Pitfalls in the Diagnosis of Hereditary Intolerance Alexander Y. Kim, MD,a Joel J. Hughes, DO,b Angela Pipitone Dempsey, RD, CNSC,a Krista Sondergaard Schatz, MS, CGC,a Tao Wang, MD, PhD,a Meral Gunay-Aygun, MDa

Establishing the diagnosis of hereditary fructose intolerance (HFI) remains abstract difficult despite the availability of specific molecular genetic testing of the ALDOB gene. This is attributable, at least in part, to the lack of a specific and practical biomarker. We report the incidental diagnosis of HFI as a consequence of nontargeted genetic testing ordered for alternative indications in 5 patients, including 3 children and 2 adults. Two of the children were diagnosed with HFI after extensive evaluations that ultimately involved clinical or research exome sequencing. The third child was diagnosed with HFI during subsequent genetic testing of at-risk family members. Both adults learned to avoid fructose and remained asymptomatic of HFI before aDepartment of Genetic Medicine, School of Medicine, Johns diagnosis. One was diagnosed with HFI during preconception, nontargeted Hopkins University, Baltimore, Maryland; and bNational Human Genome Research Institute, National Institutes of expanded carrier screening. For the other, concern for HFI was initially raised Health, Bethesda, Maryland by indeterminate direct-to-consumer genetic testing results. None of these patients presented with infantile acute failure or other acute Dr Kim was involved in direct patient care and drafted the initial manuscript; Dr Hughes, Ms decompensation. Our findings suggest that the emphasis of classic teaching on Pipitone Dempsey, Ms Sondergaard Schatz, and Dr infantile liver failure after first exposure to fructose may be inadvertently Wang were involved in direct patient care and increasing the likelihood of missing cases of HFI characterized by other contributed clinical data; Dr Gunay-Aygun was involved in direct patient care and conceptualized manifestations. HFI is likely underdiagnosed and should be considered for and designed the case series; and all authors patients with nonspecific findings as well as for individuals with significant revised and reviewed the manuscript, approved the aversion to sweets. final manuscript as submitted, and agree to be accountable for all aspects of the work. DOI: https://doi.org/10.1542/peds.2019-3324 Accepted for publication Nov 20, 2019 Hereditary fructose intolerance (HFI) The first clinical report of HFI was in Address correspondence to Alexander Y. Kim, MD, is an inborn error of a 24-year-old woman with idiosyncrasy Department of Genetic Medicine, School of Medicine, caused by biallelic loss-of-function to fructose in 1956.5 Since then, the Johns Hopkins University, 600 N Wolfe St, Blalock variants in the ALDOB gene.1,2 medical literature has reflected the 1008, Baltimore, MD 21287. E-mail: [email protected] The gene product aldolase B is difficulties in establishing the diagnosis PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). involved in the reversible catabolism during both childhood and adulthood. of fructose-1-phosphate (F-1-P) and This has been largely attributed to its Copyright © 2020 by the American Academy of Pediatrics fructose-1,6-bisphosphate.3 The nonspecific signs and symptoms, FINANCIAL DISCLOSURE: The authors have indicated biochemical consequences of including and they have no financial relationships relevant to this aldolase B deficiency include intellectual disability. Nausea, , article to disclose. , hypophosphatemia, and other forms of gastrointestinal FUNDING: No external funding. hypokalemia, hypermagnesemia, distress have been frequently reported. POTENTIAL CONFLICT OF INTEREST: The authors have hyperuricemia, hyperalaninemia, However, recurrent descriptions of indicated they have no potential conflicts of interest and lactic academia. These findings acute liver failure have underscored the to disclose. are thought to represent the effects importance of considering the of F-1-P accumulation and phosphate diagnosis of HFI for a subset of patients To cite: Kim AY, Hughes JJ, Pipitone Dempsey A, depletion on , with critical illness.1,6,7 Eventually, the et al. Pitfalls in the Diagnosis of Hereditary Pediatrics , and the tricarboxylic classic teaching evolved an emphasis on Fructose Intolerance. . 2020;146(2): e20193324 acid cycle.4 recognizing infantile acute liver failure

