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BackgroundDyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants inDYM. SMC2 is caused by variations inRAB33B. BothDYMandRAB33Bare important in intravesicular transport and function in the Golgi apparatus.MethodsDetailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirmDYMandRAB33Bvariants. Sanger sequencing of familial variants was done in all parents.Results24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height DYMorRAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) inRAB33B. The majority of these have not been reported previously.ConclusionThis large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare ‘Golgipathies’.

X-linked agammaglobulinemia (XLA) is an X-linked recessive primary immunodeficiency disorder caused due to a pathogenic variant in the Bruton tyrosine (BTK) gene with an incidence of 1:379,000 live births and 1:190,000 male births. Patients affected with XLA present with recurrent infections of the gastrointestinal and respiratory tracts. Here we report the first case series of 17 XLA patients of 10 South Indian families with a wide spectrum of clinical and genetic features. In our cohort, patients presented mainly with recurrent pneumonia, gastrointestinal infection, otitis media, pyoderma, abscesses, empyema, arthritis, and osteomyelitis. Using next-generation and Sanger sequencing we have identified 10 unique pathogenic and likely pathogenic variants in 17 patients. This encompasses three nonsynonymous, two stop-gain, two frameshifts, two structural, and one splicing variant, out of which two of them are novel. Based on the type of variant, patients had variable clinical features and treatment responses. We have also evaluated Btk protein expression for six patients in comparison to the healthy individuals and determined mosaic Btk expression patterns in four mothers. We have also performed family screening in 6 families using Sanger sequencing and identified 19 carriers for the variant. The diagnosis for the patients led to the proper treatment i.e. 15 patients were on intravenous immunoglobulin (IVIG) and the other two had successful hematopoietic stem cell transplantation (HSCT). Unfortunately, two of our patients died due to sepsis, while on IVIG. We envision the present study could help in better understanding of patients with XLA and help in family screening and prenatal diagnosis. To the best of our knowledge, this is the largest case series of patients affected with XLA from South India.

Mucolipidosis (ML) (OMIM 607840 & 607838) is a rare autosomal recessive inherited disorder that occurs due to the deficiency of golgi enzyme uridine diphosphate (UDP)- N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) responsible for tagging mannose-6-phosphate for proper trafficking of lysosomal enzymes to lysosomes. Variants in GlcNAc-phosphotransferase (GNPTAB (α, β subunits) and GNPTG (γ subunits) are known to result in impaired targeting of lysosomal enzymes leading to Mucolipidosis (ML) Type II or Type III. We analyzed 69 Indian families of MLII/III for clinical features and molecular spectrum and performed in silico analysis for novel variants. We identified 38 pathogenic variants in GNPTAB and 5 pathogenic variants in GNPTG genes including missense, frame shift, deletion, duplication and splice site variations. A total of 26 novel variants were identified in GNPTAB and 4 in GNPTG gene. In silico studies using mutation prediction software like SIFT, Polyphen2 and protein structure analysis further confirmed the pathogenic nature of the novel sequence variants detected in our study. Except for a common variant c.3503_3504delTC in early onset MLII, we could not establish any other significant genotype and phenotype correlation. This is one of the largest studies reported till date on Mucolipidosis II/III in order to identify mutation spectrum and any recurrent mutations specific to the Indian ethnic population. The mutational spectrum information in Indian patients will be useful in better genetic counselling, carrier detection and prenatal diagnosis for patients with ML II/III.

Neurological disorders are clinically heterogeneous group of disorders and are major causes of disability and death. Several of these disorders are caused due to genetic aberration. A precise and confirmatory diagnosis in the patients in a timely manner is essential for appropriate therapeutic and management strategies. Due to the complexity of the clinical presentations across various neurological disorders, arriving at an accurate diagnosis remains a challenge. We sequenced 1012 unrelated patients from India with suspected neurological disorders, using TruSight One panel. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect mutations in 197 genes in 405 (40%) cases and 178 mutations were novel. The highest diagnostic rate was observed among patients with muscular dystrophy (64%) followed by leukodystrophy and ataxia (43%, each). In our cohort, 26% of the patients who received definitive diagnosis were primarily referred with complex neurological phenotypes with no suggestive diagnosis. In terms of mutations types, 62.8% were truncating and in addition, 13.4% were structural variants, which are also likely to cause loss of function. In our study, we observed an improved performance of multi-gene panel testing, with an overall diagnostic yield of 40%. Furthermore, we show that NGS (next-generation sequencing)-based testing is comprehensive and can detect all types of variants including structural variants. It can be considered as a single-platform genetic test for neurological disorders that can provide a swift and definitive diagnosis in a cost-effective manner.

