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

Abstract

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.

Improved growth velocity of a patient with Noonan‐like syndrome with loose anagen hair (NS/LAH) without growth hormone deficiency by low‐dose growth hormone therapy

“…Unlike our case, most reported NS/LAH cases have low serum levels of IGF1 with a blunted IGF1 response to GH administration, so that they require a high dose GH (e.g., 35-45 mg/kg/day) [Capalbo et al, 2012b;Mazzanti et al, 2013] (Table III). Examination of additional GH-treated NS/LAH cases is needed to identify the precise mechanisms of growth retardation in NS/LAH and to determine the optimal dose of GH therapy according to each case.…”

“…Especially, in NS/LAH, short stature is more severe than in other types of RASopathies [Malaquias et al, 2012]. Mild to moderate GH deficiency (GHD) and insensitivity to growth hormone (GHI) have been suggested as causes of short stature in NS/LAH patients [Cordeddu et al, 2009;Mazzanti et al, 2013]. To date, only two studies have examined the effects of GH treatment on NS/LAH [Capalbo et al, 2012a;Mazzanti et al, 2013].…”

“…Mild to moderate GH deficiency (GHD) and insensitivity to growth hormone (GHI) have been suggested as causes of short stature in NS/LAH patients [Cordeddu et al, 2009;Mazzanti et al, 2013]. To date, only two studies have examined the effects of GH treatment on NS/LAH [Capalbo et al, 2012a;Mazzanti et al, 2013]. In those reports, the effectiveness of GH therapy was limited because of partial GHI.…”

“…In those reports, the effectiveness of GH therapy was limited because of partial GHI. As a result, the authors recommended a higher dose of GH for NS/LAH patients [Capalbo et al, 2012b;Mazzanti et al, 2013].…”

Cleft palate and hypopituitarism in a patient with Noonan‐like syndrome with loose anagen hair‐1

“…Individuals with NSLH1 are more likely to have intellectual disability, relative macrocephaly, sparse/loose anagen hair, and growth hormone deficiency (GHD) compared to individuals with Noonan syndrome (NS) caused by mutations in other genes. The clinical features of 84 patients with NSLH1 have been described (Table ) (Bader‐Meunier et al, ; Capalbo, Melis, et al, ; Capalbo, Scala, et al, ; Choi et al, ; Cordeddu et al, ; Ekvall, Hagenäs, Allanson, Annerén, & Bondeson, ; Ferrero et al, ; Garavelli et al, ; Gargano et al, ; Gripp et al, ; Hoban, Roberts, Demmer, Jethva, & Shephard, ; Kane et al, ; Komatsuzaki et al, ; Lo, Wang, Wong, & Lee, ; Mazzanti et al, ; Mazzanti et al, ; Şimşek‐Kiper et al, ; Tafazoli, Eshraghi, Koleti, & Abbaszadegan, ; Takenouchi et al, ; Tartaglia, Zampino, & Gelb, ; Tosti et al, ; Tosti et al, ; Tosti & Piraccini, ; Zmolikova et al, ). With the possible exception of one patient with unusual but not well‐defined palatal anatomy (Kumar, Chandar, Koduri, & Sankireddy, ), posterior cleft palate (CP) has not been reported in individuals with NS or with NSLH (Cao, Alrejaye, Klein, Goodwin, & Oberoi, ; Mallineni, Yung Yiu, & King, ).…”