Pheochromocytoma Associated with Neurofibromatosis Type 1 and Noonan Syndrome: A Case Report and Literature Review

Pheochromocytoma is a relatively rare neuroendocrine tumour which can be sporadic or fitting into apolymorphic syndromic context. These syndromes include: Multiple endocrine neoplasia, Von-HippelLindau disease, and neurofibromatosis type 1 (NF1)[1]. We report a case of a pheochromocytoma in a young woman in the context of neurofibromatosistype 1 associated with a rare genetic syndrome: the NOONAN syndrome (NS).NF1 is the most common type of neurofibromatosis, accounting for about 90% of all the cases. It isa frequent autosomal dominant genetic disease with various clinical manifestations and a weakgenotype-phenotype correlation. The diagnosis of NF1 is based on clinical findings with reference tospecific criteria.Genetic testing is not recommended for diagnosis [2,3].On the other hand, NS is a heterogeneous relatively frequent genetic disorder, with an estimatedprevalence between 1/1000 and 1/2500 live births. It is transmitted in an autosomal dominant waywith a variable phenotypic expression [4].The particularity of the case presented here is about the coexistence of NF1 and NS: an associationwhose mechanisms are not yet wellunderstood.


Introduction
Pheochromocytoma is a relatively rare neuroendocrine tumour which can be sporadic or fitting into apolymorphic syndromic context. These syndromes include: Multiple endocrine neoplasia, Von-HippelLindau disease, and neurofibromatosis type 1 (NF1) [1].
We report a case of a pheochromocytoma in a young woman in the context of neurofibromatosistype 1 associated with a rare genetic syndrome: the NOONAN syndrome (NS).NF1 is the most common type of neurofibromatosis, accounting for about 90% of all the cases.
It isa frequent autosomal dominant genetic disease with various clinical manifestations and a weakgenotype-phenotype correlation.
The diagnosis of NF1 is based on clinical findings with reference tospecific criteria.Genetic testing is not recommended for diagnosis [2,3].On the other hand, NS is a heterogeneous relatively frequent genetic disorder, with an estimatedprevalence between 1/1000 and 1/2500 live births. It is transmitted in an autosomal dominant waywith a variable phenotypic expression [4].The particularity of the case presented here is about the coexistence of NF1 and NS: an associationwhose mechanisms are not yet wellunderstood.

