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Published in final edited form as: Am J Med Genet A. 2020 Apr 15;182(7):1754–1760. doi: 10.1002/ajmg.a.61593

Inflammatory manifestations in patients with Shwachman-Diamond syndrome: A novel phenotype

Elissa Furutani 1, Ankoor S Shah 2, Yongdong Zhao 3, David Andorsky 4, Fatma Dedeoglu 5, Amy Geddis 6, Yu Zhou 1, Towia A Libermann 7, Kasiani C Myers 8,9, Akiko Shimamura 1
PMCID: PMC13326259  NIHMSID: NIHMS2170301  PMID: 32293785

Abstract

Shwachman–Diamond syndrome (SDS) is an autosomal recessive multisystem disorder characterized by exocrine pancreatic dysfunction, bone marrow failure, and leukemia predisposition. Approximately 90% of cases are due to biallelic mutations in the Shwachman–Bodian–Diamond (SBDS) gene. Additional phenotypic features variably associated with SDS include skeletal, neurologic, hepatic, cardiac, endocrine, and dental abnormalities. We report five subjects with SDS who developed a range of inflammatory manifestations. Three patients developed inflammatory eye conditions. Single cases of juvenile idiopathic arthritis, chronic recurrent multifocal osteomyelitis, and scleroderma were also noted. Clinical presentation and treatment responses are described. Proteomic analysis revealed increased inflammatory signatures in SDS subjects as compared to controls. Treatment of inflammatory manifestations in patients with SDS may be complicated by potential myelosuppressive toxicities of anti-rheumatic medications. Further research is needed to better understand the potential link between inflammatory disorders and SDS to inform effective treatment strategies.

Keywords: autoimmune, inflammation, neutropenia, Shwachman-Diamond syndrome

1 |. INTRODUCTION

Shwachman-Diamond syndrome (SDS) is a rare, autosomal-recessive disorder associated with exocrine pancreatic dysfunction, bone marrow failure, and predisposition to leukemia. Approximately 90% of cases are due to biallelic mutations in the Shwachman–Bodian-Diamond (SBDS) gene located on chromosome 7qll (Bodian, Sheldon, & Lightwood, 1964; Boocock et al., 2003; Goobie et al., 2001). SBDS functions in ribosome biogenesis by facilitating the removal of EIF6 via the EFL1 GTPase to allow the joining of the 40S and 60S ribosomal subunits to form the mature 80S ribosome (Finch et al., 2011; Shammas et al., 2005; Tan et al., 2019; Weis et al., 2015). Recently, other disorders sharing clinical features of SDS have been reported with mutations in SRP54, DNAJC21, and EFL1 (Carapito et al., 2017; Dhanraj et al., 2017; Stepensky et al., 2017; Tan et al., 2018; Tummala et al., 2016). SDS is a multi-organ system disorder that variably affects the skeletal, neurologic, hepatic, cardiac, dental, and endocrine systems (Bodian et al., 1964; Myers et al., 2014; Nelson & Myers, 2018). Several international registries are working to better understand the phenotype of SDS and characterize the pathophysiology of this complex disorder in order to improve patient management and outcomes (Dhanraj et al., 2017; Donadieu et al., 2012; Dror et al., 2001; Hashmi et al., 2011; Mercuri et al., 2015; Myers et al., 2014; Ravera et al., 2016; Rosenberg et al., 2010; Tamary et al., 2010). Characterization of the SDS clinical phenotype and natural history remains incomplete.

In this case series, we describe five patients with SDS who developed a range of inflammatory manifestations not previously reported in subjects with SDS, expanding the spectrum of inflammatory responses in SDS. These cases suggest that inflammatory manifestations may be part of the phenotypic spectrum of SDS.

2 |. METHODS

2.1 |. Study subjects

All SDS subjects and healthy controls provided written informed consent in accordance with the Institutional Review Boards of Boston Children’s Hospital and Cincinnati Children’s Hospital Medical Center. Data were obtained from medical records including clinic notes, laboratory reports, imaging, and pathology reports collected through the registry studies. This case series reports five patients with inflammatory manifestations out of a cohort of 159 subjects with biallelic SBDS mutations.

