PEDIATRICS Vol. 105 No. 3 March 2000, pp. 608-614

Use of the National Institutes of Health Criteria for Diagnosis of Neurofibromatosis 1 in Children

Kimberly DeBella, Jacek Szudek, and Jan Marshall Friedman, MD, PhD

From the Department of Medical Genetics, University of British Columbia, Vancouver, Canada.

	ABSTRACT

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Objective.  The National Institutes of Health (NIH) Diagnostic Criteria for neurofibromatosis 1 (NF1) are very useful clinically, but some individuals who are later shown to have NF1 cannot be diagnosed in early childhood using these criteria. The aim of this study is to determine the value of the NIH Diagnostic Criteria for NF1 in early childhood, to determine the age at which diagnosis can confidently be made, and to clarify the age at onset of the cardinal clinical features used in the NIH Diagnostic Criteria.

Methods.  We studied 1893 NF1 patients under 21 years old from the National Neurofibromatosis Foundation International Database to determine the age at which the features included in the NIH Diagnostic Criteria appear.

Results.  Approximately 46% of sporadic NF1 cases fail to meet the NIH Diagnostic Criteria by 1 year of age. Nearly all (97%; 95% confidence interval: 94-98) NF1 patients meet the criteria for diagnosis by 8 years old, and all do so by 20 years old. The usual order of appearance of the clinical features listed as NIH criteria is café-au-lait macules, axillary freckling, Lisch nodules, and neurofibromas. Symptomatic optic glioma is usually diagnosed by 3 years old, and characteristic osseous lesions are usually apparent within the first year of life.

Conclusion.  The diagnosis of NF1 cannot always be made in young children using the NIH Diagnostic Criteria. Modification of these criteria may be necessary for children under 8 years old.  Key words:  neurofibromatosis 1, National Institutes of Health Diagnostic Criteria, natural history.

Neurofibromatosis 1 (NF1) is a progressive multisystem disorder. This autosomal dominant disease affects between 1/2000 and 1/4500 people.^1,2 Half of all NF1 cases are familial, and half are caused by new mutations.^2-5 NF1 is diagnosed using a set of clinical criteria developed by a National Institutes of Health (NIH) Consensus Conference in 1988⁶ and recently reaffirmed by another group of experts.⁷ To meet the NIH Diagnostic Criteria for NF1, an individual must demonstrate at least 2 of the 7 features listed in Table 1.

The NIH Diagnostic Criteria for NF1 are thought to be very reliable in distinguishing adults with and without NF1 on the basis routine clinical and ophthalmological examinations.^7,8 The reliability of these criteria for diagnosing NF1 in children has not been rigorously assessed, but some NF1 patients clearly cannot be diagnosed in early childhood by the NIH Diagnostic Criteria.^9,10

Earlier diagnosis of NF1 may be beneficial to both affected children and their families. Genetic counseling could be offered to parents and other relatives earlier, and interventions for learning or developmental problems could be initiated sooner.¹¹ Diagnosis of NF1 may also be important to implement supportive care and to allow earlier detection of serious complications.

We used clinical information from the National Neurofibromatosis Foundation International Database¹² to assess the value of the NIH Diagnostic Criteria in children.

	METHODS

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Three groups of patients were selected from the National Neurofibromatosis Foundation International Database for study. The first group consisted of 1402 patients, including both probands and affected relatives, under 21 years old who were diagnosed as having NF1 by the NIH Diagnostic Criteria on their first visit to a participating neurofibromatosis clinic. Patients who had not received an ophthalmological examination with a slit lamp were excluded. For purposes of classifying café-au-lait spots, we defined prepubertal as <13 years old and postpubertal as 13 years or older. The number of cardinal clinical features that contribute to the NIH criteria present in each patient was determined and plotted against age in 3-year intervals.

A second study group consisted of 39 NF1 patients from the National Neurofibromatosis Foundation International Database who did not meet the NIH criteria for diagnosis on their first recorded examination but who did so on a subsequent examination. Only patients who were reexamined at periodic intervals of 4 years or less were included in this group.

Finally, we analyzed the age-specific prevalence rates for individual cardinal clinical features in each of 1893 NF1 patients under 21 years old who were diagnosed as having NF1 on their first examination at a participating neurofibromatosis clinic. This group of patients includes the 1402 patients in the first group as well as patients who met the NIH criteria for NF1 but who have not had a slit lamp examination. The total number of patients included for each cardinal clinical feature varies because we excluded cases in which the presence or absence of the particular feature could not be determined unequivocally from available data.

The 95% confidence intervals were calculated for all data using the method for proportions described by Zar.¹³ This method uses the relationship between an F distribution and a binomial distribution to compute a confidence interval for the binomial parameter.

