Chromosomal abnormalities detected by karyotyping among patients with secondary amenorrhea: a retrospective study

ABSTRACT BACKGROUND: Chromosomal abnormalities (CAs) have been described in patients with secondary amenorrhea (SA). However, studies on this association are scarce. OBJECTIVES: To evaluate the frequency and types of CAs detected by karyotyping in patients with SA. DESIGN AND SETTING: This retrospective study was performed in a reference clinical genetic service in South Brazil. METHODS: Data were obtained from the medical records of patients with SA who were evaluated between 1975 and 2022. Fisher's bicaudate exact test and Student's t-test were used, and P < 0.05 was considered significant. RESULTS: Among 43 patients with SA, 14 (32.6%) had CAs, namely del (Xq) (n = 3), 45,X (n = 2), 46,X,r(X)/45,X (n = 2), 46,XX/45,X (n = 1), 46,X,i(q10)/45,X (n = 1), 47,XXX (n = 1), 46,XX/47,XXX (n = 1), 46,XX/47,XX,+mar (n = 1), 45,XX,trob(13;14)(q10;q10)/46,XXX,trob(13;14)(q10;q10) (n = 1), and 46,XX,t(2;21)(q23;q11.2) (n = 1). Additional findings were observed mostly among patients with CA compared with those without CA (P = 0.0021). No difference in the mean age was observed between the patients with SA with or without CAs (P = 0.268025). CONCLUSIONS: CAs are common among patients with SA, especially those with short stature and additional findings. They are predominantly structural, involve the X chromosome in a mosaic, and are compatible with the Turner syndrome. Patients with SA, even if isolated, may have CAs, particularly del (Xq) and triple X.

Laron syndrome: A tale of two siblings / Journal of the ASEAN Federation of Endocrine Societies

@#Primary growth hormone (GH) resistance or growth hormone insensitivity syndrome, also called Laron syndrome, is a hereditary disease caused by mutations in the GH receptor or in the post-receptor signaling pathway. This disorder is characterized by postnatal growth failure resembling GH deficiency. Differentiating the two conditions is necessary. We present the cases of two siblings, a 16-year-old female and a 9-year-old male, born from a consanguineous union. Both had normal birth weights with subsequent severe short stature and delayed teeth eruption, with no features suggestive of any systemic illness. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) were both low. Suspecting GH deficiency, provocative testing with clonidine was done revealing peak growth hormone >40 ng/mL in both patients. In view of low IGF1 and IGFBP3 and high GH on stimulation, IGF1 generation test was done for both siblings, with values supporting the diagnosis of GH insensitivity or Laron syndrome.

FBN1 gene mutation in a Chinese pedigree of mild Geleophysic dysplasia type 2/Acromicric dysplasia and the exploration of growth-promoting therapy / 中华内分泌代谢杂志

Objective:To summarize the clinical and genetic features of 7 patients with a mild form of Geleophysic dysplasia type 2(GD2)/Acromicric dysplasia(AD) induced by fibrillin 1(FBN1) gene mutation from one Chinese family.Methods:A Chinese pedigree of mild GD2/AD treated at the Pediatric Endocrinology Department at the First Affiliated Hospital of Sun Yat-sen University between August 2017 and May 2022 was collected. Whole-exome genetic sequencing of the FBN1 gene were performed to establish the diagnosis. Additionally, a literature review was further conducted.Results:In this family, among 13 individuals spanning three generations, there were 7 affected cases, including 1 adult female, 1 adult male, and 5 children. All individuals exhibited postnatal growth failure, severe disproportionate short stature, and lacked typical facial features. Exome sequencing and Sanger sequencing confirmed the presence of a heterozygous missense mutation c. 5099A>G(p.Tyr1700Cys) in exon 42 of the FBNI gene in 6 affected individuals(Ⅱ-1, Ⅲ-1 to Ⅲ-5), which was identified as a pathogenic mutation. This mutation was previously reported in a Chinese classical achondroplasia(AD) family. Based on comprehensive genetic analysis, clinical features, and multisystem evaluation, 3 cases were diagnosed with mild type 2 growth hormone deficiency(GD2), and 4 cases were diagnosed with mild AD. Recombinant human growth hormone(rhGH; 1.1-1.4 IU·kg -1·week -1) was applied to all the 5 children, and additional gonadotropin releasing hormone analogue(GnRHa) was administered to the 2 girls in late puberty, resulting in certain growth-promoting effect. Conclusions:The c. 5099A>G(p.Tyr1700Cys) mutation not only leads to the classical type of achondroplasia(AD) as reported in the literature but also causes the non-classical GD2 or AD(mild GD2/AD). Further research is warranted to investigate the long-term therapeutic effects of rhGH treatment.

