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OBM Genetics

(ISSN 2577-5790)

OBM Genetics is an international Open Access journal published quarterly online by LIDSEN Publishing Inc. It accepts papers addressing basic and medical aspects of genetics and epigenetics and also ethical, legal and social issues. Coverage includes clinical, developmental, diagnostic, evolutionary, genomic, mitochondrial, molecular, oncological, population and reproductive aspects. It publishes a variety of article types (Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.). There is no restriction on the length of the papers and we encourage scientists to publish their results in as much detail as possible.

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Open Access Original Research

Clinical Variabilities of PTPN11 Pathogenic Variant in Indonesian Noonan Syndrome Patients

Nisa Ayu Thayalisha Hadi 1, Agustini Utari 2,3, Nydia Rena Benita Sihombing 3,4, Tri Indah Winarni 3,4, Nani Maharani 3,5,*

  1. Master of Biomedical Science–Majoring Genetic Counselling, Faculty of Medicine, Universitas Diponegoro, Semarang, Central Java, Indonesia

  2. Department of Pediatrics, Faculty of Medicine, Universitas Diponegoro, Semarang, Central Java, Indonesia

  3. Center for Biomedical Research (CEBIOR), Faculty of Medicine, Universitas Diponegoro, Semarang, Central Java, Indonesia

  4. Department of Anatomy, Faculty of Medicine, Universitas Diponegoro, Semarang, Central Java, Indonesia

  5. Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Diponegoro, Semarang, Central Java, Indonesia

* Correspondence: Nani Maharani

Academic Editor: Fabrizio Stasolla

Collection: Rare Genetic Syndromes: From Diagnosis to Treatment

Received: January 08, 2026 | Accepted: April 15, 2026 | Published: May 06, 2026

OBM Genetics 2026, Volume 10, Issue 2, doi:10.21926/obm.genet.2602338

Recommended citation: Hadi NAT, Utari A, Sihombing NRB, Winarni TI, Maharani N. Clinical Variabilities of PTPN11 Pathogenic Variant in Indonesian Noonan Syndrome Patients. OBM Genetics 2026; 10(2): 338; doi:10.21926/obm.genet.2602338.

© 2026 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Noonan syndrome (NS) is an autosomal dominant disorder with a wide spectrum of symptoms and clinical phenotypes, including short stature, congenital heart defects (CHD), and distinctive facial features. A pathogenic variant in the PTPN11 gene is the major cause of NS. This is a preliminary study in Indonesia involving 29 patients with clinical features of NS. Detailed clinical and echocardiography data were collected. Genomic DNA was extracted from a peripheral blood sample. Exome sequencing or PCR followed by Sanger DNA sequencing was done. Variant pathogenicity was assessed using the ClinVar database, while the novel variant was analyzed in silico using PolyPhen, Rare Exome Variant Ensemble Learner (REVEL), SIFT, FATHMM Pred, and MutationTaster. Clinical findings in 18 patients showed a typical craniofacial feature of NS, including low-posteriorly rotated ear (83.3%), microcephaly, downslanted palpebral fissures, and a short-webbed neck in 50%, and hypertelorism and a depressed nasal bridge in 44.4%. Other clinical variabilities included CHD (83.3%), thoracic and musculoskeletal deformities (77.8%), short stature (72.2%), and intellectual disability (ID) (50%). A novel variant in exon 3 of PTPN11 was found in one patient: c.140G>A (p.Arg47Lys), which was predicted to be probably damaging. A variant in exon 8, the c.907G>A (p.Asp303Asn), was found in 11 patients. This variant is not in the ClinVar database yet; however, it was reported in a case report and predicted to be probably damaging. One patient has a variant c.184T>G (p.Tyr62Asp), 1 patient has c.854T>C (p.Phe285Ser), 1 patient has c.922A>G (p.Asn308Asp), 2 patients have c.1510A>G (p.Met504Val), and 1 patient has c.1517A>C (p.Gln506Pro), those variants have been previously reported. Sequencing on the remaining exons of PTPN11 is still ongoing. NS patients with PTPN11 variants demonstrate diverse clinical manifestations. Clinicians’ awareness of suspecting NS is essential for early diagnosis, particularly in children with short stature, ID, and CHD who have a distinctive facial dysmorphism at any age.

