Hearing Defects Research Articles

Missense Variants Within GJB2 Gene Locus and the Risk of Hearing Defects in Nonsyndromic Cleft Lip and Palate.

The aim of the study was to investigate the role of variants in GJB2 gene in the etiology of hearing defects in nonsyndromic cleft lip/palate. Saliva samples were obtained from cases (subjects with orofacial clefts) and control (subjects without orofacial clefts) who consented to the study. Deoxyribonucleic acid (DNA) was extracted using standardized protocol at Butali Lab (Iowa, IA). Primers for the coding region of GJB2 was designed using Primer 3 (http://bioinfo.ut.ee/primer3-0.4.0/) and optimized in the Butali lab using a gradient polymerase chain reaction to determine the annealing temperature for each primer set (forward and reverse). We measured the DNA concentration using Qubit and XY genotyping done for quality control. A concentration of 5 ng/μL of DNA was used for Sanger sequencing. A total of 150 subjects were sequenced (66 cases; 84 controls). Mutations in GJB2 gene were detected in 2 individuals with cleft palate. We found p.Arg165Trp variant in 1 case and p.Leu81Val variant in the second case. Although p.Arg165Trp was predicted to be either benign or tolerated by SIFT/POLYPHEN, the single nucleotide change from C>T, that is, CGG>TGG leads to a premature stop codon preventing the protein formation. The p.Leu81Val variant was predicted to be probably damaging/ deleterious. The present study implicates variants in the GJB2 gene in the etiology of hearing defects in nonsyndromic cleft lip and palate in the Nigerian population. Screening for variations in GJB2 gene is important for genetic counseling especially in high-risk families.

Newborn screening: Need of the hour

Newborn screening (NBS) is the process by which newborns are screened just after birth for disorders that can cause severe illness or death unless detected and treated early. At present, there is no national NBS program in India. Although the exact incidence in India is not known, approximately 4:1000 and 5:1000 are estimated to have hearing defects and congenital heart abnormalities, respectively, whereas the incidence of IEMs is estimated to be approximately 1:1000. This high incidence is due to high prevalence of consanguinity in our country. If undiagnosed and untreated many children develop mental retardation, learning disabilities, autism, dyslexia, behavioral abnormalities, and scholastic backwardness later in life. There is also considerable burden-financial and emotional on the parents to diagnose, treat, and manage these children. The most rational and cost-effective way of preventing such tragedies would be to have a NBS program which will detect most of the preventable or treatable, if not all IEMs and other genetic disorders. Hence, all hospitals in urban areas in India should initiate NBS at least for the common disorders: CH, CAH, and G6PD deficiency.

Prevalence of the use of Hearing Aid Compared to the use of Seeing Aid among Nigerian Youths

Needed attention has not been paid to hearing defects and the use of hearing aids compared to the enormous attention given to visual problems. This study aimed to compare the prevalence of visual defect to hearing defect and by extension the frequency of use of medicated glasses compared to the use of hearing aid. A total of 500 questionnaires were distributed randomly among students of Nnamdi Azikiwe University, Nnewi campus. Four hundred and seventy eight was retrieved, out of which 11 were disqualified due to improper filling, leaving us with a total of 467 properly filled questionnaires (representing 93.4% of the total number). Results were computed in simple percentages. Our results show that only 1.5% of the study population reported positive for hearing defect. Out of this number, only one respondent uses a hearing aid (representing 0.21% of the population). This is unlike seeing defect in which 117 (25.05% of total population) reported positive and 41.81% of them attested to the use of medicated glasses (representing 15.85% of the total population). All subjects who had hearing defects are aged between 15 and 25 (15-20 = 57.14%; 21-25 = 42.86%). This is similar to the case of seeing defects where the majority (70%) is aged 15-20 and 26% are aged 21-25, totally 96% of cases. We believe the enormity of persons subscribing to seeing aids are so because of massive awareness and affordability of medicated glasses, which in some cases is made available at no cost to the patient. The lack of data on persons with hearing defect in the country as well as the lack of publicity and investment in hearing aids has contributed greatly to the lack of interest and unwillingness on the part of patients to reach for hearing aids. Our results also show that females reported more both for hearing defects and seeing defect relative to their number. We therefore propose a better information system in which hearing aids are not only made available but also affordable and the masses are rigorously enlightened as to the health and social benefits.

