Predictive Value of Café au Lait Macules at Initial Consultation in the Diagnosis of Neurofibromatosis Type 1

objective to evaluate the predictive utility of the number and morphological appearance of isolated café-au-lait macules (calma) to establish the diagnosis of neurofibromatosis type 1 (nf1) in a cohort of children referred to a clinic of subspecialty nf1.

design of a retrospective study of patients seen between 2004 and 2007.

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setting tertiary care neurofibromatosis referral clinic at children’s hospital of st louis.

Patients The study population comprised 110 patients who presented calm and no other diagnostic features of NF1. the median number of calms at initial presentation was 6, while the median age of patients was 33 months. the median age at last follow-up exam was 76.5 months.

main outcome measures number and morphological appearance of calms and diagnosis of nf1.

results thirty-four of the children met the diagnostic criteria for nf1 during the study period. thirty-two children met the criteria before 72 months and 2 children met the criteria after 72 months. The mean number of calms at presentation in children ultimately diagnosed with NF1 (11.8 calms) was significantly greater than the mean number of calms in children not diagnosed with NF1 (4.6 calms). Of the 44 children who had 6 or more typical calm at presentation, 34 children met the criteria for NF1. sixty-eight patients had calms described as ‘typical’, while 42 patients had ‘atypical’ calms. only 2 patients with atypical calm met criteria for nf1.

Conclusion Most patients with 6 or more calms will eventually meet the diagnostic criteria for NF1, typically by age 6 years, and this likelihood increases with increasing number and age. typical morphological appearance of calms.

Neurofibromatosis type 1 (NF1) is a common autosomal disorder that affects numerous organ systems, including the skin, eyes, bones, blood vessels, and central and peripheral nervous systems.1 The diagnosis of NF1 is established. when people have 2 or more of the following characteristics: 6 or more café-au-lait macules (calm); 2 or more neurofibromas of any type or 1 plexiform neurofibroma; freckles in the axillary or inguinal region; optic glioma; 2 or more lisch nodules; a distinctive bone lesion; and a first-degree relative with nf1.2 However, infants and young children most often exhibit only calm1,3-5 and cannot be diagnosed with nf1 until a second characteristic develops. Because the second defining disease manifestation of NF1, such as axillary freckles and neurofibromas, may not develop until later in childhood, it is not uncommon for children with multiple calms and no family history of NF1 to be followed up. for several years before diagnosis. from nf1 is confirmed or excluded. this presents a particular challenge for both the physician and the family and may limit adequate detection of serious problems seen in this young age group (eg, optic pathway glioma).

relatively little information is available about the natural history and diagnostic outcomes of children presenting with multiple calms alone. previous studies have shown that lonely calms are common and can occur in up to 3% of infants and 25% of healthy children.6,7 however, the presence of more than 3 calms is detected in only 0 .2% to 0.3% of children with no known evidence of an underlying disorder.6,8 Neurofibromatosis 1 is the most common condition associated with multiple calms. Multiple calms can also be seen in mccune-albright syndrome, ring chromosome syndromes, watson syndrome, and bloom syndrome, but these conditions are much less prevalent than nf1.9 a syndrome with similar phenotypic features to nf1, but caused by mutations in spred1, as well as an inherited form of multiple calms with no other characteristics of nf1, have also been described in the literature.10-13 To the best of our knowledge, the largest study to date examined 41 children with 6 or more calms .14 of these children, 80% were finally diagnosed with nf1 at the end of the study period. Although this study provided important information, it did not include children who had less than 6 calms at presentation and did not focus on the diagnostic utility of morphologic appearance or number of calms. Furthermore, this study did not address the probability of making the diagnosis of NF1 based on age or number of calms. In an effort to address these important clinical issues, we conducted a retrospective analysis of a large group of children who initially visited a tertiary referral neurofibromatosis subspecialty clinic between 2004 and 2007 with only calm and no other signs of NF1.

