Response to long‐term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data

Abstract

RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed.

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

“…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, ). GHD appears to be both more common and more severe in NSLH1 than in NS (Malaquias et al, ; Mazzanti et al, ; Tamburrino et al, ). Other hormonal deficiencies, such as primary hypothyroidism secondary to thyroiditis occasionally occur in both disorders (Ross & Shenkman, ; Sasagawa et al, ; Tamburrino et al, ; Zavras et al, ).…”

“…GHD appears to be both more common and more severe in NSLH1 than in NS (Malaquias et al, ; Mazzanti et al, ; Tamburrino et al, ). Other hormonal deficiencies, such as primary hypothyroidism secondary to thyroiditis occasionally occur in both disorders (Ross & Shenkman, ; Sasagawa et al, ; Tamburrino et al, ; Zavras et al, ).…”

Noonan syndrome and RASopathies: Clinical features, diagnosis and management

“…The height gain is varying in these studies (0.6-1.8 SDS; mean height gain: 9.5-13 cm for boys and 9.0-9.8 cm for girls), with the best results in younger age groups at the start of treatment. The results were better in both groups of the younger age of initiating rhGH therapy and the more delayed age of pubertal onset [38][39][40]. Our group has published a result of short-term efficacy of GH therapy in PTPN11 mutation positive or negative Korean Noonan patients, demonstrating short-term growth promotion efficacy in both groups [43].…”

“…However, some studies reported subnormal overnight mean GH concentration, suggestive of blunted GH secretion. There are several studies regarding the efficacy of recombinant human growth hormone (rhGH) on the final adult height outcome in subjects with NS from a rhGH registry, the KIGS International Growth Database [36,37], to several, observational studies [38][39][40]. Both the height velocity and the final adult height are improved by rhGH therapy in NS patients, despite small numbers of patients, varying age at start of rhGH therapy, treatment durations, and rhGH doses.…”

“…The longer-term data regarding adult heights for those treated with GH show no difference between mutationpositive and negative patients. Several studies have reported final adult height outcome after rhGH treatment in NS [38][39][40][41]. However, these studies were conducted in relatively small cohort, often lacking the matched or randomized control.…”