Adult Léri-Weill dyschondrosteosis coexists with endocrinal metabolic disorders: a report of two cases / 中华内分泌代谢杂志

Léri-Weill dyschondrosteosis (LWD) has typical triad: short middle limbs, short stature, Madelung deformity of wrist, and increased body mass index. Short stature and high body mass index are risk factors for metabolic syndrome, type 2 diabetes, cardiovascular diseases, and autoimmune thyroid diseases. However, metabolic disorders and thyroid diseases in adult LWD patients have not been elucidated. This paper reports two adult patients with LWD presented to the Department of Endocrinology and metabolism. By introducing clinical characteristics, genetic variations, and diagnostic methods, physicians can deepen their understanding of LWD, improve diagnosis, and be aware of the comorbid metabolic diseases and thyroid disorders with a view of early prevention and treatment.

A case of Acromicric dysplasia with FBN1 mutation / 中华内分泌代谢杂志

Acromicric dysplasia(AD) is a rare skeletal dysplasia characterized by severe short stature, short hands and feet, normal intelligence, mild facial dysmorphism, and radiological characteristics. The clinical data and genetic test results of one patient with AD in our hospital were analyzed, and the clinical characteristics of this case were summarized. The main manifestations of the child were short stature, short hands and feet, mild facial dysmorphism, short and stubby metacarpals and phalanges on hand X-ray. One mutation, FBN1: c.5141T>G(p.Met1714Arg), was identified in this child, the mutation is inherited from her short mother and grandfather. AD is a rare congenital skeletal dysplasia disorder associated with mutations in the FBN1 gene. It conforms to the pathogenesis of autosomal dominant genetic disease.

Advances in genetic etiology of isolated growth hormone deficiency / 国际儿科学杂志

Isolated growth hormone deficiency(IGHD)is a growth disorder characterized by short stature.The etiology and pathogenesis of IGHD are still not fully understood.IGHD can be caused by congenital(heredity and/or malformations)or acquired(tumors, physical trauma, inflammation, brain infections, or radiation therapy)factors.The most common genes in its genetic etiology are the growth hormone 1(GH1)and growth hormone-releasing hormone receptor(GHRHR). In rare cases, IGHD may be caused by mutations in transcription factors such as HESX1, SOX3, OTX2, POU1F1, etc.The disease phenotype of IGHD patients is highly variable.Correct diagnosis and early treatment are crucial for the long-term prognosis of IGHD patients.This review mainly discusses advance of IGHD gene mutation and disease phenotype.

Advances in the pathogenesis and treatment of short stature in Noonan syndrome / 国际儿科学杂志

Noonan syndrome(NS)is an inherited disease involving multiple systems.The main clinical manifestations include distinctive facial features, short stature, heart defects, developmental delay and chest deformity.Short stature, reported in up to 70% of NS patients, is one of the main reasons NS patients seek medical treatment.The pathogenesis is associated with the up-regulation of RAS-mitogen activated protein kinase(RAS-MAPK)signal pathway.Further study is needed for some further specific mechanisms.Recombinant human growth hormone(rhGH)therapy has been approved for NS patients with short stature and has achieved a good therapeutic effect.However, the knowledge of drug dosage, influencing factors, long-term efficacy and risk of rhGH treatment is still insufficient.This paper reviews the pathogenesis and treatment of short stature in NS, providing help for the treatment and management of the disease.

