What Are Some of the Common Overgrowth Syndromes?

Patient Presentation
A 2-month-old male came to clinic for his health supervision visit.
The parents were concerned because they had noted a small red spot on his arm that was growing over the past month.
He was otherwise well.
The past medical history and review of systems were non-contributory.
The family history was positive for a paternal cousin that died late in-utero, another cousin who had an omphalocoele repaired as a newborn, atopic dermatitis, heart disease and stroke.
The pertinent physical exam showed a smiley infant with growth parameters in the 50-90% and he was tracking along these percentiles.
His skin examination showed a 0.5 cm superficial hemangioma on his right upper arm. There were no underlying vascular structures detected on palpation or transillumination.
Limb size was grossly symmetric. He had some minor dry skin on his flexural creases but the rest of his examination was normal.
The diagnosis of a healthy infant with a superficial infantile hemangioma was made. The parents were counseled regarding the natural history and when to return.
They were also instructed to use emollients for his dry skin.
When the resident physician was discussing the patient with the attending physician, they talked about what aspects of a vascular lesion would cause concern and warrant further workup.
Discrepant limb size was discussed as a cause for concern which lead to a conversation on overgrowth syndromes.
Although they knew this patient did not have an overgrowth syndrome, the resident and attending physicians used the Online Mendelian Inheritance in Man genetic library from the National Library of Medicine to look up the latest information about Klippel-Trenaunay-Weber and also Beckwith-Wiedemann syndrome as there was a family history of omphalocoele.

Discussion
Infantile hemangiomas are common skin conditions that parents often bring to attention because they develop after the birth of the child.
Usually they have a benign course with increased growth up until about 1 year of age (but sometimes longer), and then recede.
The hemangiomas are usually gone by 5 years but can take up to 9 years to resolve.
They usually are 0.5-5 cm, well-circumscribed, nearly flat, and mostly telangiectatic.

About 50-60% resolve incompletely leaving telangiectasia, superficial vein dilation, stippled scarring and other abnormalities.
Generally they are benign but may cause problems because of location (i.e. eyelid blocking vision, high trauma location causing repetitive bleeding) or because they grow so fast that they bleed frequently.
Treatment for problem hemangiomas is by laser surgery or surgical excision in consultation with a dermatologist and/or surgeon.
Examination of the lesion should determine if it is a simple infantile hemangioma or if there are other vascular elements present such as a venous or lymphatic malformation.
While these lesions may still have a benign natural history, they usually should be evaluated by a dermatologist and monitored more closely as they may need further evaluation and treatment.

Online Mendelian Inheritance in Man from the National Library of Medicine at the National Institutes of Health and is a comprehensive genetic library that is free to use and continually updated.
It is available at http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim.

Learning Point
Overgrowth syndromes are a heterogeneous group of conditions clinically and genetically. Patients may be large at birth or have excessive growth postnatally.
The overgrowth may be localized or generalized. Some syndromes are associated with an increased risk for malignancies and some also have mental retardation.
Some syndromes have vascular malformations causing the hypertrophy. Although the gene locus is noted below, new studies are finding common mutations between some of these syndromes.

Some common overgrowth syndromes:

  • Associated with Chromosome 5
    • Parkes Weber syndrome
      • Clinical features include multiple micro arteriovenous malformations under the skin resulting in a cutaneous flush with soft tissue and skeletal hypertrophy of the affected limb.
      • Gene locus 5q13.3

    • Soto Syndrome
      • Clinical features include characteristic facial features (i.e. high broad forehead, long narrow face, down-slanting palpebral fissures, prominent jaw, sparse front-temporal hair, malar flushing), macrocephaly, and mental retardation. Head circumference, length or both are generally in the 98% or greater.
      • Associated with childhood tumors
      • Gene locus 5q35

    • Weaver Syndrome
      • Clinical features include accelerated growth and bone maturation, unusual craniofacial appearance, unusual cry (i.e. hoarse and low-pitched), hypertonia, mental retardation, looseness of skin with finger deformities, and hernias.
      • Gene locus 5q35
  • Associated with Chromosome 8
    • Klippel-Trenaunay-Weber Syndrome
      • Clinical features are large cutaneous hemangiomata with hypertrophy of the related bones and soft tissues.
      • Gene locus 8q22.3
  • Associated with Chromosome 10
    • Bannayan-Riley-Ruvalcaba Syndrome
      • Clinical features include macrocephaly, pseudopapilledema, and multiple hemangiomata, lipomas or similar dermatological problems.
      • Gene map locus 10q23.31

    • Proteus Syndrome
      • Clinical features are highly variable including asymmetric and disproportionate overgrowth of one or more body regions, vascular malformations, nevi and abnormal adipose tissue.
      • Gene locus 10q23.31
  • Associated with Chromosome 11
    • Beckwith-Wiedemann Syndrome
      • Clinical features are exomphalos, macroglossia, and gigantism. Hypoglycemia often occurs in the first few days of life also.
      • It is associated with childhood cancers.
      • Most cases are sporadic.
      • Gene locus 11p15.5,5q35

    • Hemihyperplasia, isolated
      • Previously called hemihypertrophy
      • Clinical features: caused by abnormal cell proliferation that causes asymmetric overgrowth of one or more regions of the body.
      • Incidence is estimated at 1:86,000.
      • It is associated with childhood cancers.
      • Gene locus 11p15

    • Silver-Russell Syndrome
      • Clinical features are characteristic facial features (i.e. triangular shaped face with a broad forehead and pointed, small chin with a wide, thin mouth), growth retardation (i.e. short stature, low birth weight, intrauterine growth retardation), hemihyperplasia
      • Gene locus 11p15.5, 7p11.2

    • WAGR Syndrome
      • Clinical features are Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation. Hemihypertrophy is also common.
      • Gene map locus 11p13

Questions for Further Discussion
1. What aspects of a vascular lesion would cause concern and warrant further workup?
2. What screening evaluation should be done for patients with overgrowth syndromes associated with malignancies?
3. What genetic counseling should be offered to families of patients with overgrowth syndromes?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at MedlinePlus for these topics: Benign Tumors and Birth Defects.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

National Library of Medicine. Online Mendelian Inheritance in Man.

Enjolras O, Chapot R, Merland JJ. Vascular Anomalies and the Growth of Limbs: a Review. J. Pediatric Orthopaedics 2004;13:349-357.

Cytrynbaum CS, Smith AC, Rubin T, Weksberg R. Advances in Overgrowth Syndromes: Clinical Classification to Molecular Delineation in Sotos Syndrome and Beckwith-Wiedemann Syndrome. Curr Opin Pediatr. 2005;17:740-746.

Antaya, RJ. Infantile Hemangioma. eMedicine
Available from the Internet at http://www.emedicine.com/derm/topic201.htm (rev. 3/29/07, cited 1/14/08).

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    6. Information technology to support patient care decisions and patient education is used.
    8. Health care services aimed at preventing health problems or maintaining health are provided.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    12. Evidence from scientific studies related to the patients’ health problems is located, appraised and assimilated.
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.

    15. Information technology to manage information, access on-line medical information and support the healthcare professional’s own education is used.
    16. Learning of students and other health care professionals is facilitated.

  • Interpersonal and Communication Skills
    19. The health professional works effectively with others as a member or leader of a health care team or other professional group.

  • Professionalism
    20. Respect, compassion, and integrity; a responsiveness to the needs of patients and society that supercedes self-interest; accountability to patients, society, and the profession; and a commitment to excellence and on-going professional development are demonstrated.

    Author
    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital

    Date
    February 18, 2008