Growth Hormone Treatment Research Articles

3M syndrome: Evaluating the clinical and laboratory features and the response of the growth hormone treatment: Single center experience

Introduction & objective3 M Syndrome is a rarely encountered autosomal recessive syndrome characterized by low birth weight, severe postnatal growth deficiency, and minor dysmorphic abnormalities. 3 M-related short stature has been attributed to the resistance to growth hormone (GH) to a certain extent rather than to GH deficiency. The resistance to GH, on the other hand, has been associated with impaired protein scaffolding, transport, and p53-mediated apoptosis at the IGF-1 post-receptor pathway. In this context, the objective of this study is to evaluate the clinical, laboratory, and genetic characteristics of the patients with 3 M syndrome, detect the mutations frequently observed in these patients, and assess their response to GH treatment. Material&methodsThe sample of this single-center study consisted of patients diagnosed with 3 M syndrome based on genetic tests between 2007 and 2021. Patients’ clinic, laboratory, and genetic characteristics pertaining to the time of admission and follow-up were recorded. All patients except one underwent a growth hormone stimulation test (GHST) (Levo-dopa or insulin tolerance test). Insulin-like growth factor (IGF) generation test was performed on those with sufficient GHST results (0.1 mg/kg/day for four days). ResultsThe median age of the patients, five females and three males, was 2.8 (0.25–8.12) years at admission. All but one patient were small for gestational age (SGA). The patient with normal birth weight was the baby of a diabetic mother. Obscurin-like 1 (OBSL1) variant was detected in all cases. The median height standard deviation score (SDS) at admission was −4.94 ((-5.63)- (−3.27)) SDS, and the median midparenteral height SDS was −1.27 SDS ((-3.1)- (0.34)). All patients were prepubertal at admission. The GHST response was sufficient in five cases. IGF generation test was performed in three cases. Seven patients received GH therapy (35–57 μg/kg/day). Five of these patients discontinued GH therapy since their growth velocity (GV) fell below normal during treatment. In addition, one case discontinued GH therapy because her IGF-1 value was>2 SDS, and another case received gonadotropin-releasing hormone (GnRH) analogs together with GH therapy. The median age and height SDS of the patients were 10.1 (1.79–18) years and −5.09 SDS ((-7.11)- (2.45)), respectively, as of the last follow-up visit. The height SDS values of the two cases that reached the final height were −7.11 SDS and −3.39 SDS. There were no side effects of GH treatment. ConclusionThe study findings indicated a good GV during the early stages of the long-term GH treatment administered to patients with 3 M syndrome. However, response to GH therapy decreased in the following years, and the desired improvement in height SDS could not be achieved in patients who reached their final heights. Taken together with the literature data, it has been concluded that initiating GH therapy in the prepubertal period provided better outcomes than after puberty.

Chinese patients with 3M syndrome: clinical manifestations and two novel pathogenic variants.

Background: 3M syndrome is a rare autosomal recessive disease, characterized by intrauterine and postnatal growth retardation, facial dysmorphism, large head circumference, and skeletal changes, has rarely been reported in the Chinese population. Methods: We describe the clinical manifestations and gene variants in four sporadic cases of 3M syndrome in Chinese individuals from different families. Results: All cases had significant growth retardation, relative macrocephaly, and typical facial features. Exome sequencing revealed that two patients with 3M syndrome had homozygous variants of the CUL7 gene: one novel pathogenic variant and one previously reported pathogenic variant; the other two patients were heterozygous for variants in OBSL1, one of which had not been reported previously. Clinical evaluation indicated that these Chinese patients with 3M syndrome shared similar recognizable features with those reported in patients of other ethnic backgrounds, but not all patients with 3M syndrome in this study had normal development milestones. Two patients underwent recombinant human growth hormone (rhGH) therapy and showed accelerated growth in the first 2years; however, the growth rate slowed in the third year in one case. There were no obvious adverse reactions during rhGH treatment. Conclusion: We report one novel CUL7 and one novel OBSL1 mutation in patients with 3M syndrome. Children with short stature, specific facial features, and physical symptoms should be referred for genetic testing to obtain precise diagnosis and appropriate treatment. The effects of rhGH treatment on adult height requires long-term observation and study in a large sample.

