Severe Feeding Difficulties Research Articles

Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases.

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine–Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani–Bhoj–Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.

Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features.

The Polycomb group (PcG) gene RNF2 (RING2) encodes a catalytic subunit of the Polycomb repressive complex 1 (PRC1), an evolutionarily conserved machinery that post-translationally modifies chromatin to maintain epigenetic transcriptional repressive states of target genes including Hox genes. Here, we describe two individuals, each with rare de novo missense variants in RNF2. Their phenotypes include intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Population genomics data suggest that RNF2 is highly constrained for loss-of-function (LoF) and missense variants, and both p.R70H and p.S82R variants have not been reported to date. Structural analyses of the two alleles indicate that these changes likely impact the interaction between RNF2 and BMI1, another PRC1 subunit or its substrate Histone H2A, respectively. Finally, we provide functional data in Drosophila that these two missense variants behave as LoF alleles in vivo. The evidence provide support for deleterious alleles in RNF2 being associated with a new and recognizable genetic disorder. This tentative gene-disease association in addition to the 12 previously identified disorders caused by PcG genes attests to the importance of these chromatin regulators in Mendelian disorders.

Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG.

Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man5 GlcNAc2 consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.

Bainbridge-Roper syndrome: A rare case of developmental delay

ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features – postulated by Bainbridge et al. were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe an uncertain variant present in Exon 11 of ASXL3(+) heterozygous zygosity in a female child with clinical features: truncal muscular hypotonia with significant motor delay, profound speech impairment, intellectual disability and a characteristic dysmorphic facies phenotype (open mouth, full lips, depressed nasal bridge, metopic prominence, microcephaly (45.5.cm), with camptodactyly and dysplastic fingers). Hence, we are reporting a rare case of developmental delay.

PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations.

Phosphatidylinositol Glycan Anchor Biosynthesis class H (PIGH) is an essential player in the glycosylphosphatidylinositol (GPI) synthesis, an anchor for numerous cell membrane‐bound proteins. PIGH deficiency is a newly described and rare disorder associated with developmental delay, seizures and behavioral difficulties. Herein, we report three new unrelated families with two different bi‐allelic PIGH variants, including one new variant p.(Arg163Trp) which seems associated with a more severe phenotype. The common clinical features in all affected individuals are developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies. The two siblings homozygous for the p.(Arg163Trp) variant have severe symptoms including profound psychomotor retardation, intractable seizures, multiple bone fractures, scoliosis, loss of independent ambulation, and delayed myelination on brain MRI. Serum iron levels were significantly elevated in one individual. All tested individuals with PIGH deficiency had normal alkaline phosphatase and CD16, a GPI‐anchored protein (GPI‐AP), was found to be decreased by 60% on granulocytes from one individual. This study expands the PIGH deficiency phenotype range toward the severe end of the spectrum with the identification of a novel pathogenic variant.

Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report

BackgroundAcroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes.Case presentationThe patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability.Discussion and conclusionsKey challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.

Parental feeding concerns of infants and young children with oesophageal atresia.

Feeding problems have been described in young children with oesophageal atresia (OA). The primary aim of this study was to determine the specific concerns of parents and carers of infants and young children with OA regarding introducing solids and moving up to family foods. A questionnaire was developed for parents and carers of infants and children with OA, aged 12 months to 6 years. Questionnaires were completed by 20 parents attending a multidisciplinary OA clinic between June 2016 and June 2017. Demographics and parental concern regarding feeding milestones were collected. The Montreal Children's Hospital Feeding Scale was completed. The majority of children (95%) had type C OA. Eleven (55%) parents agreed/strongly agreed that they were concerned about their child's feeding prior to the introduction of solids and about moving to more textured solids. The most common concern was choking and food impaction for both time points. Twelve (60%) parents agreed/strongly agreed that the majority of mealtimes in their child's first 1-2 years of life were stressful. Thirteen (65%) parents reported avoiding particular foods due to their child's OA. The majority of children (n = 17) had no feeding difficulty according to an objective scale, and the rest had minor difficulty. Parental concern around feeding still exists in infants and children without a severe feeding difficulty. Multidisciplinary involvement, including a dietitian and speech pathologist, from an early age is important for infants and children with OA.

Feeding characteristics of infants in a lower-middle-income country.