Graphical abstract

Click to view original image

Keywords

PTPN11; Noonan syndrome; clinical variability; short stature; intellectual disability; congenital heart disease

1. Introduction

Noonan syndrome (NS; OMIM#163950) is an autosomal dominant disorder characterized by craniofacial dysmorphism, such as short webbed neck (68.4%), downslanted palpebral fissures (46.6%), low posteriorly rotated ears (43.3%), and microcephaly (32.5%). Other features include congenital heart diseases (CHD) (83.8%), thoracic and musculoskeletal deformities (short stature) (77.4%), intellectual disabilities (ID) (20%) [1,2,3], and other additional extracardiac features. The incidence of NS is estimated to be 1 in 1000-2500 live births [4,5].

NS is a heterogeneous condition, with variable phenotypic expression and severity. The syndrome is associated with pathogenic variants in multiple genes in the Ras/Mitogen-Activated Protein Kinase (RAS-MAPK) pathway, which regulates growth and differentiation, leading to dysregulation. More than eight different genes associated with NS, such as PTPN11 (61%), SOS1 (12%), RAF1 (7%), RIT1 (5%), LZTR1 (4%), and other implicated genes, including SOS2, BRAF, KRAS, MAP2K1, MRAS, NRAS, RASA2, and RRAS2, are required to diagnose NS.

Pathogenic variants in the PTPN11 gene are the major cause of NS, with missense mutations responsible for about 50% of NS cases. This gene encodes the tyrosine protein phosphatase non-receptor (SHP2), which is involved in Extracellular Signal-Regulated Kinase (ERK) activation via the RAS-MAPK pathway [6]. PTPN11 is located on chromosome 12q24 and contains 15 exons, encoding a total of 593 amino acids. Variants in PTPN11 are most frequently found in exons 3 and 8 [7]. The hotspot variant in the PTPN11 gene associated with NS is c.922A>G (p.Asn308Asp) in exon 8. This variant has been widely studied and reported across a range of populations with prevalence of 16.3% to 43%. The second, c.1510A>G (p.Met504Val) in exon 3, is less prevalent, with a range of 4.2% to 16.3% [1]. Other recurrent variants include c.417G>C (p.Glu139Asp) in exon 8, c.836A>G (p.Tyr279Cys) in exon 7, and c.1403C>T (p.Thr468Met) in exon 13, which are also often found in populations [8].

The PTPN11 gene is expressed in various tissues and plays a crucial role in regulating eukaryotic cell responses to multiple extracellular signals, such as hormones, cytokines, and growth factors. Mutations in PTPN11 can be inherited in an autosomal dominant manner or occur de novo. The mutations involved in NS are considered gain-of-function mutations that cause inappropriate prolongation of the RAS/MAPK signaling pathway. The prolonged RAS/MAPK pathway leads to the pleomorphic characteristics in NS [9].

NS is characterized by a broad spectrum of symptoms and physical features that vary greatly in range and severity, and can change with age. The most consistent features are wide-set eyes, low-set ears, short stature, and pulmonary valve stenosis [9,10]. The diagnosis of NS syndrome depends on the identification of characteristic clinical features [10,11].

Clinical diagnosis of NS based on the diagnostic criteria for NS. Until recently, diagnosis was made based on clinical features. Molecular genetic testing can confirm approximately 70% of cases [10]. There are major and minor criteria, along with some features, for establishing the diagnosis of NS (Table 1). The features are facial features, cardiac features, height, chest wall shape, family history, and other characteristics such as ID, cryptorchidism, and lymphatic vessel dysplasia [11].