Growth hormone therapy for children with Duchenne muscular dystrophy and glucocorticoid induced short stature

ObjectiveTo evaluate the outcome of recombinant human Growth Hormone (rhGH) therapy in patients with Duchene Muscular Dystrophy (DMD) and glucocorticoid treatment with compromised growth. DesignFour DMD patients on Deflzacort 0.6–0.85 mg/kg/day or prednisolone 0.625 mg/kg/day recieved rhGH (0.24 mg/kg/week) for 6–18 months. Primary outcomes were Growth velocity and Height for age Z-scores (Height SD). ResultsGrowth velocity increased from 0 to 3.25 cm/year prior to GH therapy to 3.3–7.8 cm/year over a period of 6–18 months. The typical Height SD decline in DMD was reversed in two patients and blunted in one. No adverse events or deterioration in cardiac or respiratory parameters were associated with the rhGH treatment. ConclusionsrhGH appears to be safe and efficient in promoting growth of patients with glucocorticoid induced growth failure in DMD.

Advantages and limitations of estrogen replacement therapy on hypogonadal survivors of childhood cancer.

Hypogonadism is a significant late complication in childhood cancer survivors (CCS). The aim of this study was to elucidate the advantages and limitations of estrogen replacement therapy (ERT) for CCS with hypogonadism. Seventeen CCS were divided into two groups: gonadal hypogonadism (GH) group (n = 8) and central hypogonadism (CH) group (n = 9). Pearson correlation coefficients were used to investigate the impact of cancer management on final height, bone density, and uterine development. Seven of GH group had hematologic malignancies, and all of them underwent total body irradiation before bone marrow transplantation. The GH group showed significant positive correlations between the onset age of disease treatment and final height (p < 0.05, R = 0.712) and uterine size following ERT (p < 0.05, R = 0.775). All CCS in the CH group had brain tumors, and seven of them received chemotherapy. There were trends towards positive and negative correlations between the onset age of disease treatment and final height (p = 0.09, R = 0.598) or uterine size (p = 0.07, R = -0.669), respectively. A negative correlation trend was observed between the age at ERT initiation and final height (p = 0.07, R =-0.769) or bone density (p = 0.18, R = -0.626) in six CH patients who received growth hormone therapy. Five CCS in both groups experienced osteoporosis, despite receiving ERT. Individualized management strategies beyond ERT are essential to reduce long-term complications in CCS with hypogonadism, considering the type and timing of cancer treatment.

The Impact of Growth Hormone Therapy on Sleep-Related Health Outcomes in Children with Prader-Willi Syndrome: A Review and Clinical Analysis.

This literature review of growth hormone (GH) therapy and sleep-related health outcomes in children diagnosed with Prader-Willi syndrome (PWS) assembles evidence for the consequences of sleep deprivation and poor sleep quality: difficulty concentrating and learning at school, behavioral problems, diminished quality of life, and growth impairment. Sleep-disordered breathing (SDB) is another factor that impacts a child's well-being. We searched the electronic databases Medline PubMed Advanced Search Builder, Scopus, and Web of Science using MeSH terms and text words to retrieve articles on GH deficiency, recombinant human growth hormone (rhGH) therapy, sleep quality, SDB, and PWS in children. The censor date was April 2023. The initial search yielded 351 articles, 23 of which were analyzed for this review. The study findings suggest that while GH may have a role in regulating sleep, the relationship between GH treatment and sleep in patients with PWS is complex and influenced by GH dosage, patient age, and type and severity of respiratory disorders, among other factors. GH therapy can improve lung function, linear growth, and body composition in children with PWS; however, it can also trigger or worsen obstructive sleep apnea or hypoventilation in some. Long-term GH therapy may contribute to adenotonsillar hypertrophy and exacerbate sleep apnea in children with PWS. Finally, GH therapy can improve sleep quality in some patients but it can also cause or worsen SDB in others, leading to diminished sleep quality and overall quality of life. The current evidence suggests that the initial risk of worsening SDB may improve with long-term therapy. In conclusion, rhGH is the standard for managing patients with PWS. Nonetheless, its impact on respiratory function during sleep needs to be thoroughly evaluated. Polysomnography is advisable to assess the need for adenotonsillectomy before initiating rhGH therapy. Close monitoring of sleep disorders in patients with PWS receiving GH therapy is essential to ensure effective and safe treatment.

