Noonan syndrome and related disorders

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Abstract

Noonan syndrome is a common multiple malformation syndrome seen in children with congenital heart disease. Recently, a mutation in the PTPN11 gene was found to be present in about 50% of individuals with Noonan syndrome. Over 80% of these patients have some form of congenital heart disease with pulmonary stenosis often associated with a dysplastic valve being, by far, the most common lesion. Hypertrophic cardiomyopathy occurs in 20–30%. Characteristic facies, chest deformity, short stature, undescended testes in the male and learning disabilities comprise the Noonan phenotype but there is wide phenotypic variation and a changing phenotype with age. This phenotype is noted in several other syndromes which share similar cardiac defects. These include LEOPARD, neurofibromatosis, Noonan syndrome, cardio-facio-cutaneous syndrome and Costello syndrome. A definitive diagnosis is particularly difficult in infancy.

Introduction

Noonan syndrome is one of the most common non-chromosomal syndromes seen in children with congenital heart disease [1]. Affected individuals have characteristic facies, are usually short, often have a chest deformity and the majority have some structural cardiac abnormality. Autosomal dominant inheritance has been well documented but many cases are sporadic. Until recently, the diagnosis rested solely on clinical findings but Tartaglia et al. in 2001 [2] found a mutation in the PTPN11 gene to be present in about 50% of individuals with Noonan syndrome. There are a number of syndromes which may be difficult to distinguish from Noonan syndrome, especially in infancy, and these will also be discussed. All these syndromes have a high incidence of some form of congenital heart disease. Pediatric cardiologists should be aware of the variable clinical picture and the characteristic cardiac findings.

Section snippets

Noonan syndrome

There is wide phenotypic variation in Noonan syndrome and the phenotype also changes with time. Distinctive facial features include hypertelorism, down-slanting palpebral fissures, a high arched palate, low set posteriorly rotated ears, malar hypoplasia, ptosis and often a short neck. In the newborn, Noonan syndrome is difficult to diagnose by facial appearance alone. The forehead is often sloping and broad and the ears may be thick and posteriorly angulated. A helpful sign, if present in the

LEOPARD syndrome

In 1969, Gorlin et al. [25] introduced the acronym, LEOPARD to describe the combination of multiple lentigines (L), ECG abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), abnormalities of the genitalia (A), retardation growth (R), and deafness (D). This rare syndrome shares many features similar to Noonan syndrome including autosomal dominant inheritance, similar facial dysmorphism and similar cardiac defect including pulmonary stenosis and hypertrophic cardiomyopathy. The

Neurofibromatosis-Noonan syndrome

In 1985, Allanson et al. [27] reported the association of a Noonan phenotype with neurofibromatosis. Recently, Cooley et al. [28] examined sequentially 94 patients with neurofibromatosis and found phenotypic features of Noonan syndrome in 12 patients. In a recent paper, Baralle et al. [29] identified six patients with neurofibromatosis-Noonan syndrome. He examined the neurofibromatosis type 1 (NF1) gene in these six patients and found several mutations. Four of these patients were studied for

Cardio-facio-cutaneous syndrome

It is difficult to distinguish an infant with cardio-facio-cutaneous syndrome from Noonan syndrome although, with time, the phenotype becomes more distinctive [30], [31]. Patients with cardio-facio-cutaneous syndrome have a high forehead, a relatively large head and bitemporal constriction. They often have a downward slant of the palpebral fissures, posteriorly rotated ears and a nasal bridge similar to Noonan syndrome. The hair is usually sparse, curly and friable. In addition, sparse or

Costello syndrome

Costello syndrome is another rare syndrome which may be difficult to distinguish from Noonan syndrome in infancy [33]. These patients have a large head, sparse curly hair, short wide nose, short neck, all similar to Noonan syndrome. Unlike Noonan syndrome, Costello syndrome patients usually have thick and relatively prominent lips and tongue. They also have loose skin on the hands and feet and deep palmer and plantar creases. In time, other findings appear such as nasal papillomata. There is a

Other conditions

Turner syndrome should be ruled out in female patients with suspected Noonan syndrome, especially those with left-sided lesions such as bicuspid aortic valve, aortic stenosis or coarctation of the aorta. I have never seen a patient with Turner syndrome who had valvar pulmonary stenosis. Individual patients with Williams syndrome may cause some confusion diagnostically but the phenotype is quite distinctive. Fetal alcohol syndrome should also be excluded as well as chromosomal abnormalities

Genotype–phenotype correlations

In 1994, Jamison et al. [35] studied a large three-generation family and 20 smaller two-generation families and mapped the gene for Noonan syndrome to the distal part of chromosome 12q (12q22-qter). Not all families with Noonan syndrome studied showed this linkage suggesting more than one gene was likely to be involved in the etiology of Noonan syndrome. In 2002, Tartaglia et al. [2] found a mutation in the PTPN11 gene to be present in about 50% of patients with Noonan syndrome. This gene

Conclusion

Pediatric cardiologists are often the first to see children with these syndromes. Referral to a geneticist is important but a firm clinical diagnosis is often not possible unless there is a specific diagnostic test available. Unfortunately, less than 50% of Noonan syndrome patients will have a positive test for the PTPN11 gene. No diagnostic test is yet available for cardio-facio-cutaneous, Costello or neurofibromatosis-Noonan syndromes. However, the cardiac diagnoses are remarkably similar for

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