A family case of Shwachman-Diamond syndrome in children with a rare genetic variant of the SBDS gene с.653G>A (p.Arg218Gln)

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Introduction

Shwachman–Diamond syndrome (SDS) is a hereditary ribosomopathy characterized by exocrine pancreatic dysfunction, bone marrow failure, and increased risk of myeloid malignancies [1; 2]. SDS is the second most common cause of severe exocrine pancreatic insufficiency after cystic fibrosis. The syndrome involves immune system abnormalities (particularly severe neutropenia), hepatic impairment, dental enamel defects, neurocognitive disorders, and other multisystem manifestations [4] with variable clinical progression [6]. In rare cases (3.23 %), type 1 diabetes mellitus develops — an atypical complication that nevertheless occurs 30 times more frequently than in the general population [5].

According to literature data, the global prevalence of Shwachman–Diamond syndrome is estimated at 1:50,000–1:76,000. However, the exact number of patients in the Russian Federation remains unknown [7]. The SBDS protein (Shwachman–Bodian–Diamond Syndrome protein), involved in ribosome maturation, is present in all body cells, with the highest concentration in the nucleus (particularly in ribosome synthesis sites). This protein plays a crucial role in mitosis by maintaining genome stability [8; 9]. Approximately 90 % of SDS patients carry biallelic pathogenic variants in the SBDS gene located on chromosome 7q11 [10; 11]. The 97 % homologous SBDS Pseudogene in this region may harbor deletions and mutations that disrupt functional protein synthesis [12]. SDS is classified as an orphan disease. We present a case report of SDS in two sisters with the SBDS gene variant c.653G>A (p.Arg218Gln).

Clinical case

A one-year-old girl, M., was admitted to the Allergology-Immunology Department of Perm Krai State Budgetary Healthcare Institution “Perm City Children’s Clinical Hospital” (GBUZ PK GDKB) with complaints of atopic dermatitis exacerbation.

According to the medical history, the child was born from a second pregnancy that proceeded without complications, and from a second full-term delivery. At birth, the body weight was 2,970 g, and the length was 50 cm. At one month of age, an allergic rash appeared on the skin of the face and trunk, and atopic dermatitis was diagnosed at the local inpatient facility. The GBT showed leukopenia (2.9·10⁹/L) and severe neutropenia (absolute granulocyte count 493 cells/μL), which was interpreted as a manifestation of a previous viral infection. The allergic skin eruptions persisted. At four months of age, signs of malabsorption syndrome appeared, which were regarded as manifestations of gastrointestinal food allergy, prompting emergency hospitalization to the Allergology-Immunology Department of Perm City Children’s Clinical Hospital No. 13. Examination revealed recurrent grade 2–3 leukopenia and neutropenia on GBT, while BB showed elevated AST up to 189.9 U/L and ALT up to 270.4 U/L; immunoglobulins A, M and G were within age-appropriate ranges. The patient was discharged with the following diagnoses: atopic dermatitis (infantile form, severe course); gastrointestinal food allergy; reactive hepatitis; cytolysis syndrome. Given the persistent skin eruptions, the girl was switched to an amino acid-based therapeutic formula and received topical glucocorticosteroids along with ursodeoxycholic acid (UDCA) medication. The therapy resulted in stool normalization but the skin eruptions persisted.

At 5 months of age, due to persistent relapsing atopic dermatitis, the patient was admitted to the Early Childhood Department of Perm Regional Children’s Clinical Hospital (GBUZ PK KDKB). Examination revealed persistent leukopenia and severe neutropenia on GBT (WBC 3.4·10⁹/L, absolute neutrophils 374 cells/μL), while BB showed AST 76 U/L, ALT 92 U/L with normal IgM, IgA and IgE levels but reduced IgG (1.44 g/L; normal range 2.32–14.11). Given prolonged cytolysis syndrome, viral hepatitis was excluded, and the patient was subsequently transferred to the Gastroenterology Department of Perm City Children’s Clinical Hospital No. 13, where cystic fibrosis (normal sweat test), alpha-1-antitrypsin deficiency, Wilson’s disease and inherited metabolic disorders were excluded. Primary immunodeficiency (PID) was first suspected based on GBT and immunogram results (low IgG). TREC-KREC analysis showed mildly decreased TREC and KREC one order of magnitude below reference range.

