Can Continuous Subcutaneous Insulin Infusion Improve Health-Related Quality of Life in Patients with Shwachman–Bodian–Diamond Syndrome and Diabetes?

Introduction

Shwachman–Bodian–Diamond syndrome (SBDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow failure, skeletal dysplasia, short stature, and different levels of cognitive impairment. ^{1 –3} However, although a considerable phenotypic variability is well known in patients, cardiac or endocrine features have been rarely described. ² Up to 90% of patients meeting the clinical diagnostic criteria for SBDS have biallelic genetic mutations identified in the SBDS gene located on chromosome 7. ⁴ Indeed, some patients have clinical features consistent with SBDS without genetic known mutations. ^4,5 Recent Italian population data reported a mean of 3.0 cases per year, with several known SBDS mutations among the 1:168,000 SBDS diagnoses. ⁶ The carrier incidence among healthy subjects has been reported as 1:205. ⁶ Nevertheless, the SBDS incidence could be underestimated because of the increase of cases with very mild presentation. ⁶

One of the important features of SBDS is pancreatic insufficiency, due to fatty infiltration and atrophy of the exocrine pancreas. It has been suggested that pancreatic insufficiency results from deficient RNA processing in a pathway essential to development of the exocrine pancreas. ¹

Diabetes is a rare complication of SBDS, and only a few SBDS patients have been reported to develop diabetes. ^{7 –10} Defects in immune regulation of SBDS might play a role in the development of diabetes. ⁸ The lower prevalence of diabetes in SBDS may be justified by the nonprogression of exocrine pancreatic damage with increasing age in SBDS patients. ⁸ In 2011 Gana et al. ⁸ reported an occurrence rate of diabetes of 3.23% in 62 gene-positive individuals with SBDS from the Italian registry, a 30-fold increase over that of the general population. On the other hand, according to the North American Shwachman–Diamond Syndrome Registry, only one patient suffers from diabetes (2.7%). ² This complication leads to a further deterioration in quality of life and can exacerbate behavioral disorders.

We report the case of a patient suffering from SBDS and diabetes whose health-related quality of life (HRQoL) considerably improved as a result of continuous subcutaneous insulin infusion (CSII) implantation.

Case Report

A 19-year-old Italian boy was born at 38 weeks of gestation after an uncomplicated pregnancy to nonconsanguineous healthy parents. His birth weight was 2.040 kg (<5^th percentile), and his height was 45 cm (<5^th percentile).

At 2 months of age, he underwent sepsis with severe neutropenia and persistent slight temperature. A blood transfusion was necessary for a hemoglobin level of 4.3 g/dL.

At 7 months of age, the child presented failure to thrive, pancreatic insufficiency (72-h stool fecal fat collection, 11.9 g/day [normal value, <4 g/day]; pathological secretin pancreozymin stimulation test; fecal pancreatic elastase, <50 μg/g), eczema, persistent pancytopenia, hypertransaminasemia (aspartate aminotransferase, 228 U/L; alanine aminotransferase, 370 U/L), and hypotrombinemia. As a consequence SBDS was suspected, and a therapy with pancreatic enzymes, ursodeoxycholic acid, and granulocyte colony-stimulating factor was started. Sequence analysis of the SBDS gene using genomic DNA was subsequently performed. A compound heterozygous form for 183-184TA to CT and 258 +2T to C mutations was identified.

Acute lymphoblastic leukemia was diagnosed at the age of 31 months. The child underwent heterologous bone marrow transplant 3 months later. Seven days after bone marrow transplant, he developed acute graft-versus-host disease grade 2 involving skin and intestine. Successively he manifested chronic cutaneous graft-versus-host disease, which resolved with steroid and cyclosporine therapy.

At 9 years of age, a child psychiatrist evaluated his intellectual and emotional profile by the WISC-R test ¹¹ and clinical interviews. The test administered to our patient showed a Total Intelligence Quotient (T-IQ) within the normal range for age (T-IQ=109). Moreover, the patient presented an impaired psychosocial functioning with difficulties in the emotional area and mental health, body pain experiences, attention deficit disorder, somatic complaints, behavioral and social problems. Because of attention deficit and learning difficulties, he required a remedial teacher at school and psychotherapy in order to face his emotional problems.

No further clinical events were recorded until 13 years of age, when he developed diabetes (glycemia 282 mg/dL at 120 min of oral glucose tolerance test; glycosylated hemoglobin level, 7.5%; negative for islet-cell antibodies, insulin autoantibodies, islet antigen 2 antibodies, anti-glutamic acid decarboxylase antibodies, and anti-ZnT8 autoantibodies; glucagon test with a C-peptide level at zero-time of 1.5 ng/mL and at 6 min of 2.0 ng/mL; and HLA DR-DQ negative). A multiple injection insulin therapy was started. The glycosylated hemoglobin value was unmodified (7.4%) during multiple daily injection (MDI) therapy.

