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Current Opinion in Pediatrics Aug 2021Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening... (Review)
Review
PURPOSE OF REVIEW
Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening approach. The purpose of this review is to describe the optimal genetic approach for evaluating short stature, challenges of genetic testing, and recent advances in genetic testing for short stature.
RECENT FINDINGS
Genetic testing, such as karyotype, chromosomal microarray, targeted gene sequencing, or exome sequencing, has served to identify the underlying genetic causes of short stature. When determining which short stature patient would benefit from genetic evaluation, it is important to consider whether the patient would have a single identifiable genetic cause. Specific diagnoses permit clinicians to predict responses to growth hormone treatment, to understand the phenotypic spectrum, and to understand any associated co-morbidities.
SUMMARY
The continued progress in the field of genetics and enhanced capabilities provided by genetic testing methods expands the ability of physicians to evaluate children with short stature for underlying genetic defects. Continued effort is needed to elaborate new genetic causes of linear growth disorders, therefore, we expand the list of known genes for short stature, which will subsequently increase the rate of genetic diagnosis for children with short stature.
Topics: Body Height; Child; Dwarfism; Genetic Testing; Growth Disorders; Humans; Exome Sequencing
PubMed: 34101704
DOI: 10.1097/MOP.0000000000001033 -
Current Opinion in Pediatrics Aug 2018Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability... (Review)
Review
PURPOSE OF REVIEW
Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability to identify genetic causes of human disorders. The purpose of this review is to describe recent advances in the genetic causes of short stature.
RECENT FINDINGS
In addition to SHOX deficiency which is one of the most common causes of isolated short stature, PAPPA2, ACAN, NPPC, NPR2, PTPN11 (and other rasopathies), FBN1, IHH and BMP2 have been identified in isolated growth disorders with or without other mild skeletal findings. In addition, novel genetic causes of syndromic short stature have been discovered, including pathogenic variants in BRCA1, DONSON, AMMECR1, NFIX, SLC25A24, and FN1.
SUMMARY
Isolated growth disorders are often monogenic. Specific genetic causes typically have specific biochemical and/or phenotype characteristics which are diagnostically helpful. Identification of additional subjects with a specific genetic cause of short stature often leads to a broadening of the known clinical spectrum for that condition. The identification of novel genetic causes of short stature has provided important insights into the underlying molecular mechanisms of growth failure.
Topics: Child; Dwarfism; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genome-Wide Association Study; Growth Disorders; Humans; Exome Sequencing; Whole Genome Sequencing
PubMed: 29787394
DOI: 10.1097/MOP.0000000000000653 -
Frontiers in Endocrinology 2022Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the...
CONTEXT
Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the collagenopathies) have been reported to be associated with short stature and skeletal dysplasias. Etiological diagnosis of skeletal abnormality-related short stature is challenging, and less is known about recombinant human growth hormone (rhGH) therapy.
OBJECTIVE
This is a single-center cohort study which aims at exploring the genetic architecture of short-stature children with skeletal abnormalities and evaluating the frequency of collagenopathies to determine their phenotype, including the rhGH treatment response.
PATIENTS AND METHODS
One hundred and six children with short stature and skeletal abnormalities were enrolled who were evaluated by next-generation sequencing (NGS) to detect variants in the skeletal collagen genes including , and . The results were evaluated using American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical characteristics and rhGH treatment response were summarized.
RESULTS
Twenty-four pathogenic or likely pathogenic variants of collagen genes were found in 26 of 106 (24.5%) short-stature patients with skeletal abnormalities, of which mutations were the most common, accounting for about 57.7%. Other frequent mutations associated with skeletal development include , , , , and in 12.2%, 0.9%, 0.8%, 0.4%, and 0.4%, respectively, resulting in significantly different degrees of short stature. An overview of clinical features of collagenopathies showed growth retardation, skeletal abnormalities, and heterogeneous syndromic abnormalities involving facial, eye, hearing, and cardiac abnormalities. The average height of 9 patients who received rhGH treatment improved from a median of -3.2 ± 0.9 SDS to -2.2 ± 1.3 SDS after 2.8 ± 2.1 years. The most significant height improvement of 2.3 SDS and 1.7 SDS was also seen in two patients who had been treated for more than 6 years.