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 146, number 2, August 2020:e20193324 CASE REPORT after first exposure to fructose when experienced acute liver failure or aspartate aminotransferase (AST), weaning from breastfeeding. other acute decompensation. In alanine aminotransferase (ALT), and retrospect, she has demonstrated albumin levels, are summarized in Before the characterization of human a lifelong aversion to sweets through Table 1. An abdominal ultrasound aldolase B and the availability of her categorical avoidance of fruits revealed minimally increased liver molecular genetic testing, and vegetables. Her diagnostic echogenicity and normal-appearing establishing the diagnosis of HFI odyssey involved liver and kidney kidneys. Her preexisting dietary goal involved fructose-tolerance testing function testing, serum electrolytes, was to limit fructose intake to and a liver biopsy with an aldolase lactate and pyruvate levels, a urine ,40 mg/kg per day. Her diet did not activity assay.4,8 The true prevalence organic acid analysis, a plasma amino require substantial modification at of HFI remains unknown. Carrier acid analysis, a plasma acylcarnitine the time of her diagnosis because her screening for common ALDOB profile, fragile X syndrome testing, favorite foods were already either variants suggests that prevalence and a single-nucleotide free of or low in fructose, , varies by ethnic group and predicts polymorphism–based chromosomal and/or sorbitol (Table 2). Our an overall prevalence of ∼1:60 000 in microarray analysis. All results were recommendations included complete the United States.9 noninformative. Clinical exome elimination of fructose, sucrose, and/ We report the incidental diagnosis of sequencing ordered by her or sorbitol from her diet. HFI in 5 patients after nontargeted neurogeneticist revealed compound At the time of her follow-up visit with molecular genetic testing ordered for heterozygosity for ALDOB c.448G.C us at 5 years 9 months, she remained alternative indications. None of these (p.Ala150Pro) and c.524C.A short statured with a height of patients presented with infantile (p.Ala175Asp) variants, establishing 100.1 cm (less than the third acute liver failure. This suggests that the diagnosis of HFI. percentile with a z score of 22.74). cases of HFI characterized by other Her weight was improved at 17.6 kg manifestations may continue to be At the time of her initial clinic visit (21st percentile), and her head missed and possibly misdiagnosed. with us at 4 years 1 month, she was circumference was 50.7 cm (53rd short statured with a height of percentile). She has been doing well 89.7 cm (less than the third percentile CLINICAL REPORTS overall. She is still developmentally with a z score of 22.81). Her weight delayed but is going to school and Patient 1 is a 7-year-old girl who was 13.4 kg (seventh percentile), and making significant progress. presented at 18 months with global her head circumference was 49.5 cm developmental delay and short (34th percentile). There was no Patient 2 is a 5-year-old girl and the stature. Her past medical history was palpable . Pertinent younger sister of patient 1. At the otherwise unremarkable. She has not laboratory studies, including time of diagnosis, she was seemingly

TABLE 1 Clinical and Biochemical Findings in Patients With HFI Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Current age, y 7 5 5 32 70 Sex Female Female Female Female Male Ethnicity Scottish, Polish, English, Scottish, Polish, English, Scottish, Irish, German, Romanian Irish, German Northern European Northern European Italian Consanguinity No No No No No Positive family history Yes Yes No No No Aversion to sweets Yes Yes Yes Yes Yes Acute liver failure No No No No No AST, U/L 22–30 37–57 29–85 28–38 10–16 ALT, U/L 12–19 28–47 18–61 19–21 20 Albumin, g/dL 4.5–4.8 4.4–4.7 4.2–5.1 3.6–4.7 4.3 Coagulation testing Not performed Not performed Not performed Normal Not performed Lactic acid, mmol/L 1.7–20 1.6 1.1 0.8 0.6 Uric acid, mg/dL 2.7–3.5 4.2–4.9 4.4 3.3 5.5 Magnesium, mg/dL 2.1–2.3 2.3–2.4 1.9–2.4 1.8–1.9 2.3 Phosphorus, mg/dL 4.9–5.5 5.4–5.9 4.4–6.2 3.1–3.5 3.6 Transferrin isoelectric focusinga Mildly elevated mono- Not performed (Abnormal) type I Not performed Not performed oligosaccharide/di- pattern oligosaccharide ratio Lysosomal activities Not performed Not performed Multiple elevationsb Not performed Not performed a Transferrin isoelectric focusing is a screening test for congenital disorders of glycosylation (eg, PMM2-CDG formerly known as congenital disorder of glycosylation type Ia). b Elevations of multiple lysosomal enzyme activities in plasma is a diagnostic marker for I-cell disease (ie, mucolipidosis II).

