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Study examines challenges of diagnosing neurofibromatosis type 1–like syndrome

Date:
November 17, 2009
Source:
JAMA and Archives Journals
Summary:
An analysis of patients with a syndrome similar to the genetic disorder, neurofibromatosis type 1, indicates that diagnosis may be difficult because of shared clinical findings, such as certain pigmentary characteristics, according to a new study.

An analysis of patients with a syndrome similar to the genetic disorder, neurofibromatosis type 1, indicates that diagnosis may be difficult because of shared clinical findings, such as certain pigmentary characteristics, according to a study in the November 18 issue of JAMA.

Neurofibromatosis type 1 (NF1), an autosomal dominant disorder affecting approximately 1 in 3,000 individuals worldwide, is characterized by multiple café au lait macules (CALMs; small areas of discoloration of the skin [light-brown]), skin-fold freckling and tumors of the nervous system. Other frequently observed features are certain bone abnormalities, short stature, macrocephaly (an abnormally large head) and learning problems, according to background information in the article. NF1 diagnostic criteria were established by the National Institutes of Health (NIH) and are widely used to make the diagnosis using information obtained from physical examination, family history, and radiologic studies. A genetically distinct but similar disorder, caused by mutations of the gene SPRED1 was recently identified (and recently named Legius syndrome). The authors write that this disorder, characterized mainly with CALMs, axillary freckling and macrocephaly, may be underestimated.

Ludwine Messiaen, Ph.D., of the University of Alabama at Birmingham, and colleagues conducted a study to determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS; Legius syndrome). The study included 23 unrelated probands (first affected family member who seeks medical attention for a genetic disorder) carrying a SPRED1 mutation identified through clinical testing, who participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1,318 unrelated anonymous blood samples collected in 2003-2007 from patients with a broad range of signs typically found in NF1 but no detectable NF1 germline mutation underwent SPRED1 mutation analysis.

The researchers found that among 42 SPRED1-positive individuals from the clinical cohort, 20 (48 percent) fulfilled NIH NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. "None of the 42 SPRED1-positive individuals had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous [composed of or containing bone] lesions, or symptomatic optic pathway gliomas [brain tumors]," the researchers write.

"In the anonymous cohort of 1,318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73 percent) had an NF1 mutation and 18 (19 percent) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9 percent of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS."

"The dermatologic phenotype in young children with a SPRED1 mutation could not be differentiated from NF1 and nearly half of individuals (20/42) with a SPRED1 mutation fulfilled the NF1 diagnostic criteria based on presence of more than 5 CALMs with or without skinfold freckling and with or without familial history," they write.

The authors add that although an NF1 diagnosis may become apparent with the passage of time, the diagnosis will remain uncertain for individuals who do not develop other signs of NF1, and that molecular genetic testing can resolve the diagnosis in most such cases. "In case of diagnostic uncertainty, we recommend that NF1 should be analyzed first and, if negative, SPRED1 testing should be considered in patients with CALMs with or without freckling and no other NF1 diagnostic features. Identification of a SPRED1 mutation may relieve a psychological burden from families who otherwise would be in a waiting mode for potential serious NF1-associated manifestations."

"… it is important that clinicians, including general practitioners, clinical geneticists, pediatricians, ophthalmologists, dermatologists, neurologists, and oncologists, who are involved in the care, diagnosis, and treatment of individuals with NF1, should be aware that Legius syndrome can resemble NF1."

Editorial: Pigmentary Findings in Neurofibromatosis Type 1-like Syndrome -- Potential Diagnostic Dilemmas

In an accompanying editorial, David Stevenson, M.D., and David Viskochil, M.D., Ph.D., of the University of Utah, Salt Lake City, comment on the findings of this study.

"The study by Messiaen et al provides important information about Legius syndrome and enables clinicians to use good clinical judgment in situations where it is now realized that there is phenotypic overlap for distinct disorders. As new genes resulting in phenotypes similar to NF1 and Legius syndrome are discovered, clinicians must adapt diagnostic approaches and clinical management protocols to meet the needs of patients affected with these disorders."


Story Source:

The above story is based on materials provided by JAMA and Archives Journals. Note: Materials may be edited for content and length.


Journal References:

  1. Ludwine Messiaen; Suxia Yao; Hilde Brems; Tom Callens; Achara Sathienkijkanchai; Ellen Denayer; Emily Spencer; Pamela Arn; Dusica Babovic-Vuksanovic; Carolyn Bay; Gary Bobele; Bruce H. Cohen; Luis Escobar; Deborah Eunpu; Theresa Grebe; Robert Greenstein; Rachel Hachen; Mira Irons; David Kronn; Edmond Lemire; Kathleen Leppig; Cynthia Lim; Marie McDonald; Vinodh Narayanan; Amy Pearn; Robert Pedersen; Berkley Powell; Lawrence R. Shapiro; David Skidmore; David Tegay; Heidi Thiese; Elaine H. Zackai; Raymon Vijzelaar; Koji Taniguchi; Toranoshin Ayada; Fuyuki Okamoto; Akihiko Yoshimura; Annabel Parret; Bruce Korf; Eric Legius. Clinical and Mutational Spectrum of Neurofibromatosis Type 1-like Syndrome. JAMA, 2009; 302 (19): 2111-2118 [link]
  2. David Stevenson; David Viskochil. Pigmentary Findings in Neurofibromatosis Type 1-like Syndrome (Legius Syndrome): Potential Diagnostic Dilemmas. JAMA, 2009; 302 (19): 2150-2151 [link]

Cite This Page:

JAMA and Archives Journals. "Study examines challenges of diagnosing neurofibromatosis type 1–like syndrome." ScienceDaily. ScienceDaily, 17 November 2009. <www.sciencedaily.com/releases/2009/11/091117161015.htm>.
JAMA and Archives Journals. (2009, November 17). Study examines challenges of diagnosing neurofibromatosis type 1–like syndrome. ScienceDaily. Retrieved August 2, 2014 from www.sciencedaily.com/releases/2009/11/091117161015.htm
JAMA and Archives Journals. "Study examines challenges of diagnosing neurofibromatosis type 1–like syndrome." ScienceDaily. www.sciencedaily.com/releases/2009/11/091117161015.htm (accessed August 2, 2014).

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