Nasal Polyposis in mucopolysaccharidosis type II

Abstract

Mucopolysaccharidosis (MPS) type II is a rare multisystem disorder resulting from the accumulation of breakdown products of glycosaminoglycans in the body tissues. Many patients with this disease undergo ENT (ear, nose and throat) surgeries such as adenotonsillectomy and tympanocentesis at a very early age, much before the diagnosis of MPS. Nasal polyposis is a rare occurrence, with only one case of MPS II with polyposis reported in the literature. We present a patient who presented with recurrent nasal polyposis from the age of 2 years. Hale’s colloidal iron was used to stain these ‘nasal polyps’, which revealed that they are, in fact, mucopolysaccharide-laden sinonasal mucosa prolapsing into the nasal cavities. We believe this is the first time that this stain has been used to stain nasal polyps in MPS. In addition to the histopathological peculiarities of these nasal masses, we also discuss the natural history of nasal polyposis in MPS II.

Background

Mucopolysaccharidosis (MPS) type II (Hunter syndrome) is a rare, sex-linked, recessive, multisystem disorder. It is caused by deficiency in iduronate-2-sulfatase, which causes accumulation of glycosaminoglycans, such as heparan and dermatan sulfate, in the lysosomes of cells throughout the body. It is progressive, occurs exclusively in male patients and has an incidence of 1.3 per 100 000 live male births.¹ The Hunter Outcome Survey is a physician-led, multicentre observation database which included all cases reported on or before July 2009.¹ This survey has recorded that 51.4% of patients had to undergo tympanostomy tube insertions, 49.5% of patients adenoidectomy and 35.5% of patients tonsillectomy, in a group of 527 patients. There is no mention of surgery for nasal polyposis in this survey.¹

We report a case of nasal polyposis in a patient with MPS type II. The paucity of literature on this subject delayed our detection of the true nature of these nasal masses. In this case report, we will discuss the natural history of polyposis in MPS II, along with histopathological findings which confirmed the diagnosis.

Case presentation

A boy in his late teens presented to the ENT (ear, nose and throat) outpatient department with bilateral nasal obstruction for 3 months and bilateral nasal masses associated with mucopurulent discharge for 2 months. He was born without complications by normal vaginal delivery. His growth and developmental history were normal. The patient gave a history of similar complaints for which he was operated twice, at the age of 3 and 10 years (nasal polypectomy). These previous surgeries were not done in our hospital, but his mother had been told that the polyps were removed from the nasal cavities in both surgeries. Previous medical records, including histopathological reports, of the patient were not available.

The patient also gave a history of decreased hearing since childhood, for which he was using hearing aids. Surgery for inguinal hernia was done at the age of 12 years. From his previous records, we understood that a diagnosis of MPS was suspected; however, no genetic study has been done.

On clinical examination, the patient had greyish pink mass protruding out of the right nasal cavity (figure 1). Nasal endoscopy was difficult on the right side since decongestion with diluted epinephrine was not satisfactory. On the left side, he had nasal polyps in a previously operated cavity. He had macrocephaly, with coarse facial features, broad nose and frontal bossing. There were skeletal deformities of the forearm, palm and feet, with hallux valgus and short stubby fingers and toes. Examination of the abdomen and pelvis revealed a potbelly with umbilical hernia and hydrocoele. Ophthalmological examination detected bilateral sectoral retinitis pigmentosa.

Figure 1.

The patient during initial presentation, with nasal polyp protruding from the right nostril. He also had features such as macrocephaly, coarse facial features, broad nose and frontal bossing.

Investigations

Genetic study was done and was suggestive of MPS type II. Genomic DNA was extracted from the peripheral blood leucocytes of the proband and the parents. A known pathogenic variant, c.253G>A p.(Ala85Thr),² was identified in exon 3 of IDS (NM_000202.7). As IDS has a pseudogene IDSP1, nested PCR with primer³ followed by Sanger sequencing was done to validate the variant and segregation in the family. The variant was observed in hemizygous state in the proband and in heterozygous state in the mother. The father did not carry the variant (figure 2). Ultrasound of the abdomen and pelvis showed grade 1 fatty liver, mild splenomegaly and an umbilical hernia with left-sided hydrocoele. Two-dimensional echocardiography was normal.

Figure 2.