Table 1 Diagnostic Criteria for Noonan syndrome [12].

2. Materials and Methods

We included 29 patients who visited the Cytogenetic and Molecular Laboratory, Biomedical Research Center Laboratory (CEBIOR), Faculty of Medicine Universitas Diponegoro, Semarang, Indonesia. The inclusion criteria for subjects are age 0-18 years old who were diagnosed with NS based on Van der Burgt criteria (Table 1) and were clinically confirmed by an experienced pediatrician.

2.1 Clinical Examination

Patients were described according to craniofacial features, cardiac defects, and systemic manifestations. Short stature was defined as a height-for-age z-score (HAZ) below -2 standard deviation (SD) or less than the 3rd percentile. In contrast, severe short stature was defined as HAZ below -3 SD, plotted on World Health Organization (WHO) graphics for subjects below 5 years old, and Centers for Disease Control and Prevention (CDC) for subjects >5 years old. Clinical data were obtained from hospital medical records.

2.2 Molecular Analysis

Genomic DNA was isolated from peripheral blood samples using the QIAamp DNA Mini Kit (QIAGEN, Pune, India) at CEBIOR, Faculty of Medicine, Diponegoro University, Indonesia. The Polymerase Chain Reaction (PCR) has been performed in a 30 µl reaction volume containing 2 µl genomic DNA, 15 µl GoTaq Green Master Mix 2X (Promega Corporation Company, Madison, Wisconsin, United States), 0.5 µl 10 µM forward and 0.5 µl 10 µM reverse primer by Genetika Science Indonesia, Tangerang, Indonesia, and 12 µl nuclease-free water. Cycling parameters were 45 cycles of 95°C for 30 seconds (denaturation); 54-60°C for 30 seconds (annealing); and 68°C for 90 seconds (extension), followed by 68°C for 7 minutes (final extension step). Please refer to Table 2 for the primer sequences, annealing temperatures, and size of PCR products for each primer pair.

Table 2 Primer Sequences, Annealing Temperatures, and Product Lengths to Amplify PTPN11 [8].

Sanger DNA sequencing was performed at the Integrated Laboratory for Research and Testing (LPPT) Universitas Gadjah Mada, Yogyakarta, Indonesia. The first purification was performed using the Exo-Sap protocol with a mixture of 5 µl of PCR product and 2 µl of ExoSap-IT, then incubated in a thermalcycler at 32°C for 15 minutes and 80°C for the next 15 minutes. Cycle sequencing was performed in 1 µl BigDye Terminator Ready Mix, 2 µl Buffer 5×, 1 µl forward/reverse primer (3.2 pmol), 1 µl template DNA, and 5 µl ddH2O. Cycling parameters were 25 cycles of 96°C for 10 seconds (denaturation); 50°C for 5 seconds (annealing); 60°C for 4 minutes (extension); and 4°C for hold. The second purification was performed using BigDye X-Terminator Purification kit (BDX) (Applied Biosystems, Foster City, CA, USA) with a mixture of 10 µl of sequencing template result, 45 µl SAM solution, and 10 µl BDX. Electrophoresis was performed in an Applied Biosystem 3500 Genetic Analyzer (Applied Biosystem).

Exome sequencing was performed on five of 29 samples at the Genome Diagnostics Nijmegen, Department of Human Genetics, Radboud University Medical Center, The Netherlands, using Illumina NovaSeq 6000, after exome enrichment with the Twist Exome 2.0 plus Comprehensive Exome Spike-in Kit (Twist Bioscene, South San Francisco, United States).

