Developmental Disorders of the Lymphatics

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Saturday, May 27, 2006

Noonan Syndrome - Part Three


Normal allelic variants: Tartaglia et al (2001) identified the PTPN11 gene as causative of Noonan syndrome. The gene comprises 15 exons, with two tandemly arranged SRC-2 homology 2 (SH2) domains at the N terminus (N-SH2 and C-SH2), a single catalytic protein tyrosine phosphatase (PTP) domain, and a carbody tail with two TP sites and a proline-rich stretch. The SH2-PTP interaction maintains TP sites and a proline-rich stretch. The SH2-PTP interaction maintains the protein in an inactive state.

Pathologic allelic variants: Missense mutations in PTPN11 were identified in 50% of individuals examined. Ninety-five percent of mutations alter residues at or close to the SH2-PTP interacting surfaces, which are involved in switching between active and inactive conformations of the protein and cause catalytic activation and gain of function. Five percent of the mutations alter sensitivity to activation from binding partners. One 3-bp deletion has been described [
Tartaglia et al 2002; Fragale et al 2004].

Normal gene product: PTPN11 encodes tyrosine-protein phosphatase non-receptor type II (SHP-2), a widely expressed extra-cellular protein. The protein is a key molecule in the cellular response to growth factors, hormones, cytokines and cell adhesion molecules. It is required in several intracellular signal transduction pathways that control diverse developmental processes (including cardiac semilunar valvulogenesis and blood cell progenitor commitment and differentiation) and has a role in modulating cellular proliferation, differentiation, migration, and apoptosis [Tartaglia et al 2002, Fragale et al 2004].

Abnormal gene product: Activation of tyrosine-protein phosphatase non-receptor type II stimulates epidermal growth factor-mediated RAS/ERK/MAPK activation, increasing cell proliferation [
Tartaglia et al 2002, Fragale et al 2004].


Normal allelic variants: The gene has four exons spanning 45 kb. Alternative splicing results in two isoforms (4a and 4b) that differ at the C terminus. In 98% of transcripts, exon 4a is spliced out and only exon 4b is available for translation into protein. The effector or switch domains are part of exons 1 and 2, while binding to guanine nucleotide exchange factors occurs in exon 3.

Pathologic allelic variants: Somatic KRAS and NRAS mutations have been found in myeloid malignancies and other cancers. The association between abnormal Kras and Noonan syndrome is the first evidence of a role in embryonic development. These gain-of-function mutations confer similar biochemical and cellular phenotypes as Noonan syndrome-associated SHP-2 mutations.

Normal gene product: Ras proteins regulate cell fates by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. They are key regulators of the RAS-RAF-MEK-ERK pathway, which is important for proliferation, growth and death of cells.

Abnormal gene product: The abnormal K-Ras protein induces hypersensitivity of primary hematopoietic progenitor cells to growth factors and deregulates signal transduction in a cell lineage-specific manner. Strong gain-of-function KRAS mutations may be incompatible with life.

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

National Library of Medicine Genetics Home Reference
Noonan syndrome

The Noonan Syndrome Support Group
PO Box 145 Upperco, MD 21155
Phone: 888-686-2224; 410-374-5245

Human Growth Foundation
997 Glen Cove Avenue Suite 5
Glen Head NY 11545
Phone: 800-451-6434 Fax: 516-671-4055

The MAGIC Foundation
6645 West North Avenue
Oak Park, IL 60302
Phone: 800-362-4423; 708-383-0808 Fax: 708-383-0899


Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.

Published Statements and Policies Regarding Genetic Testing
No specific guidelines regarding genetic testing for this disorder have been developed.
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Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002. 39:571-4. (PubMed)
Menashe M, Arbel R, Raveh D, Achiron R, Yagel S. Poor prenatal detection rate of cardiac anomalies in Noonan syndrome. Ultrasound Obstet Gynecol. 2002. 19:51-5. (PubMed)
Mendez HM and Opitz JM. Noonan syndrome: a review. Am J Med Genet. 1985. 21:493-506. (PubMed)
Niihori T, Aoki Y, Ohashi H, Kurosawa K, Kondoh T, Ishikiriyama S, Kawame H, Kamasaki H, Yamanaka T, Takada F, et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J Hum Genet. 2005. 50:192-202. (PubMed)
Noonan JA. Cardiac findings in cardio-facio-cutaneous syndrome: similarities to Noonan and Costello syndromes. Proc Greenwood Gen Ctr . 2001. (PubMed)
Noonan JA, Raaijmakers R, Hall BD. Adult height in Noonan syndrome. Am J Med Genet A. 2003. 123:68-71. (PubMed)
Ogawa M, Moriya N, Ikeda H, Tanae A, Tanaka T, Ohyama K, Mori O, Yazawa T, Fujita K, Seino Y, et al. Clinical evaluation of recombinant human growth hormone in Noonan syndrome. Endocr J. 2004. 51:61-8. (PubMed) Patton MA. Noonan syndrome: a review. Growth, Genetics and Hormones. 1994. 10:1-3. (PubMed)
Pierini DO and Pierini AM. Keratosis pilaris atrophicans faciei (ulerythema ophryogenes): a cutaneous marker in the Noonan syndrome. Br J Dermatol. 1979. 100:409-16. (PubMed)
Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Santa Cruz M, McCormick F, Rauen KA. Germline Mutations in Genes within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome. Science. 2006. 311:1287-90. (PubMed)
Sarkozy A, Obregon MG, Conti E, Esposito G, Mingarelli R, Pizzuti A, Dallapiccola B. A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet. 2004. 12:1069-72. (PubMed)
Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006. 38:331-6. (PubMed)
Sharland M, Burch M, McKenna WM, Paton MA. A clinical study of Noonan syndrome. Arch Dis Child. 1992. 67:178-83. (PubMed)
Sharland M, Patton MA, Talbot S, Chitolie A, Bevan DH. Coagulation-factor deficiencies and abnormal bleeding in Noonan's syndrome. Lancet. 1992. 339:19-21. (PubMed)
Tartaglia M, Cordeddu V, Chang H, Shaw A, Kalidas K, Crosby A, Patton MA, Sorcini M, van der Burgt I, Jeffery S, et al. Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Am J Hum Genet. 2004. 75:492-7. (PubMed)
Tartaglia M, Cotter PD, Zampino G, Gelb BD, Rauen KA. Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes. Clin Genet. 2003. 63:423-6. (PubMed)
Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002. 70:1555-63. (PubMed)
Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood. 2004. 104:307-13. (PubMed)
Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt I, Palleschi A, Petrucci TC, et al. Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease. Am J Hum Genet. 2006. 78:279-90. (PubMed)
Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001. 29:465-8. (PubMed)
Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003. 34:148-50. (PubMed)
Tofil NM, Winkler MK, Watts RG, Noonan J. The use of recombinant factor VIIa in a patient with Noonan syndrome and life-threatening bleeding. Pediatr Crit Care Med. 2005. 6:352-4. (PubMed)
Troger B, Kutsche K, Bolz H, Luttgen S, Gal A, Almassy Z, Caliebe A, Freisinger P, Hobbiebrunken E, Morlot M, et al. No mutation in the gene for Noonan syndrome, PTPN11, in 18 patients with Costello syndrome. Am J Med Genet. 2003. 121A:82-4. (PubMed)
van der Burgt I, Thoonen G, Roosenboom N, Assman-Hulsmans C, Gabreels F, Otten B, Brunner HG. Patterns of cognitive functioning in school-aged children with Noonan syndrome associated with variability in phenotypic expression. J Pediatr. 1999. 135:707-13. (PubMed)
Witt DR, Hoyme HE, Zonana J, Manchester DK, Fryns JP, Stevenson JG, Curry CJ, Hall JG. Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet. 1987. 27:841-56. (PubMed)
Witt DR, Keena BA, Hall JG, Allanson JE. Growth curves for height in Noonan syndrome. Clin Genet. 1986. 30:150-3. (PubMed)
Witt DR, McGillivray BC, Allanson JE, Hughes HE, Hathaway WE, Zipursky A, Hall JG. Bleeding diathesis in Noonan syndrome: a common association. Am J Med Genet. 1988. 31:305-17. (PubMed)
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Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004. 144:368-74. (PubMed)

