How Bad Is Lipoprotein (a)

By Dominik Lajsz
and Amin H. Karim MD

1.1 What is lipoprotein(a)?

Lipoprotein(a) is a variation of low-density lipoprotein that includes a protein known as apolipoprotein(a). Research involving genetics and population studies has found that elevated levels of lipoprotein(a) is associated with an increased risk of developing atherosclerosis and related conditions like coronary heart disease and stroke.(1)

1.2. Structure of the Lipoprotein (a) particle

Lp(a) shares similarities with low-density lipoprotein (LDL), as it consists of a lipid core containing cholesteryl esters and triacylglycerols, surrounded by a phospholipid and apolipoprotein B-100 (apoB-100) particle layer.(3) In contrast to LDL cholesterol, Lp(a) contains an additional unique glycoprotein known as apolipoprotein(a) (apo(a)), which is connected to apoB-100 through a single disulfide bond. The biosynthesis of Lipoprotein(a) takes place almost exclusively in the liver.

2.1. Adverse effects of elevated lipoprotein (a) levels

Similar to LDL-cholesterol, the cholesterol found in Lp(a) can accumulate in the walls of your blood vessels. The higher your Lp(a) level, the greater the likelihood of this occurring. These deposits of cholesterol, known as plaques, have the potential to reduce blood flow to various organs such as the heart, brain, kidneys, lungs, legs, and other parts of the body. Over time, plaques can gradually grow or suddenly rupture, obstructing blood vessels and resulting in heart attacks or strokes.Lp(a) has the potential to induce heightened clotting, which in turn can result in the formation of blockages in blood vessels at a rapid pace. Lp(a) promotes inflammation which increases the likelihood that plaques will rupture.(2)Additionally, heightened levels of Lp(a) can contribute to the development of aortic stenosis, a condition characterized by the narrowing of the aortic valve due to inflammation. This chronic inflammation can lead to the accumulation of calcium on the valve, resulting in stiffness. As a consequence, blood flow may be compromised if the valve fails to open fully. In certain instances, individuals with aortic stenosis may require surgical intervention or a procedure to replace the affected aortic valve.⁽²⁾Convincing evidence has emerged from pathophysiological, epidemiological, and genetic studies on the causality of high serum lipoprotein(a) (Lp(a)) levels as a potent risk factor for coronary heart disease (CHD), ischemic stroke, peripheral artery disease, heart failure, calcific aortic valve stenosis (CAVS), mitral valve stenosis, and retinopathy in patients with diabetes.(14) (Fig. 1)

Fig. 1: The pathogenicity of lipoprotein(a). (Source: Koutsogianni et al, 2023)

Elevated levels of Lp(a), specifically exceeding 50 mg/dL (125 nmol/L), are prevalent. The median levels of Lp(a) differ according to race and gender. This condition is observed in individuals of all races and ethnicities, but it appears to be more prevalent among black individuals. Many individuals with high Lp(a) do not experience any symptoms. However, if you possess the following risk factors, your doctor may suspect that you have high Lp(a).

Poor circulation in your legs (called peripheral arterial disease)
Heart attack, stroke, or coronary artery disease before age 55 (in men) or age 65 (in women) without known risk factors, such as high LDL, smoking, diabetes, or obesity
Female family members who had a heart attack or stroke before age 65
Male family members who had a heart attack or stroke before age 55
Familial hypercholesterolemia
Aortic valve stenosis

2.2. Mechanism of action

Lp(a) favors initiation of atherogenesis by modulating recruitment of inflammatory cells in the vessel wall. In vitro and animal studies have implicated lipoprotein(a) in key processes in atherosclerosis, including foam cell formation, smooth muscle cell proliferation, and plaque inflammation and instability.(4) Lp(a) blocks plasminogen conversion to plasmin, therefore plasmin mediated TGF-β activation is inhibited. TGF-β is an autocrine inhibitor of Smooth muscle cell growth.(12) Lp(a) increases atherosclerotic plaque vulnerability, vascular smooth muscle cell proliferation and adhesion of molecules, chemotactic factors and plasma cytokines. (Fig. 2) Moreover, Lp(a) enhances platelet activation and aggregation and inhibits fibrinolysis by inhibiting plasminogen activation.(13)

Fig. 2: The impact of lipoprotein(a) on atherosclerotic process and atherothrombosis. (source:Lampsas et al, 2023)

