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Noonan syndrome

Noonan Syndrome (NS) is a relatively common congenital genetic condition which affects both males and females. The principal features include congenital heart malformation, short stature, learning problems, indentation of the chest, impaired blood clotting, and a characteristic configuration of facial features. NS is one of the most common conditions associated with congenital heart anomalies, especially those of the right heart. The syndrome is named after Dr Jacqueline Noonan, a paediatric cardiologist based in Kentucky. more...

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Noonan syndrome
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It is believed that 1 in 1,000 to 1 in 2,500 children worldwide are born with Noonan syndrome. It is one of the most common genetic syndromes associated with congenital heart malformations, similar in frequency to Down syndrome. However, the features can vary greatly in patients with NS, thus diagnosis can often be delayed.


Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. A clearly affected person had up to a 50% chance of transmitting it to a child. The fact that affected parents cannot be identified for many children with Noonan syndrome suggests that (1) a parent could carry the gene without being affected, (2) that manifestations were variably expressed and could be so subtle as to go unrecognized, (3) that a high proportion of cases represented new, sporadic mutations, or (4) that Noonan syndrome is heterogeneous, comprised of more than one similar condition of differing cause, some not inherited.

In most of the families with multiple affected members, Noonan syndrome mapped to chromosome 12q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2 (Tartaglia M, et al. Nature Genetics 2001;29:465-468). The protein SHP-2 is a component of several intracellular signal transduction systems involved in embryonic development that modulate cell division,differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves.

Noonan syndrome has been assigned OMIM number 163950 .

Manifestations by organ system

The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.

HEART(2/3 of patients have a heart defect)

Pulmonary Valvular Stenosis(50%)
Septal defects: atrial —(10%) or ventricular —(less common)
Heart murmur


Failure to thrive as an infant
Decreased appetite
Faddy eater
Digestive/Intestinal problems
Frequent or forceful vomiting
Swallowing difficulties


Cryptorchidism (undescended testicles)(almost all males)


Posterior cervical Hygroma (webbed neck)
Lymphedema (build-up of body fluid due to poor functioning of the lymphatic system)



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Turner's syndrome mosaicism in patients with a normal blood lymphocyte karyotype
From British Medical Journal, 3/27/99 by Cristina Azcona

Most doctors believe that a normal blood lymphocyte karyotype excludes the diagnosis of Turner's syndrome. However, there are patients whose dysmorphic features strongly suggest Turner's syndrome, but whose lymphocyte karyotype is normal. In the past, these patients have probably been labelled inappropriately as having Noonan's syndrome. In a girl with some of the clinical features of Turner's syndrome--growth failure,[1] gonadal dysfunction, cardiovascular abnormalities, renal anomalies, a webbed or short neck, or both, cubitus valgus, and nail dysplasia,[2 3]--it is important to make an accurate diagnosis. Turner's syndrome has serious sequelae throughout life--especially with regard to hypertension, oestrogen replacement, infertility, and skeletal integrity.

Case reports

We describe four patients who had features of Turner's syndrome (see table), but whose lymphocyte karyotype was normal. All had more than just short stature. The patients in cases 1, 3, and 4 had other clinical features of Turner's syndrome, while the girl in case 2 had no dysmorphic features but a pattern of growth failure typical of Turner's syndrome. The girls subsequently underwent skin biopsy for fibroblast culture and chromosome analysis. In one patient (case 3), an initial lymphocyte karyotype was reported as normal (46, XX), but a second investigation showed 2 out of 100 cells had a 45, XO Turner's syndrome karyotype after the analysis of skin fibroblasts.

Clinical features and skin fibroblast karyotype in four girls with suspected Turner's syndrome and normal lymphocyte karyotype


Clinical features of Turner's syndrome in patients with a normal lymphocyte karyotype point to the necessity of assessing the karyotype in other tissues, notably the skin. A skin biopsy for fibroblast analysis is quick and easy to perform, and leaves only a small scar. We diagnosed Turner's syndrome in four girls who had a normal lymphocyte karyotype, but in whom chromosomal analysis of skin fibroblasts showed Turner's mosaicism. The discrepancies between the blood and skin karyotypes found in our patients mean that previous cases of Turner's syndrome have been undiagnosed or misdiagnosed.

We suggest that in some cases of Turner's syndrome the abnormal cell lines die out in the bone marrow, thereby leaving the 46, XX cell line. This phenomenon may be explained by the rapid cell turnover in the bone marrow. It is well known that the distribution of the constituent karyotype in tissues differs in patients with a mosaic chromosome complement However, restriction of monosomy X to specific tissues such as skin,[4 5] endometrium,[5] and ovary[6] is unusual.