Chapter Notes

Revision History

16 May 2006 (cd) Revision: KRAS testing clinically available
1 May 2006 (ja) Revision: mutations in KRAS cause Noonan syndrome
9 March 2006 (me) Comprehensive update posted to live Web site
17 December 2003 (me) Comprehensive update posted to live Web site
15 November 2001 (me) Review posted to live Web site
2 August 2001 (ja) Original submission

Original Complete Article

Noonan Syndrome - Part Two

Genotype-Phenotype Correlations

PTPN11. Analysis of a large cohort of individuals with Noonan syndrome [Tartaglia et al 2001, Tartaglia et al 2002] has suggested that PTPN11 mutations are more likely to be found when pulmonary stenosis is present, whereas hypertrophic cardiomyopathy is less prevalent among individuals with Noonan syndrome caused by PTPN11 abnormalities.

Additional cohort analyses have linked PTPN11 mutations to short stature, pectus deformity, easy bruising, characteristic facial appearance [Zenker et al 2004], and cryptorchidism [Jongmans et al 2004].

The likelihood of developmental delay does not differ in mutation-positive and -negative groups, although individuals with the N308D mutation are said to be more likely to receive normal education [Jongmans et al 2004].

Mutations at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis, and identify a subgroup of individuals with Noonan syndrome at risk for JMML [Niihori et al 2005].

Knowledge of the postreceptor signalling defect causing mild growth hormone resistance in individuals with Noonan syndrome and a PTPN11 mutation [Binder et al 2005] might suggest reduced efficacy of growth hormone treatment in mutation-positive individuals. One published study supports this hypothesis [Ferreira et al 2005].

KRAS. No data are currently available as too few cases have been reported.


Penetrance of Noonan syndrome is difficult to determine because of ascertainment bias and variable expressivity with frequent subtlety of features. Many affected adults are only diagnosed after the birth of a more obviously affected infant.


Anticipation has not been described in Noonan syndrome.


An early term for Noonan syndrome, "male Turner syndrome," implied that the condition would not be found in females.

Ullrich, in 1949, reported a series of affected individuals and noted a similarity between their features and those in a strain of mice bred by Bonnevie (webbed neck and lymphedema). The term Bonnevie-Ullrich syndrome became popular, particularly in Europe.


Noonan syndrome is common, and reported to occur in between one in 1,000 and one in 2,500 persons. Mild expression is likely to be overlooked.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Turner syndrome, found only in females, is differentiated from NS by demonstration of a sex chromosome abnormality on cytogenetic studies in individuals with Turner syndrome. The phenotype of Turner syndrome is actually quite different, when one considers face, heart, development, and kidneys. In Turner syndrome, renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule.

The Watson syndrome phenotype also overlaps with that of Neurofibromatosis type 1 and the two are now known to be allelic. Like Noonan syndrome, features of Watson syndrome include short stature, pulmonary valve stenosis, variable intellectual development, and skin pigment changes, such as café au lait patches [
Allanson et al 1991].

Cardiofaciocutaneous (CFC) syndrome and Noonan syndrome have the greatest overlap in features. CFC syndrome has similar cardiac and lymphatic findings [Noonan 2001]. In CFC syndrome, mental deficiency is usually more severe, with a higher likelihood of structural central nervous system anomalies; skin pathology is more florid; gastrointestinal problems are more severe and long lasting; and bleeding diathesis is rare. Facial appearance tends to be more coarse, dolichocephaly and absent eyebrows are more frequently seen, and blue eyes are less commonly seen. CFC syndrome occurs sporadically. PTPN11 mutations were not found in a cohort of 28 affected individuals [Ion et al 2002].