2.3 Variant Analysis

The Human Gene Mutation Database (HGMD), the National Center for Biotechnology Information (NCBI) database, GnomAD (https://gnomad.broadinstitute.org/), and ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) databases were used to confirm the pathogenicity status of the variant. The novel variant was analyzed for pathogenicity in silico using Polymorphism Phenotyping (PolyPhen) (http://genetics.bwh.harvard.edu/pph2/), Rare Exome Variant Ensemble Learner (REVEL) (https://sites.google.com/site/revelgenomics/), Sorting Intolerant From Tolerant (SIFT) (https://sift.bii.a-star.edu.sg/sift4g/), and Functional Analysis through Hidden Markov Models (FATHMM_pred) (https://fathmm.biocompute.org.uk/), and MutationTaster_pred (https://www.mutationtaster.org/).

2.4 Ethics Statement

This study had been reviewed and approved by the Health Research Ethics Committee of the Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia [No. 336/EC/KEPK/FK-UNDIP/VII/2024]. Written informed consent to participate in this study, including for the publication of any potentially identifiable images in this paper, was provided by the participants’ legal guardian.

3. Results

3.1 PTPN11 Variants

We identified a total of 18 patients (62%) with PTPN11 variants in 29 patients (Table 3), all of which have been previously reported as pathogenic, and one novel variant. Thirteen patients had missense changes in exon 8: 11 patients have a missense variant in c.907G>A (p.Asp303Asn), this change was the most common variant observed in our study (37.93%), one patient has a variant in c.922A>G (p.Asn308Asp), and another in c.854T>C (p.Phe285Ser). Three patients have variants in exon 13: two patients have a variant in c.1510A>G (p.Met504Val), and one has c.1517A>C (p.Gln506Pro). Two patients have a variant in exon 3 c.184T>G (p.Tyr62Asp) and c.140G>A (p.Arg47Lys); most of these pathogenic variants have previously been reported, as shown in Table 3 [8,13,14]. A novel variant, c.140G>A (p.Arg47Lys), was identified in exon 3 and analyzed for pathogenicity in silico using PolyPhen and REVEL.

Table 3 PTPN11 variants found in this study.

3.2 Phenotype Analysis

A wide range of phenotypic variability is observed among NS patients with a PTPN11 pathogenic variant, demonstrating variable expressivity and penetrance. Of the 18 patients with a PTPN11 variant, 50% of patients were male. Age at diagnosis ranged from <1 month to 7 years 4 months. The mean HAZ was -3.28 SD, while the weight-for-height z-score (WHZ) mean was -1.66 SD. Nine of 18 patients (50%) came with the chief complaint of weight faltering and experienced feeding difficulties in infancy. Two of 18 patients (11.1%) were short in stature. Other clinical manifestations were described (Table 4) to demonstrate the clinical variabilities in PTPN11 pathogenic variants in Indonesian NS patients.

Table 4 Phenotypic features in patients with positive PTPN11 pathogenic variant.

A typical craniofacial feature of NS was observed in all patients. Features observed with high frequency in the patients with PTPN11 pathogenic variants were low-set posteriorly rotated ears found in nearly all patients (83.3%), microcephaly, downslanted palpebral fissure and short-webbed neck found in nine patients (50%), hypertelorism and depressed nasal bridge in eight patients (44.4%), while thin and curly scalp hair, tall forehead with narrow temples, bulbous nose, and upturned/downturned mouth found in five patients (27.8%). CHD diagnosed by echocardiography was present in 15 patients (83.3%), pulmonary valve stenosis was the most common, either isolated (27.8%) or combined with atrial septal defect (ASD) (38.9%). Four of eighteen patients (22.2%) also developed an isolated ASD. CHD was seen most frequently in patients with pathogenic variants in exon 8 (10 out of 12 patients). Severe short stature was observed in 8 patients (44.4%), while short stature was found in 5 patients (27.8%). Other phenotypes observed in most patients (77.8%) include thoracic deformities or musculoskeletal manifestations (sternal deformities and finger-toes deformities). All patients with PTPN11 pathogenic variants showed mild to moderate ID.

