primary carnitine deficiency (CDSP) is a rare autosomal recessive disorder caused by a defect in plasma membrane uptake of carnitine due to SLC22A5 gene mutations. A nine-mo-old boy presented with hypertrophic cardiomyopathy, massive hepatomegaly and jaundice. Metabolic testing revealed very low free carnitine levels. Genetic analysis using Sanger sequencing method revealed compound heterozygous mutations in SLC22A5 gene, c. 1354 G > A (p. Glu452Lys, previously reported) and c.231_234del (novel frame-shift). Oral carnitine supplementation resulted in improved clinical outcome with ejection fraction to 75 % and normalization of liver size and enzymes after 3 mo.     

Novel OCRL mutations in Chinese children with Lowe syndrome

Background

Lowe syndrome is a rare X-linked recessive hereditary disease caused by mutations of the OCRL gene, which encodes an inositol polyphosphate-5-phosphatase. The disease is clinically characterized by congenital cataracts, psychomotor retardation, and proximal tubulopathy.

Methods

We retrospectively reviewed three unrelated Chinese patients with Lowe syndrome, clinically diagnosed by the abnormalities of eyes, nervous system, and kidneys. Genetic analysis of the OCRL gene was done for the three patients as well as their family members.

Results

Three OCRL gene mutations were detected in our study. Two of the mutations, g.1897delT in exon 18 (patient 1) and g.1470delG in exon 15 (patient 2), were novel. A missense mutation (p.Y513C) in exon 15, which had been reported previously, was found in patient 3. The mothers of all patients were heterozygous carriers of the respective mutations.

Conclusions

Three Chinese children were diagnosed with Lowe syndrome through clinical and genetic analyses. And two novel mutations in the OCRL gene were identified.     

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??Objective??To analyze the clinical features and the results of genetic diagnosis in children with hypokalemic renal tubular diseases. Methods??The clinical data of 38 patients with hypokalemic renal tubular diseases were analyzed retrospectively??who were treated in Children’s Hospital Affiliated to Shanghai Jiao Tong University from Jan. 2010 to Jan. 2016. Results??Totally 38 patients with hypokalemic renal tubular diseases were enrolled in this study. There were 18 cases of renal tubular acidosis??RTA?? including 17 cases of type??RTA and 1 case of type?? RTA. There were 11 cases of Bartter syndrome??5 cases of Gitelman syndrome and 4 cases of Fanconi syndrome. The common clinical manifestations of hypokalemic renal tubular diseases included myasthenia??nausea??vomiting??polydipsia??polyurine and growth retardation. One case of Fanconi syndrome progressed to chronic Kidney disease??phase ????while the other
children had normal renal function. Glomerular proteinuria was found in 1??1 and 3 children with Bartter syndrome??Gitelman syndrome and Fanconi syndrome??respectively. Additionally??1 case with Fanconi syndrome has tubular proteinuria. However??urinary trace proteins associated with glomerular and tubular injury commonly elevated in these hypokalemic renal tubular diseases. Genetic analysis showed a new potential heterozygous mutations of ATPV0A4 in type??RTA and three heterozygous mutations of SLC12A3 in Gitelman syndrome. Conclusion??The clinical symptoms vary in patients and are featured mainly by myasthenia??nausea??vomiting??polydipsia??polyurine and growth retardation. Glomerular and tubular injuries are commonly found in hypokalemic renal tubular diseases. Moreover??genetic diagnosis may be helpful in diagnosis??treatment and genetic counseling.     

eIF2B-related multisystem disorder in two sisters with atypical presentations

Background

Vanishing white matter disease (VWM) is a chronic progressive leukoencephalopathy that is characterized by cerebellar ataxia and spasticity, together with cystic degeneration of the cerebral white matter as evidenced by brain magnetic resonance imaging (MRI). Here, we report two sisters with EIF2B2 variants, who presented with delayed development and failure to thrive before 1 year of age, developed cataracts, and showed diffuse leukoencephalopathy.

GLUT-1 deficiency presenting with seizures and reversible leukoencephalopathy on MRI imaging

Glucose transporter type 1 (GLUT1) deficiency syndrome is a well recognised genetic neurometabolic disorder typically presenting with progressive encephalopathy, acquired microcephaly and drug-resistant epilepsy. Imaging is normal in the majority. Here we describe a 5-month-old boy who presented with motor delay, myoclonic jerks and tonic-clonic seizures. His MRI brain scan revealed confluent symmetrical T2 hyperintense signal abnormality in both anterior frontal lobes and delayed myelination. Neurometabolic screen revealed low CSF glucose and lactate levels. A pathogenic de novo heterozygous mutation in SLC2A1 (c.275+1G > A) confirmed the diagnosis of GLUT1 deficiency. Ketogenic diet resulted in a dramatic termination of his seizures at 72 h. At 15 months, he continued to be seizure free with marked developmental catch up. Repeat imaging revealed a significant resolution of the previously seen changes. This case suggests that GLUT1 deficiency should be considered in the differential diagnosis of infants with suspected genetic leukoencephalopathies with important treatment implications.     

