Cause Of Short Stature Research Articles

Percentage of Patient with Celiac Disease among Children with Short Stature

Background: Clinical features of celiac disease vary considerably. Intestinal symptoms are common in children whose disease is diagnosed within the 1st 2 years of life. As the age at presentation of the disease shifts to later in childhood, and with the more liberal use of serologic screening tests, extra-intestinal manifestations and associated disorders, without any accompanying digestive symptoms, have increasingly become recognized, including short stature. We aim in this study to determine the percentage of celiac disease among patients with short stature. Objectives of the Study: (1) to show the percentage of patient with celiac disease in short stature children. (2) to show the effect celiac disease on treatment of short stature children. Methodology: A cross sectional study that carried out at the Endocrine Pediatrics Clinic at A Zahraa Teaching Hospital for a period in 1st of January 2013 to end of October 2013; a total of 167 children and adolescents, aged range of 2 to 18 years were registered with short stature . 91 children of them only have been enrolled in this study according to inclusion criteria. Enzyme immunoassay (Biosystems, Spain) was used to determine IgA tTG using microplate tests. Samples with concentrations >20U/mL were defined as positive. Patients with positive anti-tTGserology were referred to the gastroenterology clinic to continue investigation of celiac disease by endoscopy and biopsy. Data were analyzed by SPSS software in IBM version 20 using chi square and paired T-test. Result: A total of 167 patients were evaluated 91 of them only have been enrolled in our study according to inclusion criteria; 59 (65%) were female and 32 (35%) were male. Median age was 9 years (of 2 - 18 years).The anti-tTG assays were positive in 16.5% of patients (15/91). Out of 15 patient whose diagnosed as anti-tTG positive, 11 (73%) have been diagnosed as celiac disease by endoscopy and biopsy according to modified marsh classification. All children diagnosed to have celiac disease were kept on a gluten-free diet. Patients were followed-up for six months and showed improvement in growth rate. Conclusion: Celiac disease a cause of short stature that should be included in diagnostic investigations of short stature.Recommendation: anti-tTG antibody as routine test recommended for all patients with short statures. All patients with idiopathic short statures and anti-tTG test positive with normal IgA level should be subjected to intestinal biopsy to prove the diagnosis of celiac disease.

Causes of short stature in Pakistani children found at an Endocrine Center.

Background and Objective:Short stature is defined as height below 3rd centile. Causes of short stature can range from familial, endocrine disorders, chronic diseases to chromosomal disorders. Most common cause in literature being idiopathic short stature. Early detection and management of remedial disorders like malnutrition and vitamin D deficiency, Endocrine disorders like growth hormone deficiency & hypothyroidism can lead to attainment of expected height. Pakistani data shows idiopathic short stature as the most common cause of short stature. Our study aimed at detecting causes of short stature in children/adolescents at an Endocrine referral center.Methods:A retrospective study was conducted at WILCARE Center for Diabetes, Endocrinology & Metabolism, Lahore on 70 well-nourished children/adolescents. The patients had been evaluated clinically, biochemically and radiologically as needed. Biochemical testing included hormonal testing as well to detect endocrine causes. Data was entered and analyzed in SPSS 20.0.Results:Leading cause of short stature in our population was Growth Hormone (GH) deficiency seen in 48 out of 70 (69%) patients. Second most common endocrine abnormality seen in these patients was Vitamin D deficiency [44 out of 70 patients (63%)]. Primary hypothyroidism; pan-hypopituitarism & adrenal insufficiency were other endocrine causes. The weight for age was below 3rd percentile in 57 (81%) patients, with no association with other major causes.Conclusion:Growth hormone and Vitamin D deficiency constitute one of the major causes of short stature among well-nourished children with short stature in Pakistan.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature.

The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

Syndrome de Laron : aspects diagnostiques, thérapeutiques et pronostiques

Laron syndrome is a rare cause of short stature due to an abnormality of growth hormone receptor (GHR). It is characterized by poor phenotype-genotype correlation and geographic predilection essentially in the Mediterranean rim, the Middle East and Indian subcontinent. This syndrome corresponds to an endogenous and exogenous complete insensitivity of GH and manifests by early hypoglycemia, an extremely severe short stature and dysmorphic features contrasting with high levels of circulating GH. To date, treatment with recombinant IGF1 is the only treatment option that has improved the terrible prognosis in these patients but does not actually realize the conditions for genuine replacement therapy.

LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice.

Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility.

Syndromes with short stature

At present, factors that have been recognized as being able to influence growth are: nutritional, physical, chemical, psychological and genetic. The causes of short stature are numerous, with about 90% of cases classified as Idiopathic Short Stature and divided into 2 types familial short stature and constitutional short stature. Part of the population with growth disorders are SGA newborns (10%) who don't show recovery growth that physiologically should occur within 2-3 years in 90% of cases. Generally in this group there are both children small due to severe prematurity and children afflicted by genetic syndromes. Syndromes are the subject of our interest and we thought it would be useful to distinguish different prenatal and postnatal patterns of growth. In fact, some specific patterns can characterize syndromes. For example, very slow prenatal and postnatal growth is typical of Silver-Russell Syndrome; low prenatal and childhood growth followed by obesity after 3 years of life is typical of Prader–Willi syndrome; prenatal and postnatal overgrowth is typical of Beckwith–Wiedemann syndrome; and prenatal overgrowth followed by low postnatal growth is typical of Costello syndrome. Short stature can be harmonious or disharmonious; harmonious ones include familiar short stature, constitutional growth delays, GH deficiency, intrauterine growth restriction, dysmorphic or genetic syndrome and short stature in the presence of chronic diseases. In this paper we discuss the growth patterns of some genetic syndromes, such as achondroplasia, CHARGE syndrome, Cornelia de Lange syndrome, 22q11.2 deletion syndrome, Downs syndrome, Fetal – alcohol syndrome, Kabuki syndrome, Noonan syndrome, Prader-Willi syndrome, Rubistein–Taybi syndrome, Silver–Russell syndrome, Turner syndrome, Williams syndrome and VACTERL/VATER association.

Growth in children and adolescents with mitochondrial diseases

There is evidence that children with mitochondrial diseases tend to have short stature, but the growth of these patients has not been assessed in detail. We calculated the standard deviation (SD) of height, weight and body mass index (BMI) of 58 children and adolescents between the ages of 1.5 months and 18 years with a proven diagnosis of mitochondrial diseases. Overall, 31.03% of recorded heights, 29.31% of weights and 39.65% of BMIs were more than 2SD below the mean. In the group of children with encephalomyopathic forms of mitochondrial diseases, 34.09% of heights and weights, and 43.18% of BMIs were more than 2SD below the mean, while in the group with myopathic forms 21.42% of weights, 14.28% of heights and 28.57% of BMIs were more than 2SD below the mean. These results suggest that mitochondrial diseases are an important cause of short stature and of reduction in BMI in children and adolescents, particularly the encephalomyopathic forms.

Pituitary stalk interruption syndrome (PSIS) – a rare cause of short stature

A 16 year old girl was evaluated for short stature and delayed puberty. She was noted to be shorter than her twin sister since infancy. Her parents, twin and two other siblings had normal growth and development. Although her twin went through puberty at 12 years of age, she failed to develop any sign of puberty. There were no symptoms of hypothyroidism, adrenal insufficiency, polydipsia or polyuria.

Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence.

Growth hormone deficiency (GHD) is a rare but important cause of short stature in childhood with a prevalence of 1 in 4000. The diagnosis is currently based on an assessment of auxology along with supporting evidence from biochemical and neuroradiological studies. There are significant controversies in the diagnosis and management of GHD. Growth hormone (GH) stimulation tests continue to play a key role in GHD diagnosis but the measured GH concentration can vary significantly with stimulation test and GH assay used, creating difficulties for diagnostic accuracy. Such issues along with the use of adjunct biochemical markers such as IGF-I and IGFBP-3 for the diagnosis of GHD, will be discussed in this review. Additionally, the treatment of GHD remains a source of much debate; there is no consensus on the best mechanism for determining the starting dose of GH in patients with GHD. Weight and prediction based models will be discussed along with different mechanisms for dose adjustment during treatment (auxology or IGF-I targeting approaches). At the end of growth and childhood treatment, many subjects diagnosed with isolated GHD re-test normal. It is not clear if this represents a form of transient GHD or a false positive diagnosis during childhood. Given the difficulties inherent in the diagnosis of GHD, an early reassessment of the diagnosis in those who respond poorly to GH is to be recommended.

