Acquired growth hormone deficiency in Fanconi-Bickel syndrome

Abstract

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disease, resulting from mutations in the SLC2A2 gene, causing impaired glucose transporter 2 protein transporter protein function, impaired glucose and galactose utilisation, hepatorenal glycogen accumulation and organ dysfunction. Clinical features include failure to thrive, hepatomegaly, rickets, short stature and delayed puberty. Therapy includes electrolyte supplementation and uncooked cornstarch. We present a 15-year-old boy diagnosed with FBS in infancy. Growth velocity was normal on standard treatment until age 8.5 years, at which time growth failure led to a diagnosis of acquired growth hormone (GH) deficiency. Initiation of recombinant human GH (rhGH) replacement of 0.25 μg/kg/week resulted in marked improvement in growth velocity and height. While short stature is expected in FBS, growth velocity that falls below the normal range despite adequate therapy should prompt further evaluation. Our case suggests that acquired GH deficiency can arise in FBS and benefits from rhGH therapy.

BACKGROUND

Fanconi-Bickel syndrome (FBS, Online Mendelian Inheritance in Man (OMIM) number 227810) was first described by Guido Fanconi and Horst Bickel in 1949.¹ FBS was known as Glycogen Storage Disease Type IX until 1998, when Santer et al identified the role of glucose transporter 2 protein (GLUT2) and the SLC2A2 gene.² Approximately 200 cases with 70 different variants in the SLC2A2 gene have been reported to date.^{1 3} SLC2A2 encodes for GLUT2, a 524-amino acid low affinity, facultative glucose transporter responsible for passive bidirectional transport of monosaccharides, mainly D-glucose and D-galactose.^{4 5} GLUT2 is primarily expressed in the proximal tubules of the kidney, hepatocytes, enterocytes, pancreatic β-cells and discrete areas of the brain.^{1 6} GLUT2 normally maintains glucose homeostasis by regulating transepithelial flow of glucose across the plasma membrane of these cells.¹

FBS results from either compound heterozygous or homozygous mutations in the SLC2A2 gene, leading to decreased GLUT2 expression¹ and is characterised by hepatorenal glycogen accumulation, proximal renal tubular dysfunction and impaired utilisation of glucose and galactose.¹ Weight is often low at birth and patients typically present within the first year of life with failure to thrive, rickets, haepatomegaly, dysglycaemia and tubulopathy.¹ Long-term clinical sequelae include developmental delay, impaired statural growth, delayed puberty, osteoporosis, bone pain, pathologic fractures and decreased mobility.^{2 4 7}

Typical biochemical characteristics of FBS include postprandial hyperglycaemic, fasting hypoglycaemic and hypergalactosemia.^{1 4} The molecular mechanisms accounting for dysglycemia in FBS are not well understood.¹ Postprandial hyperglycaemic results from decreased hepatic uptake of glucose. There may also be impaired insulin secretion. Homozygous GLUT2 knockout mice lack first-phase insulin secretion,⁸ whereas the second phase of insulin secretion is preserved. This observation suggests that GLUT2 is required for first-phase insulin secretion by pancreatic β-cells.¹ Fasting hypoglycaemic has been attributed to defective glucose transport across the hepatocyte plasma membrane, resulting in reduced hepatic glucose output from glycogenolysis and gluconeogenesis and glucosuria due to renal tubular dysfunction.⁶ Glucose and galactose intolerance as well as diabetes mellitus can also occur, though the latter is uncommon.^{1 4 9}

Case presentation

Our patient was born at term after an uncomplicated pregnancy to non-consanguineous parents. Birth weight was 2835 g. He initially presented at age 6 months with pallor, hypotonia and deceleration in linear growth. His physical examination was notable for mild haepatomegaly. Biochemical evaluation at 10 months of age showed hyperphosphatasia, elevated aspartate aminotransferase and alanine aminotransferase, elevated haemoglobin A1c, low bicarbonate, low-normal insulin-like growth factor binding protein-3 (IGFBP-3) and non-specific urine amino acid abnormalities. Urinalysis showed pH 7.3 and glycosuria with concurrent serum glucose of 169 mg/dL (table 1). Sweat chloride concentration, thyroid function tests, coeliac screening, complete blood count (CBC), erythrocyte sedimentation rate (ESR), serum electrolytes, albumin, lactic acid, C-peptide and MRI of the brain were all normal. He was subsequently found to have overnight hypoglycaemic, postprandial hyperglycaemic and hypertriglyceridemia. A confirmatory fasting study showed severe hypoglycaemic, moderate ketosis, acidosis, increased free fatty acids, normal blood lactate, undetectable insulin and C-peptide levels and normal urine organic acids. The fasting growth hormone (GH) level was unremarkable. After glucagon administration, plasma glucose increased by 10 mg/dL above baseline, indicating either an inadequate or inaccessible hepatic glycogen reserve. Thereafter, he was started on supplemental uncooked cornstarch (UCCS) therapy. Trio whole-exome sequencing (Prevention Genetics, Marshfield, WI) detected two previously unidentified mutations in the SLC2A2 gene—a paternally derived c.216C>A p.Try72STOP on exon 3 and maternally derived c.1467delA p.Lys490fsSTOP513 on exon 11, which confirmed the diagnosis of FBS.