Recently, Rodriguez-Viciana et al (2006) studied 23 individuals with CFC syndrome and demonstrated mutations in three genes in the MAPK pathway. In the majority (18 of 23) a BRAF mutation was found, while more rarely a mutation in MEK1 or MEK2 was found.

Costello syndrome shares features with both NS and CFC [Noonan, personal observations]. Two series of individuals with Costello syndrome have been studied molecularly and no PTPN11 mutation has been identified [Tartaglia, Cotter et al 2003; Troger et al 2003]. Recently, germline mutations occurring exclusively in exon 2 of the HRAS proto-oncogene have been shown to cause Costello syndrome [
Aoki et al 2005].

Other. NS should be distinguished from other syndromes with developmental delay, short stature, congenital heart defects, and distinctive facies, especially Williams syndrome, Aarskog syndrome, and in utero exposure to alcohol or primidone.


Evaluations at Initial Diagnosis to Establish the Extent of Disease

At the time of initial diagnosis of NS, a series of evaluations is recommended to appropriately guide medical management:

Complete physical and neurologic examination
Plotting of growth parameters on NS growth charts [
Witt et al 1986]
Cardiologic evaluation with echocardiography and electrocardiography
Ophthalmologic evaluation
Hearing evaluation
Coagulation screen
Renal ultrasound examination with urinalysis if the urinary tract is anomalous
Clinical and radiographic assessment of spine and rib cage
Brain and cervical spine MRI, if neurologic symptoms are present
Multidisciplinary developmental evaluation
Genetics consultation

Treatment of Manifestations

Treatment of cardiovascular anomalies is generally the same as in the general population.

Any developmental disability should be addressed by early intervention programs and individualized education strategies.

The bleeding diathesis in Noonan syndrome can have a variety of causes. Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Factor VIIa has been successfully used to control bleeding caused by hemophilia, von Willebrand disease, thrombocytopenia, and thrombasthenia. It has also been used in an infant with Noonan syndrome whose platelet count and prothrombin and partial thromboplastin times were normal to control severe post-operative blood loss resulting from gastritis [Tofil et al 2005].

Results of growth hormone (GH) treatment studies from the US, UK and Japan [
Ogawa et al 2004] and aggregated European data are expected shortly. Data show that growth velocity increases with GH treatment, at least over the first three years, with maximum gain in the first year or two. Only a small number of study participants have reached final adult height. In some individuals, bone age appeared to advance disproportionately, but this phenomenon is not unique to treatment of Noonan syndrome. No abnormal impact on ventricular wall size was noted. As a result of these studies, enthusiasm for GH treatment is considerable in the US while in other countries such treatment is not initiated without a documented deficiency of GH (see review of treatment in Allanson 2005). Dutch data [K Noordam, personal communication] suggest a 1.3 standard deviation gain in final height (7 cm), leading endocrinologists in Holland to reserve use of growth hormone for affected individuals whose expected final height would be less than the mean for Noonan syndrome.


If anomalies are found in any system, periodic follow-up should be planned and lifelong monitoring may be necessary, especially of cardiovascular abnormalities.

Agents/Circumstances to Avoid

Aspirin therapy should be avoided.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Noonan syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Many affected individuals have de novo mutations; however, an affected parent is recognized in 30-75% of families [Mendez & Opitz 1985, Allanson 1987]. In simplex cases (i.e., those with no known family history), paternal origin of the mutation has been found universally to date [Tartaglia, Cordeddu et al 2004]. In this cohort, advanced paternal age was observed along with a significant sex-ratio bias favoring transmission to males, which is thus far unexplained.

It is appropriate to evaluate both parents, including a thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and review of photographs of the face at all ages, searching for characteristic features of NS. Molecular genetic testing of parents is available on a clinical basis if the proband has an identified disease-causing mutation.

Sibs of a proband

The risk to the sibs of a proband depends upon the genetic status of the parents.

If a parent is affected or has the disease-causing mutation that was identified in the proband, the risk to the sibs is 50%.

When the parents are clinically unaffected and do not have the disease-causing mutation found in the proband, the risk to the sibs of a proband appears to be low (less than 1%). No instances of germline mosaicism have been reported, although it remains a possibility.

Offspring of a proband. Each child of an individual with NS has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

High-risk pregnancy

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk for Noonan syndrome caused by a PTPN11 mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. No laboratories offering molecular genetic testing for prenatal diagnosis of Noonan syndrome caused by a KRAS mutation are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing.

Ultrasound examination. For pregnancies at 50% risk, high-resolution ultrasound examination is also available. A common prenatal indicator of NS, caused by lymphatic dysfunction or abnormality, is a cystic hygroma, which may be accompanied by scalp edema, polyhydramnios, pleural and pericardial effusions, ascites, and/or frank hydrops fetalis. The presence of these findings should suggest the diagnosis of NS. In addition, a search for a cardiac defect should be made, although a recent study has pointed out how infrequently such a defect will be detected prenatally [Menashe et al 2002].

Low-risk pregnancy. Although the ultrasonographic findings described above suggest the diagnosis of Noonan syndrome in high-risk pregnancies, they are nonspecific and may be associated with cardiovascular defects or other chromosomal and non-chromosomal syndromes.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Table A. Molecular Genetics of Noonan Syndrome
Gene Symbol
Chromosomal Locus
Protein Name

GTPase KRas

Tyrosine-protein phosphatase non-receptor type 11

Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.

Table B. OMIM Entries for Noonan Syndrome




Table C. Genomic Databases for Noonan Syndrome

Gene Symbol
Entrez Gene

3845 (MIM No. 190070)


5781 (MIM No. 163950)

For a description of the genomic databases listed, click here.