Advances in acromelic dysplasia caused by FBN1 mutation / 国际儿科学杂志

The mutation of FBN1 gene results in the abnormality of its encoded fibrillin-1 protein, which affects musculoskeletal growth and results in two opposing phenotypes of tall and short stature, with clinical manifestations of Marfan syndrome and acromelic dysplasia.Acromelic dysplasia caused by FBN1 mutation includes acromicric dysplasia(AD), geleophysic dysplasia(GD)and Weill-Marchesani syndrome(WMS). As some FBN1 mutations have been reported to cause both AD and GD.The dysregulation of TGF-β signal pathway is the underlying mechanism of acromelic dysplasia.Currently, there is no specific treatment, mainly symptomatic treatment, early identification, diagnosis and treatment will improve prognosis of patients.This article will review the pathogenesis, clinical phenotype, treatment and follow-up of acromelic dysplasia caused by FBN1 mutation.

Correlation of body mass index to Ghrelin and IGF-1 among children with short stature

Abstract Objective: To assess the BMI among children with Growth Hormone Deficiency (GHD) and Idiopathic Short Stature (ISS) and its correlation to ghrelin, Growth Hormone (GH), and Insulin-like Growth Factor-1 (IGF-1) levels. Methods: A cross-sectional descriptive study in which 42 patients attending the Pediatric endocrine clinic were enrolled, allocated into two groups: group I: GHD children; group II: ISS children. Ghrelin, IGF-1 and GH in both groups were measured. Results: Ghrelin was significantly higher among GHD group (p < 0.001). Overall, there was a strong negative correlation between IGF-1 and ghrelin (r = -0.977, p-value = < 0.001) while a moderate positive correlation between ghrelin and BMI (r = 0.419, p-value = 0.006). There was a weak positive non-significant correlation between IGF-1 and BMI (r = 0.276, p-value = 0.077). In GHD group, there was a weak positive non-significant correlation between ghrelin and GHmax measurement (r = 0.052, p-value = 0.824), while a weak negative non-significant correlation between both variables in ISS group (r = -0.243, p-value = 0.288). In GHD group, there was a moderate positive correlation between ghrelin and BMI (r = 0.500, p-value = 0.021), but weak negative non-significant correlation between both variables in ISS group (r = -0.255, p-value = 0.265). Conclusion: There was a negative feedback loop between ghrelin and IGF-1, whereas a positive feedback between ghrelin and BMI. BMI was more affected in the ISS group but was non-signifi-cantly correlated with ghrelin. There was no significant compensatory response of ghrelin suggesting its contribution to the pathogenesis of ISS.

Case report of acromesomelic dysplasia Maroteaux type caused by the NPR2 gene mutation / 中华实用儿科临床杂志

Clinical data of a child with acromesomelic dysplasia Maroteaux type (AMDM) treated in the Department of Pediatrics, Tianjin Medical University General Hospital at November 2018 was retrospectively analyzed.The female child aged 3 years and 3 months old with 83 cm height (-3.84 SD) had clinical manifestations of disproportionate short stature, disproportionate shortening of forearms and forelegs, and stubby fingers and toes.Gene sequencing identified compound heterozygous mutations, c.1640T>A(p.Val547Asp)/c.682G>A(p.Gly228Ser), in the NPR2 gene, which have not been reported in the Human Gene Mutation Database.Their protein function was predicted harmful.The child was diagnosed as AMDM.During the follow-up until 4 years and 8 months old, the child was 90 cm tall (-4.35 SD), with a growth velocity of 4.9 cm/year.She was treated with recombinant human growth hormone (rhGH) treatment for 9 months and regularly followed up.The child was now 98.2 cm height (-3.07 SD) and she had a growth velocity of 10.9 cm/year.This case report enriched the gene mutation spectrum of AMDM.Treatment with rhGH can effectively improve the height of the child, but the long-term effect needs further follow-up and observation.