This study was conducted using a protocol approved by the Human Studies Committee at the University of Washington School of Medicine, St. Louis, Missouri. We reviewed the medical records of 191 patients with international classification of diseases, ninth revision (icd-9) code 709.09 (non-specific dyschromia) who were seen by a single doctor ( d.h.g.) in the neurofibromatosis clinic of a large tertiary care pediatric hospital (st. louis children’s hospital) between 2004 and 2007. this icd-9 code was the code regularly used to designate to patients who were calm and did not have a known diagnosis of nf1. Diagnosis of NF1 was established using criteria outlined by the National Institutes of Health Consensus Development Conference.2 All patients had a comprehensive evaluation including history and physical and neurologic examination by a single physician (D.H.G.). at the time of initial presentation to the NF1 clinic. in general, patients were followed up annually. patients were referred for an annual ophthalmologic evaluation with slit-lamp examination as part of routine care, beginning at 1 year of age. Patients were excluded from this study if they met the diagnostic criteria for NF1 at their first clinic visit, had a first-degree relative with NF1, had physical examination findings consistent with segmental NF1, were incorrectly coded as calm, or they had incomplete symptoms or unavailable medical records. data were collected from the time of initial presentation in our clinic to the time of the last follow-up examination. Demographic information and clinical features, including description of calms, date of NF1 diagnosis (if applicable), and timeline of development of additional NF1 features, were recorded for each patient.

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As in previous studies, “typical” calms were defined as lesions with uniform pigmentation and well-defined regular borders, while “atypical” or “irregular” calms were defined as lesions with irregular borders, blurring, or pigmentation. nonhomogeneous (figure 1) .15 patients were classified as having atypical calms if their lesions were described as atypical or irregular at the first clinic visit.

distributions of demographic and clinical characteristics among the 3 groups of patients (patients diagnosed with nf1 during the study period, patients with typical calm who did not meet the diagnostic criteria for nf1 at the end of the study, and patients with atypical calm who did not meet the diagnostic criteria for nf1 at study completion) were summarized using means, medians, or frequencies, as appropriate. For categorical characteristics such as gender or race, differences between groups were compared using Fisher’s exact test. For continuous characteristics, such as number of calms or age at presentation, comparison was made using the Kruskall-Wallis rank sum test. p < 0.05 was considered statistically significant and all statistical tests were two-tailed.

A total of 191 patients with an icd-9 code of 709.09 were seen at the nf clinic during the period of this study. Of these patients, 110 met the inclusion criteria for our study. there were 63 boys and 47 girls in our patient population (table). 24 of the children were African American, 63 white, 1 Asian, and 2 had no racial information available in their medical records. the median age at initial presentation to our clinic was 33 months (range, 1-206 months). the median age at last follow-up was 76.5 months (range, 4-206 months). no children were diagnosed with syndromes other than nf1. no child not diagnosed with typical calms had a family history of calms. an undiagnosed child with irregular calms had a parent with calms.

The median number of calms at presentation for all patients in the study was 6 (range, 1 to ≥20). thirty-four (31%) of the children met the criteria for the diagnosis of nf1 during the study period. The mean number of calms at initial presentation in children ultimately diagnosed with NF1 (11.8 calms; range, 6 to ≥20) was significantly higher than the mean number of calms in children who were not diagnosed with NF1 (4.6 calms. ; range, 1 to 12) during the study (p < .001).

the percentage of children diagnosed with nf1 increased with increasing number of calms at initial presentation (figure 2a). Of the 26 children who had 1 to 5 typical calms at initial presentation, none met the criteria for a diagnosis of NF1. Of the 44 children who had 6 or more typical calm at presentation, 34 (77%) met the criteria for a diagnosis of nf1 at the end of the study period.

Sixty-eight patients had calms described as typical, while 42 patients had atypical calms. of the 42 patients with atypical calms, 27 had 1 to 5 calms and 15 had 6 or more calms. Thirty-two typically calm patients met the criteria for a diagnosis of NF1 during the study period. Two patients with atypical calms, both with greater than 6 calms at initial presentation, met the criteria for a diagnosis of nf1 during the study period.

