Noonan Syndrome: Symptoms and Treatment

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Table of Contents

Abstract
Introduction
Materials and Methods
Results
Discussion
Works Cited

Abstract

Noonan syndrome is an autosomal dominant disease that is characterized by short stature, congenital heart disorders, and typical facial features. The mutation of the PTPN11 gene (protein tyrosine phosphatase nonreceptor type 11) that encodes for SH2 has been shown to interfere with growth hormone (GH) and insulin-like growth factor subtype I (IGF-I) causing short stature in patients with Noonan syndrome (NS). Recombinant human growth hormone (rhGH) has been shown to boost the growth as well as the height of such patients. This study aimed to evaluate the efficacy of rhGH in promoting growth in an NS-GH deficient patient. The patient was put under rhGH subcutaneous injection for one year with concomitant measurement of height, weight, and BMI. The results were compared to those of a growth hormone deficient (GHD) patient who was under the same therapy.

Introduction

Noonan syndrome is a common autosomal dominant hereditary disorder also referred to as the Turner-like syndrome, male Turner’s syndrome, or Turner syndrome with normal karyotype. In 1963, Dr. Jacqueline Noonan termed these anomalies as a specific syndrome, which was named after her. The disease is characterized by short stature, congenital heart defects, and typical facial features that include hypertelorism, relative macrocephaly, down-slanting palpebral fissures, epicanthic folds, low-set ears, and ptosis (Massart et al. 238). Individuals suffering from the disease may also have bleeding problems, bone malformation, and retarded growth, which leads to short stature (Raynal 1).

The symptoms of the disease escalate with increasing age, and the diagnosis can be made clinically. The most commonly used diagnostic measure for the disease is genetic testing. It has been confirmed that Noonan syndrome occurs because of the transformation of genes especially those determining the proteins involved in the RAS-MAPK signaling route (Aoki et al. 174). Genetic testing of NS individuals has shown that the main gene affected by the mutation in the PTPN11 gene that encodes for tyrosine phosphatase (SHP2). Several gene mutations are associated with NS. They include SOS1, KRAS, NRAS, RAF1, BRAF, CBL, RIT1, and many others that are involved in RAS-signaling mediation (Aoki et al. 21). However, in certain cases, a patient may be devoid of any gene mutation yet present with the condition. Short physiques are a characteristic manifestation of Noonan syndrome in kids. This feature is due to defective proteins of the RAS-MARK pathway. Studies have revealed a genotype-phenotype relationship. The small build is common in patients with alterations in the PTPN11 gene, which could be because of SHP2 association with the receptors found on growth hormones. The administration of rhGH is the known therapy for Noonan syndrome and has been shown to improve the height of NS individuals. Even though the therapy has shown an improvement in the height of these patients, there are certain discrepancies in response to treatment. Factors such as the dosage of rhGH, duration of treatment, age at initiation of therapy, and mid-parental height alter the therapy outcomes. In this study, it was hypothesized that short-term rhGH therapy of one year may increase the growth of an NS patient significantly (Yaoita et al. 214).

Materials and Methods

The patient was diagnosed to establish the presence of Noonan syndrome based on Van der Burgt criteria. The diagnosis showed mutations of the PTPN11 gene, which had affected different exons. The diagnosis also showed a deficiency of growth hormone in the child thus making him an NSGHD patient. The child had other features of the disease, which included congenital heart disorders, particularly hypertrophic cardiomyopathy, ptosis, low-set ears, and skeletal malformation. The patient was put on rhGH therapy at a weekly dose of 0.25 mg/kg subcutaneously. The therapy was done for one year with continuous monitoring of the child’s standing height (taken as a mean of three readings on a Harpenden stadiometer) and weight (measured by use of digital scale). The growth was determined by the BMI obtained from the quotient of the weight and square of the height. The growth velocity was also evaluated after a six-month analysis. The PTPN11 was also analyzed for the mutation at the end of the hormonal therapy. All these treatments were performed alongside available data from a different subject being treated with insulin-like growth hormone deficiency (IGHD).

Results

Molecular Results

The genetic analysis of PTPN11 gene still showed five variants of mutations (D61N, N58D, N308D, A72G, and M504V), which were confirmed de novo by comparing with the parent’s PTPN11 sequenced gene.

rhGH Treatment Results

After one year of treatment with rhGH, there was a significant increase in the serum IGF-1 of the patient from 130±9 to 216±7 µg/liter. Growth velocity in response to rhGH also increased significantly, which had a subsequent gain in height, compared to the initial measurements. There was substantial bone development after rhGH administration compared to the baseline measurement. Other symptoms initially noted in the patients such as heart disorders and ptosis also improved. There was no substantial increase in BMI in NSGHD patients compared to the GHD patient.