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD—a non-inferiority Randomised Controlled Trial (RCT)

Background Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64–82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved.Methods/designEvidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario.DiscussionIf this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8–4.6 million (€2.05–5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects.Trial registrationEudraCT number: 2020-001006-39

Analysis of children with familial short stature: who should be indicated for genetic testing?

Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤-2 SD in child and his/her shorter parent, excluded secondary short stature, excluded Turner/Prader-Willi syndrome). Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by ACMG guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, four (11%) a variant affecting GH-IGF1 axis, and three (8%) a variant in miscellaneous genes. Lower shorter parent's height (p=0.015) and less delayed bone age (BA) before GH treatment (p=0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent heights <-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, gene variants affecting the growth plate are the most common. Shorter parent's height and bone age are clinical predictors of monogenic FSS.

Growth hormone therapy is associated with improved uterine dimensions in girls with Turner syndrome prior to oestrogen replacement.

Adult women with Turner syndrome (TS) have high rates of miscarriage, presumably due to the abnormal size and shape of the uterus. There is a paucity of data regarding the determinants of uterine volume (UtVol) in young girls with TS before the initiation of oestrogen replacement therapy (ERT). We performed a cross-sectional study on premenarchal girls with TS, aged 5-15 years, pubertal stage B1-B3, not having received ERT (n = 73) and 50 age-matched healthy controls. Anthropometric parameters and a history of growth hormone (GH) therapy (≥1 year) were noted. Uterine length (UtL), UtVol, and mean-ovarian-volume (MOV) standard-deviation scores (SDS) were determined from transabdominal ultrasonography data. Girls with TS had lower median UtVol-SDS (-1.07 vs. 0.86; p < .001), UtL-SDS (-3.72 vs. -0.41; p < .001) and MOV-SDS (-5.53 vs. 1.96; p < .001) compared to age-matched controls. Among TS girls, recipients of GH (n = 38) had higher UtVol-SDS (-0.63 vs. -1.39; p = .0001), UtL-SDS (-1.73 vs. -6.49; p < .0001) but similar MOV-SDS compared to nonrecipients (n = 35). Those with normal uterine volume for age (NUVA, n = 29) had earlier initiation (7.8 vs. 9.3 years; p = .03) and a longer duration of GH (3.71 vs. 2.14 years; p = .002) than those with low UtVol for age (n = 44). UtVol-SDS correlated with duration of GH (ρ = 0.411, p = .01) and negatively with age at GH initiation (ρ = -0.479, p = .003). In a model adjusted for pubertal status, karyotype and height-SDS, GH use could independently predict having NUVA (odds ratio: 5.09, confidence interval: 1.63-15.94, p = .005). GH therapy has a stimulatory effect on uterine dimensions in pre-and peripubertal girls with TS. Earlier initiation and longer duration of GH is important in TS girls before ERT.

Longitudinal assessment of bone health index as a measure of bone health in short-statured children before and during treatment with recombinant growth hormone.

