De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.

The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.

Predictive Performance of Population Pharmacokinetic Models for Amikacin in Term Neonates.

BACKGROUND AND OBJECTIVE: Amikacin is preferred in treating Gram-negative infections in neonates and it has a narrow therapeutic window. The population pharmacokinetic modeling approach can aid in designing optimal dosage regimens for amikacin in neonates. In this study, we attempted to identify the suitable population pharmacokinetic model from the published reports for the study population from an Indian setting. METHODS: Published population pharmacokinetic studies for amikacin in neonates were identified. Data on structural models and typical pharmacokinetic parameters were extracted from the studies. For the clinical study, neonates who met the inclusion criteria were enrolled in the study from the NICU, Kasturba Medical College, Manipal, during Jan 2020 to March 2022. Drug concentrations were estimated, and demographic and clinical data were collected. Identified population pharmacokinetic models were used to predict the amikacin concentrations in neonates. Predicted concentrations were compared against the observed concentrations. Differences between predicted and observed concentrations were quantified using statistical measures. The population pharmacokinetic model, which was able to predict the data well, is considered a suitable model for the study population. Dosing regimens were suggested for neonates using the pharmacometric simulation approach generated by the selected model. RESULTS: A total of 43 plasma samples were collected from 31 neonates. Twelve population pharmacokinetic models were found for amikacin in neonates. The predictive performance of the 12 studies was performed using clinical data. A two-compartment model reported by Illamola et al. predicted the amikacin concentrations better than other models. Illamola et al. reported creatinine clearance and body weight as the significant covariates impacting the pharmacokinetic parameters of amikacin. This model was able to predict the clinical data with 29.97% and 0.686 of relative median absolute prediction error and relative root mean square error, respectively, which is the best among the published models. The Illamola et al. model was selected as the final model to perform pharmacometric simulations for the subjects with different combinations of creatinine clearance and body weight. Dosage regimens were designed to attain target therapeutic concentrations for the virtual subjects and a nomogram was developed. CONCLUSIONS: The population pharmacokinetic model reported by the Illamola et al. model was selected as the final model to explain the clinical data with the lowest relative median absolute prediction error and relative root mean square error when compared with other models. An amikacin nomogram was developed for the neonates whose creatinine clearance and body weight ranged between 10 and 90 mL/min and between 2 and 4 kg, respectively. A developed nomogram can assist clinicians to design an optimal dosage regimen of amikacin for term neonates.

Preventable contributors to the neonatal healthcare-associated infections: a uni-center analytical study from South India.

BACKGROUND: Globally, neonatal healthcare-associated infections (HAIs) are known to cause high mortality. HAIs is a preventable condition related to the healthcare environment. The current study explored the contributors to neonatal HAIs in one of the largest tertiary care referral hospitals in South India. METHODS: Neonates from December 2016 to June 2018 were observed for the occurrence of healthcare-associated infections and compared with the matched control group. Various observations on neonatal demography, maternal contributors, and medical procedures were made and recorded to explore and analyse the contributors to neonatal HAIs. Univariate and multivariate analysis was carried out to find the contributors. The Odds ratio with 95% CI was also computed and reported. RESULTS: Bloodstream infection (83%) was prevalent among neonates; the maternal contributor was only preterm labor (Odds ratio of 11.93; 95% CI; 6.47-21.98; p<.05) to acquire HAIs. On univariate analysis, mechanical ventilation for > 3days duration, NIV for > five days, and PICC line insertion procedure were significant (p<0.05) contributors to neonatal HAIs. IV cannulation for more than three times in four consecutive days was found in 100(85%) neonates considered being associated with neonatal HAIs. On multivariate analysis, NIV, PICC line, preterm labor, and low birth weight were significant (p<0.05) contributors to neonatal HAIs. CONCLUSION: The increased duration of invasive and non-invasive therapeutic devices and catheters contributes to neonatal HAIs. Neonates are acquiring bloodstream infections; low birth weight (LBW) neonates are more susceptible to acquiring HAIs.