CONCLUSIONS
A proband-based NGS revealed that distinct genetic architecture underlies short stature in varying degrees and clinical features. Skeletal abnormality-related short stature involving multiple systems should be tested for skeletal collagen gene mutation. Limited rhGH treatment data indicate an improved growth rate and height, and close monitoring of adverse reactions such as scoliosis is required.
Topics: Cohort Studies; Collagen; Dwarfism; Human Growth Hormone; Humans; Musculoskeletal Abnormalities; Mutation; Recombinant Proteins
PubMed: 35250876
DOI: 10.3389/fendo.2022.820001 -
Frontiers in Endocrinology 2022It is well documented that the environment of the developing fetus, including availability of nutrients and presence of toxins, can have major impact on adult phenotype,... (Review)
Review
It is well documented that the environment of the developing fetus, including availability of nutrients and presence of toxins, can have major impact on adult phenotype, age-related traits and risk of chronic disease. There is also accumulating evidence that postnatal environment can impact adult characteristics related to evolutionary fitness, health, and aging. To determine whether early life hormonal interventions can alter trajectory of aging, we have examined the effects of early life growth hormone (GH) replacement therapy in Prop1 (Ames dwarf) mice which are GH deficient and remarkably long lived. Twice-daily GH injections between the ages of two and eight weeks completely normalized ("rescued") a number of adult metabolic characteristics believed to contribute to extended longevity of these mutants. Importantly, longevity of Ames dwarf mice was reduced by early life GH treatment. This was associated with histone H3 modifications. We conclude that the trajectory of mammalian aging can be modified by early life interventions. Mechanistic links among interventions during postnatal development, adult metabolic characteristics, aging, and longevity, apparently involve epigenetic phenomena.
Topics: Aging; Animals; Dwarfism; Growth Hormone; Hormone Replacement Therapy; Longevity; Mammals; Mice
PubMed: 35282433
DOI: 10.3389/fendo.2022.797581 -
Hormone Research in Paediatrics 2022People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in... (Review)
Review
BACKGROUND
People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in classical art, as well as the courts of European monarchs, and were exploited in "shows." Serious medical evaluation began in the late 19th century with the description of acromegaly and its association with pituitary tumors. In the early 20th century, multiple investigators attempted to extract a growth-promoting factor from the anterior pituitary and then, over the decades, to purify it and distinguish it from other anterior pituitary hormones. With relatively pure growth hormone (GH), its biological activity in growth promotion and as a metabolic hormone were studied, and species specificity became apparent: primate GH was the only GH active in man. Human GH was prepared from cadaveric pituitaries and distributed by the NIH to treat children with GH deficiency, but there was never enough pituitary hGH for all of the children who required it. When Creutzfeldt-Jakob disease was found in some patients who received pituitary GH, the production and FDA approval of biosynthetic hGH dramatically accelerated. With a large supply, one could treat those who were GH deficient and test its efficacy in other causes of short stature; longer acting versions of hGH have now been developed, tested, and in a few instances received FDA approval.
SUMMARY
It has been a long journey from the description of over- and underproduction of GH in animals to the production and clinical use of the biosynthetic hormones.
KEY MESSAGES
The efforts of basic scientists led to the extraction and purification of GH. Clinical scientists have expanded the appropriate use of hGH for short children with conditions in addition to GH deficiency.
Topics: Animals; Humans; Acromegaly; Dwarfism; Endocrine System Diseases; Growth Hormone; Human Growth Hormone; Pituitary Hormones, Anterior
PubMed: 36446319
DOI: 10.1159/000526440 -
Journal of Medical Genetics May 2002In 1969, Robinow and colleagues described a syndrome of mesomelic shortening, hemivertebrae, genital hypoplasia, and "fetal facies". Over 100 cases have now been... (Review)
Review
In 1969, Robinow and colleagues described a syndrome of mesomelic shortening, hemivertebrae, genital hypoplasia, and "fetal facies". Over 100 cases have now been reported and we have reviewed the current knowledge of the clinical and genetic features of the syndrome. The gene for the autosomal recessive form was identified as the ROR2 gene on chromosome 9q22. ROR2 is a receptor tyrosine kinase with orthologues in mouse and other species. The same gene, ROR2, has been shown to cause autosomal dominant brachydactyly B, but it is not known at present whether the autosomal dominant form of Robinow syndrome is also caused by mutations in ROR2.