Complete Article

Saturday, May 20, 2006

Noonan Syndrome - Part One

Judith E Allanson, MD
Department of Genetics Children's Hospital of Eastern Ottawa

View this article on the GeneTests Web site.Summary

Disease characteristics. Noonan syndrome (NS) is characterized by short stature; congenital heart defect; broad or webbed neck; unusual chest shape with superior pectus carinatum, inferior pectus excavatum, and apparently low-set nipples; developmental delay of variable degree; cryptorchidism; and characteristic facies. Varied coagulation defects and lymphatic dysplasias are frequently observed. Congenital heart disease occurs in 50-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20-50% of individuals. Hypertrophic cardiomyopathy, found in 20-30% of individuals, may be present at birth or appear in infancy or childhood. Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Length at birth is usually normal. Final adult height approaches the lower limit of normal. Mild mental retardation is seen in up to one-third of individuals. Ocular abnormalities, including strabismus, refractive errors, amblyopia, and nystagmus, occur in up to 95% of individuals.

Diagnosis/testing. Diagnosis of NS is made on clinical grounds, by observation of key features. Affected individuals have normal chromosome studies. PTPN11 and KRAS are the only genes known to be associated with Noonan syndrome. Molecular genetic testing identifies mutations in the PTPN11 gene in 50% of affected individuals and is available on a clinical basis. Molecular testing of the KRAS gene is available on a research basis only.

Management. Treatment of cardiovascular anomalies in NS is generally the same as in the general population. Developmental disabilities are addressed by early intervention programs and individualized education strategies. The bleeding diathesis in NS can have a variety of causes and the specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Growth velocity increases with growth hormone (GH) treatment. Surveillance includes monitoring of anomalies found in any system, especially cardiovascular abnormalities.

Genetic counseling. NS is inherited in an autosomal dominant manner. Many affected individuals have de novo mutations; however, an affected parent is recognized in 30-75% of families. The risk to the sibs of a proband depends upon the genetic status of the parents. If a parent is affected, the risk is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%).>DiagnosisClinical Diagnosis
Diagnosis of Noonan syndrome (NS) is made on clinical grounds, by observation of key features. Despite a lack of defined diagnostic criteria, the cardinal features of NS are well delineated [
Allanson 1987]:

Short stature
Congenital heart defect
Broad or webbed neck
Unusual chest shape with superior pectus carinatum, inferior pectus excavatum
Apparently low-set nipples
Developmental delay of variable degree
Cryptorchidism in males

Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in the newborn period and middle childhood, and most subtle in the adult [
Allanson et al 1985]. Key features found irrespective of age include low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irides; and eyes that are often wide-spaced, with epicanthal folds and thick or droopy eyelids.


Varied coagulation defects. Coagulation screens such as prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time often show abnormalities. Specific testing should identify the particular coagulation defect. Laboratory findings include von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction.
Lymphatic dysplasias

Molecular Genetic Testing

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Genes. Two genes are known to be associated with Noonan syndrome:

PTPN11mutations are observed in about 50% of individuals with Noonan syndrome.
KRASmutations are observed in about 5-10% of individuals with Noonan syndrome who do not have mutations in PTPN11 [
Schubbert et al 2006].

Other loci. Absence of linkage to 12q in some families from the original report suggested locus heterogeneity. It is unclear whether any of these families may have had KRAS mutations. It is presumed that additional loci may be identified.

Molecular genetic testing: Clinical uses

Confirmatory diagnostic testing
Prenatal diagnosis

Molecular genetic testing: Clinical methods

Sequence analysis. Sequence analysis of all exons of PTPN11 detects missense mutations in about 50% of individuals tested [Tartaglia et al 2001,Tartaglia et al 2002,Jongmans et al 2004].

Molecular genetic testing: Research. Isolation of genomic DNA and direct, bidirectional sequencing of all exons of KRAS detects mutations in 5-10% of individuals with Noonan syndrome who lack mutations in PTPN11 [Schubbert et al 2006].

Genetically Related (Allelic) Disorders


LEOPARD syndrome (lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness) is an autosomal dominant condition with variable expression. It shows significant overlap with Noonan syndrome, in which pigmentary differences such as nevi (25%), café au lait patches (10%), and lentigines (3%) are reported. Recently, mutations in exons 7 and 12 of PTPN11 have been reported in LEOPARD syndrome [Digilio et al 2002,Legius et al 2002]. These reports suggest that Noonan syndrome and LEOPARD syndrome are allelic conditions, or that a particular genotype-phenotype correlation exists with certain mutations in PTPN11 leading to the pigmentary changes observed. It is interesting to note that some families with LEOPARD syndrome show no PTPN11 mutation or linkage to chromosome 12q; thus this condition, like Noonan syndrome, is genetically heterogeneous.

Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) constitutes one-third of childhood cases of myelodysplastic syndrome (MDS) and about 2% of leukemia. Mutations in NRAS, KRAS2, and NF1 have been shown to deregulate the RAS/MAPK pathway leading to JMML in about 40% of cases. Recently, somatic mutations in exons 3 and 13 of PTPN11 have been demonstrated in 34% of a cohort of individuals with JMML [Tartaglia, Niemeyer et al 2003]. Mutations in exon 3 were also found in 19% of children with MDS with an excess of blast cells, which often evolves into acute myeloid leukemia (AML) and is associated with poor prognosis. Nonsyndromic AML, especially the monocyte subtype FAB-MD, has been shown to be caused by PTPN11 mutations. All of these mutations cause gain of function in tyrosine-protein phosphatase non-receptor type II (SHP-2), likely leading to an early initiating lesion in JMML oncogenesis with increased cell proliferation attributable, in part, to prolonged activation of the RAS/MAPK pathway.

More recently, the spectrum of leukemogenesis associated with PTPN11 mutations has been extended to include childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 8% of B-cell precursor ALL cases, but not among children with T-lineage ALL [Tartaglia, Martinelli et al 2004]. Additionally,
Bentires-Alj and colleagues (2004) have described SHP-2-activating PTPN11 mutations in solid tumors such as breast, lung, and gastric neoplasms, and neuroblastoma.

