Clinical and Genetic Characteristics of 23 Korean Patients with Haploinsufficiency of the Short-stature Homeobox-containing Gene

Abstract Background The short-stature homeobox-containing gene (SHOX) is one of the major growth genes in humans. The clinical spectrum of SHOX haploinsufficiency ranges from Léri–Weill dyschondrosteosis to idiopathic short stature. Herein, we describe the clinical and genetic characteristics of 23 Korean patients with SHOX deficiency disorders. Methods Medical records of 23 patients (19 females and 4 males) from 15 unrelated families who were genetically confirmed to have SHOX deficiency were retrospectively reviewed. SHOX gene deletions or mutations were determined by sequence analyses using multiplex ligation-dependent probe amplification, chromosomal microarray, and/or Sanger sequencing methods. Results In the 15 families, 9 probands were de novo cases. All 23 patients showed mesomelia. Madelung deformity and tibia vara were observed in 13 (56.5%) and 3 (13.1%) patients, respectively. Genetically, 11 (73.3%) of the 15 families showed SHOX deletions of various sizes, and the other 4 families harboured SHOX sequence variants. Four patients had undergone orthopaedic surgeries (3 for tibia vara and 1 for Madelung deformity). Among 7 patients who had received growth hormone treatment for ≥1 year, 5 showed good responses, with a median first-year change-in-height standard deviation score of +0.6. There were no significant differences in the clinical characteristics of the deletion and point mutation groups. Conclusions A high index of suspicion and the genetic confirmation of SHOX deficiency are helpful for the timely management of the condition and are needed to provide genetic counselling to the family members of the patients.

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Growth Hormone Treatment for Short Stature in the USA, Germany and France: 15 Years of Surveillance in the Genetics and Neuroendocrinology of Short-Stature International Study (GeNeSIS)

Hormone Research in Paediatrics ◽

10.1159/000492397 ◽

2018 ◽

Vol 90 (3) ◽

pp. 169-180 ◽

Cited By ~ 5

Author(s):

Roland Pfäffle ◽

Christof Land ◽

Eckhard Schönau ◽

Paul-Martin Holterhus ◽

Judith L. Ross ◽

...

Keyword(s):

Growth Hormone ◽

Short Stature ◽

Standard Deviation Score ◽

Measurement Data ◽

International Study ◽

Hormone Treatment ◽

Height Velocity ◽

Growth Disorders ◽

Gh Treatment ◽

The Usa

Background/Aims: To describe characteristics, auxological outcomes and safety in paediatric patients with growth disorders treated with growth hormone (GH), for cohorts from the USA, Germany and France enrolled in GeNeSIS, a post-authorisation surveillance programme. Methods: Diagnosis and biochemical measurement data were based on reporting from, and GH treatment was initiated at the discretion of, treating physicians. Auxological outcomes during the first 4 years of GH treatment and at near-adult height (NAH) were analysed. Serious and treatment-emergent adverse events were described. Results: Children in the USA (n = 9,810), Germany (n = 2,682) and France (n = 1,667) received GH (dose varied between countries), most commonly for GH deficiency. Across diagnostic groups and countries, mean height velocity standard deviation score (SDS) was > 0 and height SDS increased from baseline during the first 4 years of treatment, with greatest improvements during year 1. Most children achieved NAH within the normal range (height SDS >−2). No new or unexpected safety concerns were noted. Conclusion: GH treatment improved growth indices to a similar extent for patients in all three countries despite variations in GH doses. Data from these three countries, which together contributed > 60% of patients to GeNeSIS, indicated no new safety signals and the benefit-risk profile of GH remains unchanged.

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Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome

Cytogenetic and Genome Research ◽

10.1159/000502045 ◽

2019 ◽

Vol 158 (4) ◽

pp. 184-191 ◽

Cited By ~ 1

Author(s):

Naye Choi ◽

Jung Min Ko ◽

Seung Han Shin ◽

Ee Kyung Kim ◽

Han Suk Kim ◽

...

Keyword(s):

De Novo ◽

Genetic Disorder ◽

Left Ventricular ◽

Mitogen Activated Protein Kinase ◽

Alveolar Type ◽

Costello Syndrome ◽

De Novo Mutations ◽

Genetic Characteristics ◽

Korean Patients ◽

Skeletal Defects

Costello syndrome (CS) is a rare genetic disorder characterized by distinctive facial appearance, cardiopulmonary complications, severe growth retardation, skin and skeletal defects, developmental delay, and tumor predisposition. CS is caused by heterozygous de novo mutations in the proto-oncogene HRAS, which is a component of the RAS/mitogen-activated protein kinase pathway. Herein, we reviewed the phenotypic and genetic features of 5 Korean patients who were genetically diagnosed with CS. Atrial tachycardia and polyhydramnios, which are important prenatal features for CS, were observed in 4 and 5 patients, respectively. The distinctive coarse facial appearances of the patients and presence of deep palmoplantar creases supported the clinical diagnosis of CS, which was confirmed by HRAS sequence analysis. Extremely poor postnatal growth was observed in all 5 patients. Further, all patients exhibited cardiac abnormalities; left ventricular hypertrophy and hypertrophic cardiomyopathy were observed in 3 patients. All 5 patients suffered from airway problems; 3 of them required intubation right after birth, and 2 of them received tracheostomy. One patient with a p.Gly12Ser mutation was diagnosed with retroperitoneal rhabdomyosarcoma alveolar type at the age of 5 years. Consistent with previous reports, both patients with p.Gly12Cys mutations died within the first year of life due to cardiopulmonary failure. Our study summarizes the characteristics of these 5 Korean patients with CS and, along with previous studies, provides clues for genotype-phenotype correlation in patients with CS.