Comorbidities were also observed in this study; one patient reported suffering from juvenile myelomonocytic leukemia. Furthermore, hypothyroidism, cholestasis, multiple caries dentis and cutis marmorata were also found in several patients. Three patients were reported to have hearing loss, which was acquired beyond childhood and was severe enough to require hearing aids. Laryngomalacia was reported in one patient, which was corrected by surgery.

4. Discussion

To the best of our knowledge, this is the first study involving a relatively large NS patient cohort in Indonesia. Missense mutations in PTPN11 cause NS and involve a gain-of-function mechanism. In the present study, we identified PTPN11 changes in 18 (62%) out of 29 patients, all of whom had sporadic NS. These findings are limited as we performed only on selected exons, including PTPN11 exons 3, 4, 8, 11, and 13. The result is consistent with previous studies, which reported that PTPN11 pathogenic variants were present in 50% of NS cases [24,25,26,27]. Other genes responsible for NS, such as SOS1, SOS2, BRAF, KRAS, MAP2K1, MRAS, NRAS, RAF1, RASA2, RIT1, RRAS2, and LZTR1, may still be found in other patients. Further examination to study these genes and exons will be planned in the future as well.

Six of the 18 pathogenic variants identified in this study were previously reported missense changes. The majority of variants were found in exon 8, as reported in earlier studies, accounting for 72.2% of the PTPN11 pathogenic variants (Table 3). In this study, 18 (62%) of those with PTPN11 pathogenic variants had variants in exons 3, 8, and 13; this proportion is consistent with that observed in most studies [13,28,29,30,31].

However, one pathogenic variant (c.140G>A p.(Arg47Lys)) represents a novel finding within the N-terminal SH2 domain (N-SH2). N-SH2 plays a critical regulatory role as a key regulatory domain of the protein. This variant has not been previously reported in major population databases and literature [6]. Variants affecting the N-SH2 domain of PTPN11 are associated with NS due to a gain-of-function that destabilizes the autoinhibitory interaction between the N-SH2 and Protein Tyrosine Phosphatase (PTP) domains. Thus, SHP2 becomes excessively active, leading to hyperactivation of the RAS-MAPK pathway and dysregulated developmental signaling [32]. In silico predictive tools suggest that the variant is probably damaging, and conservation analysis demonstrates it is highly conserved across species, indicating potential functional importance [33].

The missense variant in c.907G>A p.(Asp303Asn) was the most common pathogenic variant we identified. This variant was previously reported in a case of Kawasaki disease in NS by Takai et al. In silico analysis predicted that it was “probably damaging” by Poplyphen2 with a prediction score of 0.533, adding further evidence of the occurrence of this variant in another NS patient [15]. A missense variant, c.922A>G (p.Asn308Asp), found in one patient, is consistent with earlier studies on PTPN11 pathogenic variants, which identified c.922A>G as a mutation hotspot for NS-causing missense changes [8,13,14].

Sequence variant c.907G>A p.(Asp303Asn) is likely to represent a non-synonymous single-nucleotide polymorphism (nsSNP) that causes NS in Javanese, Southeast Asian, and Indonesian populations. In our case, we have collected data on family trees; however, we have not found evidence of familial segregation. Therefore, functional studies are needed for this variant. The pathogenic nsSNPs of PTPN11 c.907G>A p.(Asp303Asn) were analyzed by five in-silico pathogenicity tools, such as PolyPhen, REVEL, SIFT, FATHMM Pred, and MutationTaster. The results support a deleterious effect on protein function in some predictors, but with the REVEL score of 0.533, it is not convincing enough to categorize it as likely pathogenic. With only one previous case report of a Noonan Syndrome patient with this variant [15], we classified it as a variant of unknown significance (VUS), which will need further evidence to reclassify it, according to the American College of Medical Genetics and Genomics (ACMG) guidelines [34]. Considering that about 30% of nsSNPs may influence clinical phenotypes by altering post-translational modifications (PTMs), protein stability, and protein-protein interactions, functional studies and clinical correlation are recommended for definitive pathogenicity confirmation [35,36].