Discussion

In this therapy, the efficacy of rhGH in promoting growth was analyzed with a child who was NSGHD, and the results were compared to a GHD patient who was not NS. The NSGHD patient was put on the same dosage used for the GHD patient. Retarded growth reflected as the short statue is one of the common features in Noonan syndrome. Most of the children affected by the disease have their heights below the third percentile with abnormal final heights (for example, an adult male being -2.5 SD and an adult female being -2.2 SD). Though the cause of short stature in Noonan syndrome patients is still unclear, the mutated SH2 gene may interfere with the normal function of the growth hormone and insulin-like growth factor resulting in the trait. In this therapeutic study, five varying mutations in the PTPN11 (D61N, N58D, N308D, A72G, and M504V) gene were found. Three of these mutations, which represent 50%, were found in exon 3 that was responsible for encoding amino SH2 domain N-SH2. The other mutations were 33.3% and 16.7% for exon 8 and exon 13 respectively, which encode for catalytic tyrosine phosphatase domain (PTP). The mutations were grouped according to amino acids that were responsible for the intermolecular binding of (N58D, D61N, and A72G) or were situated in the N-SH2 and PTP interface surface (N308D and M504V). Though no correlation study was done to show the influence of PTPN11, other studies have shown patients with these mutations have slow responses compared to those without the mutation (Raynal 216).

The patient in this therapy showed a slow increase in height and growth compared to the previous GHD patient therapy. The noted differences in rhGH could be attributed to the pubertal development of the patient. Given that sexual maturity is deferred in NS patients, timely commencement of rhGH therapy has been shown to boost height at the beginning of adolescence. The findings also showed no significant increase in the BMI of the NSGHD compared to GHD patient data. The results were consistent with other findings, which have shown that the treatment of rhGH did not affect the BMI results (Lee et al. 15). Nevertheless, there may be favorable changes in fat mass and body composition during the rhGH therapy (Raynal 218).

Works Cited

Aoki, Yoko, Tetsuya Niihori, Toshihiro Banjo, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Tsutomu Ogata, Fumio Takada, Michihiro Yano, Toru Ando, Tadataka Hoshika, Christopher Barnett, Hirofumi Ohashi, Hiroshi Kawame, Tomonobu Hasegawa, Takahiro Okutani, Tatsuo Nagashima, Satoshi Hasegawa, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Shin-ichi Inoue, Yusuke Watanabe, Toshihiko Ogura, Yoichi Matsubara. “Gain-Of-Function Mutations in RIT1 Cause Noonan Syndrome, A RAS/MAPK Pathway Syndrome.” The American Journal of Human Genetics 93.1 (2013): 173-180.

Lee, Peter A., Judith Ross, John A. Germak, and Robert Gut. “Effect of 4 Years of Growth Hormone Therapy in Children with Noonan Syndrome in the American Norditropin Studies: Web-Enabled Research (ANSWER) Program® Registry.” International Journal of Pediatric Endocrinology 2012.1 (2012): 15.

Massart, Francesco, Silvano Bertelloni, Mario Miccoli, and Angelo Baggiani. “Height Outcome of the Recombinant Human Growth Hormone Treatment in Subjects with Noonan Syndrome: A Meta-Analysis.” Journal of Genetic Syndromes & Gene Therapy 5.2014 (2014): 238.

Raynal, Patrick. “Growth Hormone and Noonan Syndrome: Update in Dysfunctional Signaling Aspects and in Therapy for Short Stature.” Hormonal Studies 2.1 (2014): 1.

Yaoita, Masako, Tetsuya Niihori, Seiji Mizuno, Nobuhiko Okamoto, Shion Hayashi, Atsushi Watanabe, Masato Yokozawa, Hiroshi Suzumura, Akihiko Nakahara, Yusuke Nakano, Tatsunori Hokosaki, Ayumi Ohmori, Hirofumi Sawada, Ohsuke Migita, Aya Mima, Pablo Lapunzina, Fernando Santos-Simarro, Sixto García-Miñaúr, Tsutomu Ogata, Hiroshi Kawame, Kenji Kurosawa, Hirofumi Ohashi, Shin-ichi Inoue, Yoichi Matsubara, Shigeo Kure, and Yoko Aoki. “Spectrum of Mutations and Genotype–Phenotype Analysis in Noonan Syndrome Patients with RIT1 Mutations.” Human Genetics 135.2 (2016): 209-222.

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