To describe feeding characteristics (such as breast feeding and complementary feeding) and determine the nature of feeding difficulties of infants in a primary health-care clinic (PHC) in South Africa. A total of 200 infants aged 6-12 months (mean = 8.54, standard deviation = 2.18) received a feeding screening by a speech-language therapist at a PHC in a semi-urban area using the Montreal Children's Hospital-Feeding Scale (MCH-FS). Children who failed screening underwent further clinical feeding evaluation using the Schedule of Oral Motor Assessment. The sample consisted of 200 participants, and most participants (n = 174; 87%) received breastfeeding, irrespective of their mothers' human immunodeficiency virus status. The longer the breastfeeding period, the less likely parents were to show concern about infants' feeding (P = 0.035). Complementary feeding was introduced between 6 and 8 months (n = 122; 82%). The MCH-FS identified 13 participants with feeding difficulties (6.5%), of which 11 were diagnosed with oral motor dysfunction (OMD) using the Schedule of Oral Motor Assessment. The 6.5% (n = 13) that failed had mild (n = 8; 61.5%), moderate (n = 2; 15.4%) and severe (n = 3; 23.1%) feeding difficulties, as reported by care givers using the MCH-FS. The MCH-FS showed that distraction during meals/following infants (n = 42; 21%); food refusal (n = 31; 15.5%); care giver unease about feeding (n = 29; 14.5%); and problems with vomiting, gagging or spitting (n = 28; 14%) were characteristics of feeding in this sample. Participants in the age groups 6 (n = 3; 27.3%) and 10 months (n = 3; 27.3%) were prone to OMD. This study is the first of its kind to describe the feeding characteristics of a group of infants during the transitional feeding stage in late infancy in South Africa. Important findings were the existence of OMD in 11 infants and feeding difficulties during transitional feeding in 13 infants. The study's findings may be used as a starting point for larger-scale studies in a similar setting, investigating the development of future care giver education and health-care professional training programmes regarding transitional feeding. Research endeavours by speech-language therapists need to prioritise late infancy and transitional feeding in order to prevent possible difficulties arising from sub-optimal care giver feeding practices. The study may be valuable to all health-care providers in PHC.

P.109Congenital myopathy in patients with Kabuki and Au-Kline syndromes - Double trouble or expansion of the phenotypes?

Congenital myopathies (CM) are heterogeneous neuromuscular disorders with hypotonia and weakness, often from birth, classified on the morphological features on muscle biopsy. Cardiac muscle involvement, facial dysmorphisms and involvement of the heart and other organs is well recognized. Here we describe 5 unrelated patients with clinical and histopathological features of CM, assessed in two tertiary UK neuromuscular centers, later diagnosed with Kabuki (KS) or Au-Kline syndrome (AUS). KS and AUS are multisystem disorders, with overlapping features such as distinctive facial dysmorphisms, hypotonia, intellectual disability, growth and skeletal defects and congenital heart defects (CHD). Age of patients ranged from 2 to 13 years. Onset was at birth, with hypotonia, global developmental delay, dysmorphisms, CHD and severe feeding difficulties. On examination patients were hypotonic, but muscle strength was overall satisfactory. Three patients were hypermobile, one had hemivertebrae and one congenital hip dislocation. Microcephaly, Chiari I malformation and craniosynostosis was seen in one patient, each. Three patients had hearing loss. One patient had 3 rhabdomyolysis episodes triggered by viral infections. Respiratory chain enzyme analysis, performed in 3 patients, was normal. Analysis of genes for CM and syndromic conditions with learning disability and CHD identified pathogenic heterozygous variants in the KMT2D (3 patients with KS) or HNRNPK gene (1 patient with AUS), confirming their diagnoses (test ongoing in 5th patient). Muscle biopsies in 3 KMT2D patients showed mild non-specific changes and increased central nuclei with markedly abnormal myofibre architecture in the third case. Biopsy of the patient with variants in HNRNPK showed striking congenital fibre type disproportion. This is the first report of myopathology in KS and AUS patients and might suggest a link between the proteins disrupted in these conditions and muscle structure.

