CME INDIA Case Presentation by Dr Ashutosh Chandan Dubey (Dr Strange), DNB, Internal Medicine, Hindalco Hospital, Renukut (UP).

CME INDIA Case Study:

Which condition has too many cats that pees too much!?

Hint: It has an increase in catecholamines that can cause excessive peeing.

Increase in urinary excretion of catecholamine.

In this case there was no history of Severe or resistant hypertension, worsening of previously stable hypertension – Malignant hypertension – or Headache, sweating and tachycardia – ‘spells’ with palpitations, headache, pallor.

History

• A 52 yr. old Man attended OPD with whitish discharge from urethra.
• No associated Dysuria, Pain in loin, Fever, but inability to maintain urine stream. No Hesitancy, Urgency or urine incontinence.
• No High-Risk behaviour, any genital lesion or inguinal lymphadenopathy. No past H/O Blood Transfusion, Tattooing etc.

Physical Examination

• O/E Patient had diffuse neurofibromatosis with Axillary freckles n Cafe au lait spots suggestive of Neurofibromatosis.

• No Past H/O DM, Thyroid disorder, Substance abuse etc. He is an old case of HTN, CAD-TVD-Post-CABG.

Why Came to OPD?

• Patient attended OPD for report review showing Proteinuria of 1200mg/24 hr. Rest Blood N Urine reports were normal.
• USG Abdomen done and based on its report CECT Abdomen done. USG was suggestive of Rt Suprarenal mass with BPH. Pt was then advised for CT Abdomen showing Rt Suprarenal mass with peripheral Enhancement.

• Further MRI of Abdomen done

Based on MRI Report, Free Plasma Metanephrine done:

• Patient   showed up with reports showing raised Serum Metanephrine of 998, raised Nor Metanephrine level of 321, raised 3 – Methoxytyramine of 92 and low Cortisol of 1.31.
• Urine flow study and urethroscopy are suggestive of Urethral stricture.
• Patient is being planned for Rt Adrenalectomy and stricture removal.

Diagnosis

Question for Spot Diagnosis

EYE Examination

Right Eye

What is this?

CME INDIA Discussion

Dr Prakash Kr Jha, Ranchi: Lisch nodule in right eye.

Dr Abhish: MEN 2b.

Dr Rajneesh Tyagi, Internist, Noida, UP: Lisch nodule, Pheochromocytoma with NFI initially was thought to be rare, but there is significant increase in incidence of simultaneous occurrence. May be another multiple endocrine disorder or a part of previous ones.

Dr Mahadevan, Dermatologist: Iris hamartomos, Lisch nodules.

Dr Suresh Nath, Gauhati: Irish nodule commonly associated with neurofibromatosis type 1 also called lisch nodules.

NF 1-PHEO -GIST is genetically inherited disorder n sometimes pheo -NF 1 n gastrointestinal stromal tumor is associated and prognosis is not good. Lisch nodules r commonly associated with NF1, mutations occur in NF 1 gene n lisch nodules generally occurs in 95% cases after the age of 20 in association with NF -1 n it doesn’t affect vision n pheochromocytoma r associated with 3-4% cases of NF 1. Also rule out optic glioma, astrocytoma which r commonly found in NF 1.

Dr Venkatesh Molio, Maregoan Goa: Lisch nodule or melanocytic hamartoma are usually associated with Type 1 neurofibromatosis. MEN 2 b. Also, need to rule out medullary carcinoma of thyroid phaeochromocytoma addition to neurofibromatosis.

Dr Harish Darla, Endocrinologist, Mysore: Lisch nodule. Neurofibromatosis with cafeuleits patches.

Dr Amit Kumar, Dermatologist, Ranchi: Lisch nodule. Neurofibromatosis with lentigines. Cafe-au-lait spots are present along with multiple lentigines. Need to examine the axillary areas for the freckles also.