Integrated Genomics Viewer snapshot depicting the variant chrX:148585007 in heterozygous state due to the presence of pseudogene. Sanger sequencing confirmed the presence of the variant in hemizygous state in the proband and in heterozygous state in the mother and not present in the father.

CT of the paranasal sinuses (with contrast) was done and showed extensive non-enhancing soft tissue densities in bilateral maxillary, ethmoid and sphenoid sinuses (figure 3). The soft tissue masses extended into the nasal cavities. A diagnosis of chronic sinonasal polyposis was made.

Figure 3.

Contrast-enhanced CT of the paranasal sinus showing non-enhancing extensive soft tissue density in both maxillary and ethmoid sinuses.

The mass protruding out from the right side nasal cavity was sent for biopsy (figure 4). The biopsy showed polyps with features of inverted papilloma (figure 4A); the surface epithelium had mucous glands which stained positive for mucicarmine (figure 4B). The stroma showed distended macrophages, delicate papilliform processes and invading squamous cell nests. There was no evidence of dysplasia. Special stain with p16 immunohistochemistry (figure 4C, D) was taken up by the epithelium and revealed its association with human papillomavirus. Since there was no dysplasia, further staining with p53 or Epidermal Growth Factor Receptor (EGFR) was not done.

Figure 4.

Preoperative biopsy images. (A) The biopsy showed polyps with features of inverted papilloma. (B) The surface epithelium had mucous glands which stained positive for mucicarmine. The stroma showed distended macrophages, delicate papilliform processes and invading squamous cell nests with no evidence of dysplasia. (C) Low magnification depicting p16 immunohistochemistry stain highlighting the epithelium (×10). (D) High magnification depicting p16 immunohistochemistry stain highlighting the epithelium (×20).

After surgical clearance, the specimen was sent for histopathological study (figure 5). Histopathological examination under low magnification revealed a pale eosinophilic myxoid material filling the subepithelial region, which is not seen in inflammatory sinonasal polyps (figure 5A). On higher magnification, a few scattered cells in the background of abundant myxoid stroma were noted (figure 5B). With the history of MPS, Periodic Acid-Schiff (PAS) staining was performed and was negative. Alcian blue staining at pH 2.5 was also negative. At this point, Hale’s colloidal iron was used to stain the slides (figure 5C, D). The staining was positive and thus confirmed the diagnosis of MPS.

Figure 5.

Postsurgical histopathology images. (A) Low magnification depicting pale, eosinophilic, myxoid material filling up the subepithelial region (H&E ×40). (B) High magnification depicting few scattered stellate cells in the background of abundant myxoid stroma (H&E ×200). (C) Hale’s colloidal iron stain highlighting hyaluronic acid-rich stroma (Hale’s colloidal iron ×40). (D) High magnification depicting few scattered cells in the background rich in hyaluronic acid (Hale’s colloidal iron ×400).

Treatment

The patient was planned for a right-sided medial maxillectomy and a left-sided revision endoscopic polypectomy, keeping in mind the biopsy report of inverted papilloma. Intraoperatively, a polypoidal mass was seen arising from the maxillary antrum and ethmoid on both sides.

Postoperatively, the patient received topical (budesonide douching and fluticasone nasal spray) and systemic (prednisolone) steroid therapy, as routinely offered in patients with nasal polyposis. Once the histopathology confirmed the MPS, enquiries were made about enzyme replacement therapy. However, the patient refused treatment due to financial constraints.

Outcome and follow-up

In spite of the oral and local steroids, at the first postoperative follow-up (second week) a polypoidal mass was seen coming out of the right operated cavity. The mass grew in size, and by the third visit (fourth week postoperatively) protruded beyond the anterior nares. At 6 months further surgical intervention was offered but the patient refused.