Mucolipidosis (ML) (OMIM 607840607838) is a rare autosomal recessive inherited disorder that occurs due to the deficiency of golgi enzyme uridine diphosphate (UDP)- N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) responsible for tagging mannose-6-phosphate for proper trafficking of lysosomal enzymes to lysosomes. Variants in GlcNAc-phosphotransferase (GNPTAB (α, β subunits) and GNPTG (γ subunits) are known to result in impaired targeting of lysosomal enzymes leading to Mucolipidosis (ML) Type II or Type III. We analyzed 69 Indian families of MLII/III for clinical features and molecular spectrum and performed in silico analysis for novel variants. We identified 38 pathogenic variants in GNPTAB and 5 pathogenic variants in GNPTG genes including missense, frame shift, deletion, duplication and splice site variations. A total of 26 novel variants were identified in GNPTAB and 4 in GNPTG gene. In silico studies using mutation prediction software like SIFT, Polyphen2 and protein structure analysis further confirmed the pathogenic nature of the novel sequence variants detected in our study. Except for a common variant c.3503_3504delTC in early onset MLII, we could not establish any other significant genotype and phenotype correlation. This is one of the largest studies reported till date on Mucolipidosis II/III in order to identify mutation spectrum and any recurrent mutations specific to the Indian ethnic population. The mutational spectrum information in Indian patients will be useful in better genetic counselling, carrier detection and prenatal diagnosis for patients with ML II/III.

Purpose :Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusión: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals. Sin financiación 8.822 JCR(2020) Q1, 15/176 Genetics & Heredity 3.509 SJR (2020) Q1, 7/96 Genetics (clinical) No data IDR 2020 UEM

Mucolipidosis-IIIγ (ML-IIIγ) is a recessively inherited slowly progressive skeletal dysplasia caused by mutations in GNPTG. We report the genetic and clinical findings in the largest cohort with ML-IIIγ so far: 18 affected individuals from 12 families including 12 patients from India, five from Turkey, and one from the USA. With consanguinity confirmed in eight of 12 families, molecular characterization showed that all affected patients had homozygous pathogenic GNPTG genotypes, underscoring the rarity of the disorder. Unlike ML-IIIαβ, which present with a broader spectrum of severity, the ML-III γ phenotype is milder, with onset in early school age, but nonetheless thus far considered phenotypically not differentiable from ML-IIIαβ. Evaluation of this cohort has yielded phenotypic findings including hypertrophy of the forearms and restricted supination as clues for ML-IIIγ, facilitating an earlier correct choice of genotype screening. Early identification of this disorder may help in offering a timely intervention for the relief of carpal tunnel syndrome, monitoring and surgery for cardiac valve involvement, and evaluation of the need for joint replacement. As this condition may be confused with rheumatoid arthritis, confirmation of diagnosis will prevent inappropriate use of immunosuppressants and disease-modifying agents. info:eu-repo/semantics/publishedVersion

Fungal phytopathogens pose a serious threat to global crop production. Only a handful of strategies are available to combat these fungal infections, and the increasing incidence of fungicide resistance is making the situation worse. Hence, the molecular understanding of plant–fungus interactions remains a primary focus of plant pathology. One of the hallmarks of host–pathogen interactions is the overproduction of reactive oxygen species (ROS) as a plant defense mechanism, collectively termed the oxidative burst. In general, high accumulation of ROS restricts the growth of pathogenic organisms by causing localized cell death around the site of infection. To survive the oxidative burst and achieve successful host colonization, fungal phytopathogens employ intricate mechanisms for ROS perception, ROS neutralization, and protection from ROS-mediated damage. Together, these countermeasures maintain the physiological redox homeostasis that is essential for cell viability. In addition to intracellular antioxidant systems, phytopathogenic fungi also deploy interesting effector-mediated mechanisms for extracellular ROS modulation. This aspect of plant–pathogen interactions is significantly under-studied and provides enormous scope for future research. These adaptive responses, broadly categorized into “escape” and “exploitation” mechanisms, are poorly understood. In this review, we discuss the oxidative stress response of filamentous fungi, their perception signaling, and recent insights that provide a comprehensive understanding of the distinct survival mechanisms of fungal pathogens in response to the host-generated oxidative burst., The oxidative burst mounted during early plant infection disrupts the cellular redox homeostasis of fungal phytopathogens. To curb the oxidative damage, various stress-responsive signaling cascades and antioxidant defense systems are activated in the pathogenic fungi. They also employ an arsenal of secreted effectors to modulate host-generated reactive oxygen species through diverse mechanisms to promote successful host colonization.