Recently, lipoprotein(a) has also been identified as the main carrier of oxidized phospholipids considered proinflammatory and proatherogenic.(5) Lipoprotein(a) has been hypothesized to contribute to wound healing (6), transporting cholesterol to sites of injury for cell replenishment, and limiting bleeding via attenuated fibrinolysis. A nonspecific wound healing effect of lipoprotein(a) may, however, explain an association with aortic valve disease considered the result of repeated valve injury and repair mechanisms (7). Recent in vitro studies, demonstrating osteogenic differentiation of valvular interstitial cells exposed to lipoprotein(a) and associated oxidized phospholipids, point to yet another possible mechanism relevant for aortic valve disease, often characterized by pronounced valve calcification (8), and perhaps also for development of advanced atherosclerotic lesions. Large genetic epidemiologic studies have generated renewed interest in lipoprotein(a) by providing strong genetic evidence of causal associations of high lipoprotein(a) concentrations with increased risk of CHD, AVS, heart failure, and mortality.(9,10,11)

3. Treatment options in high lipoprotein(a)

Lipoprotein apheresis

The most effective clinical intervention available for lowering Lp(a) is lipoprotein apheresis (LA). Following treatment, Lp(a) levels can be acutely reduced by 70–80%. However, rebound elevations between apheresis sessions, carried out weekly, biweekly, or less frequently, typically yield a mean Lp(a) reduction of 25–40%, depending on the treatment duration and initial Lp(a) levels. Although LA is not commonly utilized worldwide, except in Germany, long-term studies on patients with elevated Lp(a) undergoing LA indicate that this therapy may potentially reduce 5-year cardiovascular risk by up to 86%.(15)

Niacin

Niacin decreases Lp(a) in a dose-dependent manner by approximately 30–40% on average, but only by 18% in those with the highest Lp(a) levels. The effect of niacin is likely due to a decreased apo(a) production rate. Importantly, studies with cardiovascular outcomes showed no benefit of adding niacin to statins. Moreover, niacin use is limited by side effects, such as flushing, gastrointestinal discomfort, and new-onset diabetes. (14)

PCSK9 inhibitors

PCSK9 monoclonal antibodies, i.e., alirocumab and evolocumab, reduce Lp(a) levels by approximately 20–30%. The exact mechanism by which PCSK9 inhibitors reduce Lp(a) levels remains unclear, Current hypotheses include increased clearance of Lp(a) particles via the LDLR, increased clearance of Lp(a) via other receptors (the LDL receptor-related protein 1, the cluster of differentiation 36 receptor, toll-like receptor 2, scavenger receptor-B1, and plasminogen receptors), as well as a reduction in apo(a) production, secretion, and/or assembly.(14)

Fibrates

Bezafibrate has been shown to reduce Lp(a) levels by approximately 13–39%. (16)

Lomitapide

Lomitapide, a microsomal triglyceride transfer protein inhibitor, reduces Lp(a) levels by 15–19%(17) The possible mechanism for Lp(a)-lowering is the decrease in very-low-density lipoprotein (VLDL) and chylomicron synthesis via inhibition of MTP. MTP is located in the endoplasmic reticulum of hepatocytes and enterocytes and is most likely responsible for transferring triglycerides to nascent apoB as it enters the lumen of the endoplasmic lumen. Consequently, MTP inhibition seems to control the number of apoB-containing lipoprotein particles secreted into the bloodstream, including Lp(a) particles.(17)

Cholesteryl Transfer Protein (CETP) Inhibitors

CETP mediates the transfer of cholesteryl esters from high-density lipoprotein (HDL) to apoB100-containing particles, including VLDL and LDL, in exchange for triglycerides. Apart from raising HDL cholesterol, CETP inhibitors also decrease apoB100, LDL cholesterol, and Lp(a) levels (by approximately 24–36%). (14) Clinical outcome trials of four CETP inhibitors have been completed, including torcetrapib, dalcetrapib, evacetrapib, and anacetrapib. CETP inhibitors are not currently approved for clinical use.

Conclusions:

Lp(a) has been identified as a significant risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS), with the risk increasing in proportion to Lp(a) concentrations. It is believed that meaningful reductions in cardiovascular outcomes require substantial reductions in Lp(a) concentrations. In patients with elevated Lp(a) levels, more aggressive targets for LDL cholesterol (LDL-C) reduction are recommended compared to individuals with similar ASCVD risk but normal Lp(a) levels. Initially, the approach to reducing ASCVD risk in patients with high Lp(a) focuses on further LDL-C reduction. However, there are several promising agents in late-stage development, and the results of phase 3 outcome studies are highly anticipated. Additionally, there are other agents in various drug classes, including lipid-modifying medications, that can also impact Lp(a) levels.

