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 Table of Contents  
Year : 2017  |  Volume : 3  |  Issue : 1  |  Page : 141-150

Part 3: Differential diagnosis for an undiagnosed systemic condition

1 Lewis Katz School of Medicine at Temple University, St. Luke's University Hospital Campus, Bethlehem, PA, USA
2 Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA
3 Department of Cardiovascular Medicine and Internal Medicine, St. Luke's University Health Network, Bethlehem, PA, USA
4 Department of Pathology, St. Luke's University Health Network, Bethlehem, PA, USA
5 Department of Internal Medicine, St. Luke's University Health Network, Bethlehem, PA, USA

Date of Web Publication7-Jul-2017

Correspondence Address:
Sudip Nanda
Department of Internal Medicine, St. Luke's University Hospital Network, 801 Ostrum Street, Bethlehem, PA 18015
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJAM.IJAM_68_16

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Constructing a meaningful differential diagnosis for systemic conditions poses challenges to a medical team. While there are certain classifications of disease known for multiorgan manifestation, a thorough differential requires physicians to examine all possible symptom etiologies, especially when the symptoms are life-threatening. We present a patient with a diverse constellation of symptoms yet to be consolidated into a diagnosis. Our discussion examines the contribution of each symptom to a possible diagnosis while attempting to identify trends between the symptoms that might yield clues to the etiology of his/her condition.
The following core competencies sare addressed in this article: Medical knowledge, Patient care.

Keywords: Connective tissue disease, differential diagnosis, undiagnosed condition

How to cite this article:
Stone LE, Fegley MW, Agrawal S, Singh A, Longo S, Nanda S. Part 3: Differential diagnosis for an undiagnosed systemic condition. Int J Acad Med 2017;3:141-50

How to cite this URL:
Stone LE, Fegley MW, Agrawal S, Singh A, Longo S, Nanda S. Part 3: Differential diagnosis for an undiagnosed systemic condition. Int J Acad Med [serial online] 2017 [cited 2022 Jan 25];3:141-50. Available from: https://www.ijam-web.org/text.asp?2017/3/1/141/209859

  Case Report Top

The patient is a 26-year-old male presenting to the clinic with systemic complaints. His medical history indicates a vertebral artery aneurysm diagnosed at age 14 as well as a splenic artery aneurysm, celiac axis aneurysm, and a splenectomy at age 21. He has sustained numerous pneumothoraces and demonstrations of reduced gastrointestinal integrity, including two Mallory–Weiss tears at age 22, a Dieulafoy's lesion, and multiple intestinal bleeds. In addition, the patient has multiple café au lait macules (CALMs) on his skin, a high-arched palate (HAP), and a marked pectus excavatum. Genetic testing revealed nonmutated collagen I and III, fibrillin I, and transforming growth factor beta (TGF-beta) receptors 1 and 2 genes, associated with Ehlers-Danlos (ED) vascular type, Marfan syndrome, and Loeys–Dietz syndrome, respectively. No definitive diagnosis of his condition has been identified.

  Discussion Top

The complexity of systemic disease challenges medical teams with the task of formulating a meaningful differential diagnosis. To thoroughly assess our patient's unknown condition, we use his symptoms as a means to detect cross-system patterns hinting at the etiology of his condition. We have chosen to include lung cysts, spontaneous pneumothorax, CALMs, HAP, pectus excavatum, aortic aneurysm, muscular artery aneurysms, intracranial aneurysm, spontaneous gastrointestinal (GI) tears, and Dieulafoy's lesions (DL) in this analysis.

Lung cysts

A computed tomography (CT) of our patient [Figure 1] demonstrates numerous lung cysts, which appear as a round, often regularly shaped regions of radiolucency juxtaposed against normal lung parenchyma. Often called “bullae” or “blebs,” these epithelial or fibrous sacs vary tremendously in size and thickness and are thus difficult to rigorously categorize without a diagnosis.[1] Consequently, the molecular pathogenesis of lung cysts is also quite variable, including a range of culprits such as genetic mutations and autoimmune deregulation.[2] Nonetheless, a definitive diagnosis is critical for managing disease progression. To aid this task, a number of algorithms have been introduced to simplify the diagnostic process.[1] A comprehensive review of these algorithms is beyond the scope of this paper as many include criteria irrelevant for our patient, such as smoking dependence and advanced age. For brevity, a survey of these algorithms in the context of our patient's presentation narrows our focus to the following conditions:
Figure 1: Computed tomography of patient's lungs demonstrates numerous lung cysts

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Birt–Hogg–Dubé syndrome is a genetic condition presenting with multiple spontaneous pneumothoraces, lung cysts, and noncancerous skin tumors on the neck and face. Individuals with this condition are also highly susceptible to renal cancers, which are noticeably absent in our patient.[3]

