Café-au-lait Research Articles

The curious case of a man with freckles and obscure gastrointestinal bleed

1. Castleman B, Towne VW. CASE records of the Massachusetts General Hospital Weekly Clinicopathological Exercises: Case 40011. N Engl J Med. 1954;250:26–30. 2. Kimura T, Inoue T, Katayama K, Hirose K, Imamura Y, Yamaguchi A. Mesenteric Castleman’s disease: report of a case. Surg Today. 2002;32:651–4. 3. Rosai J. Rosai and Ackerman’s surgical pathology. 9th ed. New Delhi: Elsevier; 2004:1905–8. 4. Francis ND, Hollowood K, Gabriel R. Angiofollicular lymph node hyperplasia. J Clin Pathol. 1988;41:353–4. 5. Cesarman E, Knowles DM. Kaposi’s sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Semin Diagn Pathol. 1997;14:54–66. 6. Frizzera G. Castleman’s diesease: more questions than answers. Hum Pathol. 1985;156:202–5. 7. Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K, et al. Pathogenic significance of interleukin-6 (IL-6/ BSF-2) in Castleman’s disease. Blood. 1989;74:1360–7. unremarkable except for multiple cutaneous neurofibromas, axillary freckles and cafe au lait spots (Figure 1). Haematological tests revealed microcytic hypochromic anaemia and faecal occult blood was positive. Both upper GI endoscopy (UGIE) and colonoscopy were normal. CT angiogram of the abdomen (Figure 2) revealed the presence of two masses 3 cm × 2 cm in size, enhancing well with contrast, located in the proximal and mid jejunum and supplied by branches of the superior mesenteric artery. After obtaining an informed consent and preoperative packed cell transfusions, the patient was taken up for diagnostic laparoscopy. Findings at laparoscopy included two jejunal tumours as described above and additional

Laryngeal Plexiform Neurofibroma in a Child

Neurofibromatosis (NF) is a genetically inherited, autosomal dominant disease, characterized by multiple cafe au lait spots, cutaneous neurofibromas and "Lisch nodules." Neurofibromatosis can develop from a neural source at any age. However, neurofibroma of the larynx is extremely rare and is usually manifested by obstructive airway symptoms. We encountered a 5-year-old child presenting with stridor and dyspnea, who had a diagnosis of laryngeal plexiform neurofibroma. The purpose of our report is the consideration of laryngeal NF in the differential diagnosis of dyspnea in infants and children.

A Very Rare Assocıatıon; Coexıstence of Breast Cancer, Pheochromocytoma and Neurofıbromatosıs Type 1 in a Female Patıent

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition and patients with NF-1 risk malignant diseases, such as breast cancer. We aim to report a coexistence of both breast cancer and phochromocytoma in a NF1 patient. A female patient (47yr) with adrenal incidentaloma who had undergone? modified mastectomy for invasive ductal and lobular carcinoma 5 years ago. NF1 was diagnosed with multiple cafe au lait spots, discrete cutaneous neurofibromas over the patient’s body and freckling in the axillary region. Patient’s father who died at the age of 48 due to pancreatic cancer with liver metastasis and son (13 yr) had similar cafe au lait spots. She was still hypertensive (180/105 mmHg) under the triple anti-hypertensive drugs. Abdominal CT scan showed a 9 × 10 cm diameter mass arising from left adrenal gland with mixed consistency. Urinary metanephrine and normetanephrine levels (24 hourly) were extremely high (11125 and 15042 mic.g, respectively). We diagnosed pheochromocytoma with these results. Multiple endocrine neoplasia type 2 could not be detected and patient was redirected to a surgery clinic under suitable conditions. Although malignant tumors are reported four times as often in NF-1 patients than in the general population, coexistence of breast cancer and pheochromocytoma in NF-1 patients have never been reported before. Here we report probably the first coexistence of NF1, breast cancer and pheochromocytoma.