	RESULTS

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The frequencies by age of 2, 3, 4, or 5 or more of the clinical features that comprise the NIH Diagnostic Criteria among 1402 patients with NF1 are shown in Fig 1. The patients in this analysis include both sporadic cases and those who have inherited an NF1 mutation from an affected parent. Some familial cases are included even if they only exhibit 1 cardinal clinical feature because the NIH Diagnostic Criteria permit a diagnosis of NF1 for patients who have 1 such feature and a positive family history.

View larger version (23K): [in this window] [in a new window]   Fig. 1.   Age-specific frequency of 2, 3, 4, or 5 or more clinical features included in the National Institutes of Health Diagnostic Criteria among 1402 NF1 patients under 21 years old (including 95% confidence intervals).

Almost all these NF1 patients (97%; 95% confidence interval: 94-98) have 2 or more of the cardinal clinical features included in the NIH Diagnostic Criteria by 8 years old. All the NF1 patients have 2 or more cardinal clinical features by 20 years old. In contrast, 30% of NF1 patients under 1 year of age have only 1 of the cardinal clinical features. These infants must all have an affected first degree relative to be diagnosed with NF1.

All the patients included in Fig 1 were diagnosed with NF1 on their first visit to a participating neurofibromatosis clinic. We also studied 39 NF1 patients with an average age of 1.6 years who did not meet the NIH Diagnostic Criteria on first examination but were diagnosed as having NF1 by these criteria at a later date. The ages of these patients when they were found to meet the NIH Diagnostic Criteria are shown in Fig 2. These patients were found to have at least 2 of the cardinal clinical features at an average of 4.6 years of age, with a maximum age of 19. These findings support our observation in Fig 1 that nearly all NF1 patients meet the NIH Diagnostic Criteria by 8 years old, and all patients do so by 20 years old.

View larger version (13K): [in this window] [in a new window]   Fig. 2.   Age at which 39 NF1 patients meet 2 or more National Institutes of Health Diagnostic Criteria.

The progressive nature of NF1 results in an increased frequency of many of the cardinal clinical features with age. To determine the usual sequence of appearance of the cardinal clinical features, we plotted the prevalence of each feature among 1893 NF1 patients (probands and affected relatives) under 21 years old. The ages at which these patients met the NIH criterion for café-au-lait macules is given in Fig 3, for neurofibromas in Fig 4, for inguinal or axillary freckling in Fig 5, for Lisch nodules in Fig 6, for optic glioma in Fig 7, and for distinctive osseous lesions in Fig 8.

View larger version (13K): [in this window] [in a new window]   Fig. 3.   Age at which 1888 NF1 patients have café-au-lait spots.

View larger version (13K): [in this window] [in a new window]   Fig. 4.   Age at which 1835 NF1 patients have inguinal or axillary freckling.

View larger version (13K): [in this window] [in a new window]   Fig. 5.   Age at which 1891 NF1 patients have 2 or more neurofibromas of any type or 1 plexiform neurofibroma.

View larger version (14K): [in this window] [in a new window]   Fig. 6.   Age at which 1402 NF1 patients have 2 or more Lisch nodules.

View larger version (13K): [in this window] [in a new window]   Fig. 7.   Age at which 1807 NF1 patients have symptomatic optic glioma.

View larger version (14K): [in this window] [in a new window]   Fig. 8.   Age at which 1722 NF1 patients have a distinctive osseous lesion.

Ninety-nine percent of NF1 patients have 6 or more café-au-lait macules greater than 5 mm in diameter by 1 year of age. Inguinal or axillary freckling affects a maximum of 90% of NF1 patients by 7 years old. Lisch nodules affect >70% of patients by 10 years old. Neurofibromas are present in 48% of 10-year-old patients and 84% of 20-year-old patients. Symptomatic optic glioma is diagnosed in the first year of life in 1% of NF1 patients and reaches maximum frequency (~4%) by 3 years old. Characteristic osseous lesions are usually apparent within the first year of life and occur in ~14% of NF1 patients.

	DISCUSSION

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The number of cardinal clinical features included in the NIH Diagnostic Criteria increases in NF1 patients with age. As shown in Fig 1, 70% of NF1 patients can be diagnosed as having the disease before they are 1 year old based on 2 or more of the cardinal clinical features. The other 30% of NF1 patients under 1 year of age have only 1 of the cardinal clinical features. These children must all have an affected first degree relative to be diagnosed with NF1 according to the NIH criteria. We would expect an equal number of sporadic cases to have only 1 cardinal feature by 1 year of age because approximately half of all NF1 patients represent sporadic cases.^2-4 These sporadic cases would not be diagnosed as having NF1 before 1 year of age because they do not meet the NIH Diagnostic Criteria.

If the total number of NF1 patients diagnosed by 1 year of age is N, the number of sporadic cases that remain undiagnosed by age 1 is .3 N. The total number of individuals with NF1 mutations at 1 year of age is (N + .3 N), half of whom represent sporadic cases. The proportion of sporadic NF1 cases that remain undiagnosed by 1 year of age is, therefore, From this, we estimate that ~46% of sporadic cases lack 2 or more of the cardinal clinical features and cannot be diagnosed by the NIH Diagnostic Criteria by 1 year of age. NF1 probably cannot be diagnosed using these criteria in at least 5% of the sporadic cases by 8 years old. All NF1 probands have at least 2 of the cardinal clinical features included in the NIH Diagnostic Criteria by 20 years old.