Efficacy and Utilization Patterns of Anti-Epileptic Drugs in the Management of Neonatal Seizures: A Comparative Exploration.

Background: Management of neonatal seizures with available limited guidelines across different gestation can cause long-term neurological and cognitive impairment. Objectives: To compare utilization and observe the efficacy of anti-epileptic drugs in the treatment of neonatal seizures. The association of hypoxic-ischemic encephalopathy with NS and the etiology of HIE were also determined. Subjects and Methods: A retrospective cohort study was conducted at a tertiary care hospital for a period of one year. It was approved by IEC prior to initiation. Participants: Neonates admitted for seizure management and perinatal asphyxia with hypoxic-ischemic encephalopathy were included in the study. Both term and preterm 267 neonates from January 2014 to July 2018 were retrospectively analyzed. The drugs with the fastest seizure resolution, least recurrence, and readmission rates were considered efficient. Phenobarbitone, levetiracetam, and phenytoin were compared as they were commonly prescribed. Inpatient medical records and hospital databases served as sources of information. Results: Phenobarbitone was commonly utilized, followed by phenytoin and levetiracetam. The commonly prescribed combination was phenobarbitone (first-line agent) and phenytoin (second-line agent). Phenobarbitone immediately resolved seizures (97, 75.1%) and had the least cases of seizure recurrences (53, 41.1%) and readmissions (20, 15.5%), making it most efficient. The best second-line agent was phenytoin, with the least seizure recurrence (4, 8.51%), least readmissions (7, 14.8%), and fastest resolution (25, 53.1%). Levetiracetam was an efficient third-line agent. Hypoxic-ischemic encephalopathy was the most observed cause of neonatal seizures. Conclusion: Phenobarbitone was observed as the most utilized and efficient anti-epileptic drug, followed by phenytoin and levetiracetam. Owing to limitations in this study, there is an alarming need for standardized clinical trials to establish thorough guidelines.

Umbilical Cord Blood Acid-Base Parameters and Lactate as Predictors of Subsequent Meconium Aspiration Syndrome in Neonates.

Meconium aspiration syndrome (MAS) in neonates born through meconium-stained amniotic fluid (MSAF) causes significant morbidity and mortality. Early recognition of at-risk neonates could help optimize treatment. The aim was to determine predictive characteristics of cord blood pH, base deficit and lactate with subsequent MAS. Receiver operating characteristic (ROC) curves with area under curve (AUC) were estimated. Among 231 MSAF complicated pregnancies, 25 (10.8%) had MAS. Mean cord pH was significantly lower in neonates with MAS compared to those without MAS (7.15 ± 0.11 vs. 7.26 ± 0.07; p < 0.001). Median lactate between the two groups [5.6 (7.5, 3.7) vs. 2.7 (4.5, 2.0)] and base deficit [-10.6 (-13.2, -4.2) vs. -3.7 (-6.3, -2.6)] also differed significantly (p = 0.01). ROC curve area for cord lactate, pH, and base deficit were 0.81, 0.79, and 0.75, respectively. The predictive cutoff values for pH, lactate, and base deficit were 7.20, 3.55 mmol/L, and -5.3 mmol/L, respectively.

Assessment of Role of Platelet Indices in the Occurrence of Retinopathy of Prematurity.