Noonan-like/multiple giant-cell lesion syndrome is said to be characterized by some cardinal features of Noonan syndrome in association with giant cell lesions of bone and soft tissues (cherubism). PTPN11 mutations have been described in both familial and simplex (i.e., a single occurrence in a family) cases.

Sarkozy et al (2004) reported a girl whose early phenotype was typical of Noonan syndrome, but who, over time, developed the hearing loss and lentigines characteristic of LEOPARD syndrome. Thus, Noonan-like/multiple giant-cell lesion syndrome may be too limited and inaccurate a term; a variety of PTPN11 mutations, some of them programming the phenotype of Noonan syndrome and others the phenotype of LEOPARD syndrome, may also program the development of giant cell lesions.

One family with Noonan-like/multiple giant-cell lesion syndrome has a PTPN11 mutation that has been reported in Noonan syndrome without giant cell lesions [Tartaglia et al 2002]. Thus, additional genetic factors may be necessary for the giant cell proliferation to occur.

KRAS. Mutations in KRAS are rarely associated with cardio-facial-cutaneous syndrome (see Differential Diagnosis).

Clinical Description

Natural History

Facial features. Differences in facial appearance, albeit subtle at certain ages, are a key clinical feature.

In the neonate, tall forehead, hypertelorism with downslanting palpebral fissures, low-set, posteriorly rotated ears with a thickened helix, a deeply grooved philtrum with high, wide peaks to the vermillion border of the upper lip, and a short neck with excess nuchal skin and low posterior hairline are found.

In infancy, eyes are prominent, with horizontal fissures, hypertelorism, and thickened or ptotic lids. The nose has a depressed root, wide base, and bulbous tip.

In childhood, facial appearance is often lacking in affect or expression, resembling an individual with a myopathy.

By adolescence, facial shape is an inverted triangle, wide at the forehead, tapering to a pointed chin. Eyes are less prominent, and features are sharper. The neck lengthens, accentuating skin webbing or prominence of the trapezius muscle.

In the older adult, nasolabial folds are prominent, and the skin appears transparent and wrinkled.

Cardiovascular. Significant bias in the frequency of congenital heart disease may exist because many clinicians require the presence of cardiac anomalies for diagnosis of NS. The frequency of congenital heart disease is estimated to be between 50% and 80% [Allanson 1987, Patton 1994]. An electrocardiographic abnormality is documented in about 90% of individuals with NS [Sharland, Burch et al 1992], and may be present without concomitant structural defects.

Pulmonary valve stenosis, often with dysplasia, is the most common anomaly in NS, found in 20-50% of affected individuals [Allanson 1987; Sharland, Burch et al 1992; Ishizawa et al 1996]; it may be isolated or associated with other cardiovascular defects.

Hypertrophic cardiomyopathy is found in 20% to 30% of affected individuals [Allanson 1987; Sharland, Burch et al 1992; Patton 1994; Ishizawa et al 1996]. It may present at birth, in infancy, or in childhood.

Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot [Allanson 1987, Ishizawa et al 1996]. Coarctation of the aorta is more common than previously thought [ Digilio et al 1998].

Growth. Birth weight is usually normal, although edema may cause a transient increase [Allanson 1987, Patton 1994]. Infants with NS frequently have feeding difficulties [Sharland, Burch et al 1992]. This period of failure to thrive is self limited, although poor weight gain may persist for up to 18 months.

Length at birth is usually normal. Mean height follows the third centile until puberty, when below-average growth velocity and attenuated adolescent growth spurt tend to occur. As bone maturity is usually delayed, prolonged growth potential into the 20s is possible [Allanson 1987; Sharland, Burch et al 1992]. Final adult height approaches the lower limit of normal: 161 cm in males and 150-152 cm in females [ Witt et al 1986]. Growth curves have been developed from these cross-sectional retrospective data [ Witt et al 1986]. A recent study suggests that 30% of affected individuals have height within the normal adult range, while more than 50% of females and nearly 40% of males have an adult height below the third centile [Noonan et al 2003].

Decreased IGF1 and IGF-binding-protein-3, together with low responses to provocation, suggest impaired growth hormone release, or disturbance of the growth hormone/insulin-like growth factor axis, in some affected persons. Mild growth hormone resistance related to a postreceptor signalling defect, which may be partially compensated for by elevated growth hormone secretion, is reported in individuals with Noonan syndrome and a PTPN11 mutation [Binder et al 2005].

Psychomotor development. Early developmental milestones may be delayed, likely as a result, in part, of the combination of joint hyperextensibility and hypotonia.

Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [
Lee et al 2005] and 10% to 15% require special education [Sharland, Burch et al 1992; van der Burgt et al 1999]. Mild mental retardation is observed in up to one-third of individuals [Mendez & Opitz 1985,
Allanson 1987]. Verbal performance is frequently lower than nonverbal performance. There may be a specific cognitive disability, either in verbal or praxic reasoning, requiring a special academic strategy and school placement.

Articulation deficiency is common (72%) but usually responds well to intervention therapy. Language delay may be related to hearing loss, perceptual motor disabilities, or articulation deficiencies [
Allanson 1987].

No particular syndrome of behavioral disability or psychopathology is observed and self-esteem is comparable to age-related peers [Lee et al 2005].

Ocular. Ocular abnormalities occur in up to 95% of individuals. They include strabismus, refractive errors, amblyopia, and nystagmus. Anterior segment and fundus changes are less frequent [
Lee et al 1992; Sharland, Burch et al 1992].

Bleeding diathesis. Most persons with NS have a history of abnormal bleeding or bruising [Sharland, Patton et al 1992]. About one-third of all individuals with NS have one or more coagulation defects [Witt et al 1988]. The coagulopathy may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences.

