scholarly journals Aggrecanopathies highlight the need for genetic evaluation of ISS children

2020 ◽  
Vol 183 (2) ◽  
pp. C9-C10
Author(s):  
Ola Nilsson
Keyword(s):  
Short Stature ◽  
Osteochondritis Dissecans ◽  
Early Onset ◽  
Gene Mutations ◽  
Bone Age ◽  
Genetic Evaluation ◽  
Large Cohort ◽  
Growth Disorders ◽  
Common Causes ◽  
Work Up

Short stature is one of the most common causes for referrals to pediatric endocrinologists. However, in a majority of the children, no underlying cause can be identified and the child instead receives the unhelpful diagnosis of idiopathic short stature (ISS), often after extensive work-up and testing. Recent advances in genetic methodology have allowed for the identification of a number of different monogenic conditions within the large cohort of ISS children. Isolated short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (MIM#165800) due to heterozygous aggrecan gene mutations exemplifies how this progress is changing the way we assess, counsel and treat children with non-endocrine growth disorders.

scholarly journals ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment

2016 ◽  
Vol 102 (5) ◽  
pp. 1458-1467 ◽  
Author(s):  
Manouk van der Steen ◽  
Rolph Pfundt ◽  
Stephan J.W.H. Maas ◽  
Willie M. Bakker-van Waarde ◽  
Roelof J. Odink ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Bone Age ◽  
Hormone Treatment ◽  
Gh Treatment ◽  
Midface Hypoplasia ◽  
Short Children ◽  
Hormone Analog

Abstract Background: Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA. Objective: To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment. Methods: BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age. Results: Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation. Conclusion: This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.

scholarly journals A high proportion of novel ACAN mutations and their prevalence in a large cohort of Chinese short stature children

2021 ◽  
Author(s):  
Li Lin ◽  
Mengting Li ◽  
Jingsi Luo ◽  
Pin Li ◽  
Shasha Zhou ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Family History ◽  
Short Stature ◽  
Bone Age ◽  
Hormone Treatment ◽  
Pathogenic Variants ◽  
Common Causes ◽  
History Of ◽  
The Common ◽  
Next Generation Sequencing Ngs

Abstract Context Aggrecan, encoded by ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated. Objective We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone (GH) therapies. Patients and Methods Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by Next-generation sequencing (NGS)-based test. Result We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort, it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, five out of eleven ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SDS improvement. Conclusion Our data suggested that ACAN mutation is one of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.

scholarly journals Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations

2016 ◽  
Vol 102 (2) ◽  
pp. 460-469 ◽  
Author(s):  
Alexandra Gkourogianni ◽  
Melissa Andrew ◽  
Leah Tyzinski ◽  
Melissa Crocker ◽  
Jessica Douglas ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Short Stature ◽  
Early Onset ◽  
Autosomal Dominant ◽  
Standard Deviation Score ◽  
Bone Age ◽  
Skeletal Maturation ◽  
Disc Disease ◽  
Phenotypic Spectrum ◽  
Median Height

Abstract Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, −2.8 standard deviation score (SDS); range, −5.9 to −0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype–phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, −2.0 SDS; range, −4.2 to −0.6). Most children with ACAN mutations had advanced bone age (bone age − chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

scholarly journals Towards a Rational and Efficient Diagnostic Approach in Children Referred for Growth Failure to the General Paediatrician

2019 ◽  
Vol 91 (4) ◽  
pp. 223-240 ◽  
Author(s):  
Jan M. Wit ◽  
Gerdine A. Kamp ◽  
Wilma Oostdijk ◽  
Keyword(s):  
Short Stature ◽  
Diagnostic Yield ◽  
Secondary Growth ◽  
Growth Failure ◽  
Bone Age ◽  
Bone Diseases ◽  
Diagnostic Approach ◽  
Hormone Deficiency ◽  
Growth Disorders ◽  
Metabolic Bone Diseases

