Aspects of Noonan Syndrome by
John M. Graham, Jr., M.D., Sc.D.
Cedars-Sinai Medical Center
INFORMATION SHEET
John M. Graham, Jr., M.D., Sc.D.
Director of Clinical Genetics and Dysmorphology
Medical Genetics Birth Defects Center
Ahmanson Pediatric Center
UCLA School of Medicine
THE MEDICAL AND PSYCHO EDUCATIONAL ASPECTS OF NOONAN SYNDROME
BACKGROUND
The Noonan syndrome was first noted in 1963 by Noonan and Ehmke when these authors reported on 9 children who had congenital heart anomalies (valvular pulmonic stenosis) and a recognizable pattern of altered physical features:
short stature, learning problems or mental retardation, widely-spaced eyes (hypertelorism) that are downslanted and other alterations of facial features. The syndrome is named for Dr. Noonan, a pediatric cardiologist, but was apparently described in 1883 by Kobylinski in a German publication. Since these first reports there are at least 300 instances of Noonan syndrome reported in the scientific literature. The incidence at birth has been estimated between 1 in 1000 and 1 in 2500 births.
GENETICS
Frequently this is a sporadic syndrome affecting only one family member. However, recent studies suggest that parent to child transmission is more common than first suspected. When familial, an autosomal dominant mode of transmission is noted and wide variability is present. Mildly affected family members are recognized by careful cardiac evaluation and appreciation of the adult phenotype. About 30-75% of cases are reported to result from genetic transmission from parent to child. More commonly it is the mother who is also affected (3:1 mother:father ration). This may relate to the cryptorchidism and male infertility in affected fathers
How the altered gene causes the features of the syndrome is not entirely clear. Some authors suggest that fetal lymphedema (swelling due to lymph flow obstruction) may cause some of the findings. An alternate explanation is that the fetal branchial arch field is developmentally altered. There may be more than one way that this set of physical findings occurs.
PHYSICAL CHARACTERISTICS
Growth:
The average length at birth is 47 cm (19 inches). Birth weight is typically normal. But increased birth weight from edema is common. Detailed growth curves are available (see: Saul RA et al: Growth References from Conception to Adulthood. Proceedings of the Greenwood Genetic Center, Supplement 1, 1988). The pubertal growth spurt may be blunted or absent.
Facial Features:
Widely-spaced and down-slanted eyes are noted in the newborn period in 95%. Low-set and posteriorly rotated ears with thickened helices (90%), deeply grooved philtrum, wide peaks of the vermillion border of the upper lip (95%), highly arched palate (45%), micrognathia (small jaw) in 25%, and excess skin at the base of the neck with a low posterior hairline are all common findings.
In infancy the head appears large with prominent eyes that are not slanted. The eyes appear widely spaced with droopy or thick, hooded eyelids. In adolescence the face becomes more triangular. The nose has a pinched root and a thinner, higher root. In the older adult, there are prominent nasolabial folds, and a high anterior hairline.
Features that are often present regardless of age are strikingly blue or blue-green irides, diamond-shaped, arched eyebrows, and low-set, posteriorly rotated ears with a thick helix.
Cardiac:
Congenital heart defects are seen in 2/3 of patients: pulmonic valve anomalies (50%), atrial septal defects (10%), asymmetric septal hypertrophy (10%), ventricular septal defect (5%), and persistent ductus arteriosus (3%). Other less common anomalies have been described.
Genitourinary:
No anomalies of note. However, pubertal development may be altered or delayed in some males with incomplete secondary sexualization and impaired or deficient spermatogenesis.
Skeletal:
A characteristic chest deformity (pectus carinatum/pectus excavatum) is a diagnostic clue helpful in making the diagnosis, but of no consequence to the individual. The chest is broad, taking on an "inverted pyramid" form. Nipples are relatively low-set and axillary webbing persists into adulthood. Other skeletal signs: cubitus valgus (50%), short curved fingers with blunt fingertips (30%), vertebral and sternal anomalies (25%), dental malocclusion (35%) and recently cherubism (painless swelling of the face with fullness at the angles of the mandible) have all been reported with Noonan syndrome.
Skin:
Several patients with Noonan syndrome have had neurofibromatosis. Recent studies suggest that the gene for neurofibromatosis segregates with this phenotype.
Hematology:
Bleeding problems, generally of a minor degree, are noted in approximately 20%. The problems include: factor XI deficiency, von Willebrand disease, and platelet dysfunction sometimes associated with trimethylaminuria.
Lymphatic system:
Generalized lymphedema may be present and contribute to the recognizable findings in Noonan syndrome. These include: lymphatic channel absence or abnormality, pulmonary lymphangiectasia, intestinal lymphangiectasia, hydrops fetalis, and cystic hygroma.
PSYCHOLOGICAL CHARACTERISTICS
Cognition:
Although it is commonly stated that many individuals with Noonan syndrome will be mildly mentally retarded, the existing data do not currently support this strong a claim. In fact, there are a growing number of reports of average to superior intelligence among individuals with Noonan syndrome (Finnegan & Hughes, 1988).