References:

1: Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010

2. Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP, Kamstrup PR, et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2022; 42(1):e48-e60.

3. Ruscica M., Sirtori C.R., Corsini A., Watts G.F., Sahebkar A. Lipoprotein(a): Knowns, unknowns and uncertainties. Pharmacol. Res. 2021;173:105812. doi: 10.1016/j.phrs.2021.105812.

4. Boffa MB , Marcovina SM , Koschinsky ML. Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models. Clin Biochem 2004;37:333–43.

5. Tsimikas S , Brilakis ES , Miller ER , McConnell JP , Lennon RJ , Kornman KS , et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 2005;353:46–57.

6. Brown MS , Goldstein JL. Plasma lipoproteins: teaching old dogmas new tricks. Nature 1987;330:113–4.

7. Kamstrup PR , Tybjærg-Hansen A , Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014;63:470–7.

8. Zheng KH , Tsimikas S , Pawade T , Kroon J , Jenkins WSA , Doris MK , et al. Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis. J Am Coll Cardiol 2019;73:2150–62.

9. Thanassoulis G , Campbell CY , Owens DS , Smith JG , Smith AV , Peloso GM , et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013;368:503–12.

10. Kamstrup PR , Tybjærg-Hansen A , Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014;63:470–7.

11. Arsenault BJ , Boekholdt SM , Dubé M-P , Rhéaume É , Wareham NJ , Khaw K-T , et al. Lipoprotein(a) levels, genotype and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case-control cohort. Circ Cardiovasc Genet 2014;7:304–10.

12 Grainger D.J., Kirschenlohr H.L., Metcalfe J.C., Weissberg P.L., Wade D.P., Lawn R.M. Proliferation of human smooth muscle cells promoted by lipoprotein(a) Science. 1993;260:1655–1658.

13. Lampsas S, Xenou M, Oikonomou E, Pantelidis P, Lysandrou A, Sarantos S, Goliopoulou A, Kalogeras K, Tsigkou V, Kalpis A, Paschou SA, Theofilis P, Vavuranakis M, Tousoulis D, Siasos G. Lipoprotein(a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules. 2023 Jan 18;28(3):969.

14. Koutsogianni AD, Liamis G, Liberopoulos E, Adamidis PS, Florentin M. Effects of Lipid-Modifying and Other Drugs on Lipoprotein(a) Levels-Potent Clinical Implications. Pharmaceuticals (Basel). 2023 May 16;16(5):750.

15. Roeseler E., Julius U., Heigl F., Spitthoever R., Heutling D., Breitenberger P., Leebmann J., Lehmacher W., Kamstrup P.R., Nordestgaard B.G., et al. Lipoprotein apheresis for lipoprotein(a)-Associated cardiovascular disease: Prospective 5 years of follow-up and apolipoprotein(a) characterization. Arterioscler. Thromb. Vasc. Biol. 2016;36:2019–2027.

16. Tenenbaum A., Fisman E.Z. Balanced pan-PPAR activator bezafibrate in combination with statin: Comprehensive lipids control and diabetes prevention? Cardiovasc. Diabetol. 2012;11:140. doi: 10.1186/1475-2840-11-140.

17. Cuchel M., Meagher E.A., Theron H.D.T., Blom D.J., Marais A.D., Hegele R.A., Averna M.R., Sirtori C.R., Shah P.K., Gaudet D., et al. Efficacy and Safety of a Microsomal Triglyceride Transfer Protein Inhibitor in Homozygous Familial Hypercholesterolemia. Lancet. 2013;381:40.

Going Where No Balloon Has Gone Before!

By Dr. Salman Arain MD
McGovern Medical School, Houston, Texas.

Those of you who know me well, know that I as keen about small (and large) vessel PAD as I am about coronary CTOs. An interesting consequence of these interests has been my foray into micro-angioplasty for refractory digital ischemia. I would like to share a case from this week…

46 year old school teacher with non healing (painful!!!) finger ulcers for 2 months. Here is the baseline angio. This is what a scleroderma hand looks like. You can see the missing flow at the tips of digits #2 and 3.

We were able to wire the proper digital branches to both digits. These vessels are too small for a balloon – so we ‘open’ them by pushing microcatheters. hese are the smallest vessels that I have intervened upon – often 1 mm or less!