Neurofibromin interacts with the cytoplasmic Dynein Heavy Chain 1 in melanosomes of human melanocytes

Neurofibromin (NF1) is encoded by the NF1 tumour suppressor gene. Mutations result in a disorder known as Neurofibromatosis Type 1 (NF-1), and patients are often diagnosed due to the presence of unusual pigmentary patterns that include Café au lait macules (CALMs). Little is known about how loss of NF1 results in pigmentary defects in melanocytes. We sought to identify novel NF1 interacting proteins and elucidate the molecular mechanisms underlying the pigmentary defects. The cytoplasmic Dynein Heavy Chain 1 (DHC) was found to interact with NF1 along microtubules in vesicular structures identified to be melanosomes. Our studies suggest that NF1 is involved in melanosomal localization, and that disruptions in NF1–DHC interactions may contribute to the abnormal pigmentary features commonly associated with this debilitating syndrome.

Neurofibromatose tipo I

A neurofibromatose tipo I e uma doenca autossomica dominante cujo diagnostico presuntivo e feito com base em criterios clinicos. As tres principais manifestacoes: neurofibromas, manchas cafe com leite e nodulos de Lisch ocorrem em mais de 90% dos pacientes ate a puberdade. Relatamos o caso de um paciente jovem com diagnostico de neurofibromatose tipo I e historia familiar positiva para a doenca, comentando seus aspectos clinicos e achados nos exames de imagem.

A rare cause of systemic hypertension in an African child: Questions

A female toddler was referred to our hospital with the problem of hypertensive encephalopathy manifesting with convulsions, right hemiparesis and blindness. She had been well until the age of 17 months when she developed fever and symptoms of an upper respiratory tract infection. Her past medical history was significant only for having been a small for gestational age baby. She weighed 2 kg at birth after a term, uncomplicated pregnancy. She had achieved her milestones normally up to the age of 12 months. Thereafter her mother noticed that her neurological development was faltering—she was not talking or playing, she was disinterested in her environment and she was unusually irritable. She has no family history of hypertension, heart or kidney disease. She has one healthy sibling. On physical examination she appeared chronically ill. She was severely stunted (length 72.5 cm, Z score<−3 SD) and wasted (weight for length Z score<−3 SD). Her level of consciousness was depressed. All her pulses were present and normal and there was no radio-femoral delay. Her blood pressure was 148/92 mm Hg and was elevated in all four limbs. She had puffy eyes, but no pedal or sacral oedema. She was clinically anaemic and mildly dehydrated. She did not have any lymphadenopathy. There were no cafe au lait spots, no malar rash and no evidence of vasculitis. The left precordium was bulging. The apex was heaving in the fifth intercostal space, displaced laterally. The second heart sound was loud. There was no murmur over the heart, the subclavian or carotid vessels, over the inter-scapular area or abdominal aorta. There was weakness of the left arm and leg, and all tendon reflexes were markedly brisk. She had complete loss of vision, but her other cranial nerves were intact. Fundoscopy revealed retinal haemorrhages, but no papilloedema. Laboratory investigations revealed the following information: she had a hypokalaemic metabolic alkalosis; potassium was 2.8 mmol/l and bicarbonate was 30 mmol/l. The serum sodium, chloride, urea and creatinine levels were normal. The full blood count showed a hypochromic microcytic anaemia, with haemoglobin of 9.4 g/dl [normal 11.1–14.7 g/dl, mean corpuscular volume of 65.9 fl (normal 70–86 fl) and mean corpuscular haematocrit of 20.8 pg (normal 23–31 pg)]. The differential white cell count was normal. Further investigations showed a suppressed plasma immuno-reactive renin of <1.8 mIU/l (normal 5.4–28.8 mIU/l) and aldosterone level of <31 pmol/l (normal 28–666 pmol/l). The urine potassium was 21.7 mmol/l, urine sodium was <10 mmol/l and urine chloride was 20 mmol/l. The urine protein creatinine ratio was 0.23 g/mmol (normal <0.02 g/mmol). Steroid chromatography excluded endocrine causes of hypertension associated with hypokalaemic metabolic alkalosis. The kidney sonography showed normal-sized kidneys for her length of 72.5 cm (right 6.1×3.1 cm, left 5.8×3 cm), with decreased cortico-medullary differentiation. Renal The answers to these questions can be found at http://dx.doi.org/10.1007/ s00467-013-2446-3

