scholarly journals A SOX5 gene variant as a possible contributor to short stature

2020 ◽  
Vol 2020 ◽  
Author(s):  
Athanasios Gkirgkinoudis ◽  
Christina Tatsi ◽  
Stephanie J DeWard ◽  
Bethany Friedman ◽  
Fabio R Faucz ◽  
...  
Keyword(s):  
Short Stature ◽  
Behavioral Problems ◽  
In Silico ◽  
De Novo ◽  
Missense Variant ◽  
Idiopathic Short Stature ◽  
Growth Disorders ◽  
List Type ◽  
Dysmorphic Features ◽  
Skeletal Defects

Summary SOX5 plays an important role in chondrogenesis and chondrocyte differentiation. SOX5 defects in humans (often deletions) result in a Lamb-Shaffer syndrome (LSS), presenting with speech delay, behavioral problems and minor dysmorphic features. We present a patient with idiopathic short stature (ISS) who carried a heterozygous novel variant in SOX5. The patient had no dysmorphic features, but a skeletal survey revealed minor skeletal abnormalities. Laboratory and endocrine evaluation for known causes of growth disorders was negative. The missense variant in SOX5 gene (c.1783A>G, p.K595E) was de novo and was predicted to be deleterious by in silico programs. In summary, we present a patient whose presentation may provide evidence that gene defects in SOX5 may contribute to the etiology of short stature and/or mild skeletal defects beyond LSS. Learning points: We report a girl with idiopathic short stature and mild skeletal defects presenting with a de novo variant in SOX5 gene, predicted in silico to be deleterious. Although SOX5 has not been previously specifically associated with short stature, several evidences support its contributing effect on dyschondrogenesis. Missense variants in SOX5 gene may lead to mild phenotypes, differing from typical presentation of patients with Lamb-Shaffer syndrome.

scholarly journals Auxology Is a Valuable Instrument for the Clinical Diagnosis of SHOX Haploinsufficiency in School-Age Children with Unexplained Short Stature

2003 ◽  
Vol 88 (10) ◽  
pp. 4891-4896 ◽  
Author(s):  
Gerhard Binder ◽  
Michael B. Ranke ◽  
David D. Martin
Keyword(s):  
Short Stature ◽  
De Novo ◽  
Fragment Size ◽  
Mutation Screening ◽  
Idiopathic Short Stature ◽  
Paternal Allele ◽  
Leg Length ◽  
Sitting Height ◽  
Arm Span ◽  
Hand Radiography

Abstract SHOX (short stature homeobox-containing gene) mutations causing haploinsufficiency have been reported in some individuals with idiopathic short stature and in many patients with Leri-Weill-dyschondrosteosis. Around 80% of SHOX mutations are complete gene deletions, whereas diverse point mutations account for the rest. The aim of this study was to estimate the prevalence of SHOX mutations in children with idiopathic short stature and to give an unbiased characterization of the haploinsufficiency phenotype of such children. We recruited 140 children (61 girls), in our clinic, with idiopathic short stature, which was defined by the presence of normal IGF-I and free T4; a normal karyotype in females; the absence of endomysium antibodies, of chronic organic, psychological, or syndromatic disease; and by the lack of clear signs of any osteodysplasia. Height, arm span, and sitting height were recorded, and subischial leg length was calculated. Two highly polymorphic microsatellite markers located around the SHOX coding region (CA-SHOX repeat and DXYS233) were PCR-amplified with fluorescent primers and separated in an automatic sequencing machine. Analysis of parental DNA was performed in the probands who had only one fragment size of each of both markers. SHOX haploinsufficiency caused by a SHOX deletion was confirmed in three probands (2%), all females, who carried a de novo deletion through loss of the paternal allele. Their auxological data revealed a significant shortening of arms and legs in the presence of a low-normal sitting height, when compared with the other 137 children tested. Therefore, the extremities-trunk ratio (sum of leg length and arm span, divided by sitting height) for total height was significantly lower in the three SHOX haploinsufficient probands, in comparison with the whole group. This observation was confirmed with the auxological data of five additional patients (four females) previously diagnosed with SHOX haploinsufficiency; all but the youngest girl had height-adjusted extremities-trunk ratios more than 1 sd below the mean. All children with SHOX haploinsufficiency exhibited at least one characteristic radiological sign of Leri-Weill-dyschondrosteosis in their left-hand radiography, namely triangularization of the distal radial epiphysis, pyramidalization of the distal carpal row, or lucency of the distal ulnar border of the radius. Our observations suggest that it is rational to limit SHOX mutation screening to children with an extremities-trunk ratio less than 1.95 + 1/2 height (m) and to add a critical judgment of the hand radiography.

