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Rieger anomaly and congenital glaucoma in the SHORT syndrome

Authors:
M C Brodsky
M C Brodsky
M C Brodsky
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Julia Whiteside-Michel at JWMD
Julia Whiteside-Michel
  • JWMD
L M Merin
L M Merin
L M Merin
  • This person is not on ResearchGate, or hasn't claimed this research yet.
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... 1 Although these features provide the condition's acronym, they do not capture the full range of clinical features, which can include a recognizable facial gestalt (triangular facies, lack of facial fat, and hypoplastic nasal alae with overhanging columella), a near universal partial lipodystrophy, insulin resistance, nephrophrocalcinosis, and hearing deficits, among many others. [2][3][4][5][6][7] Notably, both developmental milestones and cognition are normal for individuals with SHORT syndrome. 3 The first description of SHORT syndrome was of a sibling pair whose parents displayed no obvious features. ...
... 1 This has been followed by several reports of sporadic occurrences, suggesting an autosomal-recessive or de novo dominant mode of inheritance. 6 However, there have also been several reports of parent-child transmissions, including male-to-male transmission, consistent with an autosomal-dominant inheritance pattern for SHORT syndrome. 3,4,8,9 The majority of affected individ-uals still appear to be simplex cases, 3 suggesting a significant contribution for de novo dominant mutations. ...
... 12 Although they appear to have a syndrome related to Axenfield-Rieger anomaly, affected individuals with PITX2 and BMP4 mutations 10,12 do not have the characteristic facial gestalt shared by the individuals in the original and subsequent descriptions of SHORT syndrome. [1][2][3][4]6,7,13 The FORGE (Finding of Rare Disease Genes) Canada Consortium is a collaborative project with the goal of identifying genetic mutations for rare childhood diseases. [14][15][16] We ascertained individuals with SHORT syndrome by contacting the members of the FORGE Canada Consortium and selected international colleagues and asking whether the physicians were aware of any individual(s) diagnosed with SHORT syndrome. ...
Mutations in PIK3R1 cause SHORT syndrome
Article
Full-text available
  • Jun 2013
  • AM J HUM GENET
SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs(∗)18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657(∗)]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.
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... Insufficiency of the adipose tissue makes the blood vessels more visible through the thin and translucent skin. Thus, the patients who suffer from the syndrome look much older than their calendar age shows and the appearance of premature aging is referred to as progeria [9][10][11][12]. ...
... It is the dysgenesis of the iris and cornea with marked hypoplasia of the iris stroma, displacement of the pupil (corectopia) and full-thickness colobomas of the iris (pseudopolycoria). This can be linked to higher ocular pressure and glaucoma development which can lead to vision loss [9]. Most patients require hearing aid implementation because of sensorineural hearing loss. ...
SHORT syndrome in a two-year-old girl - Case report
Article
Full-text available
  • Dec 2017
  • Riv Ital Pediatr Ital J Pediatr
Background SHORT syndrome is a rare genetic congenital defects condition. The frequency of the disease still remains unknown. Case presentation We report the two-year-four-month old female with SHORT syndrome who present growth retardation and dysmorphic features (triangular-shaped face, prominent forehead, ocular depression, lipodystrophy at the lumbar region and around elbows), consistent with the phenotype described for this syndrome. The molecular analysis showed the presence of heterozygous variant c.1956dupT (p.Lys653*) in exon 15 of PIK3R1. Conclusions The frequency of the disease still remains unknown; solely several dozen cases have been described worldwide.
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... There are some other common features of the SHORT syndrome, e.g. ophthalmic abnormalities such as Rieger anomaly, ocular anterior chamber dysgenesis, higher ocular pressure and glaucoma; dental abnormalities such as delayed teething, small teeth and decreased number of teeth; skeletal abnormalities such as delayed bone age, hyperextensibility of the joints as well as clinodactyly [7,11,12]. Other less common manifestations include delayed speech development, sensorineural hearing loss, congenital heart defects as well as mild cognitive delay [4,13]. ...
A novel PIK3R1 mutation of SHORT syndrome in a Chinese female with diffuse thyroid disease: a case report and review of literature
Article
Full-text available
  • Oct 2020
  • BMC MED GENET
Background SHORT syndrome is a rare genetic disease named with the acronyms of short stature, hyper-extensibility of joints, ocular depression, Rieger anomaly and teething delay. It is inherited in an autosomal dominant manner confirmed by the identification of heterozygous mutations in PIK3R1. This study hereby presents a 15-year-old female with intrauterine growth restriction, short stature, teething delay, characteristic facial gestalts who was identified a novel de novo nonsense mutation in PIK3R1. Case presentation The proband was admitted to our department due to irregular menstrual cycle and hirsutism with short stature, who had a history of intrauterine growth restriction and presented with short stature, teething delay, characteristic facial gestalts, hirsutism, and thyroid disease. Whole-exome sequencing and Sanger sequencing revealed c.1960C > T, a novel de novo nonsense mutation, leading to the termination of protein translation (p. Gln654*). Conclusions This is the first case report of SHORT syndrome complicated with thyroid disease in China, identifying a novel de novo heterozygous nonsense mutation in PIK3R1 gene (p. Gln654*). The phenotypes are mildly different from other cases previously described in the literature, in which our patient presents with lipoatrophy, facial feature, and first reported thyroid disease. Thyroid disease may be a new clinical symptom of patients with SHORT syndrome.