Mucopolysaccharidoses (MPS), a subgroup of lysosomal storage disorders, are caused due to deficiency of specific lysosomal enzyme involved in catabolism of glycosaminoglycans. To date more than 200 pathogenic variants in the alpha-l-iduronidase (IDUA) for MPS I and ∼500 pathogenic variants in the iduronate-2-sulphatase (IDS) for MPS II have been reported worldwide. The mutation spectrum of MPS type I and MPS type II disorders in Indian population is not characterized yet. In this study, we carried out clinical, biochemical, molecular and in silico analyses to establish the mutation spectrum of MPS I and MPS II in the Indian population. We conducted molecular analysis for 60 MPS-affected patients [MPS I (n = 30) (Hurler syndrome = 17, Hurler-Scheie syndrome = 13), and MPS II (n = 30) (severe = 18, attenuated = 12)] and identified a total of 44 [MPS I (n = 22) and MPS II (n = 22)] different pathogenic variants comprising missense, nonsense, frameshift, gross deletions and splice site variants. A total of 20 [MPS I (n = 14), and MPS II (n = 6)] novel pathogenic sequence variants were identified in our patient cohort. We found that 32% of pathogenic variants detected in IDUA were recurrent and 25% in MPS II. This is the first study revealing the mutation spectrum of MPS I and MPS II patients in the Indian population.

To describe the varying phenotypic spectrum of Focal Dermal Hypoplasia (FDH) and to emphasize the need for identifying the condition in mildly affected females which is crucial for offering a prenatal diagnosis in subsequent pregnancy owing to the risk of having a severely affected baby. The phenotype-genotype correlation of 4 patients with FDH, over a period of 11 y from the genetic clinic in a tertiary care centre from Kerala, India was done. All four mutation proven patients were females (2 adults and 2 children). One of the adult female subjects were mildly affected, though she had a history of having a severely affected female child who expired on day six. Among the 2 affected children, one of them had an unaffected mother and the other had an affected mother. FDH has a wide clinical spectrum from very subtle findings to severe manifestations. The lethality of the condition in males and the disfigurement and multisystem involvement in females highlights the importance of confirmation of diagnosis by molecular analysis so that the family can be offered prenatal diagnosis in subsequent pregnancy.

Pycnodysostosis is an autosomal recessive skeletal dysplasia caused by pathogenic variants in the cathepsin K (CTSK) gene. We report seven patients from four unrelated families with this condition in whom we have identified three novel pathogenic variants, c.120 + 1G > T in intron 2, c.399 + 1G > A in intron 4, and c.148T > G (p.W50G) in exon 2, and a known variant, c.568C > T (p.Q190*) in exon 5 of CTSK. We present the clinical, radiographic, and molecular findings of all individuals with molecularly proven pycnodysostosis from the present cohort. We also report the occurrence of giant cell tumor in the skull of a patient with this condition.

Screening flowchart. (PDF 196 kb)

SPIRIT checklist. (PDF 77 kb)

Preparation for magnetic resonance imaging. (PDF 303 kb)

Magnetic resonance (3 Tesla) protocol. (PDF 821 kb)

Ob­jec­ti­ve: Robinow syndrome (RS) is an extremely rare genetic disorder characterized by short-limbed dwarfism, defects in vertebral segmentation and abnormalities in the head, face and external genitalia. Mutations in the ROR2 gene cause autosomal recessive RS (RRS) whereas mutations in WNT5A are responsible for the autosomal dominant (AD) form of RS. In AD Robinow patients, oral manifestations are more prominent, while hemivertebrae and scoliosis rarely occur and facial abnormalities tend to be milder. Methods: Three unrelated patients from different parts of India were studied. These patients were diagnosed as RRS due to presence of characteristic fetal facies, mesomelia, short stature, micropenis, hemivertebrae and rib abnormalities. One of the patients had fetal facies and micropenis but unusually mild skeletal features. This patient’s mother had mild affection in the form of short stature and prominent eyes. Testosterone response to human chorionic gonadotropin was investigated in two patients and were normal. The exons and exon-intron boundaries of the ROR2 gene were sequenced for all probands. Bioinformatics analysis was done for putative variants using SIFT, PolyPhen2 and Mutation Taster. Results: Patients 1, 2 and 3 were homozygous for c.G545A or p.C182Y in exon 5, c.227G>A or p.G76D in exon 3 and c.668G>A or p.C223Y in exon 6 respectively. Prenatal diagnosis could be performed in an ongoing pregnancy in one family and the fetus was confirmed to be unaffected. Conclusion: ROR2 mutations were documented for the first time in the Indian population. Knowledge of the molecular basis of the disorder served to provide accurate counseling and prenatal diagnosis to the families.