Growth hormone responsiveness: why does it vary and can it be predicted?

Initial response to growth hormone (GH) varies considerably. In severe GH deficiency initial response varies across the group by almost 100%. In common non-GH deficient disorders such as idiopathic short stature (ISS) and children born small for gestational age (SGA) initial response varies by more than 100%. The explanation for the wide response to GH treatment can be clustered into three broad groups; (i) non-compliance with GH therapy, (ii) clinical characteristics associated with GH responsiveness and (iii) mutations and common gene variants in the GH-IGF-I axis. (i) Non-compliance with GH therapy: The commonest explanation for variable GH response is missed GH doses. In a national prospective study of GH compliance in New Zealand children; 34% of children missed more than one GH dose per week. Maori and Pacific children missed an additional GH dose each week than Caucasian children. Predictably, poor compliance (≥4 doses/week missed) was associated with a far poorer growth response than good compliance (height velocity SDS +0.4 vs +2.8). Even moderate compliance (2-3 doses/week missed) was associated with a poorer growth response (height velocity SDS +1.4 versus +2.8). Interestingly, paediatricians were unaware of GH non-compliance. GH response can only be maximised when more effective GH delivery devices are developed that record the date and time GH is administered to enable paediatricians to more effectively address compliance. (ii) Clinical characteristics associated with GH responsiveness: There is a differential response to GH therapy according to the underlying disorder. GH deficient children are more responsive than those with Turner Syndrome or idiopathic short stature who are in turn more responsive than SGA children (as shown by height velocity and serum IGF-I for a given GH dose). Furthermore, across the normal birth weight range we have recently shown that progressive reduction in birth weight SDS is associated with a progressively lower IGF-I response during IGF-I generation testing. Across growth disorders; more severe GH deficiency, taller parents, shorter stature, younger age at the start of treatment and heavier children are all parameters found to be associated with greater initial and sustained response to GH treatment. Michael Ranke has pioneered individualised GH dosing through GH prediction modelling across growth disorders. GH response can be predicted by inserting common clinical characteristics into a prediction equation that includes adjusting the dose. Prediction modelling is of greatest benefit to children with adverse clinical characteristics in whom greater initial GH doses will lead to greater growth response. (iii) Mutations and common gene variants in the GH-IGF-I axis: Downstream gene mutations in this axis (GH receptor, IGF-I and IGF-I receptor) are relatively rare causes of short stature, poor growth and GH response. Conversely common gene variants are being increasingly sought that influence stature, growth and GH responsiveness. Initial reports suggested a common GH receptor exon 3 deletion was associated with a better response to GH than the full length form in SGA and ISS children. Further studies have found little if any effect of the GH receptor deletion on initial or sustained growth response in SGA, Turner Syndrome or GH deficiency. Future studies are likely to focus on panels of common gene variants across the GH axis rather than examining individual genes to better characterise GH responsiveness.

Cytogenetic and Molecular Genetic Characterization of Children with Short Stature.

BackgroundThe deficiency of SHOX gene (short stature homeobox-containing gene) has been recognized as the most frequent monogenetic cause of short stature. SHOX gene has been associated with short stature in Turner syndrome and Leri Weill dyschondrosteosis as well with non-syndromic idiopathic short stature. The aim of this study was to determine the frequency of SHOX deletions and mutations in a cohort of Slovenian children with short stature, and to delineate indications for routine SHOX gene mutation screening.Methods and results40 selected subjects with idiopathic short stature were screened for entire SHOX gene deletion and for mutations in the SHOX gene coding region (exon 2 to 6), together with sequences flanking the exon-intron boundaries. FISH analysis on metaphase and interphase spreads revealed no entire gene deletion. Additionally, no pathogenic point mutations or smaller deletion/duplications were identified in this study group.ConclusionsSHOX gene deletions and point mutations are not a common cause of idiopathic short stature in a cohort of Slovenian children with short stature. Therefore, the frequency of SHOX mutations must be much lower as expected based on the reported data.