Table 1.

Initial biochemical and urine studies at 10 months of age

	Value	Reference range
Serum studies
Alkaline phosphatase (IU/L)	1171	110–400
AST (U/L)	94	10–65
ALT (U/L)	77	3–64
HbA1c (%)	8.3%	<6.5%
Bicarbonate (mmol/L)	16	17–29
IGFBP-3 (mg/L)	0.8	0.7–3.6
Triglyceride (mg/dL)	917	<130
Fasting BG (mg/dL)	43	60–100
Postprandial BG (mg/dL)	301	<140
Urinalysis
pH	8.0	4.6–8
Glucose (mg/dL)*	>1000	Negative
Protein	Negative	Negative
Fasting studies
Blood glucose (mg/dL)	26	56–87
BOHB (mmol/L)	1.96	0.22–2.34
Insulin (µU/mL)	<2.0	<2
C-peptide (ng/mL)	<5.0	<5
Lactate (mmol/L)	1.6	0.6–2.3
pH, venous	7.3	7.35–7.45
Bicarbonate (mmol/L)	18.8	23–30
Growth hormone (ng/mL)	2.2	2.4–14.7
Free fatty acids (µmol/L)	2130	0.84–2.74
Glucagon stimulated BG (mg/dL)	36	Increase >30

Fasting studies reference values adopted from van Veen et al.¹¹

*Concurrent serum BG 169 mg/dL.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BG, blood glucose; BOHB, beta-hydroxybutyrate; HbA1c, haemoglobin A1c; IGFBP-3, insulin-like growth factor binding protein-3.

Between the ages of 6 months and 5 years, he had stable glycaemic control, non-progressive proteinuria, no changes in hepatic function and satisfactory growth on a regimen consisting of two tablespoons (15 g) of UCCS two times nightly, supplemental phosphate, Bicitra (citric acid and hydrous sodium citrate, 1 mEq of sodium and 1 mEq bicarbonate/mL), L-carnitine and enalapril-hydrochlorothiazide. A significant decrease in growth velocity was first noted at age 8.5 years (figure 1). Serum IGF-1 and IGFBP-3 levels were in the normal prepubertal range, and a GH stimulation test with arginine and clonidine was normal (table 2). Thereafter, the family adopted a stricter lactose-free diet with good adherence.

Figure 1.

Changes in height and growth velocity before and after rhGH initiation interrupted red line indicate initiation of growth hormone therapy; interrupted blue line indicates onset of puberty. Mid-parental height 179.9 cm (~50th percentile). GH, growth hormone; rhGH, recombinant human GH; GV, growth velocity (cm/year).

Table 2.

Patient’s biochemical analysis of growth hormone status

Age	3.5 years	4.1 years	5.2 years	5.7 years	7.9 years	8.4 years	8.9 years	9.8 years	10.3 years	10.8 years	11.2 years	11.4 years
IGFBP-3 mg/L	1.9 (0.8–3)	1.6 (0.8–3)	2.1 (1.5–3.4)			1.7 (2.1–4.2)	1.3 (2.1–4.2)		4.7 (2–4.8)	5.4 (2–4.8)	3.8 (2–4.8)	4.5 (2–4.8)
IGF-1 ng/mL	67 (20–141)	71 (25–157)	82 (30–174)		68 (44–211)	69 (52–231)	95 (52–231)		176 (71–275)	141 (71–275)	133 (82–299)	216 (82–299)
GH ng/mL	2.5	1.5	1.0	14*			0.04	3.0*

Table 1 shows the biochemical analyses performed on our patient leading up to his diagnosis.

Values in parentheses are Esoterix reference ranges for age and Tanner stage.

*Peak level during GH stimulation testing in response to both arginine and clonidine; a peak GH value <7 ng/mL is considered the threshold for GH deficiency.

GH, growth hormone; IGF-1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3.

