Co-occurrence of Fanconi–Bickel syndrome and CMV infection in a child, a case report

Abstract

Introduction:

Fanconi–Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by a spectrum of clinical manifestations, the association of this syndrome with cytomegalovirus (CMV) infection makes this condition very rare.

Case presentation:

We reported a 3-month-old infant with cytomegalovirus infection with presenting hepatosplenomegaly, doll-like face, microcephaly, metabolic hyperchloremic acidosis with a normal anion gap, rachitis, hyperglycosuria, proteinuria, elevated levels of alanine aminotransferase and aspartate aminotransferase, and growth retardation.

After the prescription of ganciclovir, the levels of bilirubin and alanine aminotransferase decreased to normal, and the splenomegaly regressed. However, hepatomegaly and hyperglycosuria remained aggravating.

Discussion:

The co-occurrence of FBS and CMV infection in infants presents a complex clinical scenario, demonstrating significant challenges in diagnosis and management.

Conclusion:

Further research is needed to elucidate the interplay between genetic disorders like FBS and viral infections and facilitate the development of targeted therapeutic interventions and preventive strategies.

Introduction

Fanconi–Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose transport in the kidneys, intestines, and liver, leading to hepatorenal glycogen accumulation. Mutations in the GLUT2 gene cause it, encoding the glucose transporter protein 2 (GLUT2)^[1]. Infants with FBS typically present with hepatomegaly, failure to thrive, and renal dysfunction.

HIGHLIGHTS

• Fanconi–Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by a spectrum of clinical manifestations.

• The co-occurrence of FBS and cytomegalovirus (CMV) infection in infants presents a complex clinical scenario, demonstrating significant challenges in diagnosis and management.

• Further research is needed to elucidate the interplay between genetic disorders like FBS and viral infections.

Cytomegalovirus (CMV) is a common herpesvirus that can cause severe complications, particularly in immunocompromised individuals. In infants, CMV infection can manifest with hepatosplenomegaly, thrombocytopenia, and neurological deficits^[2].

The co-occurrence of FBS and CMV infection in infants is rare and poorly understood. Understanding this association is crucial for optimizing clinical management and improving outcomes for affected infants. Here, we present a case report of an infant with FBS complicated by cytomegalovirus infection, discussing the clinical presentation, diagnostic challenges, and management strategies^[2].

Case presentation

A 3-month-old infant, presented with a chief complaint of abdominal distension noted by the mother since the first month of life. The mother also reported intermittent fever for the past month, difficulty in breastfeeding for the last three weeks, respiratory distress with tachypnea and hyperpnea, accompanied by frequent vomiting and recurrent diarrhea for the past week. There was no history of changes in urine color or adjacent liver inflammation.

The patient was admitted to the hospital once at the age of one and a half months with complaints of bronchiolitis accompanied by dehydration due to recurrent diarrhea without emesis. There is no history of neonatal jaundice or admission to the neonatal intensive care unit.

The pregnancy was full-term, lasting 38 weeks, with a birth weight of 2500 grams, and the delivery was vaginal.

Psychomotor development was reported as normal for the age.

The exam showed generalized fatigue and malaise, tachypnea, intercostal retractions, and utilization of secondary respiratory muscles (scalene and subcostal). The breathing pattern is consistent with Kussmaul’s respiration; an expiratory grunt is noted.

Rickets rosary, doll-like face, and rachitis were noted (Fig. 1).

Figure 1.

Rickets rosary, doll-like face, and rachitis.

Anthropometric measurements reveal a weight of 4 kg (−3.7SD), length of 54 (−3.6SD), and head circumference of 36 cm (−3.2SD).

Hepatomegaly measuring 12 cm below the right costal margin and splenomegaly measuring 8 cm below the left costal margin were observed.

The arterial blood gas analysis revealed a pH of 7.29, indicating acidosis. Partial pressure of carbon dioxide (PCO2) was low at 15 mmHg, while bicarbonate (HCO3) was low at 7.5 mEq/L. Oxygenation appeared adequate with a partial pressure of oxygen (PO2) of 178 mmHg.