To describe the spectrum of congenital heart disease in children with Down syndrome and their cytogenetic profile (and that of parents of those with translocation), and thyroid profile. A cross sectional study was conducted in 418 consecutive patients with Down syndrome attending the Department of Pediatric Genetics from a tertiary care centre in Kerala with a comprehensive Pediatric Cardiac Program, from November 2005 through April 2012. All children were offered cytogenetic analysis and were subjected to echocardiography. Parental karyotyping was offered for children with translocation type of Down syndrome. The thyroid profiles of all children were checked at the first visit and once every 6 mo during follow up. Congenital heart disease was present in 256 (63.4 %) of 404 children with Down syndrome. Ventricular septal defect (72; 28.1 %) was the commonest, followed by atrio-ventricular septal defect (70; 27.3 %) and patent ductus arteriosus (43; 16.8 %). Surgical correction was accomplished in 104 (40.6 %) with excellent intermediate-term outcomes. Three hundred eighty seven of 418 children (92.6 %) underwent cytogenetic tests. The abnormalities included non-disjunction (340, 87.8 %), translocation (33, 8.5 %) and mosaicism (12, 3.1 %). Hypothyroidism was detected in 57 children (13.6 %). The prevalence of congenital heart disease in children with Down syndrome in Kerala is the highest reported (63.4 %). Ventricular septal defect is the most common heart disease in the present study. The results highlight the changing attitudes of families towards the surgical correction of congenital heart disease in children with Down syndrome. Prevalence of hypothyroidism in Down syndrome in Kerala is 13.6 %.

Background: Low birth weight is the major determinant of mortality, morbidity and disability in infancy and childhood and has a long-term impact on health outcome in adult life. The objectives of this study were to study the relationship between maternal anemia and birth weight of babies and to study anthropometric measures of babies born to anemic and non-anemic mothers and to correlate the timing of anemia with birth weight of babies.Methods: Term babies born in Institute of Maternal and Child Health, Government Medical College, Kozhikode from November 2014 to October 2016 fulfilling the criteria were divided into 2 groups, cases (term babies with birth weight 2500g) and studied and their maternal hemoglobin values were compared.Results: Maternal anaemia in all three trimesters was found to be more in cases compared to controls. Mean 1st trimester hemoglobin of cases was 10.68 g/dl which was significantly lower when compared to controls. Mean 2nd trimester hemoglobin of cases was 10.36 g/dl compared to 11.47 g/dl in controls. Mean 3rd trimester hemoglobin of cases was 10.42 g/dl which was also significantly lower compared to 11.32 g/dl in controls. SGA babies were also found to be more in cases, 89%, compared to 18% in controls. The difference in head circumference between two groups was not statistically significant. Mean length of babies were higher in controls compared to cases. Mothers with anemia at any time during pregnancy was found to have 4.3 times higher risk of giving birth to low birth weight babies compared to non-anemic mothersConclusion: Anemia during pregnancy is a risk factor for low birth weight and SGA, independent of the trimester. Length of babies born to anaemic mothers is also low. But it does not have a significant effect on head circumference of babies.

Background: Advances in neonatal care since the early days have led to an increase of survival in preterm infants. Developmental sequelae, however are still a major problem mostly because babies who would previously have been expected to die are now surviving due to neonatal intensive care. There is scarcity of data regarding the outcome of prematurity from low and middle-income countries like India in literature.Methods: 140 preterm babies born at or before 34 weeks of gestation were enrolled and followed up for 1 year. All babies were screened for retinopathy of prematurity and hearing impairment. Anthropometric measurements were taken at 40 weeks, 3 months, 6 months, 9 months and 12 months of corrected age. Neurodevelopmental assessment was done using the Bayley scales of infant and toddler development III at 1 year of age.Results: Among 140 preterm babies, 6 babies expired before 1 year. Majority had catch up growth by 1 year of age. Growth and neurodevelopment were inversely proportional to birth weight and gestational age. Incidence of severe ROP requiring intervention was 8.6% and hearing aid was needed in 4%. At 1 year 24% had cognitive delay, 27% had language delay and 29% had motor delay. Intraventricular hemorrhage, culture proven sepsis, shock and DIC in newborn period were strong predictors of neurodevelopmental impairment.Conclusions: Majority of preterm babies showed catch up growth and had good neuro developmental outcome at 1 year of corrected age.