Lymphatic. Varied lymphatic abnormalities are described in individuals with NS [
Mendez & Opitz 1985, Witt et al 1987]. They may be localized or widespread, prenatal and/or postnatal. Dorsal limb (top of the foot and back of the hand) lymphedema is most common. Less common findings include intestinal, pulmonary, or testicular lymphangiectasia; chylous effusions of the pleural space and/or peritoneum; and localized lymphedema of the scrotum or vulva.

Prenatal features suggestive of Noonan syndrome, likely of a lymphatic nature, include transient or persistent cystic hygroma, polyhydramnios and, rarely, hydrops fetalis [Gandhi et al 2004, Yoshida et al 2004, Joo et al 2005].

Genitourinary. Renal abnormalities, generally mild, are present in 11% of individuals with NS. Dilatation of the renal pelvis is most common. Duplex collecting systems, minor rotational anomalies, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, unilateral renal ectopia, and bilateral cysts with scarring are reported less commonly [George et al 1993].

Male pubertal development and subsequent fertility may be normal, delayed, or inadequate [
Mendez & Opitz 1985; Sharland, Burch et al 1992]. Deficient spermatogenesis may be related to cryptorchidism, which is noted in 60% to 80% of males [Patton 1994, personal data].

Puberty may be delayed in females, with a mean age at menarche of 14.6±1.17 years [
Sharland, Burch et al 1992]. Normal fertility is the rule.

Dermatologic. Skin differences, particularly follicular keratosis over extensor surfaces and face, are relatively common and may occasionally be as severe as those found in cardio-facio-cutaneous syndrome (see Differential Diagnosis) [Pierini & Pierini 1979; Sharland, Burch et al 1992].

Scalp hair may be curly, thick, and wooly, or sparse and poor growing with easy breakage.

Café-au-lait spots and lentigines are described in NS more frequently than in the general population [
Allanson 1987; Sharland, Burch et al 1992] (see LEOPARD syndrome discussion in Genetically Related (Allelic) Disorders).


Arnold-Chiari I malformation has been reported several times [Holder-Espinasse & Winter 2003] and the author is aware of at least three other individuals with this anomaly [author, personal observation].

Hepatosplenomegaly is frequent; the cause is unknown [Sharland, Burch et al 1992] but may be related to subclinical myelodysplasia.

Juvenile myelomonocytic leukemia (JMML) is often caused by somatic mutations in PTPN11 (see Genetically Related Disorders) [Tartaglia, Niemeyer et al 2003; Tartaglia, Martinelli et al 2004]. Additionally, individuals with Noonan syndrome and a germline mutation in PTPN11 have a predisposition to this unusual childhood leukemia. In general, JMML in Noonan syndrome runs a more benign course, a finding that may be related to the higher gain-of-function effect of somatic mutations leading to leukemogenesis [Tartaglia et al 2006].

Myeloproliferative disorders, either transient or more fulminant, can also occur in infants with Noonan syndrome [Kratz et al 2005].

Complete Article

Saturday, May 13, 2006

Swyer syndrome


Alternative titles; symbols


Gene map locus Xp22.11-p21.2



Gonadal dysgenesis, XY female type, is associated with point mutations or deletions of the SRY gene (480000), but also in some cases with changes in the X chromosome.

At birth the patients with the XY female type of gonadal dysgenesis (Swyer syndrome) appear to be normal females; however, they do not develop secondary sexual characteristics at puberty, do not menstruate, and have 'streak gonads.' They are chromatin negative and have a 46,XY karyotype.


Affected sisters were reported by Cohen and Shaw (1965), and twins by Frasier et al. (1964). Sternberg et al. (1968) observed 3 cases, each in a different sibship of a family connected through normal females (proposita, maternal cousin, and maternal aunt). A high incidence of neoplasia (gonadoblastomas and germinomas) in streak gonads of patients with the XY karyotype was claimed by Taylor et al. (1966).

Patients are of normal stature and have no somatic stigmata of Turner syndrome except, of course, the lack of secondary sexual characteristics and streak gonads. In this condition, as in the testicular feminization syndrome (300068), it was at first unclear whether the gene that was responsible was on the X chromosome or on an autosome and expressed only in chromosomal males. Whether the abnormal gene directly suppresses testis-determining loci on the chromosome or blocks some early stage of testicular morphogenesis was also unknown. The sisters reported by Cohen and Shaw (1965) had a marker autosome, which was present also in the mother. They referred to another instance of XY 'sisters' with an abnormal autosome. One of their 2 patients had gonadoblastoma.

Two sisters reported by Fine et al. (1962) were of normal stature but were chromatin negative. One of these cases and 1 of those reported by Baron et al. (1962) had gonadoblastoma. In the last family, 2 'females' and a male were affected, the male showing no testes. All 3 sibs were sex-chromatin negative. Barr et al. (1967) reported on a sibship containing 2 genetic males. The first, who had male pseudohermaphroditism, was reared as a female; he developed signs of masculinization at puberty and had undescended but otherwise normal testes and small fallopian tubes. The second genetic male (180 cm tall) had pure gonadal dysgenesis with small uterus and streak gonads. This patient was at first thought to have the testicular feminization syndrome. An unaffected sister had a son with perineal hypospadias (urethral orifice at the base of the penis). The sibship reported by Chemke et al. (1970) was similar to that of Barr et al. (1967). Espiner et al. (1970) described 5 XY females in 3 sibships of 2 generations. They emphasized that the affected persons were unusually tall for females. The height of patients with XY gonadal dysgenesis (unusually great for females) is probably explained by androgen production in the streak gonad (Rose et al., 1974). Clitoromegaly is present in some cases.

Rushton (1979) pointed out that the streak gonads of this disorder differ from those of the 45,X Turner syndrome in the presence of calcification and the increased hazard of gonadoblastoma. Comparative studies of the frequency of gonadoblastoma in Turner mosaics with normal or rearranged Y chromosomes have suggested that the integrity of the Y chromosome, and in particular the presence of the distal fluorescent band Yqh, is required in these mosaics for the tumor to develop; no cases with distal deletions of the fluorescent band on Yq had been reported (Lukusa et al., 1986).