Here is flow to the second digit.

This is the hand immediately after the intervention. Note the cyanosis and swelling…

But her hand and finger mobility is back!!

This day 2 – on Flolan.

And this day 3. The wounds are drying up and the color is almost normal. The fingers sre fully mobile and not tender.

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A Tough Chronic Total Occlusion (CTO)

By Dr. Salman Arain
McGovern Medical School, Houston, Texas.
February 10 2024

There are several ways to approach a CTO. The entire crossing process, whether antegrade or retrograde, starts with crossing the cap. Different techniques have been described. In my practice, I like to use contrast to modify and modulate the cap/plaque…

History. 68 year old man with LAD PCI 4 years ago. Presented with angina and found to have a new RCA lesion (which was stented) and this LAD CTO. The angina has resolved but the exertional dyspnea persists. The PET was very abnormal in the AW.

There are 3 sets of right to left collaterals. Not all are ‘usable’. The LAD fills in ‘stages’ which suggests disease in the native LAD beyond the CTO.

Plaque penetration was more challenging than expected. That is a Hornet 14 wire (14 gm penetration force at the tip!). As per our protocol, we stopped once the wire was a few mm distal to the hard cap. We then maneuvered our microcatheter (MC) in place.

Contrast modulation. 👆🏼Here is the intra-CTO contrast injection! Note the free passage of an tapered tip hydrophilic wire (Fielder XT).

Here is a distal tip injection. This is different than injecting into the occlusion. Transducing pressure allows is to confirm we are across before injecting. A softer tipped hydrophilic wire (Gladius Mongo) helped us track into the true LAD.

I like to perform IVUS before stenting to understand the nature of the CTO, the characteristics of the vessel wall, and the size of the lumen. This helps us choose the appropriate vessel preparation and stent therapy. Here our crossing is all intraluminal.

Here is the final run. We did multiple IVUS runs to size the LAD and optimize both the LAD and the D2. Note that all septals have been preserved! All in all a successful CTO which we completed in under an hour and a half.

Implantable Cardioverter Defibrillator (ICD)

By Amin H. Karim MD

Prof. Michel Mirowski, Chief of Cardiology at the Sinai Hospital of Baltimore, Maryland, Inventor of ICD, with Amin H. Karim (Resident in Department of Internal Medicine 1981)

The development of the ICD was pioneered at Sinai Hospital in Baltimore by a team including Michel Mirowski, Morton Mower, Alois Langer, William Staewen, and Joseph “Jack” Lattuca. Mirowski teamed up with Mower and Staewen and together they commenced their research in 1969 but it was 11 years before they treated their first patient.

I was a resident at the Sinai-Hopkins program in 1981-83. We followed the development of the ICD with interest and watched Dr. Mirowski conduct his experiments on dogs. The dog would be attached to electrodes, with a large contraption on a crash cart following the dog. The dog would be put into ventricular tachycardia by stimulation and would collapse to be followed by a auto shock and the dog would be revived! The size of the contraption was the size of a large television; Engineers with Boston Scientic and other companies then worked on it and made it compact and implantable.

The work was commenced against much skepticism even by leading experts in the field of arrhythmias and sudden death. There was doubt that their ideas would ever become a clinical reality. In 1972 Bernard Lown, the inventor of the external defibrillator, and Paul Axelrod stated in the journal Circulation – “The very rare patient who has frequent bouts of ventricular fibrillation is best treated in a coronary care unit and is better served by an effective anti-arrhythmic program or surgical correction of inadequate coronary blood flow or ventricular malfunction. In fact, the implanted defibrillator system represents an imperfect solution in search of a plausible and practical application.”

The problems to be overcome were the design of a system which would allow detection of ventricular fibrillation or ventricular tachycardia. Despite the lack of financial backing and grants, they persisted and the first device was implanted in February 1980 at Johns Hopkins Hospital by Dr. Levi Watkins Jr.

The first devices required the chest to be cut open and a mesh electrode sewn onto the heart; the pulse generator was placed in the abdomen.

ICDs constantly monitor the rate and rhythm of the heart and can deliver therapies, by way of an electrical shock, when the heart rate exceeds a preset number. More modern devices have software designed to attempt a discrimination between ventricular fibrillation and ventricular tachycardia (VT), and may try to pace the heart faster than its intrinsic rate in the case of VT, to try to break the tachycardia before it progresses to ventricular fibrillation. This is known as overdrive pacing, or anti-tachycardia pacing (ATP). ATP is only effective if the underlying rhythm is ventricular tachycardia, and is never effective if the rhythm is ventricular fibrillation.