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... The thin, wrinkled skin and readily visible veins intensify the progeroid impression (Koenig et al., 2003). Rieger anomaly may manifest at birth with congenital glaucoma and cloudy cornea (Brodsky et al., 1996) or total absence of the iris stroma. Despite speech delays in childhood, mental status appears to be normal or only slightly subnormal (Gorlin et al., 1975). ...
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Glaucoma Syndromes: Insights into Glaucoma Genetics and Pathogenesis from Monogenic Syndromic Disorders
Article
Full-text available
  • Sep 2021
Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may be the first presenting sign of a systemic syndrome. Awareness of syndromes associated with glaucoma is thus critical both for medical geneticists and ophthalmologists. In this review, we highlight six categories of disorders that feature glaucoma and other ocular or systemic manifestations: anterior segment dysgenesis syndromes, aniridia, metabolic disorders, collagen/vascular disorders, immunogenetic disorders, and nanophthalmos. The genetics, ocular and systemic features, and current and future treatment strategies are discussed. Findings from rare diseases also uncover important genes and pathways that may be involved in more common forms of glaucoma, and potential novel therapeutic strategies to target these pathways.
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SHORT SYNDROME -A BIZARRE GENETIC ODDITY
Article
Full-text available
  • Apr 2020
SHORT syndrome is a rare genetic anomaly with multiple birth defects affecting different organ systems. The terminology SHORT is an abridgment of its emblematic manifestations such as short stature, hyper extensibility of joints / hernia (inguinal), ocular depression, Rieger anomaly and teething delay.
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Ocular Pathology: Seventh Edition
Article
  • Jan 2014
Comprehensive, yet concise and clinically oriented, the new edition of Ocular Pathology brings you the very latest advances of every aspect of ocular pathology. From updated information on today's imaging techniques, to the implementation of genetic data to better understand disease, this esteemed medical reference book promises to keep you at the forefront of your fieldTake advantage of clinical "pearls" that offer you the benefits of proven strategies.Quickly reference information with help from a convenient outline format, ideal for today's busy physician. Visualize every concept by viewing 1,900 illustrations, 1,600 of which are in full color, from the collections of internationally renowned leaders in ocular pathology.
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A Translational View of the Genetics of Lipodystrophy and Ectopic Fat Deposition
Article
  • Dec 2010
A wide range of lipodystrophy syndromes exist, each with varying clinical presentations, and yet cumulatively they underscore the importance of adipocyte biology in human metabolism. Loss of the ability to retain excess lipids in "classical" adipose tissue stores can lead to the overdevelopment of ectopic fat stores, often creating severe perturbations of both glucose and lipid homeostasis. Linkage analysis and candidate sequencing efforts have successfully identified responsible mutations for multiple forms of lipodystrophy. Recently, the reduction in the cost of DNA sequencing has resulted in discovery of many novel mutations within both known and novel loci. In this review, we present the steps involved in clinical characterization of a suspected lipodystrophy case, an overview of the clinical manifestations, molecular findings, and pathogenic basis of different forms of lipodystrophy, a discussion of therapeutic options for lipodystrophy patients, and an examination of genetic advances that will be used to identify additional pathogenic mechanisms.
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Clinical Classification of Childhood Glaucomas
Article
  • Jun 2010
An updated classification of the primary and secondary childhood glaucomas is offered for clinical use, and associated systemic diseases are included to enable their early recognition in children with known glaucoma. Approximately 650 clinical records of patients with pediatric glaucoma were reviewed for type of glaucoma and associated systemic disease. A literature search was done for additional reported causes of childhood glaucoma. Previous classifications of pediatric glaucomas were also reviewed. Pertinent references to support inclusion of each clinical entity in the updated classification are included. A comprehensive and referenced classification of the pediatric glaucomas was enabled by this review. A comprehensive, etiologically based classification of the pediatric glaucomas is now available to assist with the recognition of the many causes of primary and secondary glaucoma in childhood and to support the selection of specific treatment choices.
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Review and hypothesis: Syndromes with severe intrauterine growth restriction and very short stature - Are they related to the epigenetic mechanism(s) of fetal survival involved in the developmental origins of adult health and disease?
Article
  • Feb 2010
  • AM J MED GENET A
Diagnosing the specific type of severe intrauterine growth restriction (IUGR) that also has post-birth growth restriction is often difficult. Eight relatively common syndromes are discussed identifying their unique distinguishing features, overlapping features, and those features common to all eight syndromes. Many of these signs take a few years to develop and the lifetime natural history of the disorders has not yet been completely clarified. The theory behind developmental origins of adult health and disease suggests that there are mammalian epigenetic fetal survival mechanisms that downregulate fetal growth, both in order for the fetus to survive until birth and to prepare it for a restricted extra-uterine environment, and that these mechanisms have long lasting effects on the adult health of the individual. Silver-Russell syndrome phenotype has recently been recognized to be related to imprinting/methylation defects. Perhaps all eight syndromes, including those with single gene mutation origin, involve the mammalian mechanism(s) of fetal survival downsizing. Insights into those mechanisms should provide avenues to understanding the natural history, the heterogeneity and possible therapy not only for these eight syndromes, but for the common adult diseases with which IUGR is associated.
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Insulin-resistant diabetes during growth hormone therapy in a child with SHORT syndrome
Article
  • Aug 1994
We report the case of a 13-year-old boy with SHORT syndrome, including lipoatrophy and insulin resistance, who developed diabetes mellitus while receiving growth hormone therapy. The diabetes persisted after cessation of exogenous growth hormone but oral hypoglycaemic therapy was successful and could be discontinued eight months later.
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