Advances in congenital Zika syndrome and its pathogenesis

<p indent=0mm>Zika virus (ZIKV), originally discovered in a sentinel rhesus monkey in Zika valley in Uganda in 1947, has long been viewed as a classical mosquito-borne flavivirus. Due to its association with only a mild and self-limiting illness, ZIKV was a neglected pathogen following <sc>60 years</sc> since its identification. However, this virus became a serious public health concern in 2015−2016 outbreak in the Americas because of its association with congenital Zika syndrome (CZS). World Health Organization (WHO) declared the ZIKV outbreak a public health emergency of international concern in 2016. CZS is a pattern of birth defects found among fetuses and babies infected with ZIKV during pregnancy. The main clinical features of CZS are variable including severe microcephaly, decreased brain tissue, meningitis, damage to the back of the eye, hearing defects, arthrogryposis as well as hypertonia restricting body movement soon after birth. Benefiting from close collaboration of the international scientific community, intensive studies have been performed in development of experimental models to gain insights into the molecular basis of CZS in humans. These models include cultured neuroprogenitor stem cells, cortical organoids, especially mouse and nonhuman primate animal models which recapitulate many features of CZS in humans. Thanks to these models, questions related to how ZIKV infection causes congenital disease have been largely answered. For example, ZIKV was found to directly infects human neural progenitor cells (hNPCs) of the cerebral cortex, resulting in reduced hNPC proliferation; ZIKV also exhibits tropism for microglia in the brain, leading to production of inflammatory cytokines that inhibit neuronal precursor cell proliferation and differentiation. Additionally, studies have suggested that ZIKV can infect and trigger inflammasome pathways and innate antiviral immune responses of glial cells. While remarkable progress has been made to explain the associated underlying mechanisms, many unanswered key questions remain as follows: (1) How is the placenta in different developmental stage susceptible to ZIKV infection? (2) How is ZIKV transmitted across the placenta to infect the fetus? (3) What is the neurodevelopmental sequelae of congenital infection? (4) How does pre-existing maternal flavivirus immunity impact pregnancy-associated disease? Overall, due to collaborative and multidisciplinary efforts, a large body of knowledge of ZIKV biology has been obtained that has deepened our understanding of the CZS and informed the development of candidate vaccines and therapies. The lessons we have learned from ZIKV could enable effective preparation for the ultimate control of emergence of new congenital viral diseases in the future.

Pre-operative and post-operative audiological assessment in cleft lip and palate patients-a prospective study

PurposeTo assess association of audiological defects in cleft lip and palate (CLP) following two stage cheiloplasty and palatoplasty using clinical evaluation and otoscopy and effect of the surgical repair at an interval of one year. Materials and methodsA pilot research study was performed on sixty CLP patients of 1–6 years of age reporting at Craniofacial & Research Centre, Dharwad, India between October 2016 to October 2018.Subjects were assessed based on history, clinical examination and otoscopy for audiometric defects including Serous otitis media (SOM), retraction pockets, impacted wax pre-palatoplasty and findings were compared with control group. Study group were followed up postoperatively at 1, 3, 6 and 12 months and statistical analysis was carried. ResultsHigher incidence of conductive audiological defects were noted in study group (96.6%) to control group (8.33%). Of the sixty cleft patients subjected to screening otoscopy, 58 subjects had significant findings like serous otitis media(12.07%), retraction pockets(23.14%), impacted wax(62.04%), bulging of tympanic membrane(3.45%) which were clinically unnoticed. Post palatoplasty no changes were noted at 1 and 3 months, however at 6- and 12months significant improvement was noted (55.17%), with three subjects lost to follow up (6.90%) and none presenting with permanent deafness.results. ConclusionCleft anomalies occur in different degrees of severity and configuration with greater incidence of conductive hearing defects of 97%. Positive correlation was noted in cleft palate cases with significant improvement after palatoplasty at an earlier age. However, future long term studies are warranted for long term assessment of Eustachian tube function.conclusion.