Health-related quality of life in children after laparoscopic gastrostomy placement

IntroductionA gastrostomy placement (GP) is an established treatment to provide enteral feeding in pediatric patients with feeding difficulties aiming to improve nutritional status and health-related quality of life (HRQoL). The aim of this study was to evaluate HRQoL in children with severe feeding difficulties who have undergone GP.Materials and methodsA cross-sectional study was performed including 128 patients who had undergone laparoscopic GP (2004–2011). HRQoL was evaluated using the validated Pediatric Quality of Life 4.0 Inventory. Multiple regression analysis was performed to identify predictors of HRQoL.ResultsAfter a mean follow-up of 4.0 years (interquartile range 2.9–6.2) after GP, mean HRQoL was 53.0 out of 100 (standard deviation 21.1). HRQoL was significantly lower in children with neurologic impairment, with a mean difference of −21.4 points between neurologically impaired and neurologically normal children (p < 0.001). HRQoL was also lower in children with cardiac disease (−19.0 points; p = 0.01) and in children with a history of previous gastrointestinal surgery (−15.2 points; p = 0.03). Feeding through a gastrojejunostomy tube (−33.0 points; p = 0.01) and higher age at the time of operation (−1.2 points per year; p = 0.03) were also associated with lower HRQoL. GP-related complications requiring reintervention were associated with lower HRQoL, although this association was not statistically significant (p = 0.06).ConclusionsChildren with severe feeding difficulty, who have undergone GP, have significantly lower HRQoL compared to a healthy pediatric population. Neurologic impairment, cardiac disease, a history of gastrointestinal surgery, older age, and the need for jejunal feeding through the gastrostomy were predictive of even lower HRQoL.

P2B.18: Feeding difficulties in children with Intestinal Failure

Introduction: Children with intestinal failure (IF) may be at risk for developing feeding difficulties given the negative stimuli associated with feeding, chronic illness and prolonged hospitalization. There is no literature on the prevalence of feeding difficulties in the IF population, its associated factors or intervention strategies. As a first step, we sought to screen for the frequency of the feeding difficulties and eating behaviours in children and herein provide the results of a preliminary sample. Methods:Children who were greater than 1 year of age with IF and on home PN for > 3 months were included from two centres: Alberta Children’s Hospital (ACH), Canada and Hôpital Necker-Enfants Malades, France. The validated MCH-Feeding Scale was used to screen for mild, moderate and severe feeding difficulty. The validated parent-rated Child Eating Behaviour Questionnaire (CEBQ) was used to screen for eating styles and food avoidant behaviours. Results: Preliminary data was gathered for n=34 subjects, median age 6 years with diagnoses of short bowel syndrome (n=22), chronic intestinal pseudo-obstruction (n=4), or other (n=8). Analysis of the MCH-Feeding Scale indicated that 24% of the subjects had no feeding difficulty, while 29%, 18%, and 29% reported mild, moderate and severe difficulty respectively. The subset of n=21 completing the CEBQ rated very high on food fussiness, very high on food enjoyment and very low for emotional over-eating relative to the UK reference sample (Fig 1). In particular, the ACH children scored very high on satiety responsiveness. Conclusions: Preliminary data indicate that approximately half of children with IF have moderate to severe eating difficulties. Interestingly, both food fussiness and enjoyment of food are more commonly featured eating behaviours in this sample. It is unclear whether the feeding difficulties of children with IF are related to the impact of the disease etiology and severity, early feeding history, degree of gastrointestinal symptomatology and/or attempts to assert some control. Future work will examine how IF specific factors including the use of tube feeds are associated with feeding difficulties.

DOZ047.20: Growth, feeding difficulties, and developmental scores in children born with esophageal atresia: a single-center study

Abstract Background Children with repaired tracheoesophageal fistula/oesophageal atresia (TOF/OA) often have ongoing feeding difficulties and poor growth related to esophageal dysmotility, strictures, gastroesophageal reflux, aspiration, and respiratory infections. The impact of neurocognitive development on feeding in this cohort is less well studied. Objective The objective of this study was to investigate the growth, parent-reported feeding difficulties, and developmental scores of children with TOF/OA at The Children's Hospital at Westmead in Sydney, Australia. Methods The validated Montreal Children's Hospital Feeding Scale (MCH-FS) was completed by parents of patients aged 6 months to 6 years at a multidisciplinary aerodigestive clinic between February 2016 and October 2018. Growth, developmental outcomes (using the Bayley Scales of Infant and Toddler Development [BAYLEY-III]), demographic information, OA subtype, and associated comorbidities were reviewed. Results Forty-three caregivers completed the MCH-FS at least once, with questionnaires returned up to five times, totaling 101 reviews. The mean age was 4 years (± 1.9) and 53% were female. Thirty percent of patients were born prematurely and 30% had VACTERL association. Mean [± SD] growth z-scores were below WHO/CDC means for weight (−0.86 ± 1.37), length/height (−0.70 ± 1.2), and weight-for-length/BMI (−0.35 ± 1.15). BAYLEY-III scores were available for 27 children at 13 (± 1) months. Mean scores for four domains were within ‘average’ range (8–12): cognition (11 ± 2), receptive language (8 ± 3), expressive language (8 ± 2), and fine motor skills (9 ± 2). The mean gross motor score was below average (7 ± 3). Parent-reported feeding difficulties were moderate. When first completed, cumulative MCH-FS scores indicated 44% of patients had severe feeding difficulties, 40% moderate, and 14% mild. Sixty percent of patients required referral to a speech pathologist. However, most parents did not feel that these feeding difficulties influenced the relationship with their child or their family (88% and 84%, respectively). Conclusions The majority of patients in the cohort experienced significant feeding difficulties and some below average developmental scores, underscoring the need for multidiscplinary support for children born with TOF/OA. Further work in correlating growth, developmental, and feeding outcomes within subjects will assist in identifying early risk factors that may highlight infants most predisposed to these challenges, and who may benefit from early intervention.