In a review of 63 paper covering 121 individuals, Mendez and Opitz (1985) found that only 24% were described as mentally retarded. In a study of affected individuals from 18 families, Collins and Turner reported higher incidence of retardation with 19 of the 27 individuals studied (70%) functioning in or close to the mentally retarded range. Fourteen of these 19 were noted to fill within the mildly retarded to borderline range. On the other hand, Money and Kalus (1979) performed indepth psychological evaluations of 8 individuals recruited from local pediatric endocrinology, medical genetics and pediatric clinics. For these individuals, IQ scores ranged from 64 to 127. Only one individual's performance fell within the mildly retarded range. However, this individual would more accurately be classified as learning disabled since he exhibited nonverbal abilities in the low average range and verbal abilities in the moderately retarded range. The remaining individuals performed within the average to above-average range with a median IQ of 102.
There is some suggestion in the literature that individuals with Noonan syndrome may tend to exhibit a psychological profile similar to that observed in individuals with Turner syndrome: that is, better performance nonverbal tasks and relative deficits in visual-construction or perceptual types of tasks. However, current evidence is weak and somewhat contradictory. For example, Money and Kalus (1979) found that four of their 8 subjects exhibited marked verbal-performance discrepancies. One individual, mentioned above, exhibited better nonverbal than verbal skills. The remaining three exhibited better verbal than nonverbal skills. However, one of these subjects was blind. Wilson and Dyson (1982) reported two cases of individual of normal intelligence. The 7 year old exhibited a significant weakness in nonverbal, perceptual tasks and a significant math disability. The 5 year old exhibited psychomotor delays. Both had strengths in verbal skills. On the other hand, Finegan and Hughes report the opposite pattern in a case study of a child with superior intelligence. Thus, further investigation on larger numbers of children is needed before commonalities in cognitive profile can be proposed with any degree of certainty.
Language:
Few studies have examined the language characteristics of individuals with Noonan syndrome. In a study of individuals, Nora et al. (1974) reported that 72% exhibited articulation disorders and 12% exhibited hearing deficits. In a case study of a girl whose overall development was obviously delayed, Wilson and Dyson (1982) found that phonological development was deviant and interfered significantly with her speech intelligibility.
Behaviour:
There is no evidence that specific behavioural characteristics, a specific behavioural disability or psychiatric disorder are consistently associated with this condition (Money & Duch, 1981).
NATURAL HISTORY AND INTERVENTION
Failure to thrive has been reported in 40% of infants. Motor and language delays are reported in approximately 30-25% of younger children (Allanson, 1987).
PSYCHO EDUCATIONAL
Implications:
It is clear that there is wide variability in the intellectual and adaptive functioning of individuals with Noonan syndrome. Therefore, offering parents premature expectations of mental retardation is not appropriate. In the cases where an individual seems to be developing more slowly than is typical, a psychological evaluation should be obtained and attention given to possible learning disabilities.
If developmental delays are apparent in the early years, early intervention is appropriate and may enhance the child's developing abilities. The possibility of hearing problems should be investigated early. Speech and Language therapy should be considered when articulation is an area of concern. Special Education services will be needed in some cases.
As with any child, assessment of strengths and weaknesses must be performed on an individualized basis and decisions made on the basis of each child's unique pattern of strengths and needs.
Infancy:
Failure to thrive is noted in 40%, motor delays in 26%.
Childhood:
Learning disability with specific visual-constructual problems, and verbal performance discrepancy (15%). Language delay (29%) may be secondary to perceptual motor disabilities, mild hearing loss (12%), or articulation abnormalities (72%). IQ ranges between 64 and 127 with a median of 102. One study indicated IQ scores of children with Noonan syndrome were, on average, 10 points below that of unaffected family members. Mild mental retardation is seen in up to 35% of cases.
RESOURCES References and Recommended Reading (*)
* Allanson, J.E., Hall, J.G., Hughes, H.E., Preus, M. and Witt, R.D.
(1985). Noonan Syndrome: The Changing Phenotype. American Journal of Medical Genetics,
21:507-514.
Mendes, Heirie, M.M. and Opitz, John M. (1985). Noonan Syndrome: A Review. American
Journal of Medical Genetics 21:493-506.
Money, John, and Kalus, Morton E., Jr. (1979). Noonan's Syndrome: IQ and specific
disabilities. American Journal Disease Child, 133:846-850.
Hopkins-Acos, P. and Bunker K. (1979). A child with Noonan syndrome. Journal Speech
Hearing Disorders 44:494-503.
* Saul R.A. et al (1988). Growth References from Conception to Adulthood. Proceedings of
the Greenwood Genetic Center, Supplement 1, 194-195.
Wilson, M. and Dyson, A. (1982). Noonan's syndrome: Speech and language characteristics.
Journal Communication Disorders, 15:347-352.
Written by John B. Moeschler, M.D. and Elizabeth D. Gibbs, Ph.D. of the Information and
Resource Project, Clinical Genetics and Child Development Center, Dartmouth Medical
School, and reviewed by John M. Graham, Jr., M.D. Sc.D., Cedars-Sinai Medical Center, UCLA
School of Medicine, Los Angeles, CA.
Supported by grants from the Office of Special Education Programs, Department of
Education, Washington, D.C. and the Jessie B. Cox Charitable Trust.
The Noonan Syndrome Support Group, Inc. and any associated parties will not be held responsible for any actions readers take based on their interpretation of published or disseminated material. Please review medical treatment and decisions with your physician.