Noonan‐like syndrome with loose anagen hair: A new syndrome?

Mazzanti, Laura; Cacciari, E; Cicognani, Alessandro; Bergamaschi, R.; Scarano, Emanuela; Forabosco, Antonino

doi:10.1002/ajmg.a.10923

Cited by 78 publications

(71 citation statements)

References 21 publications

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“…25,26 The pathogenesis of loose anagen hair remains unknown. A scalp biopsy in a patient with loose anagen hair showed marked cleft formation between the inner root and the irregularly shaped hair shafts.…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies

et al. 2010

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Noonan syndrome is an autosomal dominant disease characterized by dysmorphic features, webbed neck, cardiac anomalies, short stature and cryptorchidism. It shows phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Noonan syndrome and related disorders are caused by germline mutations in genes encoding molecules in the RAS/MAPK pathway. Recently, a gain-of-function mutation in SHOC2, p.S2G, has been identified as causative for a type of Noonan-like syndrome characterized by the presence of loose anagen hair. In order to understand the contribution of SHOC2 mutations to the clinical manifestations of Noonan syndrome and related disorders, we analyzed SHOC2 in 92 patients with Noonan syndrome and related disorders who did not exhibit PTPN11, KRAS, HRAS, BRAF, MAP2K1/2, SOS1 or RAF1 mutations. We found the previously identified p.S2G mutation in eight of our patients. We developed a rapid detection system to identify the p.S2G mutation using melting curve analysis, which will be a useful tool to screen for the apparently common mutation. All the patients with the p.S2G mutation showed short stature, sparse hair and atopic skin. Six of the mutationpositive patients showed severe mental retardation and easily pluckable hair, and one showed leukocytosis. No SHOC2 mutations were identified in leukemia cells from 82 leukemia patients. These results suggest that clinical manifestations in SHOC2 mutation-positive patients partially overlap with those in patients with typical Noonan or CFC syndrome and show that easily pluckable/loose anagen hair is distinctive in SHOC2 mutation-positive patients.

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Section: Discussionmentioning

confidence: 99%

Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies

et al. 2010

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“…Two patients (M-1 and F-1) (Table I) had already been described in detail in a previous report [Mazzanti et al, 2003]. In all patients anthropometric measurements were obtained at baseline and every 6 months.…”

Section: Methodsmentioning

confidence: 99%

“…A single missense mutation resulting in the p.Ser2Gly amino acid substitution in SHOC2, which encodes a docking protein that positively modulates the RAS-MAPK pathway, underlies the clinically distinctive and genetically homogeneous RASopathy previously termed Noonan-like syndrome with loose anagen hair (NS/LAH) [Mazzanti et al, 2003;Cordeddu et al, 2009]. The disease causative mutation in SHOC2 introduces an N-myristoylation site, resulting in aberrant constitutive targeting of the mutated protein to the plasma membrane and increased ERK activation in a cell context-specific fashion [Cordeddu et al, 2009].…”

Section: Introductionmentioning

confidence: 99%

“…Final height (FH) data in NS after GH therapy have also been reported [Ferreira et al, 2005]. At present, only a few NS/LAH patients treated with GH-therapy have been described [Mazzanti et al, 2003;Capalbo et al, 2012b], and no FH data are available. We report growth and pubertal behavior in seven patients sharing the c.4A>G SHOC2 mutation, treated with long-term GH therapy, and FH in three of them.…”

Section: Introductionmentioning

confidence: 99%

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GH Therapy and first final height data in Noonan‐like syndrome with loose anagen hair (Mazzanti syndrome)