Based on a recent Dutch national guideline, we propose a structured stepwise diagnostic approach for children with growth failure (short stature and/or growth faltering), aiming at high sensitivity for pathologic causes at acceptable specificity. The first step is a detailed clinical assessment, aiming at obtaining relevant clinical clues from the medical history (including family history), physical examination (emphasising head circumference, body proportions and dysmorphic features) and assessment of the growth curve. The second step consists of screening: a radiograph of the hand and wrist (for bone age and assessment of anatomical abnormalities suggestive for a skeletal dysplasia) and laboratory tests aiming at detecting disorders that can present as isolated short stature (anaemia, growth hormone deficiency, hypothyroidism, coeliac disease, renal failure, metabolic bone diseases, renal tubular acidosis, inflammatory bowel disease, Turner syndrome [TS]). We advise molecular array analysis rather than conventional karyotyping for short girls because this detects not only TS but also copy number variants and uniparental isodisomy, increasing diagnostic yield at a lower cost. Third, in case of diagnostic clues for primary growth disorders, further specific testing for candidate genes or a hypothesis-free approach is indicated; suspicion of a secondary growth disorder warrants adequate further targeted testing.

scholarly journals A study of clinical profile of children with short stature

2021 ◽  
Vol 8 (9) ◽  
pp. 328-330
Author(s):  
Kumar Angadi ◽  
Mohammed Mukeeb Ahmed ◽  
Shivanand S Bhimalli ◽  
Sharanagouda Patil
Keyword(s):  
Short Stature ◽  
Bone Age ◽  
Clinical Profile ◽  
Inclusion Criteria ◽  
Indian Children ◽  
Community Based ◽  
Indian Context ◽  
Common Causes ◽  
Constitutional Delay ◽  
The Common

Background: Short stature is one of the common concerns among the Indian children. However, community-based studies in Indian context are rare compared to studies performed in Western countries. Aim: Here, we aimed to study the clinical profile of children with short stature and the different causes of it. Methods: This study was a hospital-based prospective study that included 65 children ?18 years (female: 57%, male: 43%) who met the inclusion criteria. Detailed history, physical examination, anthropometry, laboratory tests, bone age, and chromosomal analysis were included for evaluation. Results: The most common age group affected was 11–15 years (40%) followed by 6–10 years (34%) and <5 years (21.5%). Growth hormone (GH) deficiency (21.4%), followed by malnutrition (18.5%), familial short stature (13.9%), hypothyroidism (10.8%), turner syndrome (10.8%), constitutional delay of growth and puberty (9.2%), systemic diseases (6.2%), and miscellaneous (6.1%) were identified as the common causes of short stature. Conclusion: Commonly observed etiology of short stature was identified in this study. Proportionate and disproportionate short statures were 90.7% and 9.3%, respectively. About 23% of the cases were of physiological short stature and 77% were of pathological short stature.

scholarly journals Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

2002 ◽  
pp. 319-323 ◽  
Author(s):  
Y Rakover ◽  
A Silbergeld ◽  
I Lavi ◽  
R Masalha ◽  
IB Shlomo
Keyword(s):  
Short Stature ◽  
Binding Protein ◽  
Standard Deviation Score ◽  
Bone Age ◽  
The Other ◽  
Provocative Test ◽  
Igf I ◽  
Parental Height ◽  
The Difference ◽  
Igfbp 3

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.

scholarly journals Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Nami Mohammadian Khonsari ◽  
Sahar Mohammad Poor Nami ◽  
Benyamin Hakak-Zargar ◽  
Tessa Voth
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Hormone Receptors ◽  
Bone Growth ◽  
Synergistic Effects ◽  
Signs And Symptoms ◽  
Bone Age ◽  
Pathogenic Mutation ◽  
Paracrine Factors ◽  
Severe Short Stature

Abstract Background Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature. Case presentation We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient’s phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient’s father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature. Conclusion We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

scholarly journals Turner Syndrome, Uncommonly Diagnosed Cause of Short Stature: Case Report and Review of Literature

2013 ◽  
Vol 33 (1) ◽  
pp. 74-76
Author(s):  
S Basnet ◽  
A Eleena ◽  
AK Sharma
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Turner Syndrome ◽  
Age Estimation ◽  
Bone Age ◽  
Review Of Literature ◽  
X Ray ◽  
Dysmorphic Features ◽  
The Past ◽  
Hormone Analysis

Many children are frequently brought to the paediatric clinic for evaluation of short stature. Evaluation for these children does not go beyond x-ray for bone age estimation and growth hormone analysis. Most of them are considered having constitutional or genetic cause for their short stature. However, shuttle dysmorphic features could be missed in many of them. Hence, many children might be having chromosomal anomaly as an underlying cause. We report a case of 40 months who had been evaluated several times in the past for pneumonia, otitis media and short stature is finally diagnosed to have Turner syndrome. DOI: http://dx.doi.org/10.3126/jnps.v33i1.8174 J Nepal Paediatr Soc. 2013;33(1):74-76

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