Jaffe-Campanacci syndrome resulted in amputation: A case report.

BACKGROUND: Jaffe-Campanacci syndrome (JCS) is a very rare syndrome. The treatment of JCS is more conservative, and most authors recommend that no surgery should be done in asymptomatic patients. The conventional concept holds that the natural course of non-ossifying fibromas (NOFs) grows with the development of bones, and the osteolytic region gradually stops expanding and self-healing through bone ossifying around the lesion and ossification within the lesion. But in this case, the bone lesions were potentially biologically aggressive, which led to severe limb deformities and pain. CASE SUMMARY: We present the case of a 5-year-old girl with JCS presenting with not only NOF sand café-au-lait macules, but also showed features not mentioned before, severe limb pain, and at last resulted in amputation. She was admitted to our hospital after presenting with claudication and mild pain over her right thigh, which worsened when stretching or being touched. Skin examination revealed multiple café-au-lait macules on the neck, arm, axilla, and torso, including the nipples and perineum. Radiographs revealed multiple lytic lesions in the proximal part of the right humerus, distal part of the right clavicle, proximal and distal parts of the right femur, and proximal parts of the right tibia and fibula. Curettage and biopsy were performed on the distal part of the right femur. At the age of 7, the girl was re-admitted to our hospital for a pathological fracture in the middle in the right femur and underwent Intralesional excision, internal fixation, bone grafting, and spica casting. At the age of 10, the girl came to our hospital again for severe pain of the right leg. Amputation from the middle level of the right femur was performed. We present the case of a 5-year-old girl with JCS presenting with not only NOFs and café-au-lait macules, but also showed features not mentioned before, severe limb pain, and at last resulted in amputation. She was admitted to our hospital after presenting with claudication and mild pain over her right thigh, which worsened when stretching or being touched. Skin examination revealed multiple café-au-lait macules on the neck, arm, armpit, and torso, including the nipples and perineum. Radiographs revealed multiple lytic lesions in the proximal part of the right humerus, distal part of the right clavicle, proximal and distal parts of the right femur, and proximal parts of the right tibia and fibula. Curettage and biopsy were performed on the distal part of the right femur. At the age of 7, the girl was re-admitted to our hospital for a pathological fracture in the middle in the right femur and underwent Intralesional excision, internal fixation, bone grafting, and spica casting. At the age of 10, the girl came to our hospital again for severe pain of the right leg. Amputation from the middle level of the right femur was performed. CONCLUSION: In our opinion, education on preventing pathological fractures and explaining the consequent serious consequences to the parents is a matter of prime significance. At the same time, prophylactic treatment (restricted exercise, support, or surgery) is also considerable for JSC.

Epidemiology and Outcomes of Neurofibromatosis Type 1 (NF-1): Multicenter Tertiary Experience.

Purpose: The aim of this manuscript was to assess the epidemiology and clinical features of Neurofibromatosis type 1 (NF-1) based on the newly published revised NF-1 diagnostic criteria and to evaluate complications of NF-1 including neurodevelopmental disorders. Patients and methods: A retrospective cross-sectional observational study was conducted in the Ministry of National Guard Health Affairs (MNGHA) healthcare organization branches including four tertiary hospitals and 51 primary health care centers in different regions in Saudi Arabia. This study included all patients diagnosed with NF1 using the revised NIH diagnostic criteria published in 2021 that were registered at the electronic medical records (EMR) from 2015 to 2021. Results: A total of 184 patients fulfilled the diagnostic criteria and were included in this study. The median age at diagnosis was 11 years (IQR: 4.00-20.25). The most encountered diagnostic criteria in this study were Café-au-lait macules (85.3%), and (42.9%) were found to have two or more neurofibromas with plexiform neurofibroma being the most common subtype (23.36%), approximately (36.4%) of the patient with optic pathway glioma. Nearby (26.6%) of the patients displayed different type of tumors. Iris Lisch nodules were presented in 36.4% of patients at a median age of 12 years (IQR: 9.0-21.8). Cardiovascular abnormality was encountered in 9.8% of the patients. Around 27.7% of the patients reported headache and 11.4% of the patient suffered from different type of epilepsy. Besides, 10.5% of the patients had intellectual disability, 33.8% suffered from communication disorders, and 4.9% patients had ADHD. Conclusion: The results of this study will enable practitioners to adopt a more holistic approach and prioritize numerous attributes, which they can subsequently incorporate into their therapeutic methodologies. Furthermore, the identification of these attributes will facilitate an expeditious and accurate diagnosis. Hence, the implementation of intervention during its nascent phase may result in a more advantageous consequence.