Mazzanti

Tamburrino

Scarano

et al. 2013

American J of Med Genetics Pt A

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Noonan-like syndrome with loose anagen hair (NS/LAH or Mazzanti Syndrome) is caused by a single missense mutation in SHOC2 promoting tN-myristoylation of the encoded protein.Cardinal features include facial features resembling NS, short stature often associated with proven growth hormone deficiency (GHD), typical ectodermal anomalies, and distinctive behavior. Overall, the clinical features are more severe than those generally observed in NS, even though the phenotype improves with age. We report on growth and pubertal trend in seven patients heterozygous for a mutated SHOC2 allele, treated with longterm GH-therapy, and final height (FH) in three of them. They were approximately À3 SDS below the Italian general population standards, they had very low IGF1 levels at baseline and GHD at pharmacological tests. All patients were treated with GH (0.035 mg/kg/day) for a mean period of 8.49 AE 5.72 years. After the 1st year of GH-therapy, IGF1 level and height velocity had increased. Three of 7 patients reached the FH (À2.34 AE 0.12 SDS) at 18.25 AE 0.73 years, after GH administration for 12.39 AE 2.12 years. Pubertal development was variable, showing a prolonged and delayed puberty or rapid pubertal progression that could impair the FH. Overall, our data in this small cohort suggest that NS/LAH patients benefit from long-term GH-therapy, although they do not show the characteristic catch-up growth of isolated GHD. While the observed growth and pubertal behavior is consistent with a dysfunction of the hypothalamic-pituitarygonadal axis, the functional link between SHOC2 and the GH/ IGF signaling pathways remains to be clarified.

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“…Many of the myristoylated proteins such as the non-receptor tyrosine kinases, fyn, lyn, and src, are involved in oncogenic processes (Summy and Gallick 2003;Lieu and Kopetz 2010), and the levels of the myristoylated tyrosine kinases, pp60 c-src and pp60 c-yes , have been observed to be several fold higher in colonic preneoplastic lesions and neoplasms compared with normal colon cells (Bolen et al 1987;Weber et al 1992;Termuhlen et al 1993). Myristoylation has also been linked to several other pathogenic states such as Noonan-like syndrome, which is a rare developmental disorder (Mazzanti et al 2003;Schubbert et al 2007;Cordeddu et al 2009), diabetes (King et al 1993(King et al , 1995 and ischemia-reperfusion injury (Rajala et al 2002). Other than their direct involvement in these disorders, NMTs also play a role in human immune deficiency (HIV) infections and several other viral diseases that have been discussed in detail elsewhere (Maurer-Stroh and Eisenhower 2004;Selvakumar et al 2007;Wright et al 2010;Martin et al 2011).…”

Section: Introductionmentioning

confidence: 99%

N-myristoyltransferase in the leukocytic development processes

et al. 2011

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The lipidic modification of proteins has recently been shown to be of immense importance, although many of the roles of these modifications remain as yet unidentified. One of such key modifications occurring on several proteins is the covalent addition of a 14-carbon long saturated fatty acid, a process termed myristoylation. Myristoylation can occur during both co-translational protein synthesis and posttranslationally, confers lipophilicity to protein molecules, and controls protein functions. The protein myristoylation process is catalyzed by the enzyme Nmyristoyltransferase (NMT), which exists as two isoforms: NMT1 and NMT2. NMT1 is essential for growth and development, during which rapid cellular proliferation is required, in a variety of organisms. NMT1 is also reported to be elevated in many cancerous states, which also involve rapid cellular growth, albeit in an unwanted and uncontrolled manner. The delineation of myristoylation-dependent cellular functions is still in a state of infancy, and many of the roles of the myristoylated proteins remain to be established. The development of cells of the leukocytic lineage represents a phase of rapid growth and development, and we have observed that NMT1 plays a role in this process. The current review outlines the roles of NMT1 in the growth and differentiation of the cells of leukocytic origin. The described studies clearly demonstrate the roles of NMT1 in the regulation of the developmental processes of the leukocytes cells and provide a basis for further research with the aim of unraveling the roles of protein myristoylation in both cellular and physiological context.

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Noonan‐like syndrome with loose anagen hair: A new syndrome?

Cited by 78 publications

References 21 publications

Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies

Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies

GH Therapy and first final height data in Noonan‐like syndrome with loose anagen hair (Mazzanti syndrome)

N-myristoyltransferase in the leukocytic development processes

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