ED Type IV-vascular type is a genetic connective tissue disease with possible lung manifestations. Patients experience systemic disruption due to lifelong lessened connective tissue integrity. This tends to present as weakened vasculature and hollow organs, yielding aneurysms, and spontaneous organ rupture, particularly in the GI tract, both of which are present in our patient.[4]

Neurofibromatosis Type-1 is a well-studied genetic condition presenting with six or more CALMs, cutaneous neurofibromas, optic gliomas, and lisch nodules. Learning disabilities are often a common finding, accounting for roughly 50% of the patient population.[5] Findings in the lungs commonly include upper lobe lung cysts, lung fibrosis, and rarely, pneumothorax possibly as a complication of lung cysts.[6],[7]

Langerhans cell histiocytosis is typified by the infiltration and accumulation of Langerhans cells into nonnormal tissue sites, resulting in aberrant granulomas. There are many classes of this condition, some of which include systemic involvement. Patients with more lung-associated symptoms frequently display lung cysts and spontaneous pneumothorax. It is worth noting for our purposes, however, that upward of 90% of patients with this condition are self-reported smokers although our patient is not.[8]

Sjogren's syndrome is an autoimmune disorder presenting with xerostomia, keratoconjunctivitis sicca, and generalized connective tissue disorder symptoms.[9] It is the latter of these conditions that provide the most diversity in symptomology, often creating symptoms paralleling ED vascular type or Marfan syndrome (see “Pneumothorax” section below). Small lung cysts have been reported in Sjogren patients although the mechanism of formation is unclear.[7]

Amyloidosis is a condition of systemic presentation caused by accumulated, misfolded amyloid proteins that disrupt normal tissue function.[10] Most commonly, these depositions occur in the heart, kidneys, liver, and nervous system, causing progressively worsening symptoms as protein accumulations increase.[11],[12]

A review on “Lung Cysts” and other associated conditions is given in [Table 1].[3],[4],[5],[9],[10],[13],[14],[15],[16],[17],[18],[19]
Table 1: Differential by symptom category

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A pneumothorax occurs when air enters the pleural space, disrupting the pulmonary unit transmural pressure gradient and subsequently collapsing the lung. This is potentially life-threatening if not treated quickly, partly due to pressure-induced shifting of the mediastinum.[20] Pneumothoraces are categorized according to their underlying pathology. In the absence of an associated disease, they are termed “primary pneumothoraces.” These cases are linked to lung bleb, bullae, cyst rupture on the visceral pleura. The blebs, though perhaps connected to some pathology, are typically considered subclinical and therefore are not associated with disease. Molecular analysis of these blebs often reveals abnormal elastic and/or collagen fibers, components of the lung extracellular matrix crucial for efficient pulmonary recoil action.[21],[22] This dysfunction intensifies the elastodynamic strain experienced by the lung parenchyma during normal breathing, causing the bleb/bullae to burst and releasing air into the pleural space.[22]

If a pneumothorax develops secondary to parenchyma-compromising disease, the case is considered a “secondary pneumothorax.” The pathogenesis of pulmonary collapse is similar to what is observed in a primary pneumothorax, with the added classification of a diagnosable insult causing the parenchymal weakness. Consequently, many diagnosed cystic lung and connective tissue diseases present with a pneumothorax.[1],[22],[23] However, the disease-induced, pathogenically weakened lung tissue reduces a patient's pulmonary reserve, resulting in a more prolonged recovery than what may be seen from a primary pneumothorax.[24]

The third main classification category refers to those pneumothoraces not provoked by any traumatic event or disease, termed “spontaneous.”[24]

Given the standard clinical classifications for pneumothorax diagnosis, and the likelihood that our patient possesses an underlying systemic condition, his diagnosis would be appropriately classified as a “secondary pneumothorax” possibly associated with pathologic lung cyst formation. Many of these conditions have been enumerated in the “lung cysts” section of this article. In addition to those already mentioned, we also expand our discussion to include the following:

Marfan syndrome is a connective tissue disease specifically affecting the integrity of elastic fibers within the extracellular matrix. Patients with this condition present with diffuse systematic symptoms, including widespread aneurysms, cardiac abnormalities, and pectus excavatum. Spontaneous pneumothorax is more common in Marfan syndrome than in other connective tissue disease.[23]

A review of “Pneumothorax” and other associated conditions is given in [Table 1].[23]