Many modern ICDs use a combination of various methods to determine if a fast rhythm is normal, supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation.

Rate discrimination evaluates the rate of the lower chambers of the heart (the ventricles) and compares it to the rate in the upper chambers of the heart (the atria). If the rate in the atria is faster than or equal to the rate in the ventricles, then the rhythm is most likely not ventricular in origin, and is usually more benign. If this is the case, the ICD does not provide any therapy, or withholds it for a programmable length of time.

Rhythm discrimination will see how regular a ventricular tachycardia is. Generally, ventricular tachycardia is regular. If the rhythm is irregular, it is usually due to conduction of an irregular rhythm that originates in the atria, such as atrial fibrillation. In the picture, an example of torsades de pointes can be seen; this represents a form of irregular ventricular tachycardia. In this case, the ICD will rely on rate, not regularity, to make the correct diagnosis.

Morphology discrimination checks the morphology of every ventricular beat and compares it to what the ICD knows is the morphology of normally conducted ventricular impulse for the patient. This normal ventricular impulse is often an average of a multiple of normal beats of the patient acquired in the recent past and known as a template.

The integration of these various parameters is very complex, and clinically, the occurrence of inappropriate therapy is still occasionally seen and a challenge for future software advancements.

Lead II electrocardiogram (known as “rhythm strip”) showing torsades de pointes being shocked by an implantable cardioverter-defibrillator back to the patient’s baseline cardiac rhythm.

Torsades de Pointes converted by ICD

A number of clinical trials have demonstrated the superiority of the ICD over AAD (antiarrhythmic drugs) in the prevention of death from malignant arrhythmias. The SCD-HeFT trial (published in 2005)showed a significant all-cause mortality benefit for patients with ICD. Congestive heart failure patients that were implanted with an ICD had an all-cause death risk 23% lower than placebo and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population.1 Reporting in 1999, the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial consisted of 1,016 patients, and deaths in those treated with AAD were more frequent (n = 122) compared with deaths in the ICD groups (n = 80, p < 0.001) In 2002 the MADITII trial showed benefit of ICD treatment in patients after myocardial infarction with reduced left ventricular function (EF<30). (Copied from Wikipedia)

Prof. Mirowski of Sinai Hospital of Baltimore, Maryland in his office.

Mirowski, M; Reid, PR; Mower, MM; Watkins, L; Gott, VL; Schauble, JF; Langer, A; Heilman, MS; Kolenik, SA; Fischell, RE; Weisfeldt, ML (7 August 1980). “Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings”. The New England Journal of Medicine. 303 (6): 322–4. doi:10.1056/nejm198008073030607. PMID 6991948.

Neurofibromatosis

By Dr. Shifa Younus
Nishtar Medical College, Multan, Pakistan.
Amin H. Karim MD

Case Presentation:

A 65-year-old patient, presents in the office with multiple raised lesions all over his body more so on face and extremities. The patient has had these lesions since childhood. He had a few lesions in the beginning, but these progressively increased in number with time. The Patient complains of high blood pressure readings for one year. There is no history of neurological tumors, intellectual disability, or renal involvement.

Family History: The Patient has a family history of similar lesions in his son and grandson. Both have these lesions with associated symptoms.

Physical Examination:
Extremity Examination: There are multiple lesions which are raised, mobile, and painless with no associated ulcers or change in coloration of the surrounding skin.

Diagnosis:
Based on the symptoms and history, Mr. Mccray was diagnosed with Neurofibromatosis type 1 or Von Recklinghausen’ disease.

Neurofibromatosis type 1 or Von Recklinghausen’s Disease:

Neurofibromatosis type 1 (NF-1) was formerly known as Von Recklinghausen’s disease after the German pathologist, Friedrich Daniel von Recklinghausen (1822-1910). He was the student of a famous pathologist Rudolph Virchow in University of Berlin. and served as the professor of pathology in various universities. He is best known for his description of three disorders: multiple neurofibromatosis, osteitis fibrosa cystica, and hemochromatosis.[1]

NF-1 is one of the most common neurocutaneous genetic disorders with autosomal pattern of inheritance. It accounts for 1 out of 3000 live births. It is caused by the mutations in NF-1 gene, present on chromosome 17, which encodes a cytoplasmic protein, neurofibromin present in neurons, leukocytes, oligodendrocytes, and Schwann cells. [2]