The aim of our study was the longitudinal assessment of bone health index (BHI) in short-statured children during growth hormone (GH) treatment to estimate changes in their bone health. 256 short-statured children (isolated GH deficiency (IGHD) n=121, multiple pituitary hormone deficiency (MPHD) n=49, intrauterine growth retardation (small for gestational age (SGA)) n=52, SHOX (short stature homeobox gene) deficiency n=9, Ullrich Turner syndrome (UTS) n=25) who started with GH between 2010 and 2018 were included. Annual bone ages (Greulich and Pyle, GP) and BHI were, retrospectively, analysed in consecutive radiographs of the left hand (BoneXpert software) from GH therapy start (T0) up to 10 years (T10) thereafter, with T max indicating the individual time point of the last available radiograph. The results are presented as the median (25 %/75 % interquartile ranges, IQR) and statistical analyses were performed using non-parametric tests as appropriate. The BHI standard deviation scores (SDS) were reduced (-0.97,-1.8/-0.3) as bone ages were retarded (-1.6 years,-2.31/-0.97) in all patients before start of GH and were significantly lower in patients with growth hormone deficiency (GHD) (-1.04,-1.85/-0.56; n=170) compared to non-GHD patients (-0.79,-1.56/-0.01; n=86; p=0.022). BHISDS increased to-0.17 (-1/0.58) after 1 year of GH (T1, 0.5-1.49, p<0.001) and to-0.20 (-1/-0.50, p<0.001) after 5.3 years (T max, 3.45/7.25). BHI SDS are reduced in treatment-naive short-statured children regardless of their GH status, increase initially with GH treatment while plateauing thereafter, suggesting sustained improved bone health.

Somatropin for Turner Syndrome

&#x0D; Early initiation of growth hormone therapy is recommended in children with Turner syndrome if the child already has growth failure or has a high chance of short stature (1 guideline).&#x0D; Growth hormone treatment can be started at 45 mcg/kg/day to 50 mcg/kg/day (1 guideline).&#x0D; Monitor treatment by regular height measurements and assessment of levels of insulin-like growth factor-I (1 guideline).&#x0D; Continue treatment until the desired height is achieved or when no more growth potential remains (1 guideline).&#x0D;

Somatropin for Growth Hormone Deficiency

&#x0D; We identified 2 evidence-based guidelines that provide recommendations for the clinical management of children and adults with growth hormone deficiency.&#x0D; The American Association of Clinical Endocrinologists and American College of Endocrinology guideline provides recommendations on assessment, screening, diagnostic testing, treatment, and monitoring for a range of patients with different causes of adult growth hormone deficiency. The recommendations emphasize accurate diagnosis using appropriate growth hormone cut points for different growth hormone–stimulation tests and careful interpretation of serum growth hormone and insulin-like growth factor-1 levels. Treatment with recombinant human growth hormone should be carried out with consideration of the benefits and risks specific to each individual patient.&#x0D; The Pediatric Endocrine Society guideline provides recommendations for the clinical management of children and adolescents with growth failure due to growth hormone deficiency. The guideline lists various conditions for which growth hormone deficiency can be diagnosed by conventional approaches without growth hormone–stimulation testing. The treatment dose of growth hormone should be calculated based on weight and body surface area and not on insulin-like growth factor-1 levels. The guideline highlights that the initial growth hormone dose, subsequent dosing, and discontinuation of pediatric doses should be assessed based on each individual patient.&#x0D; Both guidelines recognize the uncertainty of long-term safety (i.e., posttreatment effects) of growth hormone treatment, which is a limitation of both guidelines.&#x0D;

Evaluating the Usefulness and Ease of Use of a Next-Generation-Connected Drug Delivery Device for Growth Hormone Therapy: Qualitative Study of Health Care Professionals' Perceptions.