CME INDIA Learning Points

• Pheochromocytoma is classically described as presenting with paroxysms of adrenergic symptoms, such as palpitations, headaches, anxiety, and sweating, associated with labile hypertension.
• According to the “rule of 10”, in 1/10 patients with pheochromocytoma it is malignant, in 1/10 of cases the tumor is bilateral, in 1/10 extra-adrenal and in 1/10 familial. 
• Most pheochromocytomas, however, present with persistent hypertension.
• The clinical manifestations of a pheochromocytoma depend on the predominant catecholamine that the tumour produces and whether the secretory pattern is continuous or paroxysmal.
•  Although pheochromocytomas are rare, autopsy studies suggest that they are present more often than they are diagnosed. These patients tend to have a decreased intravascular volume status, and thus both PRA and PAC levels are elevated
• Twenty-four-hour urinary fractionated metanephrines and catecholamines may be the preferred diagnostic test, but some advocate the use of plasma-fractionated free metanephrine because of its ease of collection and high sensitivity.
• If pheochromocytoma is suspected, urinary catecholamines and fractionated metanephrines are the tests of choice.
•  Plasma fractionated metanephrines have specificity, but their sensitivity is too low for screening purposes.
•  Urinary vanillylmandelic acid (VMA) is no longer recommended because of its poor sensitivity and specificity.
• TELL WHAT ARE POINTS IN FAVOUR OF MEN Syndrome
• MEN Type 2B disease.
• Multiple endocrine neoplasia type 2B can consist of
  • Medullary thyroid cancer
  • Pheochromocytomas
  • Growths around nerves (neuromas)
• Many people with type 2B disease have no family history of it. In these people, the disease is the result of a new gene defect (genetic mutation).
• Lisch nodules are dome-shaped gelatinous masses developing on the surface of the iris. Gold-tan to brown in color, they may grow up to 2 mm in diameter and attain variable sizes on the same iris. The presence of Lisch nodules is the most common clinical sign of NF1.
• Two or more of the following clinical features signify the presence of NF1 in a patient.  
  1. More than 6 cafe au lait macules over 0.5 cm in greatest diameter in prepubertal individuals and over 1.5 cm in greatest diameter in postpubertal individuals.
  2. Two or more neurofibromas of any type or one plexiform neurofibroma.
  3. Freckling in the axillary or inguinal regions.
  4. Optic glioma.
  5. Two or more Lisch nodules (iris hamartomas).
  6. A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudoarthrosis.
  7. A first-degree relative (parent, sibling or offspring) with NF1 as defined by the above criteria.

• MEN stands for “Multiple Endocrine Neoplasia”.   The MEN syndromes are conditions which cause overactivity and enlargement in certain endocrine glands.  MEN syndromes are usually (but not always) inherited conditions and therefore they run in families. When they are inherited, they are passed from one generation to the next.
• There are three main types of multiple endocrine neoplasia (MEN) – MEN 1, MEN 2a and MEN 2b. Each type of MEN is associated with a specific cluster of illnesses. 

• MEN 1 = Parathyroid tumors, pancreatic tumors, and pituitary tumors.
• MEN 2a = Medullary thyroid cancers (MTC), pheochromocytoma, and parathyroid tumors.
• MEN 2b = Medullary thyroid cancers, pheochromocytoma and neuromas.

• Phaeochromocytoma: false positive results
  • Any acute illness, esp CV/MI/CCF/OSA
  • Tricyclic anti-depressants
  • Decongestant cold remedies
  • Amphetamines/cocaine
  • Buspirone and most psychoactive agents
  • Prochlorperazine • Ethanol

• Imaging in phaeochromocytoma
  • CT or MRI both very sensitive but 70% specificity due to ‘incidentalomas’ – Heterogeneous, vascular, cystic, dense adrenal lesions
  • No concern about use of IV contrast if not alpha-blocked
  • Diagnostic 123I-MIBG if: – Large phaeo (>10 cm) – ParagangliomaCT or MRI both very sensitive but 70% specificity due to ‘incidentalomas’ – Heterogeneous, vascular, cystic, dense adrenal lesions
  • No concern about use of IV contrast if not alpha-blocked
  • Diagnostic 123I-MIBG if: – Large phaeo (>10 cm) – Paraganglioma

• Majority of hypertension is ‘primary’
  • Consider screening if: – Young – Malignant hypertension – Resistant hypertension – Newly uncontrolled hypertension
  • Main screening tests: – ARR (beware but don’t be put off by drugs) – 24h urinary metanephrines – Renal ultrasound – Renal doppler or MRA renal arteries

• Multiple Endocrine Neoplasia (MEN) type 2 is characterized by alife-long risk of developing medullary thyroid carcinoma (MTC),which occurs in more than 95% of patients.
• Pheochromocytoma(PCC) is associated withtwo of the MEN2 clinical subtypes, MEN2A and MEN2B, but rarelyin familial MTC (FMTC)
• Neurofibromatosis type 1 (NF1)
• Patients with NF1 present manifestations that are obvious at physical examination, most commonly including café-au-lait macules, neurofibromas and axillary and inguinal freckling by the time they are at risk of developing a PCC.
• Genetic testing is thus generally not necessary to establish a correct NF1 diagnosis
• The average age of onset is in the fourth decade, but it can also occur in childhood and examples of multi-generational PCCs have been reported.

NF1-related clinical features

1. Café-au-lait spots
2. Cutaneous and subcutaneous neurofibromas
3. The presence/absence of intertriginous skin freckling
4. Lisch nodules
5. Plexiform and spinal neurofibromas
6. Optic gliomas
7. Other neoplasms (in particular cns gliomas, malignant peripheral nerve sheath tumors (mpnsts))
8. Juvenile myelomonocytic leukaemia
9. Rhabdomyosarcoma
10. Phaeochromocytoma
11. Gastrointestinal stromal tumors
12. Juvenile xanthogranuloma, and lipoma
13. Evidence of learning difficulties

Source:

1. https://doi.org/10.1016/j.ijsu.2014.04.001Current concepts of pheochromocytoma International Journal of Surgery. Volume 12, Issue 5, May 2014, Pages 469-474
2. Hum Genomics,2012 Aug 13;6(1):12.doi: 10.1186/1479-7364-6-12

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