Dr Eric L. Friedland z’l

Eric Friedland was born in New York City in 1941. Soon after birth it was found he had defective hearing and his mother faced hardship as his father left home six months later. His mother moved to Boston to be near relatives. She made the decision that Eric would not learn sign language as she said this would destine him to move largely among deaf people. Instead he became proficient in lip reading. Initially he did go to a school for the hearing impaired, but his life took off when he moved to Hebrew Teachers College in Boston. Here was founded his deep and wide Jewish knowledge, as all lessons were taught in Hebrew. He graduated from Brookline High School in 1957 and from Boston University in 1960.

Molecular alteration in the Gap Junction Beta 2 (GJB2) gene associated with non-syndromic sensorineural hearing impairment.

Non-syndromic sensory neural hearing defect is one of the genetic diseases inherited from parents to offerings. The autosomal recessive form affects a large population worldwide and has become a major concern in the social and professional lives of many people. There are many factors and genes which are involved in hearing loss but the Gap Junction Beta 2 (GJB2) gene which encodes the connexin 26 protein, is a major cause of non-syndromic recessive deafness (NSRD). This study aims to record and analyze GJB2 gene mutations in the hearing-impaired population of North Karnataka, India. In this study, we included 368 congenitally hearing-impaired children from North Karnataka, India, under 18 years of age. After thorough clinical examinations, patient's history and proper audiological results, peripheral blood samples were collected and subjected to genetic analysis. We recorded that 54.8% of the NSRD cases have an autosomal recessive mutation in the coding region of the GJB2 gene. The frequency of W24X (25%) mutation was found to be high in the present study population. From this study we can suggest that, identifying this mutation in new-borns definitely helps in the early diagnosis of hearing loss.

Identification of novel compound heterozygous variants in SLC19A2 and the genotype-phenotype associations in thiamine-responsive megaloblastic anemia

Background and aimsThiamine-responsive megaloblastic anemia (TRMA), caused by SLC19A2 loss-of-function variants, is characterized by the triad of megaloblastic anemia, progressive sensorineural deafness, and non-type 1 diabetes mellitus. Here, we present the case of a Chinese infant with two novel variants segregating in compound heterozygous form in SLC19A2 and reviewed genotype–phenotype associations (GPAs) in patients with TRMA. Materials and methodsWhole-exome sequencing was performed to establish a genetic diagnosis. The clinical manifestations and genetic variants were collected by performing a literature review. The bioinformatics software SIFT, PolyPhen2, and Mutation Taster was applied to predict variant effects and analyze GPAs. ResultsTwo novel variants segregating in compound heterozygous form in SLC19A2 (NM_006996.2: exon2:c.336_363del:p.W112fs; exon2:c.358G>T:p.G120X) was identified. Thiamine supplementation corrected anemia and diabetes mellitus but did not improve the hearing defect. In the literature, 183 patients with TRMA with 74 variants in SLC19A2 have been reported, with high incidence in the Middle East, South Asia, and the northern Mediterranean. Patients with biallelic premature termination codon variants presented with more severe phenotypes, and truncating sites on extracellular domains was a protective factor for the hemoglobin level at diagnosis. ConclusionTwo novel compound heterozygous variants (NM_006996.2: exon2:c.336_363del:p.W112fs; exon2:c.358G>T:p.G120X) were identified, and GPAs in TRMA indicated the predictability of clinical manifestations.