The 730 nm picosecond titanium sapphire laser for treatment of café-au-lait macules in all skin types.

OBJECTIVES: Café-au-lait macules (CALM) are benign birthmarks presenting as uniformly pigmented, well demarcated, brown patches that can be distressing to patients, especially when located in cosmetically sensitive areas. As with all pigmentary lesions in skin of color patients, CALMs have been particularly challenging to treat. Here we present the first case series characterizing treatment parameters and clinical outcomes utilizing the 730-nm picosecond titanium sapphire laser for the treatment of CALMs. This device provides an additional safe and effective treatment option for these challenging cases. METHODS: We performed a retrospective review of patients treated at a single institution between April 2021 and December 2023. Clinical photographs were graded by 3 outside board-certified dermatologists using a 5-point visual analog scale. RESULTS: Fourteen patients (age range: 10 months-66 years, mean age: 27.4 years, Fitzpatrick skin types II-VI) were treated for CALM on the face (11) or body (3). On average, patients received 4.3 treatments, with treatment intervals ranging from 4 to 40 weeks. Treatment remains ongoing with the 730-nm picosecond laser for eight patients. Overall, patients were rated to have a mean improvement of 26%-50%. Two patients (FST III and VI) achieved 100% clearance after 4-5 treatment sessions. Our study included four patients whose CALM were of the smooth bordered "coast of California" subtype, three of whom had a mean improvement rating of only 1%-25%. The fourth patient had near complete resolution. Follow up for these patients has ranged from 6 weeks to 1.5 years. Of the patients treated, one patient experienced transient post-inflammatory hyperpigmentation and another transient post-inflammatory hypopigmentation, while a third patient experienced mild persistent guttate hypopigmentation. Three patients experienced partial recurrence indicating that maintenance treatments may be needed in some patients. CONCLUSION: The 730-nm picosecond titanium sapphire laser is a safe and efficacious treatment option, in the right morphologic setting, to improve the cosmetic appearance of CALMs in a wide range of ages and skin types. To our knowledge, this is the first reported treatment of CALMs with picosecond lasers in FST V and VI patients. Our study also supports prior studies which have found that CALM with smooth-bordered "coast of California" morphology have a poor response to laser therapy as compared to those with jagged or ill-defined bordered "coast of Maine" morphology.

Novel pathogenic variants in KIT gene in three Chinese piebaldism patients.

Background: Piebaldism is a rare autosomal dominant disease, and roughly 75% patients had KIT gene mutations. Up to date, approximately 90 KIT mutations causing piebaldism were reported. Methods: To identify KIT gene mutations in three pediatric piebaldism patients from different families and explore the genotype-phenotype correlation, peripheral blood DNA were collected from probands and their parents. Whole-exome sequencing was performed to detect potential disease-causing variants in the three probands. Putative variants were validated by Sanger sequencing. Results: Heterozygous variants of c.2469_2484del (p.Tyr823*), c.1994G > C (p.Pro665Leu), and c.1982_1983insCAT (p.662_663insIle) in KIT gene were detected in three probands. These variants were all novel and classified as pathogenic/likely pathogenic variants according to the interpretation guidelines of American College of Medical Genetics and Genomics and the Association for Molecular Pathology. The probands carrying variants located in tyrosine kinase domain exhibited a more severe phenotype. Conclusion: The piebaldism in three families was caused by novel heterozygous KIT variants. The severity of phenotypes is related with the types and locations of different mutations. Our results further provided evidence for genetic counseling for the three families.