Mean age at diagnosis of nf1 was 33.5 months (range, 12-96 months). Twenty-six (76%) met the diagnostic criteria before 48 months, 32 (94%) met the diagnostic criteria before 72 months, and 2 (6%) met the diagnostic criteria after 72 months (Figure 2b). ) . Of the typically calm children who remained undiagnosed at the end of the study period, 62 (89%) were older than 48 months at last follow-up examination and 57 (81%) were older than 72 months at last follow-up. until the exam. Of the children with atypical calm who remained undiagnosed at the end of the study period, 33 (79%) were older than 48 months at their last follow-up exam and 25 (60%) were older than 72 months at their last follow-up exam.

There were no significant differences in gender (p = 0.61), race (p = 0.54), or mean age at last follow-up examination ( p = 0.31), but the age at presentation of the children in the diagnosed group was younger than that of the undiagnosed group (p < 0.001).

in children ultimately diagnosed with nf1, the second most common feature used to establish the diagnosis of nf1 was axillary or inguinal freckles, which occurred in 26 (77%) patients (figure 2c) . other signs that occurred as the second (confirmatory) diagnostic feature included the following: lisch nodules in 6 children, plexiform neurofibroma in 2 children, and tibial nonunion in 1 child. Following a diagnosis of NF1, children in this clinical population developed the following additional features of NF1 during the course of our study: 33 patients developed axillary or inguinal freckles, 15 developed lisch nodules, 8 developed neurofibromas, 4 developed skeletal abnormalities, 3 developed macrocephaly, 2 developed optic gliomas, 4 developed plexiform neurofibromas, 1 developed precocious puberty, and none developed malignant peripheral nerve sheath tumors or pheochromocytomas; 6 of 8 patients who underwent neuroimaging were found to have t2 hyperintensities on MRI.

Because of the association of calms with NF1, current guidelines support evaluation of children with multiple calms for this common genetic disorder.9,16,17 In some cases, the presence of other associated clinical findings or a positive family history of NF1 will allow a diagnosis of NF1 to be made at initial evaluation.18 However, a notable number of children will present to medical care only calmly and without other diagnostic features of NF1. Currently, there are few data to estimate the probability that a child exhibiting only calm will develop NF1. To better characterize the clinical course of these patients, we performed a retrospective analysis of children with calmness and no other diagnostic features of NF1 who were seen at our NF clinic over a 3-year period.

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We identified 110 children who were referred to our clinic for an nf1 assessment based on the presence of calms. To the best of our knowledge, this is the largest series to date of children calmly presenting themselves. however, this was a retrospective study and was limited to data collected at the time of office visits. in this sense, 13 patients with typical calm and 17 patients with atypical calm who were less than 6 years old at the last follow-up examination remained undiagnosed. some of these patients may eventually develop other features and meet the diagnostic criteria for nf1 at a later date. therefore, our data may underestimate the number of patients with multiple calms who ultimately meet criteria for nf1.

the median age at which children first visited our nf clinic was 33 months, with a median of 6 calms. several experts recommend referral or further evaluation of children who report 3 or more calmness.9,16 In our cohort, most referring physicians appeared to follow this guideline, as 6% of referred children were less than three calm down.

Thirty-four patients (31%) were finally diagnosed with nf1 during the follow-up period. This is consistent with a previous large study of all children evaluated in an NF clinic (including children with less than 6 calm), which found that 67% of patients had only 1 diagnostic feature of NF1, most commonly calm. , and did not develop other features.5 In our series, patients with a greater number of calms at presentation were more likely to develop nf1: 77% of patients who had 6 or more typical calms at initial presentation eventually were diagnosed with nf1. this is consistent with the previous study, in which 75% of 41 patients with 6 or more calms were diagnosed with nf1.14 These findings suggest that the majority of children with NF1 who display 6 or more calms at initial presentation will be diagnosed with nf1. nf1. however, it is important for pediatricians to recognize that there will be a small number of children who present with only 2-3 calms at an early age and warrant monitoring for the development of additional calms or other NF1 features over time.4,5,9 no children were diagnosed with syndromes other than nf1. an undiagnosed child with patchy calm had a calm parent. it is possible that this represented a case of multiple familial calms with no other characteristics of nf1; however, no information was available on other family members and no genetic analysis was performed.