Potassium levels were low at 2.5 mmol/L. Ionized calcium was low at 0.7 mmol/L, and chloride levels were elevated at 122 mmol/L. The anion gap was normal at 14, indicative of metabolic acidosis with a normal chloride gap. Blood ketones were negative.

Liver enzymes revealed elevated alanine aminotransferase levels at 80 U/L and aspartate aminotransferase at 228 U/L. Total calcium was low at 7.5 mg/dL, while total bilirubin was elevated at 2.47 mg/dL, with direct bilirubin at 1.17 mg/dL. Lactate and ammonia levels were within the normal range. Gamma-glutamyl transferase (GGT) was markedly elevated at 1757 U/L serum.

The random urine sample showed significant levels of urinary glucose (++++), elevated protein at 42, and high potassium at 21. Additionally, there was a notable decrease in creatinine to 3.6, while the protein creatinine ratio was elevated at 11.8, indicative of renal impairment.

The 24-hour urine collection revealed a pH of 5 and a density of 1.015. Protein excretion was markedly elevated at 607 mg/24 h, with sodium excretion also significantly elevated at 221 mmol/24 h and potassium excretion at 23.6 mmol/24 h

Serological testing for Toxoplasmosis and EBV antibodies yielded negative results for both IgG and IgM. However, CMV antibodies were positive for IgG and IgM with a value of 20, suggesting a current exposure. Further testing for CMV DNA in urine revealed a high viral load of 85 500 copies/ml.

Glucose monitoring between meals indicated recurrent hypoglycemic episodes, with values dropping as low as 45 mg/dL.

Abdominal ultrasound revealed hepatomegaly measuring 14 cm and splenomegaly measuring 12 cm. Enlargement of the kidneys was also noted. Cranial CT demonstrated no intracranial calcifications. Ophthalmological examination showed no abnormalities. A diagnosis of FBS was made.

Correction of acidosis and intravenous potassium replacement therapy were initiated. The patient received treatment with ganciclovir for 6 weeks. A diet avoiding breastfeeding and including cornstarch and lactose-free milk was implemented. Electrolyte abnormalities were managed with polysisterate solution and sodium bicarbonate at high doses.

Splenic enlargement normalized without hepatic regression. Blood sugar levels exhibited postprandial elevation and fasting reduction.

Discussion

One of the eight human herpesviruses, human cytomegalovirus, also known as human herpesvirus 5, can reactivate after going into permanent latency in its host^[3]. However, the majority of congenital CMV infections most likely occur via non-primary routes because the incidence of CMV vertical transmission to a fetus in primary infection is substantially higher than in the reactivation of latent infection^[4].

Cytomegalovirus, which affects 0.2–6.1% of live newborns, is a major global source of congenital infections. The rates of CMV tend to be greater in South America, Africa, and Asia, at roughly 10–20 per 1000 live births^[5]. However, the actual incidence and frequency of FBS is unknown. Between 1949 and 2002, 88 families from around the world had about 109 instances detected. This condition is more common in consanguineous families and is primarily seen in the Middle East.^[6].

Defective GLUT2 (SLC2A2 gene, chromosome 3q26.1–26.3), which is expressed in hepatocytes, pancreatic β-cells, enterocytes, and renal tubular cells, is the etiology of GSD type XI (FBS)^[7]. In our case, we cannot detect if our patient has this mutation due to the lack of genetic analysis abilities.

A liver biopsy can offer valuable insights into understanding this rare disease; however, it does not serve as conclusive evidence for diagnosing FBS. Consequently, biopsies are generally reserved for atypical cases of FBS, particularly those associated with severe acute acidosis or hepatocellular carcinoma^[8].

85–90% of infected with CMV infants are categorized as asymptomatic, and 10–15% are classified as symptomatic. Infants are defined as either having symptoms at birth (symptomatic) or not having any symptoms at all (asymptomatic)^[4]. Infants with a symptomatic CMV infection typically have a wide variety of symptoms. The reticuloendothelial system and the central nervous system are particularly vulnerable to the virus. Hepatitis, petechiae, hepatomegaly, splenomegaly, intrauterine growth restriction, hearing loss, and thrombocytopenia are among the symptoms of a very symptomatic infection. Microcephaly, seizures, and abnormalities in neuroimaging (ventriculomegaly, intracerebral calcifications, periventricular echogenicity) are the symptoms indicating central nervous system (CNS) involvement in CMV. Optic atrophy or chorioretinitis may be discovered during an ophthalmologic examination^[4,5].