The SNPs in the coding region of human genes were associated with genetic disorders. A large number of SNPs have been reported in the database, making it difficult to screen them all for a particular phenotype. Computational analysis tools help narrow down and examine pathogenic SNPs for specific genetic disorders, thereby minimizing risk [37,38].

In many previous studies, genotype-phenotype correlations have been widely investigated. However, the result obtained is that within the same pathogenic variant location, a wide range of clinical variability is observed [24]. Several studies describe the role of SHP2 in regulating various developmental processes and the possible causes of this variation [39,40,41].

Variability in craniofacial features may vary due to subjective assessment. Low-set posteriorly rotated ears (83.3%) are the most commonly observed in our study, followed by microcephaly, downslanted palpebral fissure, and short-webbed neck (50%). Hypertelorism and depressed nasal bridge are present in eight (44.4%) patients, while prominent eyes are present in seven (38.9%) of the 18 cases. The mean age is 1 year 11 months, with children being the majority of cases, consistent with the literature on craniofacial features in childhood with NS. In the childhood category, the head is relatively abnormal in shape, with low-set, posteriorly rotated ears, downslanted palpebral fissures, a wide forehead, epicanthal folds, a short-webbed neck, and sternal deformities (pectus carinatum or excavatum). Hypertelorism, ptosis, or thick, hooded eyelids are characteristics. The nose is short and wide with a depressed root [42]. Thereafter, due to age changes, the craniofacial features become less noticeable in adulthood.

Severe short stature (HAZ below -3 SD) and short stature (HAZ below -2 SD or at the 3rd percentile) were seen in 13 (72.2%) of 18 patients with PTPN11 pathogenic variants. Proportionate short stature is present in more than 50% of cases. The molecular mechanism by which NS-causing SHP2 mutants induce growth retardation had been reported previously [43]. SHP2 mutations in NS by a postreceptor signaling defect cause mild Growth Hormone (GH) resistance, which is partially compensated by increased GH secretion. In children with SHP2 mutations who have a poor response to rhGH, this defect may contribute to the short stature phenotype [44]. Growth delay was associated with low Insulin-like Growth Factor 1 (IGF-1) levels during the early postweaning growth phase. Impaired IGF-1 production contributes to growth retardation in NS. This is in agreement with clinical data showing that NS patients, notably those carrying a PTPN11 mutation, display low IGF-1 levels [39]. GH treatment in NS is thought to be beneficial because the dysmorphic findings are similar to those in Turner syndrome. Therefore, GH has been administered at the same dose used in the treatment of Turner syndrome [45,46].

NS is the second most common syndromic cause of congenital heart disease, exceeded in prevalence only by trisomy 21 [23]. Clinical manifestations of CHD problems are the most common reasons that prompt patients to see a doctor. In this study, CHD was found in 15 patients (83.3%) with PTPN11 pathogenic variants. Pulmonary valve stenosis, seen in 9 patients (50%), was the most common finding in the present study, followed by atrial septal defects in 6 patients (33.3%), either isolated or combined with other types. Compared to the data from the previous study, NS patients with the PTPN11 pathogenic variant are more likely to be associated with pulmonary valve stenosis or ASD [47]. PTPN11 encodes the Src homology-2 domain-containing protein tyrosine phosphatase and is reported to be associated with enlargement of the aortic annulus and aortic root [48,49].

Thoracic and musculoskeletal deformities of NS consist of insufficient and/or delayed growth, causing short stature, and axial skeletal deformities, including sternal deformities, vertebral anomalies, cubitus valgus, and finger-toes abnormalities. Sternal deformities, such as pectus carinatum and/or excavatum, were presented in 10 (55.6%) of the 18 cases with PTPN11 pathogenic variants. Four patients (27.8%) had widely-spaced nipples, and the chest circumference was measured across the internipple line. The internipple index was calculated according to the formula: internipple distance (cm) multiplied by 100 and divided by chest circumference (cm). The internipple distance and chest circumference increased with age. The internipple index in the neonatal period was the highest among all ages (26.4 ± 1.6 for males and 26.3 ± 2 for females), and will gradually decrease until the age of four years (23.8 ± 1.2 for males and 23.8 ± 1.4 for females), thereafter it would be relatively constant through the age of 18 years in males and the age of 11 years in females [48].