Downloaded from www.aappublications.org/news by guest on September 23, 2021 2 KIM et al TABLE 2 Most Recently Reported Diet of Patients With HFI Patients 1 and 2 Patient 3 Patient 4 Patient 5 Breakfast Cereal in -free whole Waffles, cereal, eggs, bacon, None Raw unsalted almonds, sprouted milk, cheesy eggs and hash sausage, grits grain cereal and oats in soy browns, waffles with butter milk, seeds (eg, chia, flax, hemp), nutritional yeast, raw greens (eg, kale, broccoli, spinach), brown lentils, white beans Lunch Chicken noodle soup without Pasta, grilled cheese Deli meat sandwich (eg, salami, Brown lentils, white beans carrots, turkey and cheese sandwiches, scrambled pastrami), potato chips sandwiches, hotdogs eggs, fried bologna Dinner Chicken nuggets, cod fillets, Chicken, steak, homemade Arugula salad with chicken and Bok choy, mushrooms, onions, meatballs, shrimp, french hamburgers, hotdogs french fries, cheesy pasta ginger, and noodles in tofu fries, macaroni and cheese, sauce; tempeh and sprouted cheesy rice with spinach grain bread sandwiches with homemade sauerkraut, pickles, and avocado; cooked greens (eg, collard, swiss chard) Snack(s) Cheese-flavored crackers Cheese-flavored crackers, Cheese-flavored crackers None popcorn, pretzels Beverage(s) Lactose-free whole milk, water Chocolate milk, flavored water, Water Water flavored electrolyte beverage

asymptomatic of HFI. However, like percentile). Her development has (Fig 1). Targeted clinical testing her older sister, she demonstrated been normal. She remains healthy confirmed this and, thus, established a lifelong aversion to sweets. After and compliant with her dietary goal the diagnosis of HFI at 12 months. her sister’s diagnosis with HFI, she of eliminating fructose, sucrose, and/ Dietary restriction of fructose to had targeted analysis of the ALDOB or sorbitol intake (Table 2). Unlike ,40 mg/day was initiated before gene, which established the diagnosis her older sister, she is interested in transfer of her metabolic (Fig 1). At the time of her initial clinic dextrose-based sweets, motivated by management to our institution. At the visit with us at 2 years 3 months, her a desire to participate in social time of her initial clinic visit with us height was 83.1 cm (10th percentile), events, such as birthday parties. She at 23 months, she was short statured her weight was 12.5 kg (49th once inadvertently ate a fructose- with a height of 81 cm (10th percentile), and her head containing cookie and developed percentile) and continued to have circumference was 48.2 cm (49th diarrhea. failure to thrive with a weight of percentile). Her liver was not 9.7 kg (less than the third percentile Patient 3 is a 5-year-old girl who palpable. The AST level was with a z score of 22.14). Her head presented at 3 months with profound minimally elevated, whereas ALT and circumference was 46.3 cm (ninth failure to thrive, hepatomegaly, and albumin levels were normal (Table 1). percentile). Her hepatomegaly had hepatic synthetic dysfunction. Before Her abdominal ultrasound revealed resolved. She demonstrated the her diagnosis and dietary treatment, increased liver echogenicity with characteristic aversion to sweets, as she also had language and gross coarsened echotexture and normal- reflected by her favorite foods. We motor delays requiring speech and appearing kidneys. She had the same recommended further reducing her physical therapy sessions. Her preexisting goal for limiting fructose exposure to fructose, sucrose, and/or diagnostic evaluation, which has been as her older sister. She also had the sorbitol by eliminating it from her described previously, included same favorite foods and ate the same diet (Table 2). biochemical testing that revealed meals. We recommended removing as increases in multiple lysosomal At the time of her follow-up visit at much fructose, sucrose, and/or enzyme activities concerning for I-cell 5 years 7 months, her height, weight, sorbitol from