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

2014 ◽  
Vol 171 (2) ◽  
pp. 253-262 ◽  
Author(s):  
Ana P M Canton ◽  
Sílvia S Costa ◽  
Tatiane C Rodrigues ◽  
Debora R Bertola ◽  
Alexsandra C Malaquias ◽  
...  
Keyword(s):  
Short Stature ◽  
Candidate Genes ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Comparative Genomic ◽  
Growth Disorders ◽  
Genomic Regions

BackgroundThe 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.ObjectiveTo analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause.Patients and methodsA 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.ResultsIn 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.ConclusionPathogenic 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.

scholarly journals Hypercalcitoninaemia in pseudohypo­parathyroidism type 1A and type 1B

2019 ◽  
Vol 2019 ◽  
Author(s):  
Maria P Yavropoulou ◽  
Efstathios Chronopoulos ◽  
George Trovas ◽  
Emmanouil Avramidis ◽  
Francesca Marta Elli ◽  
...  
Keyword(s):  
Clinical Diagnosis ◽  
Genomic Dna ◽  
Methylation Status ◽  
Missense Variant ◽  
Endocrine Disorders ◽  
List Type ◽  
Serum Calcitonin ◽  
Thyroid Pathology ◽  
Skeletal Defects ◽  
Exon 1

Summary Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology. Learning points: We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A. Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling. GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.

Impact of growth hormone treatment on scoliosis development and progression: analysis of 1128 patients with idiopathic short stature

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Se-Jun Park ◽  
Keun-Ho Lee ◽  
Chong-Suh Lee ◽  
Ki-Tack Kim ◽  
Jun Hyuk Jang ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Cox Regression ◽  
De Novo ◽  
Recombinant Human Growth Hormone ◽  
Idiopathic Short Stature ◽  
Radiographic Examination ◽  
The Impact ◽  
Rhgh Treatment ◽  
Scoliosis Progression

AbstractObjectivesThe purpose of this study was to evaluate the impact of recombinant human growth hormone (rhGH) on the development and progression of scoliosis in patients with idiopathic short stature (ISS).MethodsPatients with ISS who underwent rhGH treatment from 1997 to 2017 and were followed up for scoliosis screening with serial radiographic examination were included. For assessing scoliosis development, patients who did not have scoliosis at the time of rhGH treatment were included and followed up to determine whether de novo scoliosis developed during the treatment. For evaluating scoliosis progression, patients who already had scoliosis were analyzed. Univariate and multivariate Cox regression analyses of demographic and radiographic variables were performed to determine the related factors in the development and progression of scoliosis.ResultsFor assessing scoliosis development, 1093 patients were included. The average duration of rhGH treatment was about 2 years. De novo scoliosis developed in 32 patients (3.7%). The analysis revealed that sex (p=0.016) and chronological age (p=0.048) were statistically significant factors associated with scoliosis development. However, no relationship was observed between scoliosis development and rhGH treatment types or duration. Among 67 patients who already had scoliosis at the time of rhGH treatment, 11 (16.4%) showed scoliosis progression. However, the rhGH types and duration also did not affect scoliosis progression.ConclusionsDe novo scoliosis developed in 3.7% and scoliosis progressed in 16.4% of the patients during rhGH treatment. However, scoliosis development or progression was not affected by the types or duration of rhGH treatment in patients with ISS.

scholarly journals A de novo frameshift variant of ANKRD11 (c.1366_1367dup) in a Chinese patient with KBG syndrome

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jing Chen ◽  
Zhongmin Xia ◽  
Yulin Zhou ◽  
Xiaomin Ma ◽  
Xudong Wang ◽  
...  
Keyword(s):  
Short Stature ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Slow Wave ◽  
In Silico ◽  
De Novo ◽  
Triangular Face ◽  
Whole Exome ◽  
Kbg Syndrome

Abstract Background KBG syndrome is a rare autosomal dominant genetic disease mainly caused by pathogenic variants of ankyrin repeat domain-containing protein 11 (ANKRD11) or deletions involving ANKRD11. Herein, we report a novel de novo heterozygous frameshift ANKRD11 variant via whole exome sequencing in a Chinese girl with KBG syndrome. Case presentation A 2-year-2-month-old girl presented with a short stature and developmental delay. Comprehensive physical examinations, endocrine laboratory tests and imaging examination were performed. Whole‐exome sequencing and Sanger sequencing were used to detect and confirm the variant associated with KBG in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools. The patient was diagnosed as KBG syndrome with a short stature and developmental delay, as well as characteristic craniofacial abnormalities, including a triangular face, long philtrum, wide eyebrows, a broad nasal bridge, prominent and protruding ears, macrodontia of the upper central incisors, dental crowding, and binocular refractive error. Her skeletal anomalies included brachydactyly, fifth finger clinodactyly, and left-skewed caudal vertebrae. Electroencephalographic results generally showed normal background activity with sporadic spikes and slow wave complexes, as well as multiple spikes and slow wave complexes in the bilateral parietal, occipital, and posterior temporal regions during non-rapid-eye-movement sleep. Brain MRI showed a distended change in the bilateral ventricles and third ventricle, as well as malformation of the sixth ventricle. Whole exome sequencing revealed a novel heterozygous frameshift variant in the patient, ANKRD11 c.1366_1367dup, which was predicted to be pathogenic through in silico analysis. The patient had received physical therapy since 4 months of age, and improvement of gross motor dysfunction was evident. Conclusions The results of this study expand the spectrum of ANKRD11 variants in KBG patients and provide clinical phenotypic data for KBG syndrome at an early age. Our study also demonstrates that whole exome sequencing is an effective method for the diagnosis of rare genetic disorders.