Endoscopic Findings in Children with Short Stature : A Single Center Experience

Objective: This study was conducted to evaluate the diverse findings of endoscopy in patients that might assist in their diagnosis. Celiac disease was of special concern as it is a well known cause of short stature which can be its only presentation. Methods: A retrospective review of thirty two (32) records of children referred to the pediatric gastrointestinal clinic in Prince Ali Bin Al-Hussein Hospital in Al-Karak with short stature was done. It was conducted over six month's period. All patients were subjected to full history, physical examination and the following investigations: complete blood count, kidney function test, liver function test, thyroid function test, tissue transglutaminase antibodies and abdominal ultrasound. Upper gastrointestinal endoscopy was done to all patients whom we were not able to reach for a diagnosis, mainly to rule out celiac disease. Results: There were 32 children included in this study, 14 female and 18 male with a mean age of 7.75 years, ranges from 2.5-13 years. Normal gross endoscopy was noticed in the majority of patients (25 patients, 78%), most of them had normal histopathological reports (19 patients, 79%). Nevertheless, four patients out of 25 (16%) were diagnosed to have celiac disease based on the histopathology report. Abnormal endoscopy was noticed in only six patients out of 32 patients, showing D2 effacement and scalloped folds. Two of them were diagnosed to have celiac in histopathological reports (33%). One patient only (9%) has the combination of short stature and diarrhea. Five patients were having positive tissue transglutaminase antibodies (15%), but only two of them were proved have celiac disease (40%). Total number of patients with celiac disease in this study was six (18.75%), regardless of their gross endoscopic appearance.

Clinical Features and Management of Cartilage-Hair Hypoplasia: A Narrative Review

Context: Cartilage-hair hypoplasia is a rare hereditary cause of short stature. The aim of this study was to familiarize physicians with this rare but important disease. Evidence Acquisition: This article is a narrative review of the scientific literature to inform about clinical features and management of Cartilage-hair hypoplasia. A systematic search identified 127 papers include original and review articles and case reports. Results: Cartilage-Hair Hypoplasia characterized by short-limb dwarfism associated with metaphyseal chondrodysplasia. The inheritance is autosomal recessive. Other findings include hair hypoplasia, anemia, immunodeficiency, propensity to infections, gastrointestinal disorders (Hirschsprung disease, anal stenosis, esophageal atresia and malabsorption), defective spermatogenesis, increased risk of malignancies and higher rate of mortality. Immunodeficiency in cartilage-hair hypoplasia may be an isolated B-cell or isolated T-cell immunodeficiency or combined B and T-cell immunodeficiency; however, severe combined immunodeficiency is rare. There is no known treatment for hair hypoplasia. Growth hormone was used with conflicting results for short stature in children with Cartilagehair hypoplasia. Skeletal problems must be managed with physiotherapy and appropriate orthopedic interventions. Hirschsprung disease, anal stenosis and esophageal atresia should be surgically corrected. Patients with severe hypoplastic anemia require repeated transfusions. Bone marrow transplantation may be required for patients with severe combined immunodeficiency or severe persistent hypoplastic anemia. Treatment with G-CSF is useful for neutropenia. Patients should be monitored closely for developing malignancy such as skin neoplasms, lymphomas and leukemias. Conclusions: Cartilage-hair hypoplasia is an important hereditary disease with different medical aspects. The high rate of consanguineous marriages in Iran necessitates considering CHH in any child with severe short stature or other clinical features of disorder.