PURPOSE: Platelets have a major role in the regulation of angiogenesis. Platelets have proangiogenic factors like vascular endothelial growth factor, which causes neovascularization of immature retina. However, there is no conclusive evidence to show that platelet indices have a role in retinopathy of prematurity (ROP). This study is aimed at assessing the role of platelet indices in the occurrence and need for treatment of ROP. METHODS: This prospective cohort study included the screening of preterm babies (<37 weeks of gestation with birth weight <2000 g). The samples of platelet indices (mean platelet volume [MPV], platelet count [PLT], plateletcrit [PCT], and platelet distribution width [PDW]) collected within 1st week of life were obtained from the electronic medical records and correlated to ROP status. Statistical analysis was done using SPSS version 22, and the Chi-square test and odds ratio were used for analysis. RESULTS: A total of 300 preterm babies were screened, of whom, 55 (18.3%) babies had ROP changes. The association of the presence of ROP changes and platelet indices was not statistically significant (P value being MPV [0.22], PLT [0.58], PCT [0.98], and PDW [0.17]). Similarly, the requirement of treatment for ROP (Type I ROP) could not be correlated with abnormal platelet indices (odds ratio at 95% confidence interval - MPV [6 (0.44-81.44)], PLT [1.7 (0.25-11.37)], PCT [3 (0.44-20.90)], and PDW [0.32 (0.33-3.05)]). CONCLUSION: Abnormal platelet indices did not show any significant risk with the occurrence or need for treatment of ROP.

Neonatal PT Improves Neurobehavior and General Movements in Moderate to Late Preterm Infants Born in India: An RCT.

PURPOSE: To examine whether a structured neonatal physical therapy program (SNP) improves neurobehavior and general movements in moderate to late preterm (MLP) infants. METHODS: Sixty MLP infants participated in this clinical trial. After baseline assessment using the Neurobehavioral Assessment of Preterm Infant (NAPI) and Prechtl General Movements (GMs) Assessment, infants were randomly allocated to a usual care (n = 30) or an SNP group (n = 30) and continued receiving usual care. The SNP group received intervention for 90 minutes/day, 6 days/week until discharge. Changes in neurobehavior and GMs were assessed at hospital discharge. RESULTS: Changes in scores on scarf sign and motor development and vigor clusters of NAPI document an improvement in the SNP group. The proportion of infants with poor repertoire GMs also decreased more in the SNP group than in the usual care group. CONCLUSION: The SNP may be effective in improving some aspects of neurobehavior and quality of GMs in MLP infants. WHAT THIS ADDS TO THE EVIDENCE: The addition of a structured neonatal physical therapy program to usual care can promote neurobehavioral organization and improve the quality of general movements in moderate and late preterm infants in India.

Validation of an HPLC method for estimation of cefotaxime from dried blood spot: alternative to plasma-based PK evaluation in neonates.

Aim: Pharmacokinetic evaluation of cefotaxime in neonates is currently a challenge due to the large volume requirement of blood for its analysis by existing methods. A dried blood spot (DBS) based method is the best alternative. Materials & methods: We validated an HPLC method for estimation of cefotaxime from DBS and plasma. Extraction employed a simple procedure using acetonitrile and buffer. Selective separation of cefotaxime was achieved on a C8 column using gradient programming. Results & conclusion: The linearity of the method ranged from 2 to 200 µg/ml with acceptable precision and accuracy for both plasma and DBS. Hematocrit was not affecting the assay accuracy. A strong correlation and interchangeability observed with the plasma method proves its clinical validity for application to PK evaluations.

Lay abstract Cefotaxime is a widely used antibiotic in the neonatal population for treating bacterial infections. At the same time, determining the dosage for this antibiotic in the vulnerable population is always a challenge for the treating doctor. In the case of neonates, organs are not fully developed and their response to drugs will be different from that of adults. In the current clinical practice, dosage for neonates is deduced from pediatric dose without addressing this difference in the response. The major challenge in addressing this issue is the collection of blood by venipuncture from neonates for drug analysis. In this report, a microsampling technique called dried blood spot is used for sampling and bioanalysis of cefotaxime. The method is validated for estimation of cefotaxime from the neonatal blood.

Locus and allelic heterogeneity and phenotypic variability in Waardenburg syndrome.