Neurological manifestations and cognitive and behavioral changes in individuals with NS are highly variable. Heterogeneity in cognitive abilities within RAS-MAPK signaling pathway syndromes has been observed, which depends on the affected gene and the variant type. IQ tests were not examined; instead, the cognitive & behavioural changes were assessed by a Social Pediatric Consultant using the Denver II as a screening tool to identify potential ID. This assessment evaluated four developmental areas: personal-social, fine-motor-adaptive, language, and gross-motor skills. Eight patients (44.4%) were found to have global developmental delay, as their screening test results did not align with their actual age. In these patients, neurodevelopmental and hearing function evaluations should be performed [50].

Cryptorchidism may be present in males with NS and have an increased risk of infertility. While females with NS generally have normal puberty and fertility, males may experience delayed puberty and reduced fertility due to cryptorchidism and other potential gonadal issues. Male gonadal dysfunction has also been reported and is suggested to be caused by primary Sertoli cell dysfunction rather than cryptorchidism [51]. Among the nine male patients in this study, four have cryptorchidism, although all the patients have undergone orchidopexy as corrective surgery.

Lymphatic vessel dysplasia with a clinical lymphatic abnormality is a major feature of NS. Six NS patients (33.3%) with PTPN11 pathogenic variants had lower limb lymphedema. Lower limb lymphedema and genital lymphedema are the two most reported types of lymphedema that develop after birth [52]. The presentation of lymphedema in NS may vary, including differences in timing and resolution of edema at different ages. Haque et al. [53] reported prenatal and postnatal onset of lymphatic abnormalities in NS, whereas postnatal onset might result in a milder phenotype.

A broad spectrum of ophthalmologic features is found in NS, with downslanted palpebral fissures (50%) being the most common finding in PTPN11 pathogenic variants, followed by depressed nasal bridge, hypertelorism (44.4%), and prominent eyes (38.9%). Marin et al. [54] reported that the most common ophthalmologic feature finding (74%) in patients with PTPN11 pathogenic variants was downslanted palpebral fissures. Refractive errors are not examined. Based on the literature, refractive errors and ptosis are often detected and reported in patients with PTPN11 pathogenic variants [55].

Several hematological disorders are predisposed to occur in NS, including transient monocytosis, thrombocytopenia, and myeloproliferative disorder [56]. The most common haematologic disorders are coagulation defects, manifested as bleeding abnormalities [57]. In this study, one NS patient with a PTPN11 pathogenic variant had severe anemia, while other patients had haemangioma and juvenile myelomonocytic leukemia. Several hematological cancers have been reported in patients with NS during childhood, including juvenile myelomonocytic leukemia, acute myelogenous leukemia, and B-cell acute lymphoblastic leukemia [57].

Despite a few studies reporting an autoimmune thyroiditis in NS, an earlier study showed an association between hypothyroidism and NS. In a patient with NS, primary hypothyroidism is an uncommon condition that may develop either separately or in conjunction with NS. Although the precise etiology of this condition is unknown, age, excessive iodine intake, and heredity can make an individual more susceptible. One NS patient in this study was found to have hypothyroidism and undertreatment with Euthyrax. A multidisciplinary approach is required for these individuals with comorbidities or related conditions to NS [58].