in children ultimately diagnosed with nf1 after an initial presentation with calm only, 76% met criteria for nf1 at 4 years, 94% met criteria for nf1 at 6 years, and all patients They met the nf1 criteria at 8 years. the 2 children in our series who were diagnosed after 72 months of age were lost to a follow-up period prior to diagnosis, and it is possible that a diagnosis would have been made before 72 months of age had they been seen earlier. this is similar to what was previously reported by korf,14 who found that 75% of patients diagnosed with nf1 met the criteria before 6 years and 92% met the criteria before 10 years. In our series, the second most common feature of NF1 to appear was axillary or inguinal freckles, similar to that reported by Korf.14 Taken together, these data suggest that most children who present only calmly will meet the requirements. diagnostic criteria at 6 years of age. 8 years and justifies following these children as if they had nf1 for most of the first decade of life.

active nf referral centers are often asked to assess children with unusual forms of calm. in our series, the morphological appearance of the calms was an important indicator of the diagnostic result. Typical calms in children with NF1 are circular or ovoid macules with uniform pigment and well-defined borders.9,16 We found that patients with atypical calms were less likely to be diagnosed with NF1. Although 47% of patients with typical calms were ultimately diagnosed with nf1, only 2 patients (5%) with atypical calms developed nf1. Although various experts have stated that the morphological appearance of calms does not predict diagnostic outcome, one small study found that 8 of 14 patients with typical calms were diagnosed with NF1, while only 1 of 5 patients with atypical calms were diagnosed with nf1. .15 the use of the morphological appearance of calms as a prognostic indicator has limitations, in particular the difficulty of assessing this parameter with a high degree of reliability; however, in the absence of definitive histologic or other more objective criteria to differentiate NF1-associated from non-NF1-associated calms, this information may provide useful guidance for clinicians caring for this group of patients.

Overall, our results from this large series of patients presenting with calms confirm the findings of earlier, smaller studies that most children with 6 or more calms will ultimately meet criteria for nf1, even if they have no other signs Of the same. disorder on initial presentation. Given the high percentage of children with 6 or more calms who will eventually be diagnosed with NF1, we recommend referring all such children to specialists experienced in caring for children with NF1. we also recommend that these patients be followed throughout childhood as if diagnosed with nf1, even in the absence of other signs of the disorder. Due to the rarity of 3 or more calms in the general population without an associated systemic disorder, we continue to support current recommendations that these children be referred to a specialist for further evaluation. our data further indicate that children with less than 6 calms or calms with an atypical appearance are rarely diagnosed with nf1. With few exceptions, the diagnosis of NF1 is established at 72 months of age using clinical criteria established by the National Institutes of Health. In addition to the number of lulls, the morphological appearance of lulls may also be a useful predictive feature in the diagnosis of NF1. in some cases, genetic testing for nf1 may be helpful in providing a definitive diagnosis; however, this analysis remains cost-prohibitive for many patients.19 In conclusion, our findings regarding the number and morphologic appearance of calms should help clinicians provide more accurate advice to parents with children harboring multiple calms in the absence of other characteristics of nf1.

correspondence: david h. gutmann, md, phd, department of neurology, university of washington school of medicine, box 8111, 660 s euclid ave, st louis, mo 63110 ([email protected]).

accepted for publication: March 11, 2009.

Author contributions: All authors had full access to all study data and took responsibility for data integrity and accuracy of data analysis. study concept and design: nunley, bayliss and gutmann. data acquisition: nunley and albers. data analysis and interpretation: nunley, gao, bayliss and gutmann. manuscript writing: nunley and gutmann. critical review of the manuscript for important intellectual content: gao, albers, bayliss and gutmann. statistical analysis: gao. administrative, technical and material support: albers. study supervision: bayliss and gutmann.

financial disclosure: not reported.

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