A Mystery Case of Proptosis, Optic Neuropathy, and Peripheral Neuropathy

Six months later, she noticed proptosis of the right eye and her diplopia persisted. Our examination showed acuity of 20/20 OU and a left relative afferent pupillary defect. She had 3 mm of right proptosis, -3 adduction deficit in her right eye and -2 abduction deficit in her left eye with -1 elevation deficit bilaterally. There was no nystagmus. Saccades were normal. She had one Lisch nodule and one cafe au lait spot less than 2 cm. The optic nerves appeared pale OS > OD. She had weakness of dorsiflexion, absent reflexes, absent vibration sense, and high arches.

Ventrally located cervical dumbbell ganglioneuroma producing spinal cord compression.

Ganglioneuroma is an uncommon benign tumor and arise from neural crest cells or sympathetic and peripheral nerves. A 13-year-old boy was referred to our institute and presented with three-day history of right upper extremity weakness associated with neck pain for nearly one month. Magnetic resonance imaging showed right side dumbbell shaped extramedullary lesion at the C2-3 level extending outside through neural foramen. Paraspinal and posterior neck mass, cafe au lait spot was identified. We performed surgical decompression of the spinal cord by resection of intradural portion mass. Histopathological diagnosis was ganglioneuroma.

Oral manifestations of McCune-Albright syndrome

McCune- Albright Syndrome (MAS) is a rare fibrosseous lesion, characterized by a classic triad of polyostotic fibrous dysplasia (PFD), café –au-lait macules (CALM) and underlying endocrinopathies. We present the oral findings of an interesting case of MAS with relevant review of literature. A 30-year-old male presented to us with swelling of both jaws over a period of two years. Cutaneous examination revealed café - au – lait macule over the back, crossing the midline. Skeletal survey showed expansile, osteolytic, mixed radiolucent- radiopaque lesions in skull and jaw bones. Serum alkaline phosphatase was elevated (388 IU/L), with normal calcium, phosphorus, parathyroid hormone and 25 hydroxy vitamin D levels. Diagnosis of McCune- Albright syndrome was made and he was treated with parenteral bisphosphonates (intravenous Zoledronate 4 mg) and is under follow up for surgical recontouring of the jaws. Early recognition facilitates better treatment and improves prognosis by reducing the morbidity.

A novel mutation in &amp;lt;i&amp;gt;NF1&amp;lt;/i&amp;gt; gene in a Chinese patient with Legius syndrome like caf&amp;#233; au lait spots

Neurofibromatosis type I (NF1) (OMIM, 162200) and Legius syndrome (OMIM, 611431) both have multiple cafe au lait spots. It is a challenge to differentiate the two diseases. Here we report a Legius syndrome-like patient who finally was identified as NF1 with a novel mutation in NF1 exon1 (c.55G > T). The mutation caused a substitution of a glutamic acid (GAG) with a terminator codon (TAG). For those patients with only multiple cafe au lait macules, axillary and inguinal freckling, but without any other clinical signs in NF1 and Legius syndrome, a gene testing is necessary to give a final diagnose. We suggested to use “Neurofibromatosis type 1—like syndrome” to describe those patients just like our patient reported here.