Gastrointestinal manifestations such as liver problems, including elevated liver enzymes, autoimmune hepatitis, and even human hepatocellular carcinoma (HCC), can occur in NS due to its genetic basis affecting the RAS-MAPK pathway, which is commonly seen in other RASopathies like progressive familial intrahepatic cholestasis (PFIC) [59]. We reported one NS patient with a pathogenic PTPN11 variant with cholestasis. Liver problems in NS are less frequent; a previous study by Rippert [60] revealed a strong association between NS and neonatal liver disease, particularly neonatal hyperbilirubinemia and cholestatic disease. Since the pathogenesis of these conditions has not been definitively linked to NS, understanding the spectrum of liver phenotypes in NS remains a subject of ongoing investigation.

NS is linked to various orodental manifestations reported in several studies. High-arched palate, micrognathia, and macrodontia, which can result in malocclusion and misalignment of teeth, have been reported repeatedly in case reports and retrospective studies [61]. High arched palate and caries dentis are common dental problems in NS.

Cutis marmorata teleangiectatica congenita (CMTC), a cutaneous or ectodermal manifestation of NS, was found in one patient in this study. CMTC is a possible associated anomaly in NS, even though it is not a primary feature. Cutaneous findings are common in NS with BRAF, KRAS, and SHOC2 variants [62].

The study’s retrospective design had some limitations. We tried to combine the correlations between genotypes and phenotypes based on follow-up results in the medical records from the last examination. Due to the high cost and the fact that genetic testing is not covered by national health insurance, genetic testing has only been performed on selected exons, those frequently reported to cause NS mutations, which were evaluated. Moreover, the relatively small cohort may not adequately represent the broader population variability and may have biased the results. However, this study is, to the best of our knowledge, the first to explore genotype-phenotype correlations of NS. in the Indonesian population, which might be a basis for further study in NS.

5. Conclusions

NS has broad clinical manifestations, and each patient presents with mixed clinical features. Clinicians need to raise awareness of suspecting NS, since the incidence rate is relatively high, and be concerned about comorbidities. Early diagnosis can be achieved by maintaining a high index of suspicion in children with short stature, ID, CHD, and musculoskeletal deformities that have a distinctive facial dysmorphism at any age. Whole exome sequencing or gene panel is the gold standard for NS and other RASopathies. However, in this developing country, Indonesia, where most of the cases come from families with low economic backgrounds, genetic testing is very expensive and not covered by government health insurance. In these situations, based on the results of our study, we might suggest molecular testing, such as Sanger sequencing, for patients clinically suspected of having NS, performed only at several mutation hotspots, such as exons 3, 8, and 13.

Acknowledgments

The authors thank the subjects and their families for participating in this study. We thank Radboud University Medical Center for invaluable technical assistance with exome sequencing and a multiple gene panel for Noonan syndrome. Also, the authors would like to thank the patient and his parents for their willingness to participate in this study.

Author Contributions

All authors contributed to the study’s design, data analysis, and manuscript preparation. Nisa Ayu Thayalisha Hadi led data collection, interpretation, and statistical analysis, while Agustini Utari and Nydia Rena Benita Sihombing assisted in manuscript writing. Tri Indah Winarni and Nani Maharani provided critical revisions to the manuscript and supervised the research project.

Funding

The study was fully supported by RPI grant from LPPM Universitas Diponegoro (Undip) number 609-46/UN7-D2/PP/VIII/2023. LPPM Undip had no direct role in study design, sample collection, data interpretation or manuscript preparation. The study was also supported by the Center for Biomedical Research (CEBIOR) Faculty of Medicine Undip.

Competing Interests

The authors have declared that no competing interests exist.

Data Availability Statement

A list of genes involved in the Table 3 is available on the Human GRCh3/hg19 database on the UCSC Human Genome Browser website.

AI-Assisted Technologies Statement

Artificial intelligence (AI) tools were used solely for basic grammar correction and language refinement in the preparation of the manuscript. Specifically, Grammarly was employed to improve the readability and linguistic clarity of the English text. All scientific content, data interpretation, and conclusion were developed independently by the author. The authors have thoroughly reviewed and edited the AI-assisted text to ensure its accuracy and accept full responsibility for the content of the manuscript.

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