The age-specific prevalence rates of the individual cardinal clinical features that comprise the NIH Diagnostic Criteria are displayed in Figs 3 to 8. The usual order of appearance of these features is café-au-lait macules, axillary freckling, Lisch nodules, and neurofibromas. Optic glioma is usually diagnosed within the first 3 years of life, and characteristic osseous lesions within the first year.

Café-au-lait macules, which are present within the first year of life in most NF1 patients, are not likely to develop after 4 years old if not already present. Inguinal or axillary freckling is commonly present by 7 years old and does not usually develop after this age. Lisch nodules usually develop before 10 years of age. Neurofibromas are usually present by 20 years old if they are going to develop.

The frequencies of the individual cardinal clinical features seen in this study are similar to those previously reported.^1,3,14,15 The data used for these analyses are cross-sectional in nature and are, therefore, not ideal for examining progression of features. A more accurate representation of NF1 patients could be obtained from a large longitudinal study, but only limited longitudinal data are available.

The diagnosis of NF1 cannot always be made or ruled out with confidence in young children using the NIH Diagnostic Criteria. Diagnosis of NF1 can confidently be made using these criteria by 8 years old in most children and by 20 years old in all children. However, we recommend that young children who have 6 or more café-au-lait spots greater than 5 mm in largest diameter but do not have any of the other cardinal clinical features be followed as if they had NF1. Almost all these children will develop other clinical manifestations of NF1 with time.^9,10

Modification of the NIH Diagnostic Criteria may be necessary to provide more reliable diagnosis for young children. The inclusion of other clinical features that are both sensitive and specific for NF1 in pediatric patients may improve diagnosis. Short stature,¹⁶ macrocephaly,¹⁶ and unidentified bright objects on head magnetic resonance imaging^17-19 have been suggested as potentially useful in this regard. Routine radiographic screening for common osseous lesions, such as pseudarthrosis, sphenoid wing dysplasia, and dysplastic vertebrae, should also be considered. We are currently studying the value of adding these features to the NIH Diagnostic Criteria.

	ACKNOWLEDGMENTS

This work was supported in part by the Department of the Army, USAMRMC, Grant NF960003, the National Neurofibromatosis Foundation, and the British Columbia Neurofibromatosis Foundation.

We thank Patricia Birch for her contributions. Data for this study were contributed by the following National Neurofibromatosis Foundation International Database participants: Wylie Burke and Robin Bennett, University of Washington, Seattle; J. M. de Campos, Fundacion Jimenez Diaz, Madrid; J. M. Friedman and Patricia Birch, University of British Columbia; Bruce Korf, Boston Children's Hospital; Wilma Krause and Kim Uhas, Scottish Rite Children's Medical Center, Atlanta; Michihito Niimura and Yoshikata Inaba, Jikei University, Tokyo; Kathryn North, Children's Hospital, Sydney, Australia; June Ortenberg and Vazken Der Kaloustian, Montreal Children's Hospital; Minna Poyhonen, Oulu University Hospital, Finland; Allan Rubenstein, Mount Sinai Medical Center, New York; Priscilla Short and Kathleen Bové, Massachusetts General Hospital; Susan Stine and Linda Nicholson, Dupont Institute, Wilmington; Romano Tenconi, University of Padova, Italy; Elaine Zackai, Children's Hospital of Philadelphia, John Carey and David Viskochil, University of Utah Medical Center, Salt Lake City; Nikolay Bochkov, I. M. Sechenov Moscow Medical Academy, Russia; Elizabeth Schorry, Children's Hospital, Cincinnati; Sigrid Tinschert, Institut für Medizinische Genetik, Berlin; Thaddeus Kelly, University of Virginia Medical Center, Charolettesville; Jana Klein, Cedars-Sinai Medical Center, Los Angeles; Eniko Pivnick, Le Bonheur Children's Medical Center, Memphis; Alison Colley, Newcastle Western Suburbs Hospital, Australia; Marcus Schülke, Freien Universität Berlin; Mauro Signorini, Clinica Pediatrica dell Universita, Italy; Pierre Wolkenstein, Hopital Henri-Mondor, France; and Adrian Danek, Neurologische Universitaetsklinik, Muenchen, Germany.

	FOOTNOTES

Received for publication Feb 18, 1999; accepted Jun 14, 1999.

Reprint requests to (J.M.F.) University of British Columbia Department of Medical Genetics, 6174 University Blvd, Room 222, Vancouver, BC Canada V6T 1Z3. E-mail: frida{at}interchange.ubc.ca

	ABBREVIATIONS

NF1, neurofibromatosis 1; NIH, National Institutes of Health.

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