Waardenburg syndrome (WS) is a disorder of neural crest cell migration characterized by auditory and pigmentary abnormalities. We investigated a cohort of 14 families (16 subjects) either by targeted sequencing or whole-exome sequencing. Thirteen of these families were clinically diagnosed with WS and one family with isolated non-syndromic hearing loss (NSHL). Intra-familial phenotypic variability and non-penetrance were observed in families diagnosed with WS1, WS2 and WS4 with pathogenic variants in PAX3, MITF and EDNRB, respectively. We observed gonosomal mosaicism for a variant in PAX3 in an asymptomatic father of two affected siblings. For the first time, we report a biallelic pathogenic variant in MITF in a subject with WS2 and a biallelic variant in EDNRB was noted in a subject with WS2. An individual with isolated NSHL carried a pathogenic variant in MITF. Blended phenotype of NSHL and albinism was observed in a subject clinically diagnosed to have WS2. A phenocopy of WS1 was observed in a subject with a reported pathogenic variant in GJB2, known to cause isolated NSHL. These novel and infrequently reported observations exemplify the allelic and genetic heterogeneity and show phenotypic diversity of WS.

NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses.

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

There is Only a Modest Increase in Neonatal Respiratory Morbidity Following Early Term Elective Cesarean in a South Indian Population.

OBJECTIVES: Elective cesarean deliveries (ECD) are still performed prior to 39 weeks. This study aimed to identify risk of neonatal respiratory morbidity (NRM) following ECD near term, in a South Indian population. Specifically, study aimed to measure the additional healthcare burden due to large number of ECDs performed prior to 39 weeks, in this local population. METHODS: We analyzed NRM among 1329 deliveries (584 ECD and 745 spontaneous vaginal delivery, SVD) in a tertiary hospital over 2 years. Neonates were grouped into: A: 35+0-36+6 weeks, B: 37+0-38+6 weeks, and C: ≥39 weeks. NRM was compared between ECD versus SVD. RESULTS: Majority (433/584) of ECDs were performed between 37+0 and 38+6 weeks. Overall, 32% received steroid prophylaxis. Of 1329 newborns, 18/584 (3.82%) in ECD and 6/745 (0.8%) in SVD group developed NRM (p value of 0.004, OR 3.9, CI 1.54-9.93). Need of respiratory support among ECD was 4.28% compared to 0.53% in SVD (p < 0.001, OR 8.28; CI 2.86-23.94). However, comparing neonates born by ECD between groups B Vs C; there was only a modest increase in NRM (2.07 vs 0.9%; p 0.48, OR 2.3 with CI 0.29-18.4) and in need of respiratory support (2.54 vs 0.9%; p 0.47, OR 2.84; CI 0.36-22.2). CONCLUSION: NRM following early term ECD continues to be a healthcare burden in India. Interestingly in this South Indian population, early term ECDs caused only modest increase in NRM, and this ethnic variation requires further evaluation to determine ideal time for ECD in local population.

A national survey of knowledge, attitude and practices among pediatricians towards newborn hearing screening in India.

INTRODUCTION: Pediatricians have a key role in ensuring that infant has undergone hearing screening and required follow-up. Attempts in various countries and centers have been made at exploring their knowledge, attitude and practices towards universal newborn hearing screening. In India, such a program is at its preliminary stage, and hence a need was felt to study this aspect in pediatricians working in India. METHOD: A cross-sectional online survey was carried out among 112 pediatricians working in India. The questionnaire was framed after reviewing the existing questionnaires. Descriptive statistics was used to summarize the findings. RESULTS: A response rate of 7.99% (112/1402) was obtained of which only 20.5% reported of availability of screening program in their work set-up. The majority of the pediatricians (95%) were aware of the newborn hearing screening while 98.3% were affirmative about the importance of screening of all infants. Very few pediatricians reported of a screening program in their set-up or in their close locality. Overall the pediatricians were confident about their knowledge on this topic yet expressed a need to know more about several intricacies about hearing screening. The pediatricians also provided an input on the most preferred method of receiving more information. SUMMARY AND CONCLUSION: The success of the universal newborn hearing screening program lies in the support and cooperation of health care providers such as pediatricians. The present study draws attention to the positive attitude and practices exhibited by them. It also sheds light on the knowledge gaps that are present and need the due attention of the policy makers. Further, it highlights the need for having more continuing medical education program and awareness drives for ensuring a better implementation of UNHS.