DOZ047.07: Parental feeding concerns of infants and children with esophageal atresia

Abstract Background Feeding problems have been described in children with esophageal atresia (EA). This can cause high levels of parental/caregiver concern. Aims The primary aim of this study was to determine specific feeding concerns of parents/caregivers of infants and young children with EA, including introducing solids and grading up to family foods. Methods A questionnaire was developed for parents/caregivers of infants/children with EA, aged 12 months to 6 years. Questionnaires were completed by 20 parents of infants/children attending a multidisciplinary EA clinic between June 2016 and June 2017. All children had type C EA. Demographics, feeding history, and parental concerns around feeding were assessed. The Montreal Children's Hospital Feeding Scale was also completed by parents. Results Eleven (55%) parents agree/strongly agree that they were concerned about their child's feeding prior to the introduction of solids and about moving from a smooth puree to more textured solids. The most common concerns were choking and food impaction for both time points. Twelve (60%) parents agree/strongly agree that the majority of mealtimes in their child's first 1–2 years of life were stressful. Thirteen (65%) parents reported avoiding particular foods due to their child's EA. The majority of children (n = 17) had no feeding difficulty according to an objective scale, with the rest minor. Conclusions This study highlights that parental concern around feeding still exists in infants and children without a severe feeding difficulty and needs to be addressed. Multidisciplinary involvement including a dietitian and speech pathologist from an early age is important for infants and children with EA. Further education provided to parents/caregivers may assist with reduced stress around feeding and create more positive mealtime behaviours.

A recurrent de novo missense pathogenic variant in SMARCB1 causes severe intellectual disability and choroid plexus hyperplasia with resultant hydrocephalus

PurposeSMARCB1 encodes a subunit of the SWI/SNF complex involved in chromatin remodeling. Pathogenic variants (PV) in this gene can give rise to three conditions. Heterozygous loss-of-function germline PV cause rhabdoid tumor predisposition syndrome and schwannomatosis. Missense PV and small in-frame deletions in exons 8 and 9 result in Coffin–Siris syndrome, which is characterized by intellectual disability (ID), coarse facial features, and fifth digit anomalies. MethodsBy a gene matching approach, individuals with a similar SMARCB1 PV were identified. Informed consent was obtained and patient data were collected to further establish genotype–phenotype relationship. ResultsA recurrent de novo missense PV (c.110G>A;p.Arg37His) in exon 2 of SMARCB1, encoding the DNA-binding domain, was identified in four individuals from different genetic centers. They shared a distinct phenotype consisting of profound ID and hydrocephalus due to choroid plexus hyperplasia. Other shared features include severe neonatal feeding difficulties; congenital heart, kidney, and eye anomalies; obstructive sleep apnea; and anemia. ConclusionThe p.Arg37His PV in the DNA-binding domain of SMARCB1 causes a distinctive syndrome, likely through a gain-of-function or dominant-negative effect, which is characterized by severe ID and hydrocephalus resulting from choroid plexus hyperplasia. This report broadens the phenotypic spectrum associated with PV in SMARCB1.

Gastrointestinal Conditions in Children With Severe Feeding Difficulties.