Legius Syndrome, an Update.Molecular Pathology of Mutations in SPRED1

Multiple café-au-lait macules (CALMs) are the hallmark of Von Recklinghausen disease, or neurofibromatosis type 1 (NF1). In 2007 we reported that some individuals with multiple CALMs have a heterozygous mutation in the SPRED1 gene and have NF1-like syndrome, or Legius syndrome. Individuals with Legius syndrome have multiple CALMs with or without freckling, but they do not show the typical NF1-associated tumors such as neurofibromas or optic pathway gliomas. NF1-associated bone abnormalities and Lisch nodules are also not reported in patients with Legius syndrome. Consequently, individuals with Legius syndrome require less intense medical surveillance than those with NF1. The SPRED1 gene was identified in 2001 and codes for a protein that downregulates the RAS-mitogen activated protein kinase (RAS-MAPK) pathway; as does neurofibromin, the protein encoded by the NF1 gene. It is estimated that about 1-4% of individuals with multiple CALMs have a heterozygous SPRED1 mutation. Mutational and clinical data on 209 patients with Legius syndrome are tabulated in an online database (http://www.lovd.nl/SPRED1). Mice with homozygous knockout of the Spred1 gene show learning deficits and decreased synaptic plasticity in hippocampal neurons similar to those seen in Nf1 heterozygous mice, underlining the importance of the RAS-MAPK pathway for learning and memory. Recently, specific binding between neurofibromin and SPRED1 was demonstrated. SPRED1 seems to play an important role in recruiting neurofibromin to the plasma membrane.

Pulmonary Hypertension in Neurofibromatosis Type 1: A Case Report

Neurofibromatosis type I is a genetic disease caused by mutations in the neurofibromin 1 (NF1) gene. Although it is characterized by a number of distinct clinical features, including cafe au lait macules, freckling in the axillary or inguinal regions, neurofibromas, and Lisch nodules (iris harmartomas), it can affect all physiological systems in the body [1]. Neurofibromatosis-related pulmonary hypertension has also been reported, and some patients showed a poor prognosis despite having received proper medical treatment [2-4]. We herein describe a case of pulmonary hypertension in a patient with neurofibromatosis type I who had no identified risk factors of pulmonary hypertension. To our knowledge, this is the first such report in Korea. (Korean J Med 2013;85:521-525)

Multiple gastrointestinal stromal tumors and pheochromocytoma in a patient with von Recklinghausen's disease

INTRODUCTIONNeurofibromatosis type 1 is a genetic disease characterized by neoplastic and non neoplastic disorders involving tissues of neuroectodermal and mesenchymal origin. Herein, we present a case with von Recklinghausen's disease, right adrenal heochromocytoma and multiple gastrointestinal stromal tumors. PRESENTATION OF CASEA forty-eight year old male patient was admitted to our Emergency Department with melena. His physical examination revealed multiple neurofibromas all over the skin, kyphosis, multiple cafe au lait spots and Lisch nodules on the eye and, melena on digital rectal examination. Abdominal computerized tomography scan showed a mass on right adrenal gland and multiple soft tissue mass lesions between distal part of pancreas and small bowel. Adrenal mass was determined as a pheochromocytoma and small bowel lesions were verified as stromal tumors. DISCUSSIONIn patients with NF1, pheochromocytomas and GISTs are well known neoplasms seen with increased incidence than the general population. CONCLUSIONIn patients with NF1, any symptoms with other systems should be managed carefully for underlying malignity.

Diagnostic and pathogenetic role of café-au-lait macules in nevoid basal cell carcinoma syndrome

Café au lait spots (CALS) are common dermatologic findings that can at the same time arise in a variety of pathologic conditions such as Neurofibromatosis type 1 (NF1), together with numerous hereditary syndromes for which they represent either diagnostic criteria or associated elements (McCune Albright, Silver-Russell, LEOPARD, Ataxia-Telangiectasia). A review of the literature also revealed two cases of association with NBCCS. We report here the case of a female proband with CALS associated to Nevoid Basal Cell Carcinoma Syndrome (NBCCS) with known PTCH1 germline mutation (C.1348-2A>G) who had been misdiagnosed with NF1 in her childhood because of 5 CALS and cutaneous nodules. The patient presented a giant cell tumor of the skin, palmar and calcaneal epidermoidal cystic nodules, odontogenic keratocystic tumors and deformity of the jaw profile. Her family history brought both her brother and father to our attention because of the presence of KCOTs diagnosed at early age: after genetic testing, the same PTCH1 germline mutation was identified in the three family members. Clinical criteria are used for discerning NF1 diagnosis (size, number and onset age), while there are no definite guidelines concerning CALS except for their presence. In our experience, we have noted an association of CALS with NBCCS; this seems interesting because we already know clinical criteria are a dynamic entity and can be modified by epidemiologic evidences.