her diet as possible. disease and an abnormal type I and head circumference were At the time of her follow-up visit with transferrin isoelectric focusing improved at 109.2 cm (28th us at 3 years, 11 months, her height pattern suggestive of a congenital percentile), 16.2 kg (ninth percentile), was improved at 96.3 cm (18th disorder of glycosylation.10 Research and 49.2 cm (13th percentile), percentile), her weight was 16.8 kg exome sequencing revealed respectively. Her liver was not (70th percentile), and her head homozygosity for the common ALDOB palpable. The AST level was mildly circumference was 50.5 cm (67th c.448G.C (p.Ala150Pro) variant elevated, whereas ALT and albumin

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 146, number 2, August 2020 3 FIGURE 1 A, Ages at presentation and diagnosis (arrows). B, ALDOB gene with patient variants (arrows). levels were normal (Table 1). She was hypothalamic . Her past baby foods. During childhood, her compliant with her dietary goal and medical history and pertinent typical meals consisted of hotdogs ate a larger variety of foods. She biochemical findings were and cheeses, whereas cheese-flavored showed interest in dextrose-based unremarkable (Table 1). She has crackers were staple snack items. She sweets. Notably, her development attained a high level of academic found that her specific dietary normalized to an age-appropriate achievement, including postgraduate restrictions were a significant source level. She has been doing well overall. training. Although she did not have of frustration and social conflict any readily apparent manifestations because there was no explanation. As Patient 4 is a 32-year-old woman who of HFI growing up, she did have a part of her infertility evaluation, she presented at 30 years with concerns a lifelong aversion to sweets. As an met with a genetic counselor and for infertility attributable to infant, she refused to eat fruit-based pursued preconception, nontargeted

Downloaded from www.aappublications.org/news by guest on September 23, 2021 4 KIM et al expanded carrier screening. This genetic evaluation in our clinic, The emphasis of classic teaching on unexpectedly revealed compound including ALDOB sequence and infantile acute liver failure and heterozygosity for ALDOB c.524C.A deletion and duplication analysis. nonspecific biochemical (p.Ala175Asp) and c.113_115GGTA This revealed homozygosity for the derangements, such as hypoglycemia variants (Fig 1) and established the common c.448G.C (p.Ala150Pro) and hypophosphatemia, after first diagnosis of HFI. variant (Fig 1) and established the exposure to fructose may be diagnosis of HFI. inadvertently increasing the At the time of her initial clinic visit likelihood of missing cases of HFI with us, her weight was 57.7 kg, and At the time of the patient’s diagnosis characterized by other her height was 176 cm. There was no at 67 years, his weight was 63.3 kg, manifestations. The clinical hepatomegaly. The AST level was and his height was 167.5 cm. His liver symptoms observed in our patients minimally elevated, whereas ALT and was nonpalpable. AST, ALT, and and those described by others are albumin levels were normal (Table 1). albumin levels were normal (Table 1). nonspecific. Aversion to sweets has Her abdominal ultrasound was A previous abdominal computed been recognized as a specific finding reassuring. She espoused continued tomography revealed normal- of HFI since the time of its initial aversion to sweets and had learned to appearing liver and kidneys. He description.5 However, patients may avoid fructose, sucrose, and/or espoused continued aversion to not be routinely asked about this sorbitol (Table 2). sweets, and his diet required minimal during evaluations for nonspecific Patient 5 is a 70-year-old man who modification (Table 2). After presentations, such as failure to presented at 67 years with inadvertent exposure to fructose at thrive, particularly in the setting of