At 11 months of age, the girl was readmitted to the Allergology-Immunology Department of Perm City Children’s Clinical Hospital No. 13. The GBT continued to show leukopenia and severe neutropenia, while the BB indicated cytolysis syndrome. Lymphocyte CD-typing revealed no abnormalities. Given the clinical presentation of persistent neutropenia, malabsorption syndrome, and cytolysis syndrome, at 1 year of age the child was hospitalized in the Allergology-Immunology Department of Perm Regional Children’s Clinical Hospital to rule out Shwachman–Diamond syndrome. Upon admission to Perm Regional Children’s Clinical Hospital, her condition was assessed as moderate in severity with good general wellbeing and normal activity levels. Her height was 84 cm (SDS –1.42), weight 13.1 kg, with BMI 18.6 kg/m² (SDS +1.9). No musculoskeletal deformities were observed. Physical examination revealed generalized dry skin with mild erythema and crusting in the elbow folds and forehead. Lung auscultation demonstrated puerile breath sounds, with clear and rhythmic heart tones. The liver edge was palpable 1 cm below the costal margin. Stool was formed. Fecal pancreatic elastase-1 level was severely reduced at 10.7 μg/g (normal >200 μg/g), confirming severe exocrine pancreatic insufficiency. Vitamin D status showed deficiency with 25(OH)D3 level of 13.1 ng/mL (normal range 30-100 ng/mL). Coprogram revealed soap ++, with persistent cytolysis syndrome. Genetic testing using the “Primary Immunodeficiencies and Inherited Anemias” panel identified two pathogenic SBDS gene variants in compound heterozygous state: c.653G>A (p.Arg218Gln) and c.258+2T>C. Parental genetic testing was performed to exclude cis-positioning of SBDS gene variants. The mother was found to carry the c.258+2T>C variant in heterozygous state, while the father carried the c.653G>A (p.Arg218Gln) variant in heterozygous state. Thus, Shwachman-Diamond syndrome in the child was confirmed through genetic testing methods.

Analysis of the child’s serial GBT results (Table) revealed nearly persistent leukopenia and neutropenia, progressing to agranulocytosis except during respiratory infections. Following SDS diagnosis, the child received regular follow-up with pediatric, allergology-immunology, and gastroenterology specialists. The girl was treated with UDCA, vitamins D3, A and E, pancreatic enzyme replacement therapy, and nutritional support. Monthly GBT monitoring was implemented. At the age of 2, a single administration of the granulocytopoiesis stimulator “Filgrastim” was required when granulocytes dropped to 323 cells/μL during a respiratory infection.

 

Dynamics of GBT parameters in patient M. during the first year of life

Age, months	RBC, ×10¹²/L	Hb, g/L	Colour Index	Plt, ×10⁹/L	WBC, ×10⁹/L	Eos, %	Meta, %	Band , %	Seg, %	ANC, cells/μL	Lymph, %	Mono, %	ESR, mm/hr
1	4.0	120		200	2.9	-	-	1	16	493	54	20	2
1	3.7	114		301	4.1	1	-	1	18	820	60	20	12
*3	4.8	133	27.7	308	5.5	-	-	2	29	1705	59	10	3
4	4.69	127	27.1	415	4.3	1	1	1	32	1376	56	9	2
5	4.2	126	29.0	271	4.57	-	-	6	6	552	79	9	1
5	4.1	117	28.0	253	3.4	1	-		11	408	84	9	2
8	4.9	142	29.0	193	2.4	1	-	1	19	504	69	10	1
*8	4.8	138	28.7	216	5.2	-	-	7	28	1820	55	10	3
*8,5	3.8	111		196	6.4	-	9	10	26	2880	38	17	11
*9	3.8	106		278	7.7	-	-	4	55	4543	31	10	3
9	4.45	128	28.8	183	2.7			-	7	189	92	1	2

Note: * – GBT values were obtained during respiratory infections.

 

At the same age, follow-up fecal pancreatic elastase-1 testing showed 376 μg/g (normal). Coprogram while on pancreatin revealed moderate steatorrhea (soap +) and amylorrhea (starch +). By age 2, the child’s BMI increased to 18.6 (BMI SDS = +1.97), prompting discontinuation of pancreatin and nutritional support. Given the hereditary nature of SDS, genetic testing was performed on the patient’s 7-year-old sister, identifying the same compound heterozygous SBDS variants: c.653G>A (p.Arg218Gln) and c.258+2T>C, confirming SDS diagnosis. The sister’s history revealed frequent fatty stools in early childhood.

Clinical evaluation of the sister (age 7) at our clinic showed: height 122 cm (SDS -1.62), weight 25.2 kg, BMI 17.2 (SDS +0.56). Physical exam noted normal skin, vesicular breath sounds (RR 20/min), clear heart sounds (HR 80/min), soft non-tender abdomen with liver/spleen non-palpable. Stool was formed (2x/day) with normal urination. GBT revealed leukopenia (WBC 5.8·10⁹/L) and neutropenia (ANC 696 cells/μL). Coprogram showed steatorrhea (soap ++) and amylorrhea. Fecal elastase-1 was severely deficient (40 μg/g) with vitamin D deficiency (14 ng/mL). Immunoglobulins were normal; BB showed no cytolysis.