Cafe au Lait Macules

Cafe-au-lait macules (CALMs) are common hyperpigmented and flat skin lesions found in the general population. They are usually present at birth (congenital) or occur early in life. They may grow in number and size with age. The color varies from light brown to dark brown, and they may be present on any body parts, but the most common location is the trunk and the extremities. The term cafe-au-lait is a French word meaning coffee with milk.There are two main types of CALMs. CALMs with regular and clearly demarcated margins (coast of California), which is more common. They range in size from a few millimeters to several centimeters (>20cm) and may be present as solitary or multiple spots. The second type of CALM has an irregular margin (coast of Maine), which is less common and is usually larger and solitary. The coast of Maine pattern is seen in a segmental pigmentary disorder, while the coast of California pattern is seen neurofibromatosis 1 (NF1) and related conditions.CALMs are seen in 95% of patients with NF1. Although solitary CALMs are common in the general population and are familial and inherited as autosomal dominant, multiple spots accompanied by other manifestations may indicate an underlying genetic disorder, and they require further evaluation. A family history of CALMs should be evaluated in any patient with multiple CALMs.

Neurofibromatosis Type 1 with Unusual Oral Manifestations

ABSTRACT Neurofibromatosis (NF) is a genetically transmitted autosomaldominant disorder with variable penetrance and about 50% ofcases representing new mutations. It is progressive in natureand one of its unique feature is the diversity of clinical expressionfrom one patient to another and even within a family. The diseaseis often characterized by complex and multicellularneurofibroma. It may also lead to different complicationsthroughout the life of an affected individual. We report a case ofNF involving alveolus of maxilla and mandible causing expansionof the buccal and lingual cortical plates in a 10-year-old girl. Keywords: Neurofibromatosis, Mandible, Hypoplastic, Cafe aulait spots. How to cite this article: Kini R, Naik V, Baliga A.Neurofibromatosis Type 1 with Unusual Oral Manifestations.J Indian Aca Oral Med Radiol 2012;24(3):229-232. Source of support: Nil Conflict of interest: None declared INTRODUCTION Neurofibroma is the most common type of peripheral nerveneoplasm, arising from Schwann cells, perineural fibroblastsor both. The term neurofibroma was coined by vonRecklinghausen in 1881.

Phacomatosis melanorosea, unearthed

ejd.2012.1749 Auteur(s) : Daniele Torchia daniele.torchia@unifi.it Via della Scala 58, 50123 Florence, Italy Reprint: D. Torchia Two recent EJD reports described two cases characterized by an allegedly undescribed association between a large hypermelanotic macule of cafe-au lait color (HM) and naevus roseus (NR), both occurring in a block-like pattern reminiscent of cutaneous mosaicism [1, 2]. This condition was named “phacomatosis melanovascularis” [1] or, more appropriately, “phacomatosis melanorosea” [...]

