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      Syndromic Disorders with Short Stature

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          Abstract

          Short stature is one of the major components of many dysmorphic syndromes. Growth failure may be due to a wide variety of mechanisms, either related to the growth hormone (GH)/insulin-like growth factor axis or to underlying unknown pathologies. In this review, the relatively more frequently seen syndromes with short stature (Noonan syndrome, Prader-Willi syndrome, Silver-Russell syndrome and Aarskog-Scott syndrome) were discussed. These disorders are associated with a number of endocrinopathies, as well as with developmental, systemic and behavioral issues. At present, GH therapy is used in most syndromic disorders, although long-term studies evaluating this treatment are insufficient and some controversies exist with regard to GH dose, optimal age to begin therapy and adverse effects. Before starting GH treatment, patients with syndromic disorders should be evaluated extensively.

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          Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

          M. Tartaglia, E. L. Mehler, R. Goldberg … (2001)
          Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.
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            Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

            Bruce Gelb, Gianfranco Bocchinfuso, Robin Foà … (2006)
            Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.
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              Clinical and molecular studies in a large Dutch family with Noonan syndrome.

              I der Weid, Sjef van der Linden, Paul B. Hamel … (1994)
              We describe the largest Noonan syndrome (NS) family reported to date. The manifestations of the affected relatives are discussed. In the absence of a biochemical marker NS is still a clinical diagnosis. The diagnostic criteria that were used are presented compared with other published criteria for diagnosing NS. The large size of this family enabled us to test the possible involvement of candidate regions by multipoint linkage analysis. Both the region surrounding the NF1 locus on chromosome 17 and the proximal part of chromosome 22 could be excluded. Since NS may well be heterogeneous, the use of such a large family in linkage studies of NS should prove indispensable.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Res Pediatr Endocrinol
                Journal ID (iso-abbrev): J Clin Res Pediatr Endocrinol
                Journal ID (publisher-id): JCRPE
                Title: Journal of Clinical Research in Pediatric Endocrinology
                Publisher: Galenos Publishing
                ISSN (Print): 1308-5727
                ISSN (Electronic): 1308-5735
                Publication date (Print): March 2014
                Publication date (Electronic): 5 March 2014
                Volume: 6
                Issue: 1
                Pages: 1-8
                Affiliations
                [1 ] Ankara University School of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
                Author notes
                * Address for Correspondence: Ankara University School of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey Phone: +90 312 595 66 35 E-mail: zeynepsklr@ 123456gmail.com
                Article
                Publisher Item ID: 1194
                DOI: 10.4274/Jcrpe.1149
                PMC ID: 3986733
                PubMed ID: 24637303
                SO-VID: 76a9812b-7cd4-4dec-8dd1-861b9f6e15bd
                Copyright © © Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 2 August 2013
                Date accepted : 17 November 2013
                Categories
                Subject: Review

                ScienceOpen disciplines: Pediatrics
                Keywords: short stature,noonan syndrome,prader-willi syndrome,aarskog syndrome,silver-russell syndrome
                Data availability:
                ScienceOpen disciplines: Pediatrics
                Keywords: short stature, noonan syndrome, prader-willi syndrome, aarskog syndrome, silver-russell syndrome

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