NF-1 is an age specific disease which becomes apparent during infancy, but it can also appear in adulthood due to hormonal changes. The severity of the disease varies from person to person. However, about 60% of the patients present with mild disease with no effect on their daily life. Neurofibromas, the most common presentation related to NF-1, are the peripheral nerve sheath tumors arising from Schwann cells and fibroblasts. [3]

NF-1 comprises of multiple manifestations ranging from cutaneous lesions to serious neurological and systemic manifestations which include:

Cutaneous manifestations:

Café au lait spots
Inguinal or axillary freckling (Crowe’s sign)
Neurofibromas; cutaneous or plexiform

Ocular manifestations:
Optic glioma
Lisch nodules, brown pigmented hamartomatous nodule affecting iris.

Musculoskeletal manifestations:
Kyphosis
Scoliosis
Macrocephaly
Sphenoid dysplasia

Craniofacial manifestations:
Orbital dysplasia
Intraosseous neurofibroma of maxilla and mandible
Pheochromocytoma.
Attention deficit hyperkinetic disorder.

NF-1 can lead to some serious complications including bone tumors and peripheral nerve damage that may also lead to vision loss. Some neurofibroma may rarely degenerate into malignant tumors. However, early diagnosis and treatment plays an important role in improving the prognosis. The National Institute of Health Consensus Development Conference in 1988 put forth a diagnostic criterion for NF-1. If the patient has two or more of the following:

Six or more café au lait macules
Two or more neurofibromas of any type or one plexiform neurofibroma
Freckling in the axillary or inguinal regions
Optic glioma
Two or more iris Lisch nodules
Distinctive osseous lesion such as sphenoid dysplasia
Family history of the first-degree relative with neurofibromatosis. [4]

Other diagnostic techniques include:

Slit-lamp examination may be performed on children to look for Lisch nodules.
T2 weighted MRI of the brain and spine which may reveal hyperintense lesions due to aberrant myelination or gliosis of neurons. [5]
Biopsy of the neurofibromas which may reveal non-encapsulated tumor composed of fascicles of slender, spindle-shaped cells.
Prenatal diagnosis of NF-1 can be made by genetic testing.

The management of neurofibromatosis is done by a multidisciplinary team which includes dermatologists, neurologists, oncologists, pediatricians, and genetic counselors. Café au lait spots and cutaneous neurofibromas are particularly benign and do not require treatment. However, symptomatic lesions or ones with malignant potential may require surgical excision but their recurrence is very common. [6] Apart from the mainstay treatment by surgery there are certain medical treatments that target at the molecular level and inhibit the pathway involved in pathophysiology of neurofibromas. These include selumetinib, mirdametinib, binimetinib which have proven to be helpful in decreasing the overall volume of neurofibromas and providing symptomatic relief. NF-1 has a considerable impact on general quality of life (QoL) of the patients due to it dermatological manifestations. Therefore, psychosocial support is of immense importance in such patients and cannot be neglected. [7]

1.Britannica, T. Editors of Encyclopaedia (2023, November 28). Friedrich Daniel von Recklinghausen. Encyclopedia Britannica. https://www.britannica.com/biography/Friedrich-Daniel-von-Recklinghausen 

2.Ghalayani P, Saberi Z, Sardari F. Neurofibromatosis type I (von Recklinghausen’s disease): A family case report and literature review. Dent Res J (Isfahan). 2012;9(4):483-488.

3.Nallanchakrava S, Mallela MK, Jeenepalli VSK, Niharika HM. A rare case report of neurofibromatosis type 1 in a 12-year-old child: A 15-month follow-up. J Oral Maxillofac Pathol. 2020;24(Suppl 1):S106-S109. doi:10.4103/jomfp.JOMFP_35_20

4. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81-88. doi:10.1136/jmg.2006.045906

5. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81-88. doi:10.1136/jmg.2006.045906

6. Taylor LA, Lewis VL Jr. Neurofibromatosis Type 1: Review of Cutaneous and Subcutaneous Tumor Treatment on Quality of Life. Plast Reconstr Surg Glob Open. 2019;7(1):e1982. Published 2019 Jan 18. doi:10.1097/GOX.0000000000001982

7. Taylor LA, Lewis VL Jr. Neurofibromatosis Type 1: Review of Cutaneous and Subcutaneous Tumor Treatment on Quality of Life. Plast Reconstr Surg Glob Open. 2019;7(1):e1982. Published 2019 Jan 18.

Month: February 2024