TRAINING PSYCHOLOGISTS TO WORK WITH CHILDREN WITH AUTISM SPECTRUM MANIFESTATIONS

The article is devoted to the problem of training specialists, in particular psychologists, to work with children with autism. Recently, more and more attention is paid to the study and correction of various mental disorders in children. There is a lot of literature, including recommendations on mental retardation, learning and upbringing disorders, behavioral and communication disorders. However, many more issues need to be explored. Thus, it is advisable to dwell on the problem of early childhood autism (hereinafter – RDA), in which communication disorders predominate in all behavior of the child and dominates in the formation of its abnormal development, while in other defects of mental development communication disorders are secondary and significantly reduced or disappear with the correction of the underlying disorder: mental retardation, neurotic disorders, speech and hearing defects, etc. Correction of early childhood autism has a special, quite complex nature. This leads to the need to improve the training of psychologists.

Case report of a novel homozygous variant in a Saudi patient with alpha mannosidosis

Background: Alpha-mannosidosis [Online Mendelian Inheritance in Man (OMIM): 248500] is an autosomal recessive disorder due to a deficiency of the lysosomal enzyme alpha-mannosidase. It is an ultra-orphan disease. In this paper, we report a case of alpha-mannosidosis in a Saudi boy of consanguineous parents, who was referred to our hospital to be worked up for possible mucopolysaccharidosis. Case Presentation: The patient was presented with dysmorphic features, global developmental delay, hearing defect, and recurrent respiratory tract infections. On examination, he had short stature, a short neck, cataracts, hearing impairment, chest deformity, hepatomegaly, umbilical hernia, right inguinal hernia, and two Mongolian spots in the back. He had normal peripheral blood smear: urinary oligosaccharide and dry blood spot for mucopolysaccharide enzyme assay founded to be negative. Definitive diagnosis was performed by directly sequencing the MAN2B1 gene of the peripheral blood leukocytes. It showed a homozygous variant c.1065delC; p.Ala356fs*7 (NM_001173498.1) as likely pathogenic. Conclusion: We report a novel variant mutation in MAN2B1 gene mutation. Also, to the best of authors' knowledge, this is the first reported case of alpha-mannosidosis in a Saudi patient.

Assessment of the Status of Contralateral Ear in Post-Operative Subjects of Unilateral Chronic Otorrhoea

Introduction: Chronic otitis media is one of the most common ear diseases in developing countries like Nepal and is important cause of the hearing loss. Chronic otitis media is rarely an isolated entity, because the responsible factors for its development in one ear in similar way will impact the contralateral ear, since both ears have a common “nasopharyngeal” drainage. Contralateral ear is defined as asymptomatic ear in cases of unilateral chronic otitis media. Aims: To evaluate the audiological profile of Contralateral ear in post-operative subjects of unilateral otorrhoea. Methods: Patients fulfilling criteria underwent Otoscopic examination, tuning fork test and pure tone audiometry. The findings of contralateral ear like retraction, tympanosclerotic patch (TS patch), thin, dull and atrophied tympanic membrane were noted. The final diagnosis with the type of surgery of diseased ear, as well as status of contralateral ear were entered into the proforma. All the patients were followed till three months in relation to anatomy of Tympanic membrane onotomicroscopy and pure tone audiometry respectively. Results: In postoperative cases of mucosal disease, the cases with abnormality in the contralateral ear reduced from 17 to 10 patients (30.3%) and the normal patients increased from 16 to 23 cases (69.7%). Likewise, in postoperative squamous disease, the cases with abnormality in the contralateral ear reduced from 14 to 11 patients (64.7%) and the normal patients increased from 3 to 6 cases (35.3%). Out of 50 cases, 14 cases (28%) had defective hearing while 36 cases (72%) had normal hearing in the contralateral ear respectively. Conclusion: The high incidence of occurrence of abnormality in contralateral ear indicate that both ears should be regarded as a pair. Unilateral Chronic otitis media should not be taken as a static phenomenon but as a continuous process in the other ear too.