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The Clinical Cases of Geleophysic Dysplasia: One Gene, Different Phenotypes

Case Reports in Endocrinology ◽

10.1155/2018/8212417 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Evgenia Globa ◽

Nataliya Zelinska ◽

Andrew Dauber

Keyword(s):

Short Stature ◽

Tracheal Stenosis ◽

De Novo ◽

Clinical Symptoms ◽

Hormone Treatment ◽

Joint Movement ◽

Multisystem Disorder ◽

Severe Short Stature ◽

Hands And Feet ◽

Autosomal Recessive Pattern

Background. Geleophysic dysplasia is a rare multisystem disorder that principally affects the bones, joints, heart, and skin. This condition is inherited either in an autosomal dominant pattern due to FBN1 mutations or in an autosomal recessive pattern due to ADAMTSL2 mutations. Two patients with unaffected parents from unrelated families presented to their endocrinologist with severe short stature, resistant to growth hormone treatment. Routine endocrine tests did not reveal an underlying etiology. Exome sequencing was performed in each family. Our two patients, harboring de novo heterozygous FBN1 mutations p.Tyr1696Asp and p.Cys1748Ser, had common clinical symptoms such as severe short stature, characteristic facial features, short hands and feet, and limitation of joint movement. However, one patient had severe cardiac involvement whereas the other patient had tracheal stenosis requiring tracheostomy placement. Conclusions. Patients with severe dwarfism, skeletal anomalies, and other specific syndromic features (e.g., tracheal stenosis and cardiac valvulopathy) should undergo genetic testing to exclude acromelic dysplasia syndromes.

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Growth Hormone Improves Short-Term Growth in Patients with Temple Syndrome

Hormone Research in Paediatrics ◽

10.1159/000496700 ◽

2018 ◽

Vol 90 (6) ◽

pp. 407-413 ◽

Cited By ~ 2

Author(s):

Diana S. Brightman ◽

Oluwakemi Lokulo-Sodipe ◽

Beverly A. Searle ◽

Deborah J.G. Mackay ◽

Justin H. Davies ◽

...

Keyword(s):

Growth Hormone ◽

Short Stature ◽

Growth Hormone Treatment ◽

Standard Deviation Score ◽

Uniparental Disomy ◽

Hormone Treatment ◽

Height Velocity ◽

Short Term ◽

Temple Syndrome ◽

Hands And Feet

Background/Aims: Temple syndrome is an imprinting disorder caused by maternal uniparental disomy of chromosome 14 (mat UPD14), paternal deletion of 14q32 or paternal hypomethylation of the intergenic differentially methylated region (MEG3/DLK1 IG-DMR). Patients with Temple syndrome have pre- and postnatal growth restriction, short stature, hypotonia, small hands and feet and precocious puberty. We sought to determine whether treatment with growth hormone improves growth outcomes in patients with Temple syndrome. Methods: This was a retrospective observational study reviewing the medical records of 14 patients with Temple syndrome, 7 of whom were treated with growth hormone. Results: After 1 year of growth hormone treatment, the height standard deviation score (SDS) increased a median of 1.31 SDS with a median increased height velocity of 5.30 cm/year. Conclusions: These results suggest short-term improvement in height SDS with growth hormone treatment similar to the response in patients treated under the small for gestational age indication. We recommend considering growth hormone therapy in all patients with Temple syndrome who have short stature.

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Faculty Opinions recommendation of Growth hormone treatment for childhood short stature and risk of stroke in early adulthood.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718529849.793499006 ◽

2014 ◽

Author(s):

Phyllis Speiser

Keyword(s):

Growth Hormone ◽

Short Stature ◽

Growth Hormone Treatment ◽

Early Adulthood ◽

Hormone Treatment

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Growth hormone treatment for short stature in children with intrauterine growth retardation

10.1002/14651858.cd006293.pub2 ◽

2009 ◽

Author(s):

Hui Ming Yang ◽

Meng Mao ◽

Chao Min Wan ◽

Fan Yang

Keyword(s):

Growth Hormone ◽

Short Stature ◽

Growth Retardation ◽

Intrauterine Growth Retardation ◽

Growth Hormone Treatment ◽

Hormone Treatment ◽

Intrauterine Growth

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A de novo missense variant in MED13 in a patient with global developmental delay, marked facial dysmorphism, macroglossia, short stature, and macrocephaly

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.62238 ◽

2021 ◽

Author(s):

Alice P. Rogers ◽

Kathryn Friend ◽

Lesley Rawlings ◽

Christopher P. Barnett

Keyword(s):

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Missense Variant ◽

Global Developmental Delay ◽

Facial Dysmorphism

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Paediatric chronic myeloid leukaemia presenting in de novo or secondary blast phase ‐ a comparison of clinical and genetic characteristics

British Journal of Haematology ◽

10.1111/bjh.17378 ◽

2021 ◽

Vol 193 (3) ◽

pp. 613-618

Author(s):

Stephanie Sembill ◽

Gudrun Göhring ◽

Elke Schirmer ◽

Friederike Lutterloh ◽

Meinolf Suttorp ◽

...

Keyword(s):

Chronic Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

De Novo ◽

Blast Phase ◽

Genetic Characteristics

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

Acta Endocrinologica ◽

10.1530/eje.0.1460319 ◽

2002 ◽

pp. 319-323 ◽

Cited By ~ 9

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.

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