Feeding aversion in children may progress to severe feeding difficulties. While oral-motor and sensory issues are usually the leading causes, organic etiologies should be considered. This study aimed to assess the prevalence of gastrointestinal conditions in children with severe feeding difficulties. We conducted a retrospective study of 93 children requiring an intensive feeding program. The medical records, radiologic and diagnostic tests, use of gastric tube feedings, preexisting medical conditions, and medications were reviewed. Fifty-two percent (52%) had esophagitis, 26.2% gastritis, and 40.7% lactase deficiency in upper endoscopy. In those who underwent an upper endoscopy, 26% of patients that were also tested for small intestinal bacterial overgrowth were found to be positive. Allergy testing was abnormal in 56.6% of those tested, while 27.5% and 75% had abnormal gastric emptying times and pH impedance results, respectively. Constipation was present in 76.3%. Thirteen of 32 were weaned off tube feedings. We conclude that gastrointestinal conditions are common in children with feeding disorders and should be investigated prior to feeding therapy.

What is the association between feeding difficulties in early infancy and speech problems and severe feeding difficulties at age five years in children with CP

What is the association between feeding difficulties in early infancy and speech problems and severe feeding difficulties at age five years in children with CP

Hypomethylation of HOXA4 promoter is common in Silver-Russell syndrome and growth restriction and associates with stature in healthy children

SRS is a rare congenital disorder, characterized by intrauterine growth restriction, postnatal growth impairment and a wide range of signs and symptoms such as dysmorphic features, severe feeding difficulties, body asymmetry, and neurodevelopmental delay. The molecular etiology is heterogeneous. Loss of methylation on chromosome 11p15 (11p15LOM) is detected in 20-60% and maternal uniparental disomy of chromosome 7 (mUPD7) in approximately 5-10%. Other chromosome abnormalities may occur in single cases. Nevertheless, in 40% of SRS cases the molecular etiology is unknown. SRS is currently a clinical diagnosis based upon the Netchine-Harbison scoring system (NH-CSS) [31].

A novel EXT2 mutation in a consanguineous family with severe developmental delay, microcephaly, seizures, feeding difficulties, and osteopenia extends the phenotypic spectrum of autosomal recessive EXT2-related syndrome (AREXT2)

We report a consanguineous family where 2 boys presented with developmental delay, hypotonia, microcephaly, seizures, gastro-intestinal abnormalities, osteopenia, and neurological regression. Whole exome sequencing performed in one of the boys revealed the presence of a novel homozygous missense variant in the EXT2 gene: c.11C > T (p.Ser4Leu). Segregation analysis by Sanger sequencing confirmed homozygous by descent autosomal recessive transmission of this mutation. Another family was previously reported with homozygous mutations in this gene in four siblings affected with a nearly similar clinical condition (Farhan et al., 2015). We discuss the similarities and differences between the two syndromes and propose AREXT2 as a new acronym for EXT2-related diseases.

Bainbridge-Ropers syndrome with ASXL3 gene variation in a child and literature review

Objective: To investigate the clinical manifestations and genetic features of a child with Bainbridge-Ropers syndrome caused by ASXL3 gene variation and review the literature. Methods: Clinical data and genetic features were collected and analyzed from a child with Bainbridge-Ropers syndrome who was diagnosed in Bao'an Maternity and Child Health Hospital in November 2016. "ASXL3" and "Bainbridge-Ropers" were used as key words to search at China National Knowledge Infrastructure, Wangfang Data Knowledge Service Platform, PubMed and Human Gene Mutation Database up to June 2017. Results: A 2(9/12) years old girl was presented with psychomotor retardation, feeding difficulty, hypotonia and specific craniofacial phenotype. She showed severe growth retardation (height: 84 cm, body weight: 8.0 kg (both were less than 3(rd) percentile rank of the children at the same age) and head circumference: 46 cm(=3rd percentile rank)), without obvious abnormalities in laboratory tests and neuroimaging tests. A de novo heterozygous nonsense variation: c.3349C>T(p.R1117*) in ASXL3 gene was identified by the whole exome sequencing, and the novel variation was classified into pathologic variant based on Standards and guidelines for the interpretation of sequence variants from ACMG. According to literature retrieval, no Chinese cases with ASXL3 variation had been reported. Totally 28 cases including the present girl harboring ASXL3 variations with detailed clinical information were reported. Thirty-one variations in ASXL3 gene were involved, including 1 missense variation and 30 loss of function variations, which were all de novo variations. Conclusions: The clinical features of Bainbridge-Ropers syndrome include severe psychomotor retardation, feeding difficulties, hypotonia and specific facial features. The heterozygous nonsense variation in ASXL3 gene is the cause of the patient. All the pathogenic variations in ASXL3 gene are de novo and loss of function variations.

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

BackgroundDe novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.ObjectivesTo delineate the...