Of the 151 patients in the original cohort, 34 (22.5%) dropped out of the study and 10 (6.6%) had died. On assessment of the remaining 107 individuals, three were found to have developed multiple lentigines and were given an alternative diagnosis of LEOPARD syndrome. The phenotype of a further two cases was felt to be inconsistent with Noonan syndrome, and so all five of these individuals were excluded from the analysis. The study cohort therefore comprised 112 individuals (57 males, 55 females) from 92 families, of whom 70 were fully assessed, 32 partially assessed and 10 deceased (for whom hospital records were obtained). The mean (median) age at assessment was 25.3 (22) years (range 12–71 years), and the mean follow‐up interval was 12.02 (range 10.7–13.6) years. PTPN11 analysis was performed in 79 probands and mutations were identified in 28 (35%) patients. Mutations were more common in familial cases and were found in 6 of 12 (50%) probands from affected families (50%) compared with 22 of 67 (33%) sporadic cases (33%). Table 1 gives a list of all identified mutations.
Table 1Mutations in PTPN11 identified in the study cohort
Analysis of the facial features captured by 3D imaging are published elsewhere.14
Table 2 shows the cause and age of death for the 10 patients who were deceased.
Table 2Mortality in the study cohort
Height standard deviation score (SDS) was calculated for all individuals with available growth data from ascertainment and follow‐up using UK standard data. The mean SDS of 92 subjects at ascertainment was –2.184 (range –6.968 to +0.940), and the mean of 64 subjects at follow‐up was –1.755 (range –6.209 to +1.395). Growth data were available from both ascertainment and follow‐up on the same individual in 56 cases. Table 3 shows the mean height SDS in these subjects, the data being grouped by growth hormone treatment and genotype. No statistically significant differences were detectable between the two groups. Although the group with PTPN11 mutations had a similar mean height SDS, the distribution was much narrower, with all cases between –4 and 0 SDS compared with a range of –7 to +1 for the no mutation group.
Table 3Height standard deviation scores for the 56 subjects with accurate data at both ascertainment and follow‐up
There were 53 subjects who had reached their final adult height at follow‐up. The mean final height of the 25 males and 28 females was 167.4 and 152.7 cm, respectively. Growth hormone treatment had been given to seven men and three women, and once these individuals were excluded, mean final heights were 169.8 cm (male n
18) and 153.3 cm (female n
25). The seven men and three women who had been treated with growth hormone in childhood were shorter than the untreated group both before and after treatment, but represent an insufficient sample to perform meaningful analysis. When grouped by genotype, the final height in those with a PTPN11
mutation was approximately 4 cm less than those without a mutation in both sexes, but the difference was not statistically significant.
The mean adult occipitofrontal circumference was 56.4 cm in males (range 50–64 cm) and 54.9 cm in females (range 52–59 cm).
Pulmonary stenosis was present in 73 (65%) individuals overall, and was more prevalent in those with PTPN11 mutations (table 4). No intervention had been required to relieve the stenosis in 42 (58%) subjects. Percutaneous balloon valvuloplasty had been performed as a primary procedure in nine individuals; three of these went on to have an open valvuloplasty at a later date. Open surgical valvuloplasty was performed as a primary procedure in 22 cases, and three of these individuals required a repeat procedure.
Table 4Prevalence of cardiac abnormalities by PTPN11 mutation status
HCM was present in 21 (19%) patients; nine also had pulmonary stenosis, one had an atrial septal defect and one had a ventricular septal defect. Mortality was high in this group, with five subjects dying during the follow‐up interval, three from complications relating to their cardiac condition. All the cardiac‐related deaths were secondary to progressive heart failure. No subject had a sudden unexpected cardiac arrest or symptoms suggestive of an arrhythmia. Given the mean follow‐up interval of 12.02 years, the annual cardiac‐specific mortality in the HCM group was 1.2%. β‐Blocker therapy had been prescribed in 9 (43%) subjects. Amiodarone had been given to one individual who later had a heart transplant. Two patients had a remission of their HCM, to the point at which β‐blocker therapy was withdrawn. Surgical myectomy as a treatment for HCM had been performed in one case at ascertainment and in one further case at follow‐up. Heart transplantation had been performed in two subjects at ascertainment and in one further patient at follow‐up. Table 4 gives the genotype–cardiac phenotype data.
At ascertainment, infant feeding histories were obtained and a feeding difficulty score derived, based on the level of problems experienced in the first months of life (0
no problems; 1
weak suck, each feed takes >1 h; 2
weak suck and vomiting after 50% of feeds or more; 3
nasogastric tube feeding for >2 weeks in a term infant). A feeding score obtained from the original study data was available for 104 of the follow‐up group. The null hypothesis that feeding score had no long‐term association was tested for each outcome measure using the Mann–Whitney U test (ranked feeding score v
categorical variable) or Kruskal–Wallis test (ranked feeding score v
continuous variable). Table 5 summarises these results.
Table 5Outcome measures compared with infant feeding difficulties score (0–3)
Education and employment
On enquiry about education, 78 of 107 (73%) individuals reported having attended mainstream school, with 23 of them requiring extra help or tuition, and 29 (27%) reported having attended a school for children with learning difficulties. A statement of special educational need had been issued to 44%. Prevalence of PTPN11 mutations was similar in each group.