Digital solutions targeting children's health have become an increasingly important element in the provision of integrated health care. For the treatment of growth hormone deficiency (GHD), a unique connected device is available to facilitate the delivery of recombinant human growth hormone (r-hGH) by automating the daily injection process and collecting injection data such that accurate adherence information is available to health care professionals (HCPs), caregivers, and patients. The adoption of such digital solutions requires a good understanding of the perspectives of HCPs as key stakeholders because they leverage data collection and prescribe these solutions to their patients. This study aimed to evaluate the third generation of the easypod device (EP3) for the delivery of r-hGH treatment from the HCP perspective, with a focus on perceived usefulness and ease of use. A qualitative study was conducted, based on a participatory workshop conducted in Zaragoza, Spain, with 10 HCPs experienced in the management of pediatric GHD from 7 reference hospitals in Spain. Several activities were designed to promote discussion among participants about predefined topics based on the Technology Acceptance Model and the Unified Theory of Acceptance and Use of Technology to provide their perceptions about the new device. Participants reported 2 key advantages of EP3 over previous easypod generations: the touch screen interface and the real-time data transmission functionality. All participants (10/10, 100%) agreed that the new device should be part of a digital health ecosystem that provides complementary functionalities including data analysis. This study explored the perceived value of the EP3 autoinjector device for the treatment of GHD by HCPs. HCPs rated the new capabilities of the device as having substantial improvements and concluded that it was highly recommendable for clinical practice. EP3 will enhance decision-making and allow for more personalized care of patients receiving r-hGH.

Noonan syndrome: rhGH treatment and PTPN11 mutation.

To analyze the clinical data and genetic characteristics of Noonan syndrome, both the effect and side effects of recombinant human growth hormone (rhGH) treatment. We collected clinical data from 8 children with Noonan syndrome diagnosed from November 2017 to June 2021. The diagnosis was clarified by exome second-generation sequencing and parental PCR-NGS validation and interpretation of the preceding evidence, and growth hormone therapy was administered. Of the cases, four males and four females were seen for slow height growth and the median age at diagnosis was 8 years 7 months (1 year 7 months to 12 years 6 months). Here, 7 children were treated with rhGH. Compared to the pre-treatment period, the growth rate increased after rhGH treatment [3.7 ± 0.5 cm/year before treatment and 8.0 ± 1.0 cm/year after treatment, p < 0.01], with the maximum growth rate between 3 and 6 months of treatment and decreasing with the duration of treatment thereafter. The growth hormone treatment was discontinued and the orthopedic consultation was ordered with regular follow-up, which was considered to be related to the PTPN11 mutation. Noonan syndrome is characterized by slow growth, short stature, mental retardation, peculiar facial features, structural heart abnormalities and abnormal bone metabolism. and osteochondroma was found after case 2 rhGH treatment. Genetic examination is mostly caused by PTPN11 mutation. It is recommended to pay attention to bone metabolism abnormalities before growth hormone treatment, especially in children with PTPN11 mutations.

Growth Hormone Injection Log Analysis with Electronic Injection Device for Qualifying Adherence to Low-Irritant Formulation and Exploring Influential Factors on Adherence.

Although the treatment success of long-term growth hormone therapy (GHT) is dependent on maintaining patients' adherence to treatment, marked variations in adherence levels among children with GHT (eg, 7-71% nonadherence) have been reported. Barriers to or promoters of GHT adherence have been discussed and investigated, and digital health technologies, such as electronic GH injection devices, may have the potential to assess adherence to GHT more accurately. Thus, we conducted a multicenter, retrospective cohort study using GH injection log analysis of an electronic GH device, GROWJECTOR®L, to qualify adherence and explore the factors influencing adherence. This study enrolled 41 patients (median[range] age, 5.8[3.0 ~ 17.0] years) with short stature from nine Japanese medical institutions. The injection log data (12-48 weeks) were read by smartphones and collected into the data center through a cloud server. Although cumulative adherence rates remained higher than 95% throughout the observation period, five (12.2%) patients had low adherence (<85%). Subsequently, subgroup and logistic regression analyses for exploring factors affecting adherence revealed that self-selection of GH device and irregular injection schedule (ie, frequent injections after midnight) significantly affected adherence rate (p=0.034 and 0.048, respectively). In addition, higher rates of irregular injections significantly affected low adherence (median[range], 11.26[0.79 ~ 30.50]% vs 0.26[0.00 ~ 33.33]%, p = 0.029). Our study indicated that injection log analysis using an electronic GH device could detect irregular injection schedules due to a night owl or disturbance in lifetime rhythm affecting low adherence and had significant potential to encourage collaborative monitoring of adherence with healthcare providers and patients themselves/caregivers, along with growing autonomy and shared decision-making. Our study suggests the significance of narrative and personal approaches to adherence of patients with GHT and the usefulness of digital devices for such an approach and for removing various barriers to patient autonomy, leading to improvement and maintenance of adherence.