Turner's syndrome is believed to occur in 1 per 2500 liveborn girls, and in approximately one third of cases analysis shows mosaics on the lymphocyte karyotype.[7] Normal lymphocyte karyotypes with chromosomal aberrations in skin fibroblast cultures have probably been observed in some cytogenetic laboratories, but have rarely been reported. Thus, doctors may be unaware of the indications for chromosomal analysis of a second tissue in some patients.

Although rare, mosaicism limited to certain tissues has been described previously in disorders such as trisomy 21,[8 9] trisomy 8 mosaicism,[10] and triploidy.[11] The factors influencing survival of an aneuploid cell line in given tissues are unknown, as are the mechanisms by which mosaicism occurs. Several observations in vivo[12 13] and in trisomy 8 mosaicism[10] suggest that aneuploid cell lines may be lost over time in lymphocytes of people who have persistent euploid/ aneuploid mosaicism in skin fibroblasts. Our observations contradict the assumption that the determination of blood karyotype is an absolute test, and the principles we have described may well be applicable to other chromosomal disorders.

Turner's syndrome should be suspected in any girl with two or more of the clinical features of that disorder. For example, growth failure in a girl with short stature or primary ovarian failure or osteoporosis in a short woman are indications for skin karyotype determination if the blood chromosome complement is normal. In conclusion, we believe that Turner's syndrome is such an important diagnosis that some patients with a normal lymphocyte karyotype warrant cytogenetic evaluation of a second tissue, usually the skin, when this diagnosis is strongly suspected.

Contributors: RS coordinated the study and had the original idea for performing skin biopsies in girls when there was suspicion of Turner's syndrome; he is guarantor for the paper. CA and PB collected the data and wrote the manuscript.

Funding: CA was funded by the Fundacion Ramon Areces, Spain. PB was funded by the Child Growth Foundation. We are grateful to Serono (UK) for secretarial support.

[1] Lyon A, Preece M, Grant D. Growth curve for girls with Turner syndrome. Arch Dis Child 1985;60:932.

[2] Ulrich O. Turner's syndrome and status Bonnevie-Ulrich. Am J Hum Genet 1949;1:179.

[3] Turner H. A syndrome of infantilism, congenital webbed neck and cubitus valgus. Endocrinology 1938;23:566.

[4] Pagon R, Hall J, Davenport S, Aase J, Norwood T, Hoehn H. Abnormal skin fibroblasts cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes. Am J Hum Genet 1979;31:54-61.

[5] Kava H, Klinger H. Secondary infertility in a phenotypically normal 45,X/46XX female. Fertil Steril 1968;19:835-9.

[6] Goldstein D, Kelly T, Johanson A, Blizzard R. Gonadal dysgenesis with 45,X0/46,XX mosaicism demonstrated only in streak gonad. J Pediatr 1977;90:604-5.

[7] Smith DW. Recognizable patterns of human malformation. 3rd ed. Philadelphia: Saunders, 1982:46-51.

[8] Richards B. Mosaic mongolism. J Ment Defic Res 1969;13:66-83.

[9] Ladda R, Maisels M, Dosset J, Dobelle Y. Chromosomal mosaicism in Down's syndrome. A diagnostic challenge. J Genet Hum 1973;21:215-22.

[10] Schinzel A, Biro Z, Schmid W, Hayashi K. Trisomy 8 mosaicism syndrome. Helv Paediatr Acta 1974;29:531-40.

[11] Ferrier P, Ferrier S, Stalder G, Bithler E, Bamatter F, Klein D. Congenital asymmetry associated with diploid-triploid mosaicism and large satellites. Lancet 1964;i:80-2.

[12] Atkins L, Sceery R, Kennan M. An unstable ring chromosome in a female infant with hypotonia, seizures and retarded development. J Med Genet 1966;3:134-8.

[13] Porter I, Brown C, Gergosian L, Paul B. Evidence of selection in mosaicism.J Med Genet 1969;6:310-3.

(Accepted 26 June 1998)

A normal blood karyotype does not exclude the diagnosis of Turner's syndrome

Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children and Middlesex Hospital (UCLH), London WC1N 8AA

Cristina Azcona, research fellow

Philippe Bareille, research fellow

Richard Stanhope, consultant

Correspondence to: Dr Stanhope r.stanhope@

BMJ 1999;318:856-7

COPYRIGHT 1999 British Medical Association
COPYRIGHT 2000 Gale Group

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