Restrictive dermopathy is a rare entity that is fatal in the neonatal period itself. The rigidity of the skin leads to erosions, contractures, and restriction of respiratory movements. Diagnosis is often made clinically with classical features such as low-set ears, micrognathia, small, and persistently open fixed “o”-shaped mouth, translucent, shiny, rigid skin with prominent superficial blood vessels, and pseudocontractures of limb joints. We report two cases of restrictive dermopathy observed in our center within 2 years period and suggest that this condition may not be as rare as believed.

Glutaric acidemia I (GA I, #231670) is one of the treatable, autosomal recessively inherited metabolic disorders. Macrocephaly, acute encephalitis-like crises, dystonia and characteristic frontotemporal atrophy are the hallmarks of this disease. In this communication, we present the clinical, biochemical and molecular profile of seventeen GA I patients from 15 unrelated families from India and report seven novel mutations in GCDH gene (c.281G>A (p.Arg94Gln), c.401A>G (p.Asp134Gly), c.662T>C (p.Leu221Pro), c.881G>C (p.Arg294Pro), c.1173dupG (p.Asn392Glufs*5), c.1238A>G (p.Tyr413Cys) and c.1241A>C (p.Glu414Ala)). Out of these, c.662T>C (p.Leu221Pro) in exon 8 and c.281G>A (p.Arg94Gln) allele in exon 4 were low excretor alleles, whereas c.1241A>C (p.Glu414Ala), c.1173dupG and c.1207C>T (p.His403Tyr) in exon 11 were high excretor alleles. We conclude that c.1204C>T (p.Arg402Trp) is probably the most common mutant allele. Exons 11 and 8 are the hot spot regions of GCDH gene in Indian patients with GA I. An early diagnosis and timely intervention can improve the underlying prognosis. Molecular confirmation is helpful in providing genetic counselling and prenatal diagnosis in subsequent pregnancy.

UnlabelledAlthough brain injury after neonatal encephalopathy has been characterised well in high-income countries, little is known about such injury in low- and middle-income countries. Such injury accounts for an estimated 1 million neonatal deaths per year. We used magnetic resonance (MR) biomarkers to characterise perinatal brain injury, and examined early childhood outcomes in South India.MethodsWe recruited consecutive term or near term infants with evidence of perinatal asphyxia and a Thompson encephalopathy score ≥6 within 6 h of birth, over 6 months. We performed conventional MR imaging, diffusion tensor MR imaging and thalamic proton MR spectroscopy within 3 weeks of birth. We computed group-wise differences in white matter fractional anisotropy (FA) using tract based spatial statistics. We allocated Sarnat encephalopathy stage aged 3 days, and evaluated neurodevelopmental outcomes aged 3½ years using Bayley III.ResultsOf the 54 neonates recruited, Sarnat staging was mild in 30 (56%); moderate in 15 (28%) and severe in 6 (11%), with no encephalopathy in 3 (6%). Six infants died. Of the 48 survivors, 44 had images available for analysis. In these infants, imaging indicated perinatal rather than established antenatal origins to injury. Abnormalities were frequently observed in white matter (n = 40, 91%) and cortex (n = 31, 70%) while only 12 (27%) had abnormal basal ganglia/thalami. Reduced white matter FA was associated with Sarnat stage, deep grey nuclear injury, and MR spectroscopy N-acetylaspartate/choline, but not early Thompson scores. Outcome data were obtained in 44 infants (81%) with 38 (79%) survivors examined aged 3½ years; of these, 16 (42%) had adverse neurodevelopmental outcomes.ConclusionsNo infants had evidence for established brain lesions, suggesting potentially treatable perinatal origins. White matter injury was more common than deep brain nuclei injury. Our results support the need for rigorous evaluation of the efficacy of rescue hypothermic neuroprotection in low- and middle-income countries.