2.2 |. SomaScan

Blood plasma proteins from six patients with SDS and six healthy controls were quantified using SOMAscan; an aptamer-based proteomic platform (SomaLogic, Boulder, CO; Gold, Walker, Wilcox, & Williams, 2012). Samples were prepared and run using the SOMAscan Assay Kit for Human Plasma, 1.3k (cat.#900–00011), according to the manufacturer’s protocol as previously described (Joyce et al., 2019). Samples were normalized by Iog2 transformation. Differentially expressed proteins between SDS and normal subjects were identified by t-test. To adjust for multiple-hypothesis testing, permutation-based false discovery rate (FDR) was computed using “DEDS” R package. Proteins with FDR <0.05 and fold change >1.5 were analyzed for the Gene Ontology Biological Processes enrichment via DAVID (Database for An- notation, Visualization and Integrated Discovery) v6.8 software package (http://david.abcc.ncifcrf.gov/).

3 |. RESULTS

Case 1 is a 4-year-old girl born full-term with birth weight of 6 lbs 4 oz. She had loose stools since birth, elevated liver transaminases, exocrine pancreatic insufficiency, and deficiency of fat-soluble vitamins. She developed frequent febrile illnesses and recurrent acute otitis media requiring tympanostomy tubes and adenoidectomy. Details of hematologic, pancreatic phenotype, genetic mutations, and family history are detailed in Table 1 and Tables SI and S2.

TABLE 1.

Inflammatory manifestations in five Shwachman-Diamond syndrome (SDS) subjects

Case Gender SDS genetics Inflammatory manifestations (age at presentation in years) Treatment and response ESR/CRP Immunologic phenotype
1 F c.285+2T>C (IVS2 +2), c,107delT (Val26AlafsX23) Bilateral blepharoconjunctivitis (4)
Topical prednisolone and erythromycin with some improvement ESR ranged <1 to 18 mm/hr, CRP ranged <0.03 to 0.83 mg/dl IgG 770, IgA 40 (L), IgM 44, IgE 5, Normal lymphocyte subsets and memory T/B cell panel. Normal vaccine titers and normal T cell proliferation to mitogens.
2 F c.183 184 TA >CT (Lys62Term), c.285 +2 T>C (IVS2+2) Bilateral blepharoconjunctivitis (5) Lost to follow-up CRP 1.94 mg/dl IgG 1,490 (H), IgA 185, IgM 62
3 M Homozygous c.285 +2T>C (IVS2+2) Bilateral keratoconjunctivitis, episcleritis, blepharitis, recurrent chalazions and styes. Giemsa staining with lymphocyte predominance (12) Topical steroids with improvement CRP 1.1 mg/dl Normal immunoglobulin levels. Low B cell number (75/mm3). Mild upregulation of T cell mediated responses. Positive ANA 1:320. Negative RNP, ENA, SSA, SSB, SM.
Juvenile idiopathic arthritis of the thumb and knee (14) No response to systemic steroids, improved with Embrel and Humira, now off of all medications
4 F Homozygous c.285 +2T>C (IVS2+2) Chronic recurrent multifocal osteomyelitis (9) Improved on systemic steroids. Flared when steroids tapered, then recaptured on steroids and Humira ESR 19 mm/hr IgG 1,070, IgM 56, IgA 172. Mildly decreased NK cells (92/mm3). Normal vaccine titers. ANA negative, RF negative
5 M Homozygous c.285 +2T>C (IVS2+2) Raynaud’s syndrome and ulcerations on toes, scleroderma (26) Improved with amlodipine and antibiotics initially, subsequently worsened. Skin lesions improved with IVIG N/A Anti-RNA polymerase 3 positive
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Abbreviations: CRP, creactive protein; ESR, erythrocyte sedimentation rate.

At Age 4, she developed severe photophobia and chronic epiphora precluding the ability to go outdoors. She was found to have dry eyes and blepharoconjunctivitis. She improved with topical corticosteroids, but her symptoms recurred after discontinuing topical corticosteroids with worsening of her photophobia, and she was referred for further work-up. An exam under anesthesia demonstrated severe bilateral blepharitis and inspissation of the Meibomian glands (right worse than left), ulceration of the posterior mucocutaneous junction of the right upper and lower eyelids along with a palpebral papillary conjunctivitis, corneal neovascularization of the right eye, punctate epithelial irregularities bilaterally, and sub-epithelial corneal infiltrates of the right eye (Figure 1).

FIGURE 1.