The sister receives multidisciplinary care (pediatrician, allergist-immunologist, gastroenterologist) with PERT and fat-soluble vitamins. No granulopoiesis stimulators were needed. By age 9, her fecal elastase-1 normalized (>500 μg/g), but constipation required PERT dose reduction. Newborn screening data revealed low IRT levels in both sisters (elder: 11.5 ng/mL; proband: 13.1 ng/mL) [13]. Parental GBT showed: mother (33 y/o, SBDS c.258+2T>C carrier) had lymphocytosis (52.2%) with neutropenia (30.87%); father (34 y/o, SBDS c.653G>A carrier) had normal results.

Results and Discussion

Currently, the diagnosis of SDS is based on clinical presentation including exocrine pancreatic insufficiency and hematologic abnormalities [15]. Neutropenia [14], occurring in 88–100 % of SDS patients [15], may serve as a key diagnostic factor. Genetic testing remains the gold standard for confirming SDS diagnosis [4]. Despite early manifestations of neutropenia, primary immunodeficiency was suspected late in both children, likely due to normalization of hematologic parameters during respiratory infections. The SBDS c.653G>A (p.Arg218Gln) variant is a missense variant listed in the ClinVarMiner database (https://clinvarminer.genetics.utah.edu/) as rare and classified as likely pathogenic for SDS. This variant has been reported only in isolated cases. Donadieu et al. (2012) identified this variant in one patient with genotype p.Arg218Gln/p.Cys84fs but did not provide clinical details [16]. M.G. Ipatova et al. (2019) described two unrelated 1.5-year-old boys with the p.Arg218Gln variant in compound heterozygous state with c.258+2T>C, presenting with severe pancreatic insufficiency, marked cytolysis syndrome, neutropenia, anemia, and chest wall deformity [2]. Furutani et al. (2022) reported an adolescent with SBDS c.653G>A (p.Arg218Gln) in compound heterozygous state with c.258+2T>C, who had neutropenia (400-700 cells/μL) and pancreatic insufficiency, developing mediastinal B-cell lymphoma at age 16.9 years [17]. Our patients showed no severe malabsorption syndrome despite low fecal pancreatic elastase-1 levels. However, both children demonstrated improvement in pancreatic elastase-1 levels with age, reducing the need for continuous pancreatic enzyme replacement [6]. According to Hashmi et al. (2011), 15 % of SDS patients lack pancreatic involvement, while steatorrhea requiring treatment was observed in only 67 % of cases [12]. Nearly half of patients in the North American SDS Registry showed neither typical neutropenia nor steatorrhea. Improved exocrine pancreatic function, noted in 50 % of patients, allowed discontinuation of enzyme replacement therapy [6]. The reasons for this improvement remain unclear, though it may relate to physiological maturation of pancreatic enzyme secretion with age [3].

The IRT levels in our observed patients at birth were near the lower range, possibly reflecting impaired exocrine pancreatic function from birth. Parents reported fatty stools in both children. Further research on IRT values in children with SDS is warranted, especially given the availability of nationwide cystic fibrosis newborn screening in Russia. Considering that SDS is an extremely rare disease with clinical heterogeneity and frequent malignant complications, establishing a national SDS patient registry would be valuable for studying the genetic and phenotypic spectrum of the disease, including age-related manifestations.

Conclusion

In our observed sisters with genotypes c.258+2T>C/c.653G>A (p.Arg218Gln), despite early clinical manifestations including neutropenia, growth retardation tendencies, exocrine pancreatic insufficiency, and persistent cytolysis syndrome, the diagnosis was significantly delayed. During follow-up, normalization of fecal pancreatic elastase-1 levels and reduced need for enzyme replacement therapy were noted. The delayed diagnosis resulted from normalization of blood test parameters during respiratory infections. For timely diagnosis of neutropenias, pediatricians should pay attention to proper interpretation of GBT (knowledge of age-specific blood cell count norms and leukocyte formula variations), and calculating absolute granulocyte counts. To determine neutropenia etiology (congenital vs acquired), serial GBT monitoring is essential.

About the authors

N. N. Grymova

Ye.A. Vagner Perm State Medical University; Perm Regional Children's Clinical Hospital

Author for correspondence.
Email: tashagrymova@gmail.com
ORCID iD: 0000-0001-5217-5089

PhD (Medicine), Associate Professor of the Department of Faculty and Hospital Pediatrics, Allergist Immunologist

Russian Federation, Perm; Perm

V. V. Shadrina

Research Clinical Institute of Childhood; N. P. Bochkov Research Centre for Medical Genetics

Email: tashagrymova@gmail.com
ORCID iD: 0000-0002-2588-2260

PhD (Medicine), Associate Professor of the Department of Faculty and Hospital Pediatrics, Head of the Research Clinical Department of Hereditary and Metabolic Diseases, Leading Researcher of the Research Clinical Department of Cystic Fibrosis, Pediatrician

Russian Federation, Mytishchi; Moscow

E. G. Furman

Ye.A. Vagner Perm State Medical University

Email: tashagrymova@gmail.com
ORCID iD: 0000-0002-1751-5532

DSc (Medicine), Professor, Head of the Department of Faculty and Hospital Pediatrics

Russian Federation, Perm

References

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