Glutaric acidemia I (GA I, #231670) is one of the treatable, autosomal recessively inherited metabolic disorders. Macrocephaly, acute encephalitis-like crises, dystonia and characteristic frontotemporal atrophy are the hallmarks of this disease. In this communication, we present the clinical, biochemical and molecular profile of seventeen GA I patients from 15 unrelated families from India and report seven novel mutations in GCDH gene (c.281G>A (p.Arg94Gln), c.401A>G (p.Asp134Gly), c.662T>C (p.Leu221Pro), c.881G>C (p.Arg294Pro), c.1173dupG (p.Asn392Glufs*5), c.1238A>G (p.Tyr413Cys) and c.1241A>C (p.Glu414Ala)). Out of these, c.662T>C (p.Leu221Pro) in exon 8 and c.281G>A (p.Arg94Gln) allele in exon 4 were low excretor alleles, whereas c.1241A>C (p.Glu414Ala), c.1173dupG and c.1207C>T (p.His403Tyr) in exon 11 were high excretor alleles. We conclude that c.1204C>T (p.Arg402Trp) is probably the most common mutant allele. Exons 11 and 8 are the hot spot regions of GCDH gene in Indian patients with GA I. An early diagnosis and timely intervention can improve the underlying prognosis. Molecular confirmation is helpful in providing genetic counselling and prenatal diagnosis in subsequent pregnancy.

Item does not contain fulltext We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints.

We present the first mutation proven case of Fanconi-Bickel syndrome, a rare type of glycogen storage disease, from India. A four-year-old girl presented with severe growth retardation, genu varum and hepatomegaly. Investigations confirmed severe hypophosphatemic rickets and Fanconi syndrome. Molecular analysis confirmed a homozygous deletion insertion mutation in Glut 2 gene.

Crigler-Najjar syndrome type 2 is a rare cause for persistent unconjugated hyperbilirubinemia, inherited in an autosomal recessive manner. Even though it is compatible with normal life span, in the absence of prompt suspicion and intensive management it can prove fatal not only in the neonatal period but also during adult life. Here, we describe a case with a novel homozygous UGT1A1 p.Pro176Leu mutation.

Background Although neonatal encephalopathy (NE), accounts for 1 million neonatal deaths annually in low-and middle-income countries (LMIC), underlying brain injury and long term outcomes are not well characterised in LMIC. Objective To examine cerebral injury (using magnetic resonance (MR) biomarkers), and early childhood outcomes after NE in a government hospital in India. Design/Methods We recruited 54 newborns (>36 wk and >1.8 kg) with NE (Thompson score ≥6) at age Results MR data available from 44 cases showed evidence of acute perinatal injury. WM changes were seen in 40(91%), basal ganglia/thalamic (BGT) injury in 12(27%). Six infants died neonataly, 16(42%) and had adverse neurodevelopmental outcome. TBSS showed a reduction in FA with adverse neurological outcomes, and in those who had moderate/severe BGT or cortical injury. Conclusions Cerebral injury in this cohort appears to be of perinatal origin and may be amenable to treatment. Although NE stage and injury pattern was mild in the majority of infants, adverse outcomes were seen in 42% at 3½ years. Reduced WM FA was associated with adverse neurodevelopmental outcomes.

Background Therapeutic hypothermia improves outcomes after neonatal encephalopathy in high-income countries, however the safety and efficacy of cooling in low- and middle-income countries (LMIC) is not known. Objective To examine the feasibility of whole body cooling using an inexpensive servo-controlled cooling device developed for use in LMIC. Design We recruited 28 newborns (>36 wk and >1.8 kg) aged Results 4/16(25%) infants with moderate encephalopathy, and 8/12(67%) with severe encephalopathy died. Thrombocytopenia was seen in 19(68%) infants, gastric bleeds in 10(36%), persistent acidosis in 1(4%) and sclerema in 1(4%). Mean (SD) age and temperature at start of cooling was 4.1(1.1) h, and 35.7(1.5) ° C respectively. Mean (SD) induction time was 79(47) minutes, core temperature during cooling was 33.5(0.1) ° C, and passive re-warming rate was 0.3(0.1) ° C/h (Figure). The ambient temperature of the intensive care unit was 26–33 ° C. No additional nursing input was required to maintain cooling except refilling the machine with water every 6–8h. The cooling mattress had to be replaced once during the six month study period. Conclusions Effective therapeutic hypothermia can be provided using Tecotherm-HELIX with minimal additional nursing input in LMIC. Future clinical trials should examine the safety and efficacy of cooling in these settings.