FIGURE 1

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Inflammatory disease manifestations in subjects with SDS. Right eye of a 4-year-old girl (Case 1) with 5 months of severe photophobia and epiphora precluding outdoor activities (a–f) and Coronal intravenous immunoglobulin sequences of bilateral lower extremities in a 9-year-old girl (Case 4) (g–h). (a) The ocular surface showed trace injection to the bulbar conjunctiva with prominence of the conjunctival vasculature (#) and numerous conjunctival vessels causing inappropriate vascularization of the cornea (*) for 360° around the limbus (junction between the cornea and sclera where the most peripheral aspect of the iris is located), (b, c) Neovascularization of the cornea at the superior (b) and inferior (c) limbus with sub-epithelial, corneal haze (white patches best visualized overlying the pupil and marked with *) from inflammation, (d) Magnified image of the upper eyelid margin with the eyelashes pictured to the left and the Meibomian glands, which secrete oil onto the ocular surface for lubrication, being capped with thickened sebum (arrowheads). The mucocutaneous junction of the eyelid (located on the posterior aspect of the eyelid where the skin meets the palpebral conjunctiva) showed areas of ulceration (*) indicative of inflammation, (e, f) Eversion of the upper eyelid showed palpebral conjunctival injection and prominent vasculature (e, arrow). Fine papillae (elevations in the conjunctiva with a central vessel, which are characteristic of inflammation) area also seen as the fine, pinpoint red dots (e) and are outlined with a green, circular outline at the base with fluorescein dye under cobalt blue illumination (f). The fluorescein dye also highlights are of epithelial erosion (*). These areas correspond to the areas of ulceration in panel (d). (g) Abnormal hyperintensity within bilateral proximal tibia (arrows) while on naproxen (Case 4). (h) After 2 months of prednisone, MRI demonstrated normal marrow signal. SDS, Shwachman–Diamond syndrome [Color figure can be viewed at wileyonlinelibrary.com]

Treatment was initiated with prednisolone acetate 1% to the right eye four times daily and left eye twice daily along with erythromycin ointment (used for both its antibiotic and anti-inflammatory properties) once daily, with interval improvement in blepharitis 2 weeks later. She has been tapered to once daily prednisolone acetate 1% to each eye and continues erythromycin ophthalmic ointment to each eye every other day 1 year after her initial symptoms with a marked improvement in her photophobia and epiphora. Further tapering of her topical steroids has failed thus far.

Blepharoconjunctivitis may occur as primary dysregulation of inflammatory mediators on the ocular surface, or it may result from a cascade of events starting with pancreatic exocrine insufficiency leading to vitamin A deficiency. This in turn may cause Meibomian gland dysfunction and tear hypoproduction with the dryness causing an upregulation of inflammatory cytokines. Measurement of serial vitamin A levels showed no correlation with her symptoms (Figure SI).

Case 2 is a 16-year-old young woman diagnosed with SDS as an infant when she presented with failure to thrive and recurrent infections with severe neutropenia. She developed several severe infections including a cervical abscess at Age 10, empyema requiring chest tube placement and ICU admission, and brief treatment with G-CSF. At Age 14, genetic testing confirmed compound heterozygous mutations in SBDS (Table 1).

At Age 13, she started experiencing photophobia and epiphoria. Her symptoms persisted, and at Age 16, she underwent ophthalmologic evaluation during an inpatient admission for pneumonia and was diagnosed with blepharoconjunctivitis. She missed multiple follow-up appointments and was lost to follow-up.

Case 3 is a boy born at term with birth weight of 7lbs 2.5 oz, who presented to hematology clinic at 10 years of age for evaluation of thrombocytopenia in the 120–130 k/μl range. His medical history was notable for failure to thrive, steatorrhea, recurrent otitis media, oral aphthous ulcers in the absence of neutropenia, and an erythematous, macular, non-pruritic rash over trunk and upper arms for several years. His bone marrow demonstrated a del20q clone, and he was diagnosed with SDS following genetic testing (Table 1).

At 12 years of age, he developed macular–papular rash of the eyelid skin resulting in anterior blepharitis with recurrent chalazia (insippation of the Meibomian glands) and episcleritis in the distribution of the left lower eyelid only. He progressed to bilateral keratoconjunctivitis and developed a corneal neovascularization of his left eye, which were both treated with topical corticosteroids with some improvement. Topical cyclosporine was added without benefit and was discontinued.