Growth in small for gestational age children. Growth hormone therapy.

Growth in small for gestational age children. Growth hormone therapy.

A rare case of SCHMID metaphyseal chondrodysplasia associated with hypothyroidism,growth hormone deficiency and celiac disease: case report.

The authors present a rare case of 4-year-2-month-old boy referred to our Unit for harmonious short stature, he had a waddling gait, subtle micromelia, and hyperlordosis, no special facies. The skeletal scan made the diagnosis of SCHMID metaphyseal chondrodysplasia. The first laboratory workup showed elevated thyroid stimulating hormone and anti-tissue transglutaminase immunoglobulin A. The duodenal biopsies confirmed the diagnosis of coeliac disease. Treatment of levothyroxine was initiated with a gluten-free diet .6 years later, his re-evaluation showed a low insulin-like growth factor 1 and low growth hormone peaks confirming the diagnosis of growth hormone deficiency, Growth hormone therapy was initiated with an adjusted dose of levothyroxine. Other causes of short stature should not be missed when diagnosing chondrodysplasia, and further investigations should be carried out to detect other concomitant disorders since metaphyseal chondrodysplasia is a rare cause for short stature while hypothyroidism and coeliac disease are relatively common.

Growth hormone treatment in small for gestational age children. Experience in one center.

Introduction. Small for gestational age (SGA) children usually have a final height of 1 SD below the mean. Three groups are established based on anthropometric characteristics at birth: low birth weight (LBW), short birth length (SBL), or both. Objectives. To describe the characteristics of SGA patients seen at the Department of Pediatric Endocrinology of a tertiary care hospital and to analyze the course of SGA children without catch-up growth at 4 years of age who were receiving treatment with growth hormone (GH), according to their diagnosis. Methods. Retrospective study of SGA patients seen between 2004 and 2021. Results. A total of 89 SGA children were studied; 44/89 started treatment with GH (11/44 LBW, 8/44 SBL, and 25/44 both). Their mean age at diagnosis was 3.87 years; their mean height at treatment initiation was -2.99 SD in SGA children diagnosed by LBW, -2.85 SD in those with SBL, and -3.17 SD in those with both LBW and SBL. Their final height was -1.77, -1.52, and -1.23 SD, respectively, with a total gain of 1.22, 1.33, and 1.93 SD, respectively, thus reaching their target height with a difference of 0.36 ± 0.08 SD. Conclusion. Less than half of SGA children referred to the clinic required treatment with GH because they were not yet 4 years old or had not completed their catch-up growth. SGA patients according to birth weight and length had worse percentiles at diagnosis and a greater response to GH.

Genotypic Findings in Noonan and Non-Noonan RASopathies and Patient Eligibility for Growth Hormone Treatment.