Café au lait macules

CALMs are isolated regions of epidermal hyperpigmentation [Figure 2]. Some of the better-known conditions presenting with CALMS include neurofibromatosis Type 1 McCune–Albright syndrome, Legius syndrome, and multiple Lentigines.[25] For a more detailed review of CALMs and their proposed molecular mechanism of origin, see the first article of this series, “Part 1: CALM – presentation and genesis.”
Figure 2: Posterior view of patient with notable café au lait macule on left scapular region

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McCune–Albright syndrome affects the bones and endocrine tissues of the body. Patients exhibit abnormal bone growth, precocious puberty, and CALMs presenting on one side of the body. Hyperthyroidism or Cushing's syndrome are also sometimes present.[26]

Legius syndrome, or NF-1-like syndrome, presents with CALMs, macrocephaly, and an increased prevalence of attention deficit hyperactive disorder.[27]

Multiple Lentigines syndrome is diagnosed by the presence of cardiac electrical abnormalities, arterial stenosis, hearing loss, short stature, and abnormal genitalia. This condition is often considered to have significant overlap with Noonan syndrome (see discussion in HAP).[28]

The strongly manifesting non-CALM symptoms in each of the above-listed conditions limit the possibility that CALMS will be a focal point in assessing our patient's diagnosis. Their presence instead suggests a possibly unidentified or rare association with some other disease process.

A review of “café-au-lait” and other associated conditions is given in [Table 1].[25],[26],[27],[28],[29],[30],[31]

High-arched palate

The HAP is an anomaly of development in which the fetal palatal shelves fuse at an arched angle in the upper oral cavity [Figure 3].[32] Recent research suggests that HAP is caused by an excessive release of fibroblast growth factor 8 (FGF8) in utero, deregulating neural crest migration.[33] Neural crest cells are essential for the proper development of the facial bones and teeth, heart, enteric nervous system, melanocytes, connective tissue, and smooth muscle, to name a few.[34] Because of their involvement in multisystem development, we can hypothesize that the presence of deregulated FGF8 during an organ's critical period of development will result in that organ system displaying the strongest insult. Thus unique constellations of symptoms and abnormalities can appear in patients depending on when FGF8 is deregulated. For example, it is known that the pharyngeal arches, which contribute to the formation of the palate, will begin to appear at about week three to four of embryological development, leading to HAP if FGF8 abnormalities occur.[34]
Figure 3: Patient's high-arched palate

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For the purposes of differential diagnosis, HAP marks congenital, genetic conditions, though as a stand-alone symptom, it offers only broad suggestions of a differential diagnosis. Indeed, HAP is a documented symptom in over 300 conditions.[33] In our patient's context, we will consider HAP presentation in conjunction with connective tissue disease and systemic congenital malformations.

Despite the diversity of connective tissue diseases, HAP is a recurring commonality among the syndromes. Conditions such as Marfan syndrome, arterial tortuosity syndrome, Stickler syndrome, and Shprintzen–Goldberg syndrome are associated with HAP. Accompanying symptomology tends to be predictably clustered to blood vessel abnormalities (i.e., aneurysm or stenosis), joint and/or bone abnormalities, skin elasticity abnormalities, multiorgan parenchymal weakness as well as an increased incidence of psychiatric conditions.[35] While these listed conditions are caused by genetic variants in components of the extracellular matrix, their connection to HAP implies an inherent link between intrauterine signaling and the proper development of organ systems. Much research remains to elucidate the connection between these elements of proper development.

HAP in congenital disease is difficult to isolate into clear, classifiable categories. Better known examples include Treacher–Collins syndrome, Noonan's syndrome, and Muenke syndrome. However, because the associated symptoms of these conditions are quite marked and often appear at birth, this category of disease serves minimal function in the differential diagnosis of HAP found in an adult.

Pectus excavatum

Pectus excavatum is a congenital abnormality of the sternum and costal cartilage causing the chest to appear sunken [Figure 4]. Despite being the most common chest wall deformity, no genetic cause is yet known. It has been postulated that the cause is multifactorial with only a small subset of cases due to Mendelian inheritance.[36] Given this etiological breadth, the presence of pectus excavatum does little for a differential diagnosis as many cases are considered benign and unlinked to further pathology. It is worth noting, though that pectus excavatum frequently presents in connective tissue disease, including Loeys–Dietz, Marfan, and ED syndromes.
Figure 4: Patient's pectus excavatum

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Loeys–Dietz is a relatively newly classified connective tissue disease. It is most noted for arterial abnormalities and tortuosity as well as characteristic connective tissue findings, such as joint hypermobility and skeletal abnormalities.[37]

A review of HAP and Pectus Excavatum” and other associated conditions is given in [Table 1].[38],[39],[40],[41]