At 14 years of age, he presented with sterile arthritis of his knees and fingers. He was unable to ambulate and unable to use his hand due to debilitating pain. Infectious workup was negative. He was diagnosed with juvenile idiopathic arthritis. He had no response to systemic corticosteroids, but improved on anti-tumor necrosis factor-α therapy (switched from etanercept to adalimumab for continued symptoms). He discontinued adalimumab at age 17 years and had recurrence of mild symptoms. His immunologic workup was notable for normal immunoglobulin levels but persistently low CD19 levels.

Case 4 is a 9-year-old girl diagnosed with SDS in infancy when she presented with failure to thrive, chronic diarrhea, and moderate neutropenia with ANC of 500 cells/μl. This diagnosis was confirmed by genetic testing (Table 1).

At Age 8, she presented with left knee pain that spread to the shins, right knee, and right ankle. She developed a limp and was unable to play soccer. MRI demonstrated metaphyseal chondrodysplasia known to be associated with SDS, and edema of the right patella with a T2 hyperintense signal lesion along the anterior superomedial aspect, the right ischial synchondrosis, left distal femur, proximal tibia and fibula, and right posterior calcaneus. A bone biopsy was discussed but deferred because of her neutropenia and thrombocytopenia. Due to the lack of other signs for infection or malignancy, a diagnosis of chronic, recurrent osteomyelitis (CRMO) was made. Whole-body MRI revealed abnormal marrow signal with associated periostitis within the right ischial synchondrosis, left distal femur, left proximal tibia, left distal fibula, and right posterior calcaneus. She was treated empirically with twice daily naproxen, and she was able to ambulate again. She subsequently developed cutaneous allergic reactions to naproxen.

Due to continued symptoms and concern of marrow suppression from methotrexate, she started on prednisone, which was tapered subsequently to 5 mg per day. Repeat MRI showed complete resolution of her osteomyelitis (Figure 2). She discontinued prednisone after 7 months and developed recurrent symptoms. She restarted prednione but transitioned to Adalimumab due to concern of rising intraocular pressure.

FIGURE 2.

FIGURE 2

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Gene Ontology enrichment analysis of proteins differentially expressed between SDS patients and normal subjects. All significantly enriched biological processes of upregulated proteins in SDS patients. Benjamini-Hochberg adjusted p-value <.05 was used as significance threshold. SDS, Shwachman–Diamond syndrome

Case 5 is a 29-year-old man who was diagnosed with SDS in childhood when he presented with pancreatic insufficiency and failure to thrive. He had mild thrombocytopenia and neutropenia and developed a del20q and a transient del7q clone in his bone marrow. He developed Raynaud’s syndrome and ulcerations on his toes, and was diagnosed with cutaneous scleroderma with positive anti-RNA polymerase 3. He was treated with amlodipine and antibiotics and had initial improvement. Three years later, he developed thickened areas on the skin of his arms and legs. A biopsy showed an overlap of morphea profunda and sclerosing panniculitis. Serological testing for RNA polymerase 3 was positive, consistent with a diagnosis of systemic sclerosis. He was treated with hydroxychloroquine for 6 months without improvement, so it was discontinued. He then developed calcinosis of the skin that resulted in significant skin ulceration. His rheumatologist recommended intravenous immunoglobulin (IVIG) rather than mycophenolate or methotrexate treatment given concerns for marrow suppression with methotrexate. He was treated with IVIG 600 mg/kg Days 1–3, repeated every 28 days. His skin lesions were significantly improved after 4 months of IVIG treatment. His blood counts and bone marrow findings remained stable throughout.

To assess inflammatory pathways in patients with SDS, plasma protein levels from six SDS subjects at baseline health were compared to healthy controls using SOMAscan, an aptamer based proteomics assay (Tables S3 and S4). Gene ontology enrichment analysis of the top upregulated proteins identified increased inflammatory pathways in SDS subjects compared with healthy controls of similar age (Figure 2).

4 |. DISCUSSION

We report a variety of inflammatory conditions including blepharoconjunctivitis, arthritis, CRMO, and scleroderma in patients with SDS. To our knowledge, this is the first case series to describe these clinical features in patients with SDS. Blepharitis has been reported in other marrow failure syndromes (Tsilou et al., 2010). These findings extend previously reported immunologic manifestations in SDS including hemophagocytic lymphohistiocytosis, psoriasis, two cases of autoimmune-like liver disease which did not respond to immunosuppressive therapy, several cases of Type 1 diabetes mellitus, duodenal inflammation, and inflammatory bowel disease (Delaporta et al., 2017; Gana et al., 2011; Myers et al., 2014; Nissen et al., 2019; Schaballie et al., 2013; Shah et al., 2010; Veropalumbo et al., 2015).