Observation
A 34-year-old female, with no personal or family history, was examined by a primary-care physicianfor having a gravida hypertension that has persisted6 months after her delivery. Despite thecombination of 3 antihypertensive drugs, blood pressure was still poorly controlled. Accordingly, thepatient was admitted to our department for a diagnosis of a secondary hypertension.The patient complained of an holocranial headache with intermittent attacks of palpitations and aprofuse sweating since the last month.
She also reported having an hypoacusis and a recurrentepistaxis. The physical examination showed that her blood pressure was 210/110mmHg controlled at 140/90mmHg after taking her antihypertensive treatment without complaining of a dyspnoea or a chest pain.She was also found to have tachycardia at 111bpm.The electrocardiogram test uncovered a left ventricular hypertrophy with an elevated Sokolow-Lyonindex calculated at 40mm, without arrythmia.Morphologically, the patient had a short stature (Height: 154cm; Weight: 54kg), a scoliosis, a chestdeformation with widely spaced and low set nipples, an hypertelorism, low-set ears, and a mildmental retardation. As skin manifestations, there was multiple « café-au-lait » spots sized over 1.5cm which have progressed since the childhood. In addition to these spots, there were unesthetic   The ENT examination legitimized by the hypoacusis showed a retro tympanic air-fluid level and abilateral presbycusis on audiometry.Otherwise, given our patient's young age, morphotype, and evident skin lesions, we suspected agenetic syndrome, especially since her baby who is a 6 month-old girl presents a typical facialdysmorphism of a genetic syndrome, multiple « café au lait » spots, and a cutaneous angioma.All these clinical findings       adults [5].Up to now, the genetics of pheochromocytoma have been divided into 3 main groups:Multipleendocrine neoplasia type II, Von Hippel-Lindau disease, and Neurofibromatosis type 1 wherepheochromocytoma is not firstly seen [1].
Currently, family history is the most important predictor factor of the existence of a germlinemutation in individuals with pheochromocytoma, about 90% of whom have a family history with anidentifiable mutation. However, the absence of a family history should not preclude the indication ofa genetic assessment [5].Our The geneimplicated is a tumor suppressor gene via its product: Neurofibromin. About 50% of the cases arehereditary and 50% of them are de novo mutations [3,8,9].The clinical manifestations are diverse with the association of skin signs (« café au lait » spots in 95%of the cases, frecklings) and Lisch nodules in the iris and cutaneous and/or subcutaneousneurofibromas (40 -60% of the cases) [3].
NF1 has a weak genotype-phenotype correlation and a high inter and intra-familial phenotypicvariability [10].The diagnosis of NF1 is based on clinical findings with reference to criteria developed by "the UnitedStates National Institutes of Health (NIH)" which were published in 1987 and have remained valid.
Apatient must meet at least 2 of the following criteria to make the diagnosis of NF1 (Table 1)  The middle age of onset is around the fourth decade, but it can be in childhood. These tumorsprogress the same way as sporadic pheochromocytomas [5].Most pheochromocytomas during NF1 mainly produce normetanephrine and are most oftenmanifested by hypertension and noradrenergic signs. However, 22% of them remain asymptomatic200 [3,5].Although rare, NF1 can be responsible for an uncontrolled hypertension with large variations as it isthe case of our patient. Morbidity will be significant with a high risk of mortality if the diagnosis isdelayed or missed .This can be due to a catecholamine release by pheochromocytoma which isresponsible for the variability and the severity of hypertension as well as the myocardial infarctionand the cardiac arrhythmias [2,3].  As it is a complicated process, detection of mutations in the NF1 gene is available in specializedlaboratories, and the diagnosis of NF1 can be established by clinical findings alone. Nevertheless,some patients with an apparently sporadic pheochromocytoma had the NF1 mutation, all with mildmanifestations of the disease.
These results show the importance of careful clinical examination ofpossible clinical signs of an underlying mutation in all the cases of pheochromocytoma [7] (Table 3).Pheochromocytoma in NF1 is unilateral and not metastatic in more than 80% of cases (and has amalignant rate of about 10%)However, the particularity presented by our case, is that the tumor, clinically and radiologicallybenign, presents histological features of malignancy with a score 4 of PASS, vascular embolisms, anda focal capsular invasion.According to many authors, a PASS score <4 is more in favor of benign tumors and a PASS score ≥ 4 israther in favor of potentially malignant tumors. Others assume that tumors with a PASS score ≥ 4should be closely followed for a possible recurrence and those with a PASS score ≥ 6 are potentiallymalignant [2,5,12].  [15,17].The coexistence of NF1 and NS was explained by a coincidence of two different autosomal disorders.Some manifestations of NF1 (café-au-lait spots) can occur as a symptom of a classical NS. Themanifestations of NS in these patients are a variable form of NF1 or a discrete form of NFNS [18].The NFNS phenotype is highly heterogeneous at both the clinical and the molecular levels. Manyother causes may be intricate in the occurrence of neurofibromatosis 1 and NS [17].Our case was unusual in that the patient was presented with pheochromocytoma at the age of 34years and had not been diagnosed with neurofibromatosis-NS before.However, the main problem remains with her little baby in whom the NS was suspected. Hence theimportance of the multidisciplinary care, specializing in pediatrics and genetics, in order not tomisdiagnose associated comorbidities.

Conclusion
Although rare in patients with NF1, pheochromocytoma

Declaration of Interest
There is no conflict of interest.

Funding
This research did not receive any specific grant from any funding agency in the public,commercial or not-for-profit sector.

Author Contribution Statement
Pr.JRAD who contributed to the selection of CT-scansPr.
Rammeh and her team selected histological sections and gave the comments below. The article was written in collaboration with Dr.ROJBI, edited by members of the endocrinologyteam.