Molecular study has become an invaluable tool in the field of RASopathies. Treatment with recombinant human growth hormone is approved in Noonan syndrome but not in the other RASopathies. The aim of this study was to learn about the molecular base of a large cohort of patients with RASopathies, with particular emphasis on patients with pathogenic variants in genes other than PTPN11, and its potential impact on rGH treatment indication. We reviewed the clinical diagnosis and molecular findings in 451 patients with a genetically confirmed RASopathy. HRAS alterations were detected in only 2 out of 19 patients referred with a Costello syndrome suspicion, whereas pathogenic variants in RAF1 and SHOC2 were detected in 3 and 2, respectively. In 22 patients referred with a generic suspicion of RASopathy, including cardiofaciocutaneous syndrome, pathogenic alterations in classic Noonan syndrome genes (PTPN11, SOS1, RAF1, LZTR1, and RIT1) were found in 7 patients and pathogenic variants in genes associated with other RASopathies (HRAS, SHOC2, and PPPCB1) in 4. The correct nosological classification of patients with RASopathies is critical to decide whether they are candidates for treatment with rhGH. Our data illustrate the complexity of differential diagnosis in RASopathies, as well as the importance of genetic testing to guide the diagnostic orientation in these patients.

Predictive factors of catch-up growth in term, small for gestational age infants: a two-year prospective observational study in Algeria.

Most small for gestational age (SGA) infants show catch-up growth but the minority who do not may benefit from growth-promoting treatment. We determined the prevalence of, and risk factors for, failure to show catch-up growth in term SGA infants. Prospective observational study of infants born at 37-42 weeks gestation between December 2012 and March 2014 with birth weight <10th percentile. Length, weight and head circumference were measured from birth to 2 years. Of 457 (3.9 %) term infants with SGA, 446 (97.6 %) were followed up until 2 years. At 24 months, supine length, weight and head circumference were ≥-2 standard deviation score (SDS) in 87.9 , 96.4 and 97.1 % subjects, with persistent short stature in 12.1 %. In a multivariate analysis, the independent predictors of failure to show catch-up growth at 24 months were: maternal height <150 cm, difference between mid-parental height and birth length of ≥2.2 SDS, height at 24 months <-2 SDS below mid-parental height SDS, history of SGA, ponderal index <3rd centile and duration of breast feeding <3 months. This study provides data concerning the epidemiology of SGA in Algeria and the factors associated with post-natal growth. Establishing which children remain short at 2 years has identified a cohort of patients requiring continuing follow up, with a view to instituting growth hormone therapy in selected cases. These results favour the setting up of an integrated national program to register SGA infants at birth, with re-evaluation at 2 years. (250 words).

Response to growth hormone therapy in ring chromosome 15: Review and evidence from a new case on possible beneficial effect in neurodevelopment

Type 1 Insulin-like Growth Factor Receptor(IGF1R) plays a fundamental role in normal growth and development. Its disruption is usually characterized by severe intrauterine and postnatal growth retardation, microcephaly and neurodevelopmental delay.The efficacy of recombinant human growth hormone treatment remains a challenge for children with IGF1 resistance and pathogenic mutations of IGF1R, with limited data in patients carrying the most severe form of IGF1R defect, the ring chromosome 15. Subject and methodWe tested a high dose of rhGH in a new patient with ring chromosome 15, as confirmed by karyotype and CGH array. We performed a systematic review, and all published r(15) syndrome cases treated by growth hormone(GH) up to April 2023 were searched, and their response to GH therapy was recorded and summarized. ResultsTwelve patients with ring chromosome 15 received GH therapy according to a literature review. We expand the spectrum by the 13th case treated by GH, and we report an impressive improvement in intellectual performance and progressive catch-up growth after 5 and 20 months of follow-up. By introducing our new case in the analysis, the sex ratio was 3:10, and GH therapy was started at the age of 5.5 (3/9.4) (years) for an age of diagnosis of 4.75 (1.3/9.5) (years). The height before GH therapy was −5.1(−5.9/−4.1) SDS. The median duration of treatment was 1.7(0.9/2) (years), with a median height gain of 1(0.3/1.8) SDS and an improvement in growth velocity of 4.1(2.8/5.3) (cm/year). ConclusionGH seems to be effective for r(15) syndrome patients with short stature.