scholarly journals Mortality in Children Receiving Growth Hormone Treatment of Growth Disorders: Data From the Genetics and Neuroendocrinology of Short Stature International Study

2017 ◽  
Vol 102 (9) ◽  
pp. 3195-3205 ◽  
Author(s):  
Charmian A Quigley ◽  
Christopher J Child ◽  
Alan G Zimmermann ◽  
Ron G Rosenfeld ◽  
Leslie L Robison ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Turner Syndrome ◽  
International Study ◽  
Hormone Treatment ◽  
Idiopathic Short Stature ◽  
Growth Disorders ◽  
Gh Treatment ◽  
Increased Risk ◽  
History Of

Abstract Context Although pediatric growth hormone (GH) treatment is generally considered safe for approved indications, concerns have been raised regarding potential for increased risk of mortality in adults treated with GH during childhood. Objective To assess mortality in children receiving GH. Design Prospective, multinational, observational study. Setting Eight hundred twenty-seven study sites in 30 countries. Patients Children with growth disorders. Interventions GH treatment during childhood. Main Outcome Measure Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population. Results Among 9504 GH-treated patients followed for ≥4 years (67,163 person-years of follow-up), 42 deaths were reported (SMR, 0.77; 95% CI, 0.56 to 1.05). SMR was significantly elevated in patients with history of malignant neoplasia (6.97; 95% CI, 3.81 to 11.69) and borderline elevated for those with other serious non–GH-deficient conditions (2.47; 95% CI, 0.99-5.09). SMRs were not elevated for children with history of benign neoplasia (1.44; 95% CI, 0.17 to 5.20), idiopathic GHD (0.11; 95% CI, 0.02 to 0.33), idiopathic short stature (0.20; 95% CI, 0.01 to 1.10), short stature associated with small for gestational age (SGA) birth (0.66; 95% CI, 0.08 to 2.37), Turner syndrome (0.51; 95% CI, 0.06 to 1.83), or short stature homeobox-containing (SHOX) gene deficiency (0.83; 95% CI, 0.02 to 4.65). Conclusions No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non–GH-deficient medical conditions.

scholarly journals Atypical progeroid syndrome (p.E262K LMNA mutation): a rare cause of short stature and osteoporosis

2021 ◽  
Vol 2021 ◽  
Author(s):  
Marina Yukina ◽  
Nurana Nuralieva ◽  
Ekaterina Sorkina ◽  
Ekaterina Troshina ◽  
Anatoly Tiulpakov ◽  
...  
Keyword(s):  
Short Stature ◽  
De Novo ◽  
Age Of Onset ◽  
Gene Mutations ◽  
List Type ◽  
Metabolic Complications ◽  
Progeroid Syndrome ◽  
Progeria Syndrome ◽  
Mandibuloacral Dysplasia ◽  
Hutchinson Gilford Progeria Syndrome

Summary Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS. Learning points Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood. The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation. The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30. The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible. Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

scholarly journals Growth hormone treatment for short stature associated with duplication of the NSD1 Sotos syndrome gene

2021 ◽  
Vol 2021 ◽  
Author(s):  
Isaac T Bernhardt ◽  
Alistair J Gunn ◽  
Philippa J Carter
Keyword(s):  
Growth Hormone ◽  
Hormone Therapy ◽  
Short Stature ◽  
Developmental Delay ◽  
Growth Hormone Therapy ◽  
Growth Hormone Secretion ◽  
Dose Effect ◽  
List Type ◽  
Sotos Syndrome ◽  
Dysmorphic Features

Summary NSD1 deletions are associated with the Sotos syndrome, a syndrome of overgrowth in childhood without evidence of endocrine disturbance. Duplications involving the NSD1 gene have been reported to be associated with a ‘reverse Sotos syndrome’ phenotype, characterised by short stature, microcephaly, dysmorphic features and developmental delay. A 2-year-old girl with short stature, dysmorphic features and developmental delay was found to have duplication of 5q32.2–5q32.3, which includes the NSD1 gene. Growth hormone stimulation testing was normal. Growth hormone therapy was initiated at 5 years of age due to severe short stature and growth failure, with height 3.35 standard deviations (SDS) below the median. Growth velocity increased markedly, by +4.91 SDS in the first year of treatment. At the time of last follow-up at 9 years and 11 months, she had achieved a height within 1 SDS of the median. This is the first report of growth hormone therapy for the short stature associated with duplication of the NSD1 gene, showing that despite normal pituitary function, exogenous growth hormone can dramatically improve linear growth. Learning points Sotos syndrome is a disorder of childhood overgrowth caused by NSD1 deletions. Duplications involving NSD1 cause a ‘reverse Sotos syndrome’ phenotype characterised by short stature and microcephaly. The contrasting phenotypes of NSD1 deletions and duplications suggest a dose effect. Stimulated growth hormone secretion is normal in children with NSD1 deletions and duplications. Growth hormone therapy can be very effective in children with NSD1 duplications, comparable to the response seen in severe growth hormone deficiency.

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