PTPN11 gene mutation mediated Noonan syndrome in children with idiopathic short stature / 中华内分泌代谢杂志

Objective:To analyze the genetic etiology of idiopathic short stature(ISS) children, and to investigate the clinical characteristics of Noonan syndrome caused by PTPN11 gene mutation, and the response to recombinant human growth hormone(rhGH) as well.Methods:Genomic DNA was extracted from the peripheral blood of 232 ISS patients, and the genome was detected by whole exon sequencing. The gene variation was analyzed according to the guideline of American College of Medical Genetics and Genomics(ACMG), and clinical baseline data and follow-up data of rhGH treatment were collected from PTPN11 gene pathogenic patients.Results:Among 232 ISS patients, 6 were found to have PTPN11 pathogenic gene variants(c.1507G>C, c. 317A>G, c. 923A>G, c. 922A>G, c. 236A>G, c. 922A>G), diagnosed as Noonan syndrome. Together with 3 cases of Noonan syndrome patients(all PTPN11 gene variation C. 1510A>G) previously diagnosed in our hospital, the clinical characteristics of patients were analyzed. Among the 9 Noonan syndrome patients, 7 were boys and 2 were girls. The average age was 10.2(4.5, 14.7) years old, and their height standard deviation score was -3.06 SD(95% CI -2.29 SD--3.94 SD). Among them, 4 patients received rhGH treatment with an average treatment duration of 2.25(1.5, 3.5) years. After treatment, their height increased by 14.3(8.6, 23.9) cm, and the change in height standard deviation score improved by 0.21 SD(95% CI 0.12 SD-0.27 SD). Conclusion:Noonan syndrome has a wide range of clinical phenotypes. For children with short stature, heart defects and cryptorchidism, the possibility of Noonan syndrome should be considered. PTPN11 is the common pathogenic gene for Noonan syndrome, and genetic testing facilitates the early diagnosis, treatment, and follow-up prognosis of Noonan syndrome patients.

Clinical and Radiological Characterisation of Patients with Mucopolysaccharidosis in a Genetic Clinic

Abstract The mucopolysaccharidoses (MPS) are a relatively uncommon group of inherited metabolic disorders. MPSs should be suspected in a child with coarse facies, organomegaly, recurrent respiratory tract infections, developmental delay, and hernias. Early diagnosis and treatment can greatly improve the quality of life in these children. In this study we studied 46 MPS patients diagnosed on enzyme and/or DNA testing and we found that the MPS II was the most common type followed by MPS I and MPS IVA. While the mean age of onset of symptoms was 12 months, the mean age at diagnosis was 4.5 years, a significant delay. One of major presenting features was recurrent respiratory problems, more prevalent in MPS II cases. Many patients also had short stature and contractures. Increasing awareness among physicians is of paramount importance for the early diagnosis and optimal treatment and prevention by prenatal testing and counselling.

Study on the correlation of bone age and bone mineral density with age, height and weight in children with short stature / 公共卫生与预防医学

Objective To study the correlation of bone age and bone mineral density with age, height and weight of short children. Methods Sixty-four short children who were consulted and treated at the author's hospital from January 2016 to October 2018 were selected as research subjects. The general information including age, sex, height and weight of the children were recorded. The ultrasound bone density test was carried out at the same time. The bone mineral density and bone age were evaluated through plain carpal bone radiograph. The relationship between different bone age and bone mineral density value with age, height and weight was analyzed. Results The actual age of the enrolled children was positively correlated with bone mineral density and bone age (boys r=0.658, 0.919, girls r=0.641, 0.906). The height of the enrolled children was positively correlated with bone mineral density and bone age (boy r=0.561, 0.326, girls r=0.586, 0.349). The weight of the enrolled children was positively correlated with bone mineral density and bone age (boys r=0.340, 0.314, girls r=0.395, 0.282). Conclusion The bone age and bone mineral density of short children were positively correlated with their age, height and weight. In clinical diagnosis and treatment, the use of bone age and bone mineral density as a guide can produce more significant effects, which can be used as scientific indicators for the evaluation and prediction of short children.

Economic inequality in prevalence of underweight and short stature in children and adolescents: the weight disorders survey of the CASPIAN-IV study

