scholarly journals Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1257
Author(s):  
Anna Kutkowska-Kaźmierczak ◽  
Maria Boczar ◽  
Ewa Kalka ◽  
Jennifer Castañeda ◽  
Jakub Klapecki ◽  
...  
Keyword(s):  
Short Stature ◽  
Behavioral Problems ◽  
Chromosomal Rearrangements ◽  
Speech Development ◽  
Clinical Feature ◽  
Autosomal Dominant Disorder ◽  
Height Range ◽  
Pathogenic Variants ◽  
Hoarse Voice ◽  
Kbg Syndrome

KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of −1 SDs to −2 SDs were noted in about half of the patients; only two patients presented with short stature below −3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis.

scholarly journals Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Samina Yasin ◽  
Outi Makitie ◽  
Sadaf Naz
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Loss Of Function ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Skeletal Malformations ◽  
Tarsal Bones ◽  
The Family ◽  
Heterozygous Carriers

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

scholarly journals Floating-Harbor syndrome: Presentation of the first Romanian patient with a SRCAP mutation and review of the literature

2018 ◽  
Vol 21 (1) ◽  
pp. 83-86
Author(s):  
M Budisteanu ◽  
N Bögershausen ◽  
SM Papuc ◽  
S Moosa ◽  
M Thoenes ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Short Stature ◽  
Clinical Features ◽  
Rare Condition ◽  
Bone Age ◽  
Speech Development ◽  
Speech Delay ◽  
Mild Intellectual Disability ◽  
Intensive Program ◽  
Floating Harbor Syndrome

Abstract Floating-Harbor syndrome (FHS) is a rare autosomal dominant syndrome characterized by short stature with delayed bone age, retarded speech development, intellectual disability and dysmorphic facial features. Recently, dominant mutations almost exclusively clustered in the final exon of the Snf2-related CREBBP activator protein (SRCAP) gene were identified to cause FHS. Here, we report a boy with short stature, speech delay, mild intellectual disability, dysmorphic features, and with genetically confirmed FHS. To the best of our knowledge, this is the first molecularly confirmed case with this syndrome reported in Romania. An intensive program of cognitive and speech stimulation, as well as yearly neurological, psychological, ophthalmological, otorhinolaryngological, pediatric and endocrinological monitoring for our patient were designed. We propose a checklist of clinical features suggestive of FHS, based on the main clinical features, in order to facilitate the diagnosis and clinical management of this rare condition.

scholarly journals SAT-060 Unusual Case of Short Stature and Poor Growth in Childhood

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nivedita Patni ◽  
Fisher G Heather ◽  
Angela E Scheuerle
Keyword(s):  
Short Stature ◽  
Missense Variant ◽  
Bone Age ◽  
Lower Eyelid ◽  
Poor Growth ◽  
Pathogenic Variants ◽  
First Child ◽  
Whole Exome ◽  
Slow Progression ◽  
Progeria Syndrome

Abstract Background: Néstor-Guillermo progeria syndrome (NGPS; OMIM 614008) is caused by biallelic pathogenic variants in BANF1 (barrier-to-autointegration factor 1) on chromosome 11q13. It characterized by early onset and slow progression of symptoms including poor growth, lipoatrophy, pseudo-senile facial appearance, and normal cognitive development. Two adult patients have been reported. This is the first reported case of a child with NGPS who presented to endocrine clinic with failure to grow. Clinical Case: Two year, 8 month old Hispanic female born at 40 weeks gestation with birth weight 3.5 kg. At 1 year, she had short stature, poor weight gain, and thinning hair. There were no developmental concerns. Family history was remarkable for consanguinity. At presentation, her weight was 8.5 kilograms) and height 80 centimeters (both <1st percentile) and head circumference 45.5 centimeters (3rd percentile). Hair was sparse and fine with large areas of scalp alopecia. She had a small face with overhanging brow ridge, flattened midface, narrow nose, small mouth and bilateral lower eyelid ectropion. Fingers were shortened with thickened knuckles, widened fingertips, and distally set nails. Skin was tight throughout, particularly notable on the legs and hands with light discoloration of skin over the hand joints and reticulated dark macules over the lower abdomen. Her cardiac, respiratory, abdominal, genitourinary, neuro and joint examinations were unremarkable. Routine labwork was normal. Her bone age was normal at 2 year and 7 months but there was hypoplasia of the distal phalanges. Full skeletal survey revealed small mandible, thinning of the cranial vault, apparent crowding of the teeth, short stature, acroosteolysis-like changes involving the distal phalanges most evident in the hands, pointed distal phalanx of the great toes, and resorption of the distal clavicles. Her echocardiogram was normal. Sequencing and deletion/duplication analysis of LMNA was not diagnostic. Trio-based whole exome sequencing (WES) was performed after obtaining informed consent. WES revealed homozygosity for a pathogenic missense variant in BANF1 c.34G>A (p.Ala12Thr) inherited from each of the unaffected parents. Conclusion: Progeria syndromes are unusual but diagnosable causes of failure to grow and can be diagnosed based on clinical suspicion. This patient represents the first child reported with NGPS.