Follow-up in newborn hearing screening - A systematic review.

INTRODUCTION: The quality and efficiency of newborn hearing screening programs (NHS) rely heavily on appropriate follow-up. The Joint Committee on Infant Hearing recommends a follow-up rate of more than 95% of infants who fail the initial hearing screening. However, a 70% benchmark is considered to be more feasible. This high loss to follow-up (LTF) rate acts as a threat to the overall success of NHS programs. The objective of the study was to identify and examine the reported rates of LTF, attributed reasons for LTF and strategies undertaken to reduce LTF. METHODS: Using a systematic search, articles published between 2005 to December 2015 were identified from PubMed/Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Educational Resources Information Center (ERIC), Scopus, Ovid, ProQuest, and Cochrane Library. To be included in the review, the study should be exploring the loss to follow-up or drop-out rate in newborn hearing screening programs and be published in an indexed peer-reviewed journal in the English language. The main outcome measures were overall rate of LTF, factors leading to LTF and measures adopted to overcome LTF. RESULTS: 53 articles were short-listed for data extraction. Out of these, 27 were single-centre studies, 19 were multi-centre, 3 compared multiple databases, and 4 used survey-based methods. Overall LTF rates of 20% in single-centre and 21% in multiple-centre studies were observed. Educational disparity and lack of adequate knowledge among parents were associated with LTF. The most commonly used strategy to overcome LTF suggested by studies was the use of an adequate data management system. CONCLUSION: This review is a novel attempt to explore the LTF among NHS studies, reasons for LTF and strategies to reduce LTF. This review can act as a basis for planning and execution of effective NHS programs.

Knowledge and attitude of parents/caregivers towards hearing loss and screening in newborns - a systematic review.

OBJECTIVE: The parents/caregivers of a newborn play a pivotal role in the process of hearing screening and intervention. The decisions taken by them depend on their knowledge and attitude. The purpose of this study was to review the literature systematically on knowledge and attitude of parents/caregivers towards infant hearing loss and newborn hearing screening. DESIGN: A systematic search was conducted using electronic databases for the periods from 1990 to March 2016. Two authors scrutinized the studies and extracted the data based on predetermined criteria. STUDY SAMPLE: Ten studies. RESULTS: Ear discharge was correctly identified as a risk factor for hearing loss along with measles, drugs/medication, family history, congenital causes and noise exposure. The studies revealed mixed results for knowledge about newborn hearing screening. Overall, the parents/caregivers showed positive attitudes towards hearing screening and intervention options. However, due to heterogeneity in the studies, it's hard to derive a conclusion. CONCLUSIONS: The present review sheds light on the common areas of misconception among parents/caregivers about risk factors of infant hearing loss and newborn hearing screening. The review also draws attention to the need to have more studies exploring this knowledge and attitude of parents/caregivers among diverse populations.

Knowledge and attitude (KA) survey regarding infant hearing loss in Karnataka, India.

INTRODUCTION: The support provided and the decisions taken by mothers determine the success of Universal Newborn Hearing Screening (UNHS). Attempts at exploring the existing knowledge-attitude among mothers is crucial to create/modify the existing screening programs. The present study attempts to explore the knowledge and attitude toward infant hearing loss (HL) among mothers of newborns in the Indian state of Karnataka. METHOD: A cross-sectional survey was conducted among 219 mothers of newborns in Karnataka, India. The questionnaire was framed from existing literature and consisted of 19 questions assessing knowledge and attitude toward infant HL to be rated on a three-point scale (no, not sure, yes). Descriptive statistics and Cronbach's α were used to analyze the data. RESULTS: Mothers exhibited good knowledge of risk factors; noise (70.3%) and ear discharge (54.3%). More than 75% agreed that treatment for HL is available and that these children can attend school. The questions of superstitions and cultural beliefs yielded mixed responses. A large number of mothers expressed desire to have their children tested at birth (84.9%) and were concerned about their children's hearing (87.7%). Yet only 54.3% stated that they would allow their children to wear hearing aids. SUMMARY AND CONCLUSION: The present study is an attempt to understand the knowledge and attitude of mothers toward infant HL in Karnataka and facilitate identification of potential areas of less knowledge as a reference for endeavors of enhancement. It further highlights the need for implementing public awareness programs to improve knowledge and attitude of mothers toward infant HL for better implementation of UNHS.