Growth failure starts from early infancy in children with short stature at age 6

We compared the growth of 183 children with short stature (≤ 2SD) and 73 children of normal height at age six who were visiting the Tanaka Growth Clinic. We classified these short children as suffering from either idiopathic short stature (ISS, n = 119), GH deficiency (GHD, n = 33) or small-for-gestational-age short stature (SGASS, n = 31) on the basis of subsequent test results and other factors. We also conducted a retrospective study of changes in their height, wt and nutritional intake over time. The mean changes in height SD score from birth to 6 yr were –0.24 SD in normal height children with a normal birth length and +2.27 SD in normal height children with a low birth length. In short children, these changes were –1.93 SD for children with ISS, –2.41 SD for those with GHD and +0.58 for those with SGASS. The mean changes from birth to 6 mo were –0.84 SD, −1.03 SD and +0.38 SD in children with ISS, GHD and SGASS, respectively. The mean change in height SD score from birth to age 1 yr was –1.07 SD, –1.44 SD and +0.35 SD, respectively. The decrease in height SD score from birth to 6 mo accounted for 43.5% of the decrease in height SD score from birth to 6 yr in children with ISS and it accounted for 42.6% of the decrease in children with GHD. Only 19% of short children bottle-fed well, and 53% fed poorly, as opposed to 56% and 16% of normal height children who fed well and poorly, respectively. Post weaning, only 22% of short children ate well, and 56% fed poorly, as opposed to 53% and 17% of normal height children who fed well and poorly, respectively. These findings demonstrated that growth failure started from early infancy in ISS and GHD children. It was suggested that poor nutritional intake in infancy and early childhood was a partial cause of short stature at age 6.

Dopamine-Responsive Growth-Hormone Deficiency and Central Hypothyroidism in Sepiapterin Reductase Deficiency.

Sepiapterin reductase (SR) deficiency is a rare autosomal recessively inherited error of tetrahydrobiopterin (BH4) biosynthesis, resulting in disturbed dopaminergic and serotonergic neurotransmission. The clinical phenotype is characterized by dopa-responsive movement disorders including muscular hypotonia, dystonia, and parkinsonism. Due to the rarity of the disease, the phenotype of SR deficiency is far from being completely understood. Here, we report a 7-year-old boy, who was referred for diagnostic evaluation of combined psychomotor retardation, spastic tetraplegia, extrapyramidal symptoms, and short stature. Due to discrepancy between motor status and mental condition, analyses of biogenic amines and pterins in CSF were performed, leading to the diagnosis of SR deficiency. The diagnosis was confirmed by a novel homozygous mutation c.530G>C; p.(Arg177Pro) in exon 2 of the SPR gene. Because of persistent short stature, systematic endocrinological investigations were initiated. Insufficient growth-hormone release in a severe hypoglycemic episode after overnight fasting confirmed growth-hormone deficiency as a cause of short stature. In addition, central hypothyroidism was present. A general hypothalamic affection could be excluded. Since dopamine is known to regulate growth-hormone excretion, IGF-1, IGF-BP3, and peripheral thyroid hormone levels were monitored under L-dopa/carbidopa supplementation. Both growth-hormone-dependent factors and thyroid function normalized under treatment. This is the first report describing growth-hormone deficiency and central hypothyroidism in SR deficiency. It extends the phenotypic spectrum of the disease and identifies dopamine depletion as cause for the endocrinological disturbances.

Copy Number Variants in Short Children Born Small for Gestational Age

Background/Aims: In addition to genome-wide association studies (GWAS), height-associated genes may be uncovered by studying individuals with extreme short or tall stature. Methods: Genome-wide analysis for copy number variants (CNVs), using single nucleotide polymorphism (SNP) arrays, was performed in 49 index cases born small for gestational age with persistent short stature. Segregation analysis was performed, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates, and published information. Results: CNVs were detected in 13 cases. In 5 children a known cause of short stature was found: UPD7, UPD14, a duplication of the SHOX enhancer region, an IGF1R deletion, and a 22q11.21 deletion. In the remaining 8 cases, potential pathogenic CNVs were detected, either de novo (n = 1), segregating (n = 2), or not segregating with short stature (n = 5). Bioinformatic analysis of the de novo and segregating CNVs suggested that HOXD4, AGPS, PDE11A, OSBPL6, PRKRA and PLEKHA3, and possibly DGKB and TNFRSF11B are potential candidate genes. A SERPINA7 or NRK defect may be associated with an X-linked form of short stature. Conclusion: SNP arrays detected 5 known causes of short stature with prenatal onset and suggested several potential candidate genes.