ABSTRACT Objective: The aim of this study was to determine the determinants of socio-economic inequality in the prevalence of short stature and underweight in Iranian children and adolescents. Subjects and methods: This cross-sectional nationwide study was conducted on 36,486 participants, aged 6-18 years. This school-based surveillance (CASPIAN- IV) program and its complementary part on weight disorders evaluation was conducted in urban and rural areas of 30 provinces in Iran. In addition to physical examination, a validated questionnaire was completed from students and their parents. Socio-economic status (SES) was determined using principal component analysis, and was classified in quintile scale. Inequality in the prevalence of underweight and short stature was assessed using concentration (C) index and slop index of inequality (SII) by the Oaxaca-Blinder decomposition method. Results: The prevalence (95% CI) of underweight and short stature at national level was 10.89 (10.55, 11.23) and 4.15 (3.94, 4.38), respectively; it had a downtrend from the lowest to highest SES quintile. Furthermore, the value of C for underweight and short stature was negative, i.e. inequality was in favor of high SES groups. Moreover, the prevalence gap of underweight and short stature in the first and fifth quintiles of SES was 6.58% and 5.80%, respectively. The highest proportion of this gap was explained by living area. In the multiple logistic model, odds of underweight and short stature were significantly lower in individuals with higher SES. Compared to boys, odds of underweight were decreased in girls, whereas odds of short stature were increased in them. Odds of underweight and short stature were increased in participants from rural areas than in urban areas. With increasing age, the odds of underweight and short stature decreased significantly. Conclusions: The results of this study showed that inequality in the prevalence of short stature and underweight was in favor of high SES groups. Moreover, living area was one of the most important determinants that explained this inequality. Therefore, this issue needs to be considered in health promotion policies.

Schimke immune osseous dysplasia: a rare case report

Schimke immune-osseous dysplasia (SIOD) is primarily characterized by the combination of spondyloepiphyseal dysplasia (SED), unique clinical phenotype, immune complex nephropathy (focal segmental glomerulosclerosis) and progressive immune defects with T-cell immunodeficiency. SIOD is caused by mutations in SMARCAL1 gene. Here we report a case of a 6-year-old girl who presented to us with disproportionate short stature, short neck kyphoscoliosis, hyper pigmented macules and severe herpes zoster. On further evaluation, she had evidence of T cell deficiency and nephrotic range of proteinuria. Renal histopathology documented focal segmental glomerular sclerosis. Genetic analysis confirmed homozygous missense mutation of SMARCAL gene on exon 8 variant c1358G>c. On extensive literature survey, this is noted to be the first case of SIOD reported from India. These children need close surveillance to watch for infections and progressive renal failure and require special care during administration of certain drugs and live vaccines.

Two cases with pycnodysostosis in a family: a case report

Pycnodysostosis (Greek, pycnos - density, dys - defect, ostosis - bone) is a rare inherited disorder of the bone, first described by Maroteaux and Lamy. Pycnodysostosis is an autosomal recessive disorder, with incidence estimated to be 1.7 per 1 million births. Clinical presentation of this disorder include short stature, dolichocephalic skull, frontal bossing, obtuse mandibular angle, dysplastic clavicles, and short hands and feet, diffuse osteosclerosis, acro-osteolysis along with the finger and nail abnormalities. The main oral aspects are midfacial hypoplasia, a grooved palate, and dental abnormalities include double row of teeth, delayed eruption of permanent dentition, multiple caries. Pathological fractures of the bones occur due to sclerosis. Radiologically, skull bones appear thickened with open fontanels which look like 'lakes of bones', hypoplasia of facial bones, generalized osteosclerosis, open fontanels and cranial sutures, non pneumotization of paranasal sinuses, and fractures commonly in lower limbs.

Etiology of short stature in children attending pediatric endocrinology clinic of a tertiary care hospital in Bangladesh

Background: Short stature is a common problem to practicing pediatricians. It results from various etiologies, which are categorized as normal variants and pathological causes. Normal variant short stature consists of Familial Short Stature (FSS) and Constitutional Growth Delay (CGD), while pathological causes are subdivided into endocrine diseases, clinically defined syndromes, chronic diseases, metabolic diseases and others. There are not so much data available in Bangladesh in this respect. So, present study was conducted to know the common causes of short stature.Methods: This cross-sectional study was done in pediatric endocrinology clinic of Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from January 2017 to August 2018. One hundred children with short stature meeting inclusion criteria were recruited after taking an informed consent. The detailed history, physical examination including anthropometric measurements and relevant investigations were done. Data were recorded on a predesigned questionnaire for final analysis.Results: The common causes of short stature identified were familial short stature (FSS) 51% cases, Constitutional Growth Delay (CGD) 14% cases and hypothyroidism 12% cases. Other less common causes of short stature were Growth Hormone Deficiency (GHD) 8% cases, malnutrition 6% cases and genetic syndrome 5% cases.Conclusions: FSS and CGD were the leading cause of short stature in children. Endocrinological causes were the most common cause of short stature after normal variant while nonendocrine causes were the least.