Entire DAX1 Gene Deletion in an Indian Boy with Adrenal Hypoplasia Congenita

Objective

To report a case of Adrenal hypoplasia congenita (AHC) in an Indian boy presenting with adrenal failure in the neonatal period. Molecular diagnosis demonstrated absence of the entire DAX1 gene sequence region.

Methods

Real-time SYBR Green Polymerase Chain Reaction (PCR) amplification followed by melt curve analysis was the molecular analytical method used. Analysis of the PCR products by Agarose gel electrophoresis was also performed.

Results

Real-time SYBR Green PCR amplification carried out on a 240 bp region of Exon 1 and 320 bp region of Exon 2 of DAX1 gene did not result in any amplification for two independent DNA extractions of the patient sample. The melt curve analysis also failed to show the characteristic melt peaks. Additional analysis of the PCR products performed by Agarose gel electrophoresis of the patient samples did not reveal any DNA bands.

Conclusions

Inability to amplify two distinct regions located on two distinct exons of the DAX1 gene of the patient sample point to the possible absence of the entire DAX1 gene sequence region in the index patient. Such molecular diagnostic techniques may prove very useful in making a diagnosis as well as for genetic counseling.     

An early diagnosis of trichorhinophalangeal syndrome type 1: a case report and a review of literature

Background

Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant disorder caused by defects involving the TRPS1 gene. It exhibits distinctive craniofacial, ectodermal and skeletal abnormalities, such as sparse hair, bulbous nasal tip and short deformed fingers, with extremely variable expressivity.

Case presentation

We report the case of a 17?months old girl, who presented growth retardation and dysmorphic features. Postnatal growth was always below ??2 Standard Deviation for both weight and length and physical examination revealed relative macrocephaly, sparse hair, bulbous nasal tip, thin upper lip, protruding ears, prominent forehead, small jaw, and short hands and feet. Patient’s mother shared the same facial features, and presented sparse hair and small hands. The maternal grandfather and two uncles presented short stature, bulbous nasal tip, thin hair, and premature alopecia. Molecular analysis of TRPS1 gene showed a heterozygous c.2086C?>?T;(p.Arg696Ter) mutation both in the patient and her mother, confirming the diagnosis of TRPS, type I.

Conclusions

Clinical phenotype of TRPS can be subtle and the syndrome often remains undiagnosed. A comprehensive clinical examination and an exhaustive family history are crucial to reach the correct diagnosis, which is essential to perform adequate follow-up and timely therapeutic procedures.

     

Benign nocturnal alternating hemiplegia of childhood: A clinical and nomenclatural reappraisal

Objective

To describe the clinical spectrum of benign nocturnal alternating hemiplegia of childhood (BNAHC) including long-term follow-up data of previously published cases and to propose an underlying genetic cause of this disorder.

No relationship between mode of delivery and neonatal mortality and neurodevelopment in very low birth weight infants aged two years

Background

To compare neonatal mortality and neurodevelopmental outcomes at two years of age in very low birth weight infants (≤1500 g) born by cesarean with those by vaginal delivery.

Methods

In this retrospective, case-control study, we evaluated neonatal mortality, medical conditions and neurodevelopmental outcomes at two years of corrected age in 710 very low birth weight (VLBW) infants born between January 2005 and December 2010. Of the 710 infants, 351 were born by the cesarean and 359/710 by vaginal route.

Results

There were no significant differences in neonatal mortality between the cesarean delivery group and vaginal delivery group [56/351 (15.9%) vs. 71/359 (19.8%), P=0.20]. VLBW infants delivered by the cesarean procedure had a higher incidence of respiratory distress syndrome than those born by the vaginal route [221/351 (63.0%) vs. 178/359 (49.6%), P<0.001]. There were no differences in other neonatal morbidities, including intraventricular hemorrhage [126/351 (35.9%) vs. 134/359 (37.3%), P=0.69], bronchopulmonary dysplasia [39/351 (11%) vs. 31/359 (8.6%), P=0.38] and necrotising enterocolitis [40/351 (11.4%) vs. 32/359 (8.9%), P=0.32] between the two groups. The incidence of poor neurodevelopment after cesarean delivery was similar to that after vaginal delivery [105/351 (29.9) vs. 104/359 (29.0%), P=0.78].

Conclusions

In neither neurodevelopment nor neonatal mortality did cesarean birth offered significant advantages to VLBW infants. Moreover, the operation might be associated with an increased risk of respiratory distress syndrome for VLBW infants. The mode of delivery of VLBW infants should be largely based on obstetric indications and maternal considerations rather than perceived better outcomes for the neonate.