Moreira-Filho et al. (1979) suggested that there are 3 forms of Swyer syndrome (defined as streak gonads without other somatic features of the Turner syndrome and with a normal 46,XY karyotype). (1) Sporadic testicular agenesis syndrome (STAS) corresponds to H-Y negative Swyer syndrome. (2) Familial testicular agenesis syndrome (FTAS) is H-Y negative Swyer syndrome showing an X-linked recessive pedigree pattern. The mutation is probably homologous to that of the wood lemming. The phenotype of STAS and FTAS is identical even though the mutation is probably on the Y in STAS and on the X in FTAS. (3) In familial testicular dysgenesis syndrome (FTDS), the patients are H-Y positive and have a female phenotype and streak gonads; the streak gonads may contain testis-like tumoral structures. (See report of 3 sisters by Moreira-Filho et al. (1979) and cases of Wolf (1979).) The XY gonadal agenesis syndrome is a separate disorder (see 273250).

Passarge and Wolf (1981) pointed out that there are 2 groups of patients with XY gonadal dysgenesis (Swyer syndrome) and that each of these may be heterogeneous. One group is the H-Y antigen-positive form, which may represent a 'receptor disease.' The second is the H-Y antigen-negative form, which may be due to mutation in the H-Y generating system, either of the structural gene (presumably autosomal) or of a controlling gene (on the sex chromosomes). It may be only the H-Y antigen-positive cases that are at risk for gonadoblastoma or dysgerminoma.
See 233300 for discussion of the XX type of gonadal dysgenesis.


Simpson et al. (1981) reported 3 pedigrees of XY gonadal dysgenesis consistent with X-linked inheritance.
German et al. (1978) suggested that there is a gene on the X chromosome that blocks the testis-determining function of H-Y (which was then a leading candidate for TDF, testis-determining factor). However, it was later shown that TDF and H-Y antigen map to different parts of the Y chromosome with TDF being absent and H-Y antigen being present in XY females with Y short arm deletions (Simpson et al., 1987). See 278850. It appeared that 46,XY women had premature ovarian involution, with resulting 'streak gonads.' Families such as that of Barr et al. (1967) described above may indicate that the mutation is 'leaky.' The pedigree pattern was equally consistent with X-linked recessive or autosomal dominant inheritance. Indeed, Allard et al. (1972) observed transmission through a normal male, arguing for autosomal inheritance.
Nazareth et al. (1979) found H-Y positivity in a sporadic case occurring in an offspring of first-cousin parents. They favored recessive inheritance; see 233420.


De Arce et al. (1992) contributed further support of this hypothesis by demonstrating lack of gonadoblastoma in a 14-year-old girl who was a mosaic for 45X/46X-isodicentric Y. The anomalous Y chromosome showed no fluorescent distal Yq. In another patient, an 8-year-old girl with 45X/46XY karyotype, bilateral gonadoblastoma developed in her rudimentary ovaries at the age of 8.

Her normal Y chromosome showed the characteristic distal fluorescence seen in her father's Y chromosome. Using Y chromosome probes, De Arce et al. (1992) demonstrated the Y chromosome in the paraffin blocks of the ovarian tissue of both girls.

Wachtel (1979) and Wachtel et al. (1980) suggested the existence of 4 'causes' of XY gonadal dysgenesis: (1) mutational suppression of H-Y structural genes by regulatory elements of the X chromosome or failure of an X-linked structural gene (in association with H-Y negative somatic cell phenotype); (2) failure of H-Y antigen to engage its gonadal receptor (in association with the H-Y positive somatic cell phenotype); (3) loss of the critical moiety of H-Y genes in deleted or translocated Y chromosome (in association with H-Y negative or intermediate somatic cell phenotype); and (4) presence of XY-XO mosaicism.

(Small deletions in the short arm of the Y chromosome can result in 46,XY females (Disteche et al., 1986). The 2 patients reported by Disteche et al. (1986) had some signs of Turner syndrome, including congenital lymphedema and primary amenorrhea with streak gonads, but were of normal height. One of the patients had bilateral gonadoblastoma. Several Y-chromosome-specific DNA probes were found to be deleted in the 2 patients. DNA analysis showed that the 2 deletions were different, but included a common overlapping region likely to contain the testis-determining factor (TDF) gene.)

Bernstein et al. (1980) observed an abnormal band on Xp in a 46,XY female and her 46,XY female fetal sib. Despite the presence of an intact Y chromosome, neither had testicular differentiation and both were H-Y negative. Giemsa banding suggested duplication of p21 and p22. The maternal grandmother, mother and a younger sister, all phenotypically normal, had a karyotype 46,XXp+. The proband had profound psychomotor retardation, and both sibs had multiple congenital malformations. (The second sib was ascertained by amniocentesis for prenatal diagnosis followed by elective abortion.) Multiple congenital anomalies in the proband included ventricular septal defect, cleft palate, asymmetric skull and facies, prognathic jaw, low-set ears, and clinodactyly V. When the girl died at 5 year of age, postmortem studies showed hypoplastic uterus and fallopian tubes. Histologic examination of the uterine adnexa revealed an area of ovarian stroma with scattered degenerative follicles. There was no testicular morphology, and the external genitalia were those of a normal 5-year-old female. The second affected sib, the product of a pregnancy terminated at 20 weeks, showed ovaries containing numerous follicles and germ cells.