This study is limited by small sample size and reliance on available medical records or physician report. We note that these inflammatory conditions are rare in the general population, with annual incidence of CRMO of 1 in 250,000 and JIA of 13.9 or fewer cases per 100,000 (Lawrence et al., 1998; Peterson, Mason, Nelson, O’Fallon, & Gabriel, 1996; Towner, Michet Jr., O’Fallon, & Nelson, 1983). While a prospective study of inflammatory disorders in SDS is challenging due to the rarity of this disease, we find signatures of upregulated inflammatory pathways in SDS patients as compared to health controls. Analysis of additional SDS cohorts are warranted.

Although low B, T, and NK cell numbers (Bezzerri et al., 2019; Dror et al., 2001; Giri et al., 2015) and decreased CD3+/CD4−/CD8-T cells (Bezzerri et al., 2019) have been reported in a subset of patients with SDS, the pathophysiology of immune dysregulation in this ribosomopathy is yet to be determined. Activation of the transforming growth factor-β pathway has been reported in SDS (Joyce et al., 2019; Ruiz-Gutierrez et al., 2019) and other marrow failure syndromes (Gao et al., 2016; Ge et al., 2015; Zhang et al., 2016).

Although these cases and proteomic analysis suggest an immune dysregulation in SDS, it remains unclear whether these manifestations are primary or secondary. Although no correlation between vitamin A levels and ocular symptoms were noted in Case 1, it is possible that such manifestations may be delayed markers of prior vitamin deficiency or associated retinol binding protein deficiencies. In cystic fibrosis, a disease also characterized by pancreatic insufficiency and deficiency of fat-soluble vitamins, low plasma retinol binding protein has been associated with keratoconjunctivitis sicca (Mrugacz, Tobolczyk, & Minarowska, 2005). It is also possible that a combination of primary and secondary mechanisms may contribute to these clinical manifestations.

Data are sparse to inform the optimal treatment strategy for inflammatory conditions arising in patients with SDS. Systemic corticosteroids pose in increased risk of fungal and other opportunistic infections for patients with neutropenia. Many anti-inflammatory or immunomodulatory agents can cause cytopenias, which are problematic in patients with an underlying bone marrow failure syndrome. Additional studies to investigate potential inflammatory and immunologic abnormalities in SDS as well as optimal treatment strategies are needed.

5 |. CONCLUSIONS

We identified a series of patients with SDS who developed inflammatory manifestations and described their clinical features and treatment outcomes. These clinical findings correlated with an inflammatory proteomic signature. Treatment is complicated by the concurrent neutropenia and bone marrow failure in patients with SDS. In light of previously reported immune dysregulation in SDS and inflammation in murine models of SDS (Zambetti et al., 2016), this study suggests a potential link between inflammation and ribosomal impairment.

Supplementary Material

figure 1
table 1
table 2
table 3
table 4

SUPPORTING INFORMATION

Additional supporting information may be found online in the Supporting Information section at the end of this article.

Funding information

National Heart, Lung, and Blood Institute, Grant/Award Number: T32 HL007574-36; National Institute of Diabetes and Digestive and Kidney Diseases, Grant/Award Number: R24 DK099808

Abbreviations:

SDS

Shwachman-Diamond syndrome

ANC

absolute neutrophil count

ANA

anti-nuclear antibody screen

NK cells

natural killer cells

RF

rheumatoid factor

Footnotes

FINANCIAL DISCLOSURE

Yongdong Zhao is supported by Bristol-Meyer Squibb and Childhood Arthritis and Rheumatology Research Alliance (CARRA).

CONFLICT OF INTEREST

The authors have no conflict of interest relevant to this article to disclose.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

figure 1
NIHMS2170301-supplement-figure_1.docx (1.2MB, docx)
table 1
NIHMS2170301-supplement-table_1.docx (15.3KB, docx)
table 2
NIHMS2170301-supplement-table_2.docx (12.8KB, docx)
table 3
NIHMS2170301-supplement-table_3.docx (16.4KB, docx)
table 4
NIHMS2170301-supplement-table_4.docx (14.6KB, docx)

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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