Time to positivity of blood cultures in neonates.

Blood culture reports in neonatal sepsis aid physician in either optimizing therapy or discontinuing antibiotics. We determined the time taken for neonatal blood cultures to become positive using the aerobic BacT/Alert system. Of 944 blood cultures from 816 neonates, 139 (14.7%) were positive. Growth of all definitive bacteria, 95% of possible bacteria and 84% of fungi were detected within 48 hours of incubation.

Pfeiffer Syndrome with Extreme Proptosis, Hypothyroidism and Tail like Appendage.

Pfeiffer syndrome is a rare genetic disorder with combination of bicoronal craniosynostosis, broad thumbs, broad great toes, ankylosis of elbow and partial variable syndactyly of the hands and feet. Since the disorder was reported by Pfeiffer in 1964, new associations have been added on. Authors report a newborn with features of Pfeiffer syndrome type 3 with hypothyroidism, tail like appendage and extremely anteriorly placed anus as new associations.

A rare case of haemolytic disease of newborn with Bombay phenotype mother.

We are reporting a rare case of severe hemolytic disease of newborn (HDN) with Bombay phenotype mother. A retrospective study of a case with severe haemolytic disease of newborn with Bombay phenotype mother was done. Blood grouping, antibody screening, and lectin study was done on the blood sample of the baby and mother to confirm the diagnosis. Hematological and biochemical parameters were obtained from the hospital laboratory information system for the analysis. Blood group of the baby was A positive, direct antiglobulin test was negative. Blood group of the mother was confirmed to be Bombay phenotype, Hematological parameters showed all the signs of ongoing hemolysis and the bilirubin level was in the zone of exchange transfusion. Due to the unavailability of this rare phenotype blood unit, baby was managed conservatively. Anticipating the fetal anemia and HDN with mothers having Bombay phenotype and prior notification to the transfusion services will be of great help in optimizing the neonatal care and outcome.

Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation.

Costello syndrome is a rare developmental disorder characterized by coarse face, postnatal growth retardation, skin and musculoskeletal anomalies, cardiovascular abnormalities, mental retardation, and tumor predisposition. Dermatological manifestations usually include redundant, soft and thickened skin. Loose skin is especially present over the neck, hands, and feet. Heterozygous missense mutations in HRAS are causative for Costello syndrome, with the c.34G > A (p.G12S) mutation as the most commonly found alteration. In the majority of affected individuals pathogenic sequence changes appeared de novo, however, two individuals with somatic mosaicism for the HRAS mutation have been reported. Here, we describe a boy with somatic mosaicism for the c.34G > A mutation in HRAS. Allelic quantitation revealed the mutation in approximately 58% of his lymphocytes; however, in DNA derived from buccal cells we could not detect the sequence change. The patient presented with the typical clinical findings of Costello syndrome such as increased birth weight, severe failure to thrive, characteristic facial appearance, and skin abnormalities. The dermatological anomalies were remarkable as he showed severe skin laxity with wrinkling of skin on all parts of the body due to loss of subcutaneous fat that decreased significantly by age 13 months. This case further adds to the phenotypic variability seen in patients with somatic mosaicism for an HRAS mutation and highlights the awareness of mosaic mutations in Costello syndrome when molecular testing is performed.