Medium muscular arterial aneurysm

Aneurysms of the visceral muscular arteries vary in frequency. The splenic artery is the third most common site of abdominal aneurysm, whereas the celiac axis is rarely affected. The pathogenesis in both sites, however, is likely due to degeneration of the tunica media that gives muscular arteries their name.[42] [Figure 5] shows the CT of our patient presenting with an aneurysm near the celiac root.
Figure 5: Computed tomography of patient's abdomen reveals celiac artery aneurysm

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While muscular artery aneurysm can be a standalone condition, they are sometimes seen in connective tissue diseases, such as ED, Marfan syndrome, arterial tortuosity syndrome, and Loeys–Dietz syndrome, each of which has been discussed in this article. We add to this list Polyarteritis nodosa, a systemic vasculitis causing arterial weakness and reduced perfusion throughout the body. Reported symptoms vary by affected artery/organ although the presence of nodules or ulcers is considered a hallmark of this condition.[43]

A review of “Muscular Artery Aneurysm” and other associated conditions is given in [Table 1].[44],[45]

Intracranial aneurysm

Intracranial aneurysms are rare findings in our patient's age cohort. They are thought to be caused by weakness in the internal elastic lamina, resulting in subsequent dissection and rupture [Figure 6]. However, the actual etiology of this laminal weakness is unknown.[46] A number of conditions already previously discussed are associated with intracranial aneurysms, including ED vascular type, Marfan syndrome, Loeys–Dietz syndrome, arterial tortuosity syndrome, and amyloidosis. To this list, we add autosomal dominant polycystic kidney disease, the most common lethal autosomal dominant condition known. Aside from marked arterial abnormalities, patients present with systemic cysts, usually resulting in rapid end-stage renal failure.[47]
Figure 6: Patient's intracranial aneurysm – left vertebral artery

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A review of “Intracranial Aneurysm” and other associated conditions is given in [Table 1].[47]

Spontaneous gastrointestinal tears

GI perforation occurs when a region of the GI tract tears, releasing its luminal contents in the body cavity. It is usually a complication of GI-specific disease, including appendicitis, Crohn's disease, diverticulitis, and ulcerative colitis. However, spontaneous tears have also been reported in patients with ED Vascular Type and Marfan syndrome.[48]

ED and Marfan syndromes in their various locations in [Table 1].

Dieulafoy's lesions

DLs are described as sudden GI hemorrhaging caused by aneurysms in abnormal submucosal blood vessels [Figure 7]. Vessels affected appear histologically normal, but have larger diameters and tend to be tortuous.[49] Rupture is rare, though serious, earning DLs the nickname “stealth killers” for their 80% mortality rate.[49] While a connection has been established between age and DL presentation, the frequency of congenital lesions has since complicated efforts to classify its etiology.[50],[51] It appears, then, that DLs represent an area of research needing more attention before its presence provides satisfying diagnostic clues for our patient. We note, however, that the tortuous vessels inherent in these lesions bear similarity to the arterial coiling seen elsewhere in our patient's system. However, no research to date has linked a non-GI aneurysm and DL incidence.
Figure 7: Patient's endoscopy reveals Dieulafoy's lesions

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  Conclusion Top

Although there is value in constructing a thorough differential for our patient's systemic disease, it must be noted that none of the diseases mentioned unequivocally match his presentation. However, there are noticeable patterns worth exploring. We note that most of the symptoms discussed are related to connective tissue disease. Indeed, connective tissue disease could account for the patient's skeletal abnormalities, blood vessel weaknesses, intestinal tears and lesions, and lung abnormalities. This notion is supported at a molecular level, given our discussion of collagen and elastin as crucial players in lung and vasculature integrity, both of which are severely affected in our patient.

Furthermore, given the age and frequency of our patient's symptoms, it seems unlikely that the normal causative factors for his many conditions, i.e. age, lifelong smoking, are pertinent. We can therefore infer that the etiology of the patient's condition is more insidious, perhaps beginning with in utero deregulation. The presence of both pectus excavatum and a HAP supports this hypothesis as well as his aneurysmal frequency at such a young age.

In Part 2 of this series, we discussed the molecular deregulation of connective tissue as a foundation for approaching our patient's diagnosis. Our analysis in this review comes to the same conclusion although by means of clinical deduction. Despite unequivocal genetic testing results for the most common mutations in collagen, fibrillin, and TGF-beta receptors (mutations associated with ED, Marfan, and Loeys–Dietz syndromes, respectively), the perceived overlap of a “connective tissue syndrome” renders support to our hypothesis that some integral component, possibly an influential signaling molecules such as TGF-beta, has become deregulated in our patient. If our hypothesis is correct, this patient must possess a rare mutation or regulatory abnormality currently undetectable by genetic testing.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]

  [Table 1]


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