Between the ages of 5 and 9 years, growth velocity steadily declined (figure 1). Biochemical evaluation, which included TSH, free thyroxine, serum prolactin, a comprehensive metabolic profile, CBC, ESR, tissue transglutaminase antibody, serum IgA and gamma glutamyl transferase levels, was normal. Repeat biochemical studies revealed a low IGFBP-3 level but persistently normal prepubertal IGF-1 value (table 2). His dose of UCCS was increased to three tablespoons (22.5 g) two times nightly, as it was thought that recurrent nocturnal hypoglycaemic could be contributing to his poor growth. There were no other concurrent dietary changes during this time.

Differential diagnosis

By the age of 9 years, he was again noted to have to persistently decreasing growth velocity that reached a nadir of ~1.2 cm/year. A repeated GH stimulation test confirmed acquired GH deficiency (table 2). An MRI of the brain was normal. Treatment with nightly subcutaneous recombinant human GH (rhGH) therapy (0.25 mg/kg/week) was started and resulted in marked improvement in his growth velocity (10.35 cm/year) within 11 months of initiating therapy. To date, his height has increased from a Z-score −4.2 to −1.95. Clinical evidence of puberty was first noted at age 12 years 7 months; his most recent testicular volume at age 14 years 1 month was 8 mL bilaterally.

Discussion

While FBS is generally considered to have a favourable prognosis, more recent studies have found a wide spectrum of disease severity.⁴ It is thought that a multitude of unknown epigenetic and environmental factors contributes to phenotypic variability in FBS, with several mutations possibly associated with worse clinical phenotypes.^{4 5} One study of eight patients from a single Bedouin family in Israel, all with the same mutation, found marked differences in long-term complications, including effects on growth, skeletal and renal complications, frequency of hospitalisation and maximal required electrolyte replacement therapy.⁵ Dweikat et al studied two siblings of consanguineous parents, each initially with similar clinical presentations. The first had progressive clinical and laboratory improvement with medical therapy and ultimately had normal growth and resolution of rickets. The sibling, however, developed progressive weight loss, metabolic acidosis, polyuria, rickets and died at age 10 months.⁴

There is no specific treatment for FBS.¹ Treatment is largely supportive: the mainstay of therapy aims to prevent rickets, metabolic acidosis, poor growth and dysglycaemia. However, with adequate dietary and medical management, patients with FBS can improve their maximal growth potential and live well into adulthood.⁴ Nightly, UCCS, a slowly absorbed source of glucose, has been shown to prevent nocturnal hypoglycaemic, decrease hepatomegaly and result in significant catch-up growth.⁷ Recently, the combination of UCCS and intensive nocturnal enteral nutrition was shown to improve height outcomes in younger patients and those with severe disease previously treated with UCCS alone.¹⁰ While dietary treatment is often effective, given the phenotypic heterogeneity of FBS, not all patients respond well to therapy. There are numerous reports of patients with FBS who have continued to experience poor linear growth while receiving maximal standard therapy.4 5 7 9 For example, Berry et al described a 3-year-old boy who presented with severe growth failure and rickets, despite intensive medical therapy.⁹

Short stature is a common complication of FBS. One study showed an average height SD varying from −2 to −8.5 SD below the mean.⁷ Poor growth in patients with FBS is thought to be the result of chronic macronutrient deficiencies. However, whether decreased GH secretion occurs concurrently is unknown. GH deficiency may arise from dysfunctional GLUT2 activity and downstream perturbations in ghrelin and leptin signalling, though the mechanism is unclear.¹ Dysfunctional ghrelin secretion in FBS could lead to decreased GLUT2 transcription and translocation, ultimately resulting in GH deficiency.

We report a patient with FBS on medical therapy with good compliance and no evidence of hepatic dysfunction and stable renal disease who developed acquired GH deficiency at age 9 years. Treatment with rhGH resulted in a marked increase in growth velocity and height, and his parents reported a positive psychosocial impact. While short stature is expected in FBS patients, frank GH deficiency has not been described previously. To our knowledge, this is the first described patient with FBS and acquired GH deficiency, and the first to have a beneficial response to rhGH therapy. The mechanism accounting for his GH deficiency remains unclear; nonetheless, this case suggests that acquired GH deficiency may be a possible complication of FBS. Additional case reports are needed to support the notion that, in addition to suboptimal nutrition, GH deficiency may play a role in the pathogenesis of some cases short stature in FBS. This case highlights the importance of seeking an alternative explanation when persistent short stature and growth failure occur in a child with FBS despite good adherence to medical therapy. Further research is needed to determine the overall prevalence and mechanism of GH deficiency in patients with FBS.

Learning points.

• Acquired growth hormone (GH) deficiency has not previously been described in Fanconi-Bickel syndrome (FBS).

• Recombinant human GH therapy may be effective in treating acquired GH deficiency in FBS.

• Further research is needed to determine the mechanism of acquired GH deficiency in FBS.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).