PO-0155 Evaluation Of Growth Hormone Deficiency (ghd) In Children With Acute Lymphoblastic Leukemia (all) And Non-hodgkin’s Lymphoma (nhl)

Introduction Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer and non-Hodgkin’s lymphoma (NHL) is the most common childhood cancer.these children may suffer from some late effects of treatments such as endocrinopathies like thyroid, pituitary, metabolism disfunctions. Growth Hormone Deficiency (GHD) is one of the causes of short stature. Material and methods During a 3 years cross-sectional research in Dr Sheikh children hospital in Mashhad, we studied on 50 children with ALL (n = 25), NHL (n = 25) who received chemotherapy alone (n = 25) or plus radiation (n = 25). Patients with height less than 5th percentile, were evaluated for GHD via insulin stimulating test. Also for short stature workup in all patients thyroid function test were done. Results We found 6 (12%) children with height less than 5th percentile who 5(83.33% of them or 10% of total) had GHD. There was no statistical correlation between type of disease also type of treatment and GHD (respectively p-value = 0. 667, 0.189) due to small sample size. Among these 6 patients, 5 children (83.33% of them) undergone radiation and 4 patients (66.66% of them) had ALL. There was 2(4% total) cases of subclinical hypothyroidism but with normal height. According to BMI (body mass index) access 2(4% total) patients had overweight. Conclusion In our study ALL patients who received radiation had unfavourable state for height and endocrine side effects. So it seems more attention to radiotherapy complications in children with cancer especially ALLs is needed to improve their quality of life.

PO-0069 Terminal Deletion Of Chromosome 15q Resulting In Haploinsufficiency Of The Igf-1 Receptor And Marked Elevation Of Igf-1

<h3>Introduction</h3> Ten to fifteen percent of small for gestational age (SGA) infants demonstrate failure of catch-up growth. Haploinsufficiency of the insulin-like growth factor-1 receptor (IGF1R) gene due to monosomy 15q is an extremely rare cause with 16 cases reported in the literature. We describe the phenotype of such a patient including biochemical findings, auxology and management. <h3>Case</h3> A three-year-old female with global developmental delay and autistic spectrum disorder was evaluated for short stature. Height was 82 cm (-3.7 SDS) and weight was 12.5 kg (-1.3 SDS). She was born at term weighing 2.88 kg and was microcephalic and dysmorphic. Array CGH revealed an unbalanced translocation resulting in trisomy of the terminal portion of chromosome 10p and monosomy 15q26.3- &gt;qter which contains the region coding for IGF1R. IGF-1(243 µg/L) and IGFBP-3 (3501 ng/ml) levels were markedly elevated; +4.7 SDS and +3.3 SDS respectively. The marked elevation in IGF-1 levels was considered a relative contraindication to GH therapy. <h3>Discussion</h3> Haploinsufficency of IGF1R gene is associated with elevated levels of IGF-1 as a result of target organ resistance. Exogenous growth hormone, while further elevating IGF-1, in many cases facilitates catch-up growth albeit to a lesser extent than other ex-SGA infants. In this case IGF-1 levels were exceptionally high, precluding growth hormone therapy. <h3>Conclusion</h3> Deletions involving the IGF1R gene are a rare but treatable cause of short stature. This case is unusual however, as marked elevation of IGF-1 at baseline precluded GH therapy.

Whole Exome Sequencing to Identify Genetic Causes of Short Stature

Background/Aims: Short stature is a common reason for presentation to pediatric endocrinology clinics. However, for most patients, no cause for the short stature can be identified. As genetics plays a strong role in height, we sought to identify known and novel genetic causes of short stature. Methods: We recruited 14 children with severe short stature of unknown etiology. We conducted whole exome sequencing of the patients and their family members. We used an analysis pipeline to identify rare non-synonymous genetic variants that cause the short stature. Results: We identified a genetic cause of short stature in 5 of the 14 patients. This included cases of floating-harbor syndrome, Kenny-Caffey syndrome, the progeroid form of Ehlers-Danlos syndrome, as well as 2 cases of the 3-M syndrome. For the remaining patients, we have generated lists of candidate variants. Conclusions: Whole exome sequencing can help identify genetic causes of short stature in the context of defined genetic syndromes, but may be less effective in identifying novel genetic causes of short stature in individual families. Utilized in the clinic, whole exome sequencing can provide clinically relevant diagnoses for these patients. Rare syndromic causes of short stature may be underrecognized and underdiagnosed in pediatric endocrinology clinics.

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways.

The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders. To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause. A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature. In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation. Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.