Of the 80 individuals who had completed their education, 13 (16%) had no qualifications, 5 (6%) had completed a life‐skills course, 9 (11%) had vocational qualifications, 34 (43%) reached GCSE (UK examination sat at age 16 years) grade C or higher in at least one subject, six (8%) achieved A‐level qualifications (UK examination sat at age 18 years) and 13 (16%) had a higher educational qualification. Data from the Office for National Statistics (Newport, UK) for a comparable year (2002) show that 15% of the UK working age population had no qualifications, 14% had vocational or other qualifications, 22% had attained GCSE grades A–C, 24% had A levels and 25% had a higher educational qualification.
Of those with Noonan syndrome who were no longer in full‐time education, 32 (60%) were in full‐time employment, 7 (13%) in part‐time employment, 4 (8%) in sheltered employment, 2 (4%) unemployed and 8 (15%) unable to work due to disability. Of the overall cohort, 26% were registered disabled and 36% received some form of disability benefit.
Quality of life is a subjective variable and is difficult to measure, but most patients felt their quality of life was satisfactory or good, with only 15% reporting it was poor. A lack of social life, or an inability to fit in, was cited as the main problem. Further psychological studies on young adults with Noonan syndrome are ongoing.
Orthodontic work had been performed in 37 of 72 (51%) patients to correct dental overcrowding, compared with 14% in the general UK population (Office of National Statistics). Dental caries was a common cause of dental morbidity, with 11 of 72 (15%) patients requiring extractions due to caries.
One patient had a mandibular tumour that was surgically resected and histologically confirmed to be a giant‐cell tumour. This patient harboured a mutation in exon 3 of PTPN11
(317A→C), as did two other members of his family who did not have giant‐cell lesions. The patient's phenotype was otherwise typical of Noonan syndrome and he did not exhibit any of the unusual features said to be characteristic of Noonan‐like/multiple giant‐cell lesion syndrome.15
Hormone injections had been given to 6 of 97 (6%) individuals to induce pubertal development. In those not receiving exogenous sex hormones, puberty commenced at a mean age of 14.5 years in males and 14 years in females with a range of 10–18 years in both sexes.
Of the 18 individuals who had had or were trying to have children, 12 (67%) had experienced no problems, 2 (11%) had one miscarriage, one had a history of recurrent miscarriages, one pregnancy ended in stillbirth and one woman had difficulty conceiving. One male had a low sperm count. Too few of the subjects had considered starting a family for the effect of cryptorchidism on fertility to be assessed.
A history of easy bruising or bleeding tendency was noted at both assessments. Most subjects (n
70, 79%) gave the same history of bleeding at follow‐up. The prevalence of PTPN11
mutations in those without a history of easy bruising was 19% compared with 47% of those with a history of easy bruising or abnormal bleeding (Mann–Whitney p
0.015). A subcohort of 72 individuals from the original study had undergone a limited coagulation factor analysis (activated partial thromboplastin time, factors VIII, XI and XII), and these data were compared with genotype data acquired at follow‐up. A range of both isolated and combined partial factor deficiencies were identified, but no correlation with genotype was noted.
Refractive errors affected 71% (39 of 69) patients, of whom 53% had myopia, 14% hypermetropia and 13% astigmatism. There was no relationship between eye abnormality and genotype.
Lymphoedema affected the lower limbs of two patients. One had onset of symptoms in late childhood and had distressing lymph leakage from several sites on the skin; this man had a PTPN11 (182A→G) mutation. The other individual had severe lower limb lymphoedema from early childhood that affected his mobility, and responded poorly to treatment such as manual lymphatic drainage and bandaging. No mutation was identified in this boy.
One further patient with a 124A→G mutation in PTPN11 had recurrent problems with lymph leakage from a skin fistula in the inguinal region. He had abnormal lymphatic architecture on lymphoscintogram, but no lymphoedema.
Scoliosis was reported in 20 (13%) of the original cohort. Surgical intervention had since been performed in one subject, but the scoliosis remained mild and non‐progressive in the others. Two patients were affected with rheumatoid arthritis, and three patients described a generalised polyarthropathy with onset in their fourth decade.
Recurrent convulsions were reported in 20 (13%) of the original cohort. Some of these individuals dropped out of the study, and two subjects developed seizures in the follow‐up interval, giving a prevalence of 11/112 (10%) in the follow‐up sample. Several seizure types were reported and the mean age of onset was 11 (range 3–19) years. PTPN11 mutations were identified in two subjects with seizures.
All except four patients, who had hearing loss due to serous otitis media, reported normal hearing at follow‐up. These four individuals had unilateral or asymmetric bilateral conductive deafness. Sensorineural deafness affected three patients, and mixed conductive/sensorineural hearing loss was present in two. The symptoms in these five cases had been non‐progressive since the initial assessment. One patient with profound sensorineural deafness had a PTPN11 mutation (124A→G). No patient had undergone cranial imaging to investigate the underlying pathology.