Diagnostic challenges in a CMMRD patient with a novel mutation in the PMS2 gene: a case report.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive condition, which is caused by biallelic mutations in mismatch repair genes: MSH2, MLH1, MSH6, and PMS2. CASE PRESENTATION: We reported a unique case of an 11-year-old Chinese girl with colorectal polyposis and café-au-lait macules who had no obvious family history of Lynch syndrome-associated tumors, followed by brain gliomas and colorectal carcinoma five years later. The diagnosis of CMMRD was based on gene sequencing analysis showing a homozygous deletion NM_00535.5:c.1577delA (p.Asp526fs) in exon 11 of the PMS2 gene. Although the patient underwent surgery and radiation therapy, and close surveillances including radiological, endoscopic and hematological screening have been recommended, she died of the exacerbation of neurological symptoms at the age of 18. CONCLUSIONS: We identified a novel homozygous deletion in the PMS2 gene in a CMMRD patient with complex clinical features.

Chronic Lymphocytic Leukemia in Neurofibromatosis Type 1 Patients: Case Report and Literature Review of a Rare Occurrence.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genodermatosis that may also occur as the result of a spontaneous mutation. The diagnosis can be established by the presence of two of the seven National Institutes of Health (NIH) diagnostic criteria; several dermatologic manifestations are NIH criteria used to establish the diagnosis: axillary and inguinal freckling, café-au-lait macules, and neurofibromas. Mucosal evaluation of the eyes may detect a fourth criteria: pigmented iris hamartomas (Lisch nodules). The remaining NIH criteria include optic path glioma, distinctive osseus lesions, and a positive family history of the condition. A breast cancer 2 (BRCA2) positive woman with NF1 and chronic lymphocytic leukemia is described. Patients with NF1 have an increased lifetime risk to develop breast cancer, gastrointestinal stromal tumor, malignant glioma, malignant peripheral nerve sheath tumor, and rhabdomyosarcoma. Chronic lymphocytic leukemia occurring in NF1 patients is rare; including my female patient reported in this paper, chronic lymphocytic leukemia has only been reported in three individuals with NF1--two women and one man. The man and the other woman presented with advanced chronic lymphocytic leukemia and treatment with antineoplastic therapy at diagnosis; the man achieved clinical remission and the woman passed away from complications associated with therapy-refractory progression of her leukemia. My female patient required treatment 41 months after diagnosis and had a good clinical response; she has been without significant disease progression for 34 months. Similar to NF1, breast cancer 1 (BRCA1) and BRCA2 mutations are associated with an increased lifetime risk of developing cancer--particularly breast and ovarian carcinoma. An increased risk of chronic lymphocytic leukemia has also been demonstrated in patients with mutations of either BRCA1 or BRCA2. Also, albeit uncommon, either BRCA1 or BRCA2 mutation has been detected in women with NF1 who develop breast cancer. In conclusion, the development of chronic lymphocytic leukemia in NF1 patients may be coincidental and not associated with the underlying genodermatosis; however, the occurrence of chronic lymphocytic leukemia in my patient with NF1, in part, may be related to her BRCA2 positivity.

The recurrent plexiform neurofibroma of the scalp in neurofibromatosis type 1: illustrative case.

BACKGROUND: Plexiform neurofibroma is a benign tumor of the peripheral nerves. It is an unusual variant of neurofibroma originating from all parts of the nerve. Plexiform neurofibroma is primarily pathognomonic and exhibits an unusual variant from neurofibromatosis type 1 (NF1). The possibility of malignancy and recurrence are the main reasons for long-term, close follow-up. OBSERVATIONS: The authors report a case of a 14-year-old girl with a recurrent plexiform neurofibroma derived from the peripheral nerves, which also presented with a typical sign of NF1 disease. The aim of the tumor resection is symptomatic relief. LESSONS: Accomplishing a good outcome can be related to good perioperative planning and a precise operative procedure. The result of anatomical pathology determines the prognosis of the patient. Clinical examination and radiological studies are needed to evaluate the recurrence of complications after surgical procedures.