Impact of Using Different Growth References on Interpretation of Anthropometric Parameters of Children Aged 8-15 Years

Objective: To compare the effect of the application of threegrowth references (Agarwal, 1992; Indian Academy ofPaediatrics (IAP), 2015; and World Health Organisation (WHO),2007) on interpretation of anthropometric parameters inschoolchildren.Setting: Cross-sectional school-based study.Participants: Children 8-15 years studying in one governmentschool and one private school of Delhi.Procedure: The age- and gender-specific standard deviationscores of height-for-age and BMI-for-age were estimated foreach student enrolled, using the three growth referencesindependently.Main outcome measure: The proportion of children withshort stature, thinness and overweight/ obesity determined byeach growth reference were compared.Results: A total of 1237 students participated in the study. Asignificantly higher proportion of children (both sexes) wereclassified to have short stature using WHO 2007 reference(8.8%) as compared to the Agarwal (3.3%) charts and IAP, 2015references (3.6%). The combined prevalence of overweight andobesity was highest (34.8%) by the IAP, 2015 reference asagainst 32% by Agarwal charts and 29.1% by WHO, 2007reference. Good agreement existed between the IAP, 2015reference and Agarwal charts in classifying subjects intodifferent BMI categories (Kappa=0.82) and short stature(Kappa=0.99).Conclusions: In view of differences noted, use of nationalpopulation derived reference data is suggested to correctlydefine growth trajectories in children.

Correlation analysis of serum vitamin and trace element levels and bone age in short stature children / 公共卫生与预防医学

Objective To investigate the serum vitamin and trace element levels in children with short stature and their correlation with bone age. Methods Levels of serum VA and VD, and trace elements Ca, Fe, Zn, Mg, Cu, Pb and Cd were measured in 322 children who were referred for height consultation. Bone ages were evaluated and the correlation between bone age and serum vitamin and trace element levels was analyzed. Results The VA and VD deficiency rates of these 322 children were 22.05% and 34.16%, respectively. The deficiency rates of trace elements Ca, Fe and Zn were14.29%, 21.43% and 6.83%, respectively. The Pb excess rate was as high as 42.55%. The rates of bone age (BA) retardation in Group Ⅰ (short) and Group Ⅱ (slightly short) were 49.38% and 37.57%, respectively, which was significantly higher than that of Group Ⅲ (normal). The Ca level of BA retardation children was lower than that of the normal BA children in Group I. The VD level of BA retardation children was lower than that of the normal BA children in Group Ⅱ. BA was negatively correlated with VD, Ca, and Cu levels in children (r=-0.241; r=-0.136; r=-0.162), and positively correlated with Fe (r=0.286) . Conclusion There were significant abnormalities of vitamins and trace elements in short children. Children's bone age had a certain correlation with serum vitamin D, calcium, copper, and iron levels. Serum vitamin and trace element levels in children should be monitored to guide a reasonable diet to better promote child growth and development.

Update on new GH-IGF axis genetic defects

ABSTRACT The somatotropic axis is the main hormonal regulator of growth. Growth hormone (GH), also known as somatotropin, and insulin-like growth factor 1 (IGF-1) are the key components of the somatotropic axis. This axis has been studied for a long time and the knowledge of how some molecules could promote or impair hormones production and action has been growing over the last decade. The enhancement of large-scale sequencing techniques has expanded the spectrum of known genes and several other candidate genes that could affect the GH-IGF1-bone pathway. To date, defects in more than forty genes were associated with an impairment of the somatotropic axis. These defects can affect from the secretion of GH to the bioavailability and action of IGF-1. Affected patients present a large heterogeneous group of conditions associated with growth retardation. In this review, we focus on the description of the GH-IGF axis genetic defects reported in the last decade. Arch Endocrinol Metab. 2019;63(6):608-17