Parental Satisfaction and Involvement in the Provision of Early Childhood Special Education to their Young Children with Deafness

This qualitative study was planned to investigate into parental satisfaction and engagement in the availability of Early Childhood Special Education (ECSE) to their deaf young children studying in Govt. Deaf and Defective Hearing Schools (GDDHS) in Punjab, Pakistan. The parents of 989 deaf young children constituted the population of study. A representative sample of parents of eighty-two children who gave their consent to participate in the study was taken from ten schools at district level located in four zones of the Punjab. A semi structured and open ended interview protocol consisting of three parts (Part 1=Demographic information about children and their parents, Part 2= Parental Contentment, Part 3= Engagement of parents) was employed. The interviews were recorded on audio tape, Afterwards, transcription was made and codes were assigned. Thematic analysis was done and data was presented in tabulated form. Frequencies were run. Major findings showed that majority of parents were not contented with speech, speech reading, and reading identification skills in their children. Majority of them were not involved in teaching to their children due to being illiterate. They had no guidance about teaching to their young deaf children. On the basis of results, suggestions to Punjab Special Education Department were made.

Clinical and genetic charsteristics of the Bosch–Boonstra–Schaaf syndrome due to novel mutations in the &lt;i&gt;NR2F1&lt;/i&gt; gene

Bosch–Boonstra–Schaaf optic atrophy is autosomal dominant disorder caused by mutations in the NR2F1 gene. Its common features include optic atrophy and / or hypoplasia, developmental delay, intellectual disability, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, hypotonia, and thinning of the corpus callosum. We report of the clinical and genetic characteristics of two patients with Bosch-Boonstra-Schaaf syndrome with newly detected of the missense mutations с.329T&gt;C (p.Phe110Ser) and с.413G&gt;A (p.Cys138Tyr) in the gene NR2F1. The existence of a polymorphism of the clinical manifestations of the syndrome has been shown, and the necessity of using exome sequencing in the diagnosis of neuro-ophthalmic diseases has been substantiated.

Genetic and reproductive consequences of consanguineous marriage in Bangladesh.

IntroductionThis study aimed to assess the prevalence, sociodemographic factors, reproductive consequences, and heritable disease burdens associated with consanguineous marriage (CM) in Bangladesh.MethodsA total of 7,312 families, including 3,694 CM-families, were recruited from 102 locales of 58 districts of Bangladesh. Using a standard questionnaire, we collected medical history and background sociodemographic data of these families. Family history was assessed by pedigree analysis. Fertility, mortality, secondary sex ratio, selection intensity, lethal equivalents were measured using standard methods.ResultsThe mean prevalence of CM in our studied population was 6.64%. Gross fertility was higher among CM families, as compared to the non-CM families (p < 0.05). The rate of under-5 child (U5) mortality was significantly higher among CM families (16.6%) in comparison with the non-CM families (5.8%) (p < 0.01). We observed a persuasive rise of abortion/miscarriage and U5 mortality rates with the increasing level of inbreeding. The value of lethal equivalents per gamete found elevated for autosomal inheritances as compared to sex-linked inheritance. CM was associated with the incidence of several single-gene and multifactorial diseases, and congenital malformations, including bronchial asthma, hearing defect, heart diseases, sickle cell anemia (p < 0.05). The general attitude and perception toward CM were rather indifferent, and very few people were concerned about its genetic burden.ConclusionThis study highlights the harmful consequences of CM on reproductive behavior and the incidence of hereditary conditions. It essences the need for genetic counseling from premarital to postnatal levels in Bangladesh.