A retrospective study of FQSRL and IPL in the treatment of Café-au-lait macule.

BACKGROUND: The application of fractional Q-switched ruby laser (FQSRL) or intense pulsed light (IPL) on Café-au-lait macule (CALM) is rational and the data are lacking. OBJECTIVE: To evaluate the efficacy and safety of FQSRL and IPL in CALM. METHODS: The patients with CALM who were treated with FQSRL or IPL were retrospectively observed from April 2016 to April 2019. The laser/light treatments were conducted at an interval of 3-4 weeks. RESULTS: For FQSRL (N = 67), 88.23%, 95.46%, 100% patients achieved >50% improvement by three sessions, four sessions, and more than four sessions of treatment, respectively. A better and better efficacy was shown with the increasing number of sessions (χ2 = 89.51, p < .01). For IPL (N = 54), 45% and 87.5% achieved >50% improvement by three sessions and more than four sessions of treatments, respectively. More than four sessions achieved better efficacy than less sessions (p < .01). Under various time-points, FQSRL presented more favorable responses than IPL (p < .05). All the adverse effects were tolerable and acceptable. CONCLUSIONS: FQSRL or IPL would be an alternative and safe modality for CAML in Chinese patients.

Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder that arises due to pathogenic variants in tumor suppressor NF1. NF1 has variable expressivity that may be due, at least in part, from heritable elements such as modifier genes; however, few genetic modifiers have been identified to date. METHODS: In this study, we performed a genome-wide association analysis of the number of café-au-lait macules (CALM) that are considered a tumor-like trait as a clinical phenotype modifying NF1. RESULTS: A borderline genome-wide significant association was identified in the discovery cohort (CALM1, N = 112) between CALM number and rs12190451 (and rs3799603, r2  = 1.0; p = 7.4 × 10-8 ) in the intronic region of RPS6KA2. Although, this association was not replicated in the second cohort (CALM2, N = 59) and a meta-analysis did not show significantly associated variants in this region, a significant corroboration score (0.72) was obtained for the RPS6KA2 signal in the discovery cohort (CALM1) using Complementary Pairs Stability Selection for Genome-Wide Association Studies (ComPaSS-GWAS) analysis, suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error. CONCLUSION: rs12190451 is located in a melanocyte-specific enhancer and may influence RPS6KA2 expression in melanocytes-warranting further functional studies.

Café au Lait Macules and Associated Genetic Syndromes.

Café au lait macules (CALMs) are a common, isolated dermatologic finding in the general population. But when do these irregularly shaped, jagged-edged, flat, hyperpigmented birthmarks suggest something that may warrant referral? Most pediatric providers are familiar with the association of CALMs and neurofibromatosis type 1. There are, however, other genetic conditions associated with these seemingly benign skin spots. This article provides an overview of CALMs, followed by a summary of several conditions associated with CALMs ranging from the most common (neurofibromatosis type 1) to rare, ring chromosome syndromes. It reviews the associated gene(s), pattern of inheritance, incidence, presenting symptoms, diagnosis, and management for these genetic conditions.

Treatment of café-au-lait macules with a high-fluenced 1064-nm Q-switched neodymium:yttrium aluminum garnet laser.

Café-au-lait macules (CALMs) are light to dark brown macules or patches of increased melanin concentration found along the dermoepidermal junction. Although many attempts to treat CALMs using various kinds of laser/light-based devices have been reported, CALMs remain refractory thereto with high recurrence rates. In this case series, we describe four patients with idiopathic CALMs that were effectively and safely treated with a non-ablative, high-fluenced, Q-switched (QS), 1064-nm neodymium:yttrium aluminum garnet (Nd:YAG) laser. The typical laser parameters for treating CALMs, including a spot size of 7-7.5 mm, a fluence of 2.4-2.5 J/cm2, and one to two passes until the appearance of mild erythema, but not petechiae, were utilized in this study over 12-24 treatment sessions at 2-week intervals. We suggest that high-fluenced QS 1064-nm Nd:YAG laser treatment can be used as an effective and alternative treatment modality for CALMs with minimal risk of side effects.