The initial indications of FBS are often identified in infants aged 3–10 months^[9]. Due to the expression of GLUT2 in the colon, kidney, liver, and pancreas (β-cells), patients usually exhibit hepatomegaly as a result of glucose intolerance, glycogen buildup, and postprandial hypoglycemia, so a disruption of glucose homeostasis is seen in patients with FBS, who also exhibit proximal tubulopathy which leads to metabolic hyperchloremic acidosis with a normal anion gap^[7,10]. Hypercalciuria is consistently observed. Pubertal delay and hypophosphatemic rickets are reported in older children. Due to renal losses, hyponatremia and hypokalemia are common. An elevated osmotic load might result in polyuria. Patients who have intestinal malabsorption may experience persistent diarrhea. In addition; hyperlipidemia is noted, resulting in a moon-shaped face and the usual signs of fat deposition on the shoulders and abdomen^[7].

Hepatomegaly in a child can result from infectious causes, metabolic disorders, or a combination of hepatic and metabolic diseases. Therefore, reaching a diagnosis should not preclude further investigation of other potential underlying causes. Treating the infectious cause, being typically more straightforward than addressing metabolic disorders, may facilitate better management of the underlying metabolic condition. The pediatrician should approach hepatomegaly as a starting point, systematically investigating accompanying clinical signs and symptoms to identify the underlying etiology comprehensively.

In our case, the development of kidney enlargement, which could not be explained by CMV infection, was also noted. Since uric acid levels were within the normal range, Von Gierke disease (GSD-1) was ruled out. After treatment with ganciclovir and the incomplete regression of hepatomegaly, the suspicion of FBS increased.

CT did not show calcifications or other abnormalities characteristic of CNS involvement and there was also no suggestion of this clinically, suggesting an acquired CMV infection.

A comparison between FBS and CMV infection was made (Table 1).

Table 1.

A comparison between Fanconi–Bickel syndrome and CMV infection

Fanconi–Bickel syndrome

CMV

Normal anion gap metabolic acidosis with hyperchloremia. Decreased bicarbonate levels and its loss in the urine. Unstable blood glucose levels. Low potassium, phosphorus, and calcium, with elevated lipids and cholesterol in the serum. Presence of glycosuria and proteinuria, with increased phosphate in the urine. Lactate, LDH, and uric acid levels are within normal ranges. Presence of rickets and costochondral beading.

Hepatosplenomegaly. Elevated bilirubin. Increased PCR in urine and elevated IgM antibodies specific to CMV. Elevated liver enzymes. Partial regression of hepatosplenomegaly and decreased liver enzymes with ganciclovir treatment.

Limitations

Genetic testing was not done in our patient due to the unavailability of genetic testing in Syria.

Conclusion

In conclusion, the co-occurrence of FBS and CMV infection in infants presents a complex clinical scenario, posing significant challenges in diagnosis and management. Our case underscores the importance of a multidisciplinary approach involving pediatricians, geneticists, infectious disease specialists, and nutritionists to optimize patient care. Early recognition of FBS and vigilant monitoring for associated complications, such as CMV infection, are crucial for improving outcomes and quality of life in affected infants. Further research is warranted to elucidate the interplay between genetic disorders like FBS and viral infections, facilitating the development of targeted therapeutic interventions and preventive strategies.

Ethical approval

Our institution does not require ethical approval for reporting individual cases or case series.

Consent

Written informed consent was obtained from the patient parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

Not applicable.

Author contributions

S.A., A.A., and S.J.: drafting, reviewing, editing, and approving the final manuscript; R.E.: drafting, reviewing, editing, corresponding, and approving the final manuscript; S.A.: reviewing, supervising, and approving the final manuscript; H.H., M.K., M.A., D.A., and F.A.: drafting, editing, and approving the final manuscript.

Conflicts of interest disclosure

Not applicable.

Guarantor

Souzan Almohmd.

Research registration unique identifying number (UIN)

None.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Data sharing is not applicable to this article.