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The Genome
CMECNE

Large NT but Normal Karyotype? Noonan Syndrome Basics

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Learning Objectives and CME/Disclosure Information

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. Recall why referring to Noonan syndrome as ‘Male Turner Syndrome’ is inappropriate
2. List the possible prenatal findings on ultrasound that are suggestive of Noonan syndrome

Estimated time to complete activity: 0.25 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires faculty, planners, and others in control of educational content to disclose all their financial relationships with ineligible companies. All identified conflicts of interest (COI) are thoroughly vetted and mitigated according to PIM policy. PIM is committed to providing its learners with high quality accredited continuing education activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.

The PIM planners and others have nothing to disclose. The OBG Project planners and others have nothing to disclose.

Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.

Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

Method of Participation and Request for Credit

Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from Dec 31 2017 through Jan 25 2023, participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the test and evaluation. Upon registering and successfully completing the test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.2 contact hours.

Read Disclaimer & Fine Print

WHAT IS IT?

Noonan syndrome is an autosomal dominant disorder that is multi-systemic and occurs and affects approximately 1 in 1,000 to 2,500 people.  In the past, it was also referred to, incorrectly, as ‘Male Turner Syndrome, ‘Female Pseudo-Turner Syndrome’ and ‘Turner Phenotype with Normal Karyotype’. Noonan syndrome is a distinct disorder that can affect both males and females.

Prenatal Detection and Management

Large NT  but normal karyotype (both standard karyotype and microarray will be normal)

  • NT ≥ 3 mm in the first trimester and normal karyotype may confer approximately 10% risk for Noonan syndrome
    • Consider molecular testing (gene sequencing)  for Noonan syndrome even without additional ultrasound findings as detailed anatomy scan may be limited in the first trimester
  • Associated prenatal sonographic anomalies that should raise suspicion:
    • Polyhydramnios
    • hydrops fetalis
    • renal anomalies
    • distended jugular lymphatic sacs
    • hydrothorax
    • cardiac anomalies
    • cystic hygroma
    • ascites
  • A larger NT is especially concerning, as median measurement is approximately 8 mm
  • Pathogenic variants associated with Noonan syndrome are too small to be detected with microarray
    • Gene sequencing of DNA derived from CVS or amniocentesis necessary

KEY CLINICAL FINDINGS:

Growth

  • Postnatal short stature (50 to 70%)
  • Failure to thrive in infancy

Facial features

  • Deep, prominent philtrum
  • Wide spaced eyes (usually blue or green)

Head & neck

  • High arched palate and poor tooth alignment
  • Micrognathia
  • Low-set ears
  • Short neck
  • Cystic Hygroma and/or Excess neck skin
  • NT and nuchal fold may both be increased

Cardiovascular – may have critical congenital heart disease

  • Pulmonic stenosis (20-50%)
  • Hypertrophic Cardiomyopathy (20-30%)
  • Atrial septal defects
  • Ventricular septal defects
  • Patent ductus arteriosus
  • Aortic coarctation
  • Lymphatic disorders

Chest

  • Pectus carinatum
  • Pectus excavatum
  • Shield chest

Genitourinary

  • Males: Delayed puberty and undescended testes (cryptorchidism) are common leading to infertility
  • Females: May have delayed puberty and fertility issues but uncommon

Neurologic

  • Intellectual abilities may be mildly lowered
  • Speech Delay
  • Learning disabilities (25%)
  • Visual abnormalities
  • Deafness

Bleeding disorders

  • Von Willebrand disease
  • Thrombocytopenia
  • Coagulopathies (factors V, VIII, XI, XII, protein C)
  • Platelet dysfunction

Neoplasia

  • May have eight-fold risk for malignancies, such as leukemia

KEY POINTS:

Genetics

  • Noonan syndrome is one of the RASopathies
  • RAS/MAPK pathway critical for cell division, proliferation, differentiation and migration
  • Pathogenic variants lead to gain of function – proteins remain inappropriately ‘turned on’
  • Autosomal dominant inheritance pattern
  • A pathogenic variant will be found in one of the parents in 30 – 75% of cases, with the remainder resulting from a spontaneous de novo mutation in the following genes:
    • PTPN11 gene (50%)
    • SOS1 (10 to 15 %)
    • RAF1 (5%)
    • RIT1 (5%)
    • KRAS (< 5%)
    • NRAS (limited reports)
    • BRAF (<2%)
    • MAP2K1 (<2%)
    • Unknown
  • Recurrence risk is 50% if a parent is found to have the variant
  • Recurrence risk is <1% if de novo mutation is present

Learn More – Primary Sources:

Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings

GeneReviews: Noonan Syndrome

Noonan Syndrome – Genetics Home Reference

Testing for Noonan Syndrome after Increased Nuchal Translucency

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist:

SMFM

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Related ObG Topics:

How Common is Noonan Syndrome When the NT is Large but Chromosomes Appear Normal?
SMFM Guidance – The Role of Prenatal Ultrasound and NIPT 
Practical obstetrics info for your women's healthcare practice
Cystic Hygroma: Definition, Genetics and Prognosis
Practical obstetrics info for your women's healthcare practice
Nuchal Translucency – First Trimester Measurement
Is There Value to an Early Anatomy Scan with an Enlarged NT?

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This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information
presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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