As in the proband, there was no evidence of testicular morphology. Wachtel (1998) referred to other cases of XY sex reversal in subjects with Xp duplication and chromosomal abnormalities resembling those in the family reported by Bernstein et al. (1980). This suggested occurrence of a gene on Xp, duplication of which can block development of the testis in an XY fetus. The gonads begin to develop as ovaries, but in the absence of the second X chromosome, the germ cells die, the follicles become atretic, and the ovaries degenerate.
Cytogenetic duplication of the X chromosome in males is a rare event usually characterized by a significant degree of phenotypic abnormality, which can include sex reversal despite an apparently normal Y chromosome. Arn et al. (1994) reported 2 half brothers with maternally inherited cytogenetic duplications of Xp and sex reversal; the absence of dysmorphic features in mother and children was thought to be because of the relatively small extent of the duplication. Comparison with previous reports allowed the putative sex reversing locus (SRVX) to be assigned to a 5- to 10-Mb segment between Xp22.11 and Xp21.2, which includes the DMD locus. The regional assignment may help in the isolation of SRVX mutations that may cause sex reversal in the 90% of sex-reversed women with XY gonadal dysgenesis who do not have detectable mutations of the SRY gene.


Mapping studies by hybridization to DNA from somatic cell hybrids containing various fragments of the X chromosome suggested that the sequence on the X chromosome maps to region Xp22.3-p21 (Page et al., 1987). Arn et al. (1994) mapped the SRVX gene to a 5- to 10-Mb segment between Xp22.11 and Xp21.2, which includes the DMD locus.


Page et al. (1987) cloned a 230-kb segment of the human Y chromosome thought to contain some or all of the TDF gene. The cloned region spanned the deletion in a female who carried all but 160 kb of the Y. Homologous sequences were found within the sex-determining region of the mouse Y chromosome.
Jager et al. (1990) demonstrated a mutation in SRY in 1 out of 12 sex-reversed XY females with gonadal dysgenesis who had no large deletions of the short arm of the Y chromosome. They found a 4-nucleotide deletion in the part of the SRY gene that encodes a conserved DNA-binding motif. A frameshift presumably led to a nonfunctional protein. Mutation occurred de novo, because the father had a normal SRY sequence. This is strong evidence that SRY is TDF. The de novo G-to-A mutation led to a change from methionine to isoleucine at a residue that lies within the putative DNA-binding motif of SRY and is identical in all SRY and SRY-related genes. (TDF and SRY are written Tdy and Sry in the mouse.)


Vilain et al. (1992) described a family in which all 5 XY individuals in 2 generations had a single basepair substitution resulting in an amino acid change in the conserved domain of the SRY open reading frame (480000.0004). A G-to-C change at nucleotide 588 resulted in substitution of leucine for valine. Three of the individuals were XY sex-reversed females and 2 were XY males. One of the males had 8 children; all were phenotypic females, 2 of whom were sex-reversed XY females carrying the mutation mentioned. Several models were proposed to explain association between a sequence variant in SRY and 2 alternative sex phenotypes. These included the existence of alleles at an unlinked locus.

McElreavey et al. (1992) described an XY sex-reversed female with pure gonadal dysgenesis who harbored a de novo nonsense mutation in SRY, which resulted directly in the formation of a stop codon in the putative DNA-binding motif. A C-to-T transition at nucleotide 687 changed a glutamine codon (CAG) to a termination codon (TAG); see 480000.0005. The patient, referred to as the 'propositus,' was a phenotypic female who presented at age 20 years for primary amenorrhea. Treatment with estrogen induced menstruation and slight enlargement of the breasts which were underdeveloped. Laparotomy showed 2 streak gonads without germ cells or remnants of tubes.

Harley et al. (1992) found point mutations in the region of the SRY gene encoding the high mobility group (HMG) box in 5 XY females. (The HMG box is related to that present in the T-cell-specific, DNA binding protein TCF-1 (142410).) In 4 cases, the binding activity of mutant SRY protein for the AACAAAG core sequence was negligible; in the fifth case, DNA binding was reduced. In the SRY gene in a 46,XY female, Muller et al. (1992) demonstrated an A-to-T transversion of nucleotide 684 in the open reading frame, resulting in a change of lysine (AAG) to a stop codon (UAG). The patient had gonadoblastoma.


Page et al. (1987) advanced several hypotheses to explain the existence of the X-linked locus. One hypothesis was inconsistent with the prevailing notion of a dominantly acting sex-determining factor unique to the Y chromosome and suggested that the X and Y loci are functionally interchangeable, that both are testis determining, and that the X locus is subject to X-chromosome inactivation. According to this model, sex is determined by the total number of expressed X and Y loci: a single dose is female determining, while a double (or greater) dose is male determining. The addition of an X-derived transgene to the genome of an XX embryo should result in testis differentiation, as long as that transgene is not subject to X inactivation. Increased expression of the X-chromosomal locus could explain the presence of testicular tissue in XX hermaphrodites and the rare Y-negative XX males, who lack the TDF locus of the Y chromosome. Although some XY females lack TDF as judged by Y-DNA analysis, others do not have discernible deletions. These unexplained XY females may have point mutations in TDF or in genes that function in conjunction with or downstream of TDF. The model mentioned above suggests that mutation in the X-chromosomal locus (at Xp22.3-p21) could cause XY embryos to develop as females.

However, Berta et al. (1990) and Jager et al. (1990) presented compelling evidence that the mutation in one type of XY female gonadal dysgenesis is not on the X but on the Y chromosome. In the human sex-determining region in a 35-kb interval near the pseudoautosomal boundary of the Y chromosome, there is a candidate gene for testis-determining factor, termed SRY ('sex-reversed, Y,' from mouse terminology), which is conserved and specific to the Y chromosome in all mammals tested (Sinclair et al., 1990); see 480000. (Cherfas (1991) stated that SRY stands for 'sex-determining region Y.' This is a nice presumption and perhaps in its present usage should be so considered, but it does not indicate the true historical derivation.)


Moreira-Filho et al. (1979) suggested that the H-Y antigen status in the Swyer syndrome may be a useful indicator of whether removal of the gonads is necessary to avoid malignancy.


Boczkowski (1976); Ghosh et al. (1978); Herbst et al. (1978); Judd et al. (1970); Koopman et al. (1991); Koopman et al. (1990); Mann et al. (1983); Wolf et al. (1980)