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 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 High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature

2020 ◽  
Vol 182 (3) ◽  
pp. 243-253
Author(s):  
L Stavber ◽  
T Hovnik ◽  
P Kotnik ◽  
L Lovrečić ◽  
J Kovač ◽  
...  
Keyword(s):  
Short Stature ◽  
Phenotypic Variability ◽  
Bone Age ◽  
Growth Patterns ◽  
Comparative Genomic ◽  
Study Cohort ◽  
Pathogenic Variants ◽  
Intragenic Deletion ◽  
Number Variation ◽  
Personalized Approach

Context Defining the underlying etiology of idiopathic short stature (ISS) improves the overall management of an individual. Objective To assess the frequency of pathogenic ACAN variants in selected individuals. Design The single-center cohort study was conducted at a tertiary university children’s hospital. From 51 unrelated patients with ISS, the 16 probands aged between 3 and 18 years (12 females) with advanced bone age and/or autosomal dominant inheritance pattern of short stature were selected for the study. Fifteen family members of ACAN-positive probands were included. Exome sequencing was performed in all probands, and additional copy number variation (CNV) detection was applied in selected probands with a distinct ACAN-associated phenotype. Results Systematic phenotyping of the study cohort yielded 37.5% (6/16) ACAN-positive probands, with all novel pathogenic variants, including a 6.082 kb large intragenic deletion, detected by array comparative genomic hybridization (array CGH) and exome data analysis. All variants were co-segregated with short stature phenotype, except in one family member with the intragenic deletion who had an unexpected growth pattern within the normal range (−0.5 SDS). One patient presented with otosclerosis, a sign not previously associated with aggrecanopathy. Conclusions ACAN pathogenic variants presented a common cause of familial ISS. The selection criteria used in our study were suggested for a personalized approach to genetic testing of the ACAN gene in clinical practice. Our results expanded the number of pathogenic ACAN variants, including the first intragenic deletion, and suggested CNV evaluation in patients with typical clinical features of aggrecanopathy as reasonable. Intra-familial phenotypic variability in growth patterns should be considered.

scholarly journals Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants

2021 ◽  
Author(s):  
Hildegard Kehrer-Sawatzki ◽  
David N. Cooper
Keyword(s):  
Young Children ◽  
Diagnostic Criteria ◽  
Neurofibromatosis Type 1 ◽  
Early Adulthood ◽  
Neurofibromatosis Type ◽  
Clinical Feature ◽  
Pathogenic Variants ◽  
Legius Syndrome ◽  
Nf1 Gene

AbstractNeurofibromatosis type 1 (NF1) is the most frequent disorder associated with multiple café-au-lait macules (CALM) which may either be present at birth or appear during the first year of life. Other NF1-associated features such as skin-fold freckling and Lisch nodules occur later during childhood whereas dermal neurofibromas are rare in young children and usually only arise during early adulthood. The NIH clinical diagnostic criteria for NF1, established in 1988, include the most common NF1-associated features. Since many of these features are age-dependent, arriving at a definitive diagnosis of NF1 by employing these criteria may not be possible in infancy if CALM are the only clinical feature evident. Indeed, approximately 46% of patients who are diagnosed with NF1 later in life do not meet the NIH diagnostic criteria by the age of 1 year. Further, the 1988 diagnostic criteria for NF1 are not specific enough to distinguish NF1 from other related disorders such as Legius syndrome. In this review, we outline the challenges faced in diagnosing NF1 in young children, and evaluate the utility of the recently revised (2021) diagnostic criteria for NF1, which include the presence of pathogenic variants in the NF1 gene and choroidal anomalies, for achieving an early and accurate diagnosis.

scholarly journals De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

2019 ◽  
Vol 104 (4) ◽  
pp. 758-766 ◽  
Author(s):  
Illja J. Diets ◽  
Roos van der Donk ◽  
Kristina Baltrunaite ◽  
Esmé Waanders ◽  
Margot R.F. Reijnders ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Short Stature ◽  
De Novo ◽  
Facial Dysmorphism ◽  
Pathogenic Variants

Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature

2020 ◽  
Vol 33 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Anil Kumar ◽  
Vandana Jain ◽  
Madhumita Roy Chowdhury ◽  
Manoj Kumar ◽  
Punit Kaur ◽  
...  
Keyword(s):  
Growth Factor ◽  
Short Stature ◽  
Serum Insulin ◽  
Significant Proportion ◽  
Idiopathic Short Stature ◽  
Insulin Like Growth Factor ◽  
Phenotype Correlation ◽  
Indian Children ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation

AbstractBackgroundOur objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation.MethodsWe recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <−1 standard deviation. The genotype-phenotype correlation was studied.ResultsFour children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as ‘disease causing’, and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop.ConclusionsPathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS.

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