Health Hazards and Some Correlates among Oil Refinery Workers

Introduction: Oil is a naturally occurring liquid found in rock formations. It consists of a complex mixture of hydrocarbons of various molecular weights plus other organic compounds. The workers in Aden (Yemen) Petroleum Refinery are exposed to a wide variety of hazards that may affect their health which can be broadly classified as; physical, chemical, biological, mechanical/ergonomics and psychological hazards. Aim of work: To identify the prevalence of work-related morbidities among Aden refinery workers and to study some associated correlates. Materials and methods: A cross sectional study was conducted in Aden Refinery Company (ARC), Alburigah district, Aden governorate, Republic of Yemen and included 398 workers. Data was collected by using semi structured questionnaire which included demographic data, detailed occupational history of the current and previous jobs, and history of work related illness. Results: The mean age of the studied workers was 42.91 ± 7.89 years. The study showed that allergy (e.g. occupational asthma, allergic rhinitis, skin allergy etc) is the most frequently recorded illness among the study participants (55.5%). Hypertension (42.2%) is the second common illness among them. Hypertension and cardiovascular diseases were statistically significant higher among smokers and those with work duration of ≥ 30 years. About one third (32.7%) of the studied sample had medical history of post-employment hearing defects which was statistically significant among those with work duration of ≥ 30 years, those who had history of noise exposure (37.5%) and those who were smokers. The current study also revealed that 8 cancer cases (2%) among the studied participants were rediagnosed post-employment. We also found that 10% of the workers were suffering from symptoms (fatigue, headache, nasal irritation and difficulty of breathing) during the working hours. Conclusion: Petroleum refinery workers are exposed to hazards that affect their health especially allergic diseases. These health effects were higher among smokers and those with long work duration (≥ 30 years).

Rbm24 regulates inner-ear-specific alternative splicing and is essential for maintaining auditory and motor coordination

ABSTRACT Tissue-specific alternative splicing (AS) is emerging as one of the most exciting types of mechanisms associated with organ development and disease. In the auditory system, many hearing-related genes undergo AS, and errors in this process result in syndromic or non-syndromic hearing loss. However, little is known about the factors and mechanisms directing AS in the inner ear. In the present study, we identified a novel RNA-binding protein, Rbm24, which was critically involved in regulating inner-ear-specific AS. Rbm24 deletion resulted in hearing loss and defects in motor coordination. Global splicing analysis showed Rbm24 was required for correct splicing of a subset of pre-mRNA transcripts with essential roles in stereocilia integrity and survival of hair cells. Furthermore, we identified that Rbm24 directly regulated the splicing of Cdh23, a known disease gene responsible for human Usher syndrome 1D and non-syndromic autosomal recessive deafness DFNB12. In conclusion, our findings demonstrated that Rbm24 was a critical factor in regulating inner-ear-specific splicing and maintaining the hearing and motor coordination function of the inner ear. Our data not only offer mechanistic insights but also provide functional annotation of Rbm24 splicing targets that contribute to hearing loss.

Novel dominant-negative NR2F1 frameshift mutation and a phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been described as an autosomal-dominant disorder caused by mutations in the NR2F1 gene, whose common characteristics include developmental delay, intellectual disability, optic nerve atrophy, hypotonia, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity and thinning of the corpus callosum. Missense mutations in NR2F1 have been reported to be the major cause of BBSOAS. A possible genotype-phenotype correlation has been considered with missense mutations affecting the ligand-binding domain of NR2F1 as well as whole-gene deletions of NR2F1 showing a milder phenotype of BBSOAS. Here we report on a patient with a novel frameshift mutation in NR2F1 showing the full spectrum of BBOAS indicating an expanded clinical spectrum and a reconsideration of the observed genotype-phenotype correlation.