Hyponatremia in a child with Takayasu arteritis: Questions

A 12-year-old boy was referred to us with a 3-year history of recurrent fever and joint pains. Four months previously, the child had been admitted for generalized tonic–clonic convulsions, for which a computed tomography (CT) scan of the brain had been performed and reported to be normal. There was no recurrence of seizures, but the parents noticed that the child was losing weight, was very thirsty, and was passing large volumes of urine. Complaints of headache and diplopia during the preceding 10 days led to re-admission to hospital. However, the child developed progressive breathlessness and was therefore referred to us for further management. On examination, the child was conscious, irritable, and very thirsty. The respiratory rate was 70/min, pulse was 184/ min, and blood pressure was 160/130 mmHg in the left upper limb, 154/130 mmHg in the right upper limb, 146/ 126 in the right lower limb, and 148/128 in the left lower limb. All peripheral pulses were palpable. His weight and height were 28 kg and 126 cm, respectively, both below the 5th percentile for age and sex. The skin showed no cafe-aulait spots. There was no significant lymphadenopathy. On examination of the cardiovascular system, the jugular venous pressure was 7 cm above the sternal angle. The apical impulse was in the sixth left intercostal space lateral to the mid-clavicular line, and there was a gallop rhythm. Respiratory system examination revealed bilateral basal crepitations. The liver was tender and palpable 5 cm below the right costal margin. There was no abdominal bruit. The fundus showed disc edema, cotton wool exudates, focal hemorrhages, and arterio-venous nicking. Other organ systems were essentially normal. Further tests revealed a hemoglobin of 9.8 g/dl, total white blood cell count of 11,000/mm with a differential count of polymorphs of 68 %, lymphocytes of 30 %, and monocytes of 2 %, and platelet count of 1,86,000/mm. The erythrocyte sedimentation rate was 75 mm at the end of 1 h. Urinanalysis showedmicroscopic hematuria and 3+ proteinuria. Serum and urine electrolyte values are given in Table 1. Serum creatinine was 0.7 mg/dL. The Mantoux test showed no induration at 48 h. Chest X-ray showed cardiomegaly with a cardiothoracic ratio of 0.7 and features suggestive of pulmonary edema. Abdominal ultrasonography revealed a small atrophic right kidney (6.2×2.3 cm) with decreased vascularity within and compensatory hypertrophy of the left kidney (11.1×5.2 cm). Renal Doppler showed a poor flow in the right intra-renal arteries with poor visualization of the R renal ostium. The left kidney showed hypertrophy, and the entire left renal artery was prominent with increased flow within. Two-dimensional echocardiography showed concentric hypertrophy of the left The answers to these questions can be found at http://dx.doi.org/10.1007/ s00467-012-2189-6.

Multiple or familial café-au-lait spots is neurofibromatosis type 6: Clarification of a diagnosis

A café-au-lait macule (CALM) is an evenly pigmented macule or patch of variable size. Solitary CALMs are common birthmarks in up to 2.5 percent of normal neonates and their incidence rises to up to 25 percent in preschool-aged children. Two or more CALMs occur much less frequently. Multiple lesions may warrant investigation to identify an underlying disease including neurofibromatosis types 1 (NF1), neurofibromatosis type 2, McCune-Albright syndrome, and neurofibromatosis type 1-like syndrome. Considered a hallmark and diagnostic criteria for NF1 is the presence of 6 or more CALMs greater than 0.5 cm in prepubertal individuals. Rare reports describe families which demonstrate the phenomenon of multiple CALMs without other stigmata of NF1 or evidence of other systemic disease. Herein is a description of the condition and justification for this entity to be named Neurofibromatosis type 6.

Café‐au‐lait macules and intertriginous freckling in piebaldism: Clinical overlap with neurofibromatosis type 1 and Legius syndrome

Piebaldism is an autosomal dominant disorder characterized by congenital hypopigmented patches of skin and hair and has been found to be associated with mutations in the KIT or SLUG genes. Café-au-lait macules (CALM) may occasionally be seen in piebaldism. There are four reports describing six patients who were said to have both piebaldism and neurofibromatosis type 1 (NF1) due to the presence of multiple CALM and intertriginous freckling, but none of these patients had undergone comprehensive NF1 mutation analysis. We describe a large family with piebaldism in which two members meet diagnostic criteria for NF1 based on the presence of >5 CALM and intertriginous freckling. Interestingly, only these two family members are of mixed race, which could be of importance. A novel complex mutation in the KIT gene was identified in several family members affected with piebaldism; the proband meeting diagnostic criteria for NF1 also underwent comprehensive NF1 and SPRED1 testing with no mutations detected. These findings suggest that piebaldism may occasionally include CALM and intertriginous freckling, which may create diagnostic confusion especially in the absence of a family history of piebaldism. However, careful clinical evaluation and molecular testing if necessary should distinguish these two disorders.