Topics: Abnormalities, Multiple; Animals; Arm; Dwarfism; Facies; Genotype; Humans; Infant, Newborn; Male; Mice; Mutation, Missense; Penis; Phenotype; Radiography; Rats; Receptor Tyrosine Kinase-like Orphan Receptors; Receptors, Cell Surface; Ribs; Spinal Cord; Syndrome
PubMed: 12011143
DOI: 10.1136/jmg.39.5.305 -
Journal of Medical Genetics Aug 1988The first Scottish family with pycnodysostosis is reported. The clinical and radiological findings in the two affected men are recorded.
The first Scottish family with pycnodysostosis is reported. The clinical and radiological findings in the two affected men are recorded.
Topics: Adult; Dwarfism; Dysostoses; Humans; Male; Middle Aged; Pedigree; Radiography; Scotland
PubMed: 3172150
DOI: 10.1136/jmg.25.8.550 -
Current Osteoporosis Reports Apr 2017This review will provide an overview of the microcephalic primordial dwarfism (MPD) class of disorders and provide the reader comprehensive clinical review with... (Review)
Review
PURPOSE OF THE REVIEW
This review will provide an overview of the microcephalic primordial dwarfism (MPD) class of disorders and provide the reader comprehensive clinical review with suggested care guidelines for patients with microcephalic osteodysplastic primordial dwarfism, type II (MOPDII).
RECENT FINDINGS
Over the last 15 years, significant strides have been made in the diagnosis, natural history, and management of MOPDII. MOPDII is the most common and well described form of MPD. The classic features of the MPD group are severe pre- and postnatal growth retardation, with marked microcephaly. In addition to these features, individuals with MOPDII have characteristic facies, skeletal dysplasia, abnormal dentition, and an increased risk for cerebrovascular disease and insulin resistance. Biallelic loss-of-function mutations in the pericentrin gene cause MOPDII, which is inherited in an autosomal recessive manner.
Topics: Disease Management; Dwarfism; Fetal Growth Retardation; Humans; Microcephaly; Osteochondrodysplasias
PubMed: 28409412
DOI: 10.1007/s11914-017-0348-1 -
Genes & Development Oct 2011The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a... (Review)
Review
The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a group of human single-gene disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial dwarfism I [MOPD] types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 [origin recognition complex 1], ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR [ataxia-telangiectasia and Rad3-related]), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechanisms underlying the pathogenesis of these conditions and address whether further study of these genes could provide novel insight into the physiological regulation of organism growth.
Topics: Animals; Body Size; Cell Proliferation; Dwarfism; Growth and Development; Humans; Mutation
PubMed: 21979914
DOI: 10.1101/gad.169037 -
American Journal of Medical Genetics.... Jun 2021Dwarfism has been depicted in various Chinese art forms including literature, sculpture, and painting. This article examines several representative Chinese works of art...
Dwarfism has been depicted in various Chinese art forms including literature, sculpture, and painting. This article examines several representative Chinese works of art from different ages of Chinese history, in order to glimpse the living situations of people with dwarfism, their professions and social status, as well as the social attitude toward them in China. We highlight "" (Shan Hai Jing, translated as the Classic of Mountains and Seas), a remarkable collection of myths and illustrations which documented the existence of dwarf communities where the residents were capable of producing high-quality grains. Representations from sculptures and paintings frequently captured the images of individuals with dwarfism in royal courts, which showed their remarkable performance skills and social ability. There are also works of art associating dwarfism with rituals. In addition to portraying ordinary individuals with humble social status, there was one particular individual with dwarfism named Yan Zi () who was highly regarded as a figure of wisdom. Throughout the long Chinese history, dwarfism had been portrayed in art as either positive, neutral or derogatory, which reflected the fact that people with dwarfism, while short in stature, are usually intellectually normal, generally skillful, and often talented, in short, like the general population.
Topics: China; Dwarfism; Humans; Medicine in the Arts; Paintings; Sculpture
PubMed: 33982873
DOI: 10.1002/ajmg.c.31906