TO ASSESS THE ADVERSE EFFECT PROFILE OF SECOND LINE DRUG IN MDR TB PATIENTS

Method: Study including LPA /AFB CULTURE proven cases of MDR TB. Data will be collected from the patient attending the OPD &amp; IPD in the Dept. of Respiratory Medicine.&#x0D; Result: Out of 200 patients 71% were of male its shows that MDR T.B. more prevalent among males and female 29%. Out of 200 patients most of the patients come under 10-15 Kg/m2 BMI, so its shows that 64.5% patients comes it and disease more prevalent among under nutrition. Out of 200 patients, the present study shows that gastrointestinal side effects are the most common 42%. 09 patients have renal toxicity and 08 patients have Arthalgia and 06 patients have cutaneous reactions and 11 patients developed hepatitis and 07 patients have some psychiatric illness and 07 patients developed hearing defect.&#x0D; Conclusion: The present study shows that gastrointestinal side effects are the most common 42%. 09 patients have renal toxicity and 08 patients have Arthalgia and 06 patients have cutaneous reactions and 11 patients developed hepatitis and 07 patients have some psychiatric illness and 07 patients developed hearing defect. Overall, these findings emphasize the importance of continuing the systematic surveillance of M. tuberculosis isolates to monitor the trends of drug resistance in different patient categories.&#x0D; Keywords: Adverse, Second line &amp; MDR TB.

Baraitser-Winter syndrome in a male patient with a uterus

Introduction Baraitser-Winter syndrome (BRWS) is a rare autosomal dominant disorder with fewer than 50 cases reported in the literature. Features include facial dysmorphism, ocular coloboma, brain abnormalities, hearing defects, intellectual disability and kidney abnormalities. We describe a case of a male infant with de novo mutation for BRWS with a new and unexpected finding of a uterus and vagina in the pelvis. This is the first reported case of a …

SAT-108 Growth Hormone Deficiency in a Patient with Ectodermal Dysplasia

Background information:Ectodermal dysplasia (ED) is a rare heterogeneous group of genetic disorders of ectodermal derived tissues, characterized by abnormalities in skin, teeth, hair and eccrine glands. Growth failure in these children varies depending on the genetic mutation and has not been well characterized. This clinical case report presents a 11-year-old male with a heterozygous mutation in WNT 10 A, a variant of the hypohydrotic ED gene, who was found to have growth hormone (GH) deficiency and treated with GH.Case report:He was born at 35 weeks gestation by C-section with a birth weight of 5 lbs. 12 oz. to a mother who had invitro fertilization with donor eggs from the maternal aunt with ocular myasthenia gravis and sperm from the father. Pregnancy was complicated by twin gestation and polyhydraminos. He had transient myasthenia gravis and treated with pyridostigmine for 3 months for feeding problems and swallowing difficulty. He also had arthrogryposis of the distal upper extremities attributed to placental transfer of the maternal aunt’s myasthenia gravis antibodies.He was referred to the endocrine clinic for evaluation of his growth failure around the age of 8 years. His growth chart indicated that he grew along the 5thpercentile until age 5 year with a gradual decline to the 3rd percentile by age 7 year and close to 2nd percentile by age 8 year. His BMI was at 7th percentile. Mid parental height was 5’9”. There was no history of delayed adolescence in the family. His twin sister had very mild form of arthrogryposis with dental delay but steady linear growth. He also had decreased exercise tolerance. His body tended to become hot during sports activities and had to wrap his face and neck with cold soaked towels. His other problems included delayed dental development with conical incisor, thin nail, missing teeth and hearing defects that raised suspicion for ectodermal dysplasia. Genetic testing at the age of 4 years had demonstrated a heterozygous mutation in the WNT 10A gene, an important gene for tooth development. Physical examination revealed a mild facial dysmorphism with conical incisor, missing teeth and high arched palate. He had contracture of the proximal inter phalangeal joints of the hands. Investigations revealed a normal thyroid function test, IGF-1 and IGFBP-3 level, CBC, sedimentation rate, chemistry panel and celiac titer. The bone age was concordant with his chronological age of 8 years. A GH stimulation study demonstrated a peak GH level of 4.94 ng/ml. An MRI of the brain revealed a normal pituitary gland. He was started on GH therapy with 0.3 mg/kg/week at age 9 year. His height improved from 2nd percentile at age 9 year to 20th percentile by age 11 year on growth hormone therapy. His exercise capacity and stamina also improved.Conclusion:Growth failure and GH axis should be evaluated in children with ED. GH therapy improves growth velocity and exercise capacity in patients with ED.