After diabetes onset he perceived a more negative impact of disease, with further damage to the HRQoL. A new psychological assessment of the emotional status and behavioral issues highlighted a relevant increase in anxiety, depression, somatic complaints, behavioral and social problems, especially with peers. The HRQoL was evaluated by the Pediatric Quality of Life Inventory (PedsQL™) version 3.0 Diabetes Module. ^12,13 The patient showed low scores, especially in the scales regarding barriers to treatment, treatment adherence, worry, and communication about the disease.

Because of a relevant needle phobia and the recurrent hypoglycemia due to poor nutrition secondary to depression, in 2010 the patient started CSII, according to guidelines. ^14,15 The glycosylated hemoglobin value was 7.6%. After 3 months of CSII the patient showed a decrease of both insulin requirement (15%) and glycosylated hemoglobin value (6.3%) and also a gradually better social adaptation.

After 12 months psychosocial functioning was re-evaluated by clinical interviews and by the PedsQL version 3.0 Diabetes Module. The pre–post CSII showed a better HRQoL and no relevant differences in the scale regarding diabetes symptoms as shown in Table 1; in the clinical interviews were also observed an improvement of his self-esteem and self-efficacy and a reduction of psychosocial consequences related to diabetes, as a result of an autonomy and self-care independence by CSII more than with traditional multiple injection therapy. The patient showed a better social adaptation improving his general emotional health and his HRQoL, but a psychological counseling was suggested in order to support him.

A new psychological evaluation at 19 years of age has confirmed a stable improvement in his social adaptation by implementing physical activity, planning employment experiences, and actively having good friendship.

Discussion

We report the first case of the use of CSII in a patient with SBDS and diabetes. CSII seemed to improve HRQoL in our patient in addition to metabolic control.

According to Kerr at al., ¹⁶ children with SBDS display weaker overall intellectual reasoning, higher-order language skills, perceptual reasoning, visual-motor processing speed, visual-motor integration, visual executive problem-solving, attention and aspects of academic achievement, as well as a lower functional level of independence relative to the general population. Significant issues with behavior have also been identified, including prior formal diagnoses and social problems. Neurocognitive deficits in subjects with SBDS are largely independent of family environment, likely as a consequence of SBDS gene dysfunction. ¹⁶ There is a need for a broad-based approach for assessing of the cognitive function and appropriate remediation of individuals with SBDS. ¹⁶

HRQoL has increasingly been acknowledged as an essential health outcome measure in pediatric medicine, available also for children with chronic illness. The development and use of pediatric HRQoL measures are important for identifying at-risk children and applying early intervention programs. Studies have shown that enhancing the HRQoL and well-being for children with diabetes is as important as metabolic control in preventing secondary morbidity. ^{17 –19}

The PedsQL is a modular instrument designed to measure HRQoL in children and adolescents 2–18 years of age. ^12,13 The PedsQL consists of a core measure of global HRQoL suitable for the pediatric population and a supplemental module assessing specific diabetes symptoms and treatment domains suitable for pediatric patients with diabetes. The PedsQL version 3.0 Diabetes Module ^12,13 is designed to measure diabetes-specific HRQoL with both self-report responses and proxy-report of their parents and consists of 28 items divided into five scales: (1) diabetes symptoms (11 items), (2) barriers to treatment (four items), (3) treatment adherence (seven items), (4) concern (three items), and (5) communication (three items).

The use of CSII as an alternative option to treatment with insulin MDI is increasing and is proving to be acceptable and successful. ¹⁴ Although randomized studies in the preschool-age group have failed to show better glycemic control, CSII is generally successful for patients with diabetes in improving the HRQoL. ^{17 –19} Two trials demonstrated improved HRQoL for adults on CSII compared with MDI with particular improvement in lifestyle flexibility. ^20,21 A large-scale pre/post study found similar results in children and adolescents, ²² although other studies have found no difference in the HRQoL of child and adolescent CSII users and those on injection therapy, or improvements in only some HRQoL components. ^{23 –25} Recently Lukács et al. ²⁶ demonstrated that youths with diabetes treated with CSII therapy had better HRQoL than those treated with MDI.

According to International Diabetes Federation/International Society for Pediatric and Adolescent Diabetes 2011 guidelines, ¹⁴ in our case an insulin pump has been an alternative to treatment with MDI considering recurrent hypoglycemia and a needle phobia. On the other hand, our patient did not have a reduced T-IQ despite the underlying disease.

Several genetic diseases have been identified as being associated with the occurrence of diabetes, including Down's syndrome, Klinefelter's syndrome, Turner's syndrome, chromosome 22q11.2 deletion syndrome, Rett's syndrome, and Kabuki syndrome. ^{27 –32} CSII therapy is safe, more physiological, more accurate, and easier to manage than injections. It may offer an interesting therapeutic tool in this group of patients with chronic disease in order to improve HRQoL and glycemic control. Actually, only a case of a child suffering from Down's syndrome treated with CSII after the onset of diabetes has been reported. ³³ CSII improved glycemic control, nutritional status, and decreased glycemic excursion. At our knowledge this is the first patient with SBDS and diabetes who uses CSII and seems to have improvement in several aspects of quality of life, thanks also to a face-to-face interaction involving the patient, family, and caregivers.