A novel germline POLE mutation causes an early onset cancer prone syndrome mimicking constitutional mismatch repair deficiency.

In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in 'ultramutated' sporadic cancers. This is the youngest reported cancer patient with polymerase proofreading-associated polyposis indicating that POLE mutation p.(Val411Leu) may confer a more severe phenotype than previously reported POLE and POLD1 germline mutations. The patient had multiple café-au-lait macules and a pilomatricoma mimicking the clinical phenotype of constitutional mismatch repair deficiency. We hypothesize that these skin features may be common to different types of constitutional DNA repair defects associated with polyposis and early-onset cancer.

Nevus anemicus in neurofibromatosis type 1: a potential new diagnostic criterion.

BACKGROUND: Children with multiple café-au-lait macules (CALMs) may be followed for years before a second National Institutes of Health clinical criterion of neurofibromatosis type 1 (NF1) develops to confirm the diagnosis. OBJECTIVE: We sought to assess the prevalence of nevus anemicus (NA) in NF1 and its association with neuro-ophthalmologic complications. METHODS: This was a prospective multicenter case-control study of 210 consecutive patients with multiple CALMs. Patients with NF1 were matched for age, sex, and center with control subjects. We documented the number, location, and morphologic appearance of NA; dermatologic features of NF1; magnetic resonance imaging results; and family history. RESULTS: In all, 77 (51%) patients with NF1 had NA compared with 6 (2%) control subjects. NA was not detected in 26 patients with other genodermatoses associated with CALMs. Patients with NF1 and NA were younger than those without NA (median age: 17 years) (P = .002). NA was mostly localized to the upper anterior aspect of the chest. NA was not significantly linked with other clinical manifestations of NF1, including optic glioma and unidentified bright objects. LIMITATIONS: A potential referral bias associated with tertiary care centers is a limitation. CONCLUSIONS: NA appears to have a high prevalence and specificity in NF1 and might serve as a marker for NF1 in children with multiple CALMs.

Agminated Lentiginosis with a Family History / 대한피부과학회지

Agminated lentiginosis (AL) is a rare pigmented disorder that is characterized by numerous lentigines in a unilateral distribution or often in a segmental pattern corresponding to one or more dermatomes. AL coexists with other several diseases and some researchers have suggested it is a variant of dermatomal neurofibromatosis if AL is accompanied by cafe-au-lait (CAL) macules or neurofibromas. We report here on a case of a 12-year-old female who presented with multiple lentigines on her right neck and shoulder (the C2 and C3 dermatomes) combined with CAL macule and ipsilateral axillary freckling. On checking the family history, her mother had grouped lentigines on her right chest (the T4, T5 dermatomes). But there were no neurofibromas, Lisch nodules and neurologic or skeletal abnormalities in both of them.

A Case of Hemifacial Hypertrophy due to Plexiform Neurofibroma with the Cafe-au-lait Macules / 대한피부과학회지

Plexiform neurofibromas are among the most pathognomonic features of neurofibromatosis type 1 (NF1). Although characteristically benign, plexiform neurofibroma can cause pain, disfigurement and functional changes, and more importantly, it may turn malignant. We present here the case of a 3-year-old boy with progressive hemifacial hypertrophy that was colocalized with light brown-colored macules. The biopsy specimen showed that the bundles of nerve fibers were arranged in a concentric manner with myxoid changes. On the evaluation of the pigmented lesion, only the basal melanin pigments were increased in the epidermis without any melanin-laden pigmented cells in the dermis. We have demonstrated that neurofbroma needs to be considered in the differential diagnosis of hemifacial hypertrophy since this is likely to have implications for the further management of these patients. The absence of other findings does not exclude NF1 as the underlying disease since many NF1 patients have not yet developed cafe-au-lait macules or freckles in early childhood.