indeterminate direct-to-consumer a dinner party, he demonstrated nonmetabolic clinics. They may be (DTC) genetic testing results. His past intolerance characterized by subjected to unnecessarily prolonged medical history was notable for gastrointestinal distress and diarrhea. diagnostic odysseys as a result. They Hashimoto thyroiditis and chronic Subsequent evaluation has been may also be misdiagnosed with other macrocytosis but not for liver or reassuring. nongenetic and genetic conditions, kidney disease. Laboratory testing including eating disorder, recurrent results were not concerning for HFI hepatitis, and storage 11–13 complications (Table 1). He has been DISCUSSION disease. This set of doing well overall. Before retirement, circumstances may be further he worked as a scientist. In Our report and the existing medical complicated by the suggestion that retrospect, he has demonstrated literature suggest the possibility and/ fructose intolerance may not be a lifelong aversion to sweets based on or necessity of a paradigm shift in the pathognomonic for HFI alone, given taste, smell, and sight. As an infant, he diagnosis of HFI. Three of our 5 the description of rare patients with refused to eat fruit-based baby foods. patients were asymptomatic of HFI, fruit-induced, food protein–induced As a child, he had unsweetened cereal including both adults. The 2 overtly enterocolitis syndrome.14 in skim milk for breakfast, bologna symptomatic patients presented with Additionally, not all patients can be fi and cheese sandwiches for lunch, and nonspeci c signs and symptoms, and expected to initially present after a “meat and potatoes” entrée with only 1 of our 5 patients developed transitioning to baby foods during canned vegetables for dinner. His hepatic synthetic dysfunction. All midinfancy. As demonstrated by the “birthday cakes” were meatloaves were eventually diagnosed with HFI recent report of several cases of HFI with mashed potato “frosting.” In after nontargeted molecular genetic presenting with acute neonatal and adulthood, his wife has been testing for themselves or for family early infantile liver failure with fi supportive in maintaining his specific members. Although speci c analysis initiation of formula feeding, it is dietary restrictions. For example, she of the ALDOB gene is widely available underrecognized that commonly used tastes sauces first when they eat at as a clinical diagnostic test, this was standard infant formulas contain restaurants. He was always aware not ordered for our overtly fructose and other fructogenic that his aversion to sweets symptomatic patients because HFI compounds, such as sucrose (often distinguished him from others. was not suspected. In retrospect, all 5 labeled as sugar).15 However, it was not until his son had patients demonstrated the strong DTC testing revealing carrier status aversion to sweets characteristic of Furthermore, the lack of a specific for HFI that he considered the HFI. Furthermore, those who were and practical biomarker for HFI possibility of an underlying genetic inadvertently exposed to fructose, means that neither newborn condition. His own DTC testing sucrose, and/or sorbitol were screening nor biochemical testing can results for HFI could not be intolerant and developed be used to establish the diagnosis. In determined. He then pursued formal gastrointestinal signs and symptoms. fact, biochemical testing results may

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 146, number 2, August 2020 5 fructose intolerance mimicking potentially lead to misdiagnosis. ABBREVIATIONS Reversible abnormalities in a biochemical phenotype of transferrin glycosylation have been ALT: alanine aminotransferase mucolipidosis: a review of the literature AST: aspartate aminotransferase of secondary causes of lysosomal well described in the setting of HFI Am DTC: direct-to-consumer enzyme activity elevation in serum. and are thought to represent J Med Genet A. 2017;173(