Discussion

The multisystem manifestation of MPS II is due to accumulation of glycosaminoglycans throughout the body. The signs and symptoms of MPS II occur in early childhood, although the actual diagnosis of this syndrome may well be delayed. The Hunter Outcome Survey is the only global outcome survey of the natural history of MPS II. An initial report of disease manifestations was published in 2008.⁴ Otorhinolaryngological manifestations were otitis media (74%, median age 1.2 years), nasal obstruction (34%, median age 2 years), enlarged tongue (70%, median age 3.4 years) and enlarged tonsils or adenoids (68%, median age 2.9 years). The prevalence of nasal polyps was not specifically mentioned; however, the authors have noted that nasal obstruction and rhinorrhoea are the major nasal symptoms. In 2010, data on surgical history of MPS II were published.¹ Of the cases 83.7% (527 patients by 2009) had at least one surgical procedure. Patients had their first surgical procedure at a median age of 2.6 years. Of these patients 46% underwent more than one surgical intervention by 3.3 years of age and 80% by 10 years. The most commonly performed procedures were tympanostomies, adenotonsillectomies and hernia repairs. Surgical procedures were performed before the diagnosis of MPS II in 56.8% of patients.¹ There was no mention of nasal polyposis in this report.

Nasal polyposis in childhood is not unusual. The most common cause of polyposis is chronic sinusitis. However, underlying pathology such as cystic fibrosis has to be ruled out in children. In addition to nasal polyposis, if the patient has coarse facial features, micrognathism, low nasal bridge and dwarfism, a diagnosis of MPS has to be considered.⁵

The only other case report of polyposis in MPS II is from Taipei. The patient was a 3.6-year-old boy with bilateral recurrent serous otitis media for which he underwent multiple tympanostomy tube placements. He had severe snoring, nasal obstruction and mouth breathing. Nasopharyngoscopy revealed unilateral nasal polyposis, bilateral choanal polyps, deviated septum and marked adenoid hypertrophy. The dysmorphic features of the patient alerted the paediatrician, and the patient was referred for genetic and biochemical studies. Further management of the patient was not elaborated on in this short article (letter to the editor).⁶

There is a case report on nasal polyposis in MPS I (Hurler-Scheie syndrome).⁵ The patient was diagnosed with MPS I at the age of 10 months. At 18 years, he presented with a history of chronic rhinorrhoea and mass protruding from the nasal cavity (like our patient). Since he showed minimal response to oral steroids, he was taken up for endoscopic surgery. Histopathology revealed moderately oedematous stroma with minimal chronic inflammatory cells and no eosinophils. Electron microscopy showed single, membrane-bound vacuoles occupying the distended cytoplasm of the stromal fibroblasts and vascular endothelial cells. The vacuoles were filled with loose, slightly osmiophilic materials consistent with mucopolysaccharides. Although the patient had immediate relief from symptoms after surgery, he expired due to pulmonary complications. Hence the natural history of nasal polyposis in MPS was not studied in this article.⁵

Our patient had multiple nasal polypectomies from the age of 3 years. Although we did a complete endoscopic excision of the nasal masses, by 1 month they recurred to their presurgical extent. The polyps did not regress with systemic and topical steroids or with leukotriene receptor antagonist. This is not surprising as nasal lesions in MPS are not the usual polyposis that ENT surgeons are familiar with, but are nasal masses filled with glycosaminoglycans.

On H&E staining, the slide resembled polyposis, but lacked the abundant inflammatory cells usually seen in a nasal polyp. Special stains were required to reveal the true nature of polyps. Although there are no reports of nasal polyps being stained with colloidal iron in the literature, the atypical presentation of this patient, such as the early age of presentation, the multiple recurrences and poor response to treatment, prompted us to persist with special stains. PAS and Alcian blue at pH 2.5 were negative, which ruled out neutral and acidic mucin. Colloidal iron identifies acidic mucin and hyaluronic acid. Since the tissue stained with colloidal iron, it revealed the deposition of hyaluronic acid in the cells. We believe this is the first time that Hale’s colloidal iron has been used to stain nasal depositions in MPS.

Learning points.

• Although nasal polyposis is a rare occurrence in mucopolysaccharidosis (MPS) II, it presents at a very early age in this disease and only a high index of suspicion can direct physicians towards genetic and biochemical tests required for the diagnosis of MPS.

• We advise that once genetic confirmation of MPS has been achieved, all children with nasal obstruction should undergo a fibreoptic nasal examination to rule out polyposis.

• Our case report has demonstrated that Hale’s colloidal iron stain can help reveal the true nature of nasal polyps in MPS.

• Routine surgical and medical management is ineffective in the treatment of nasal polyposis in MPS II.

• Enzyme replacement therapy is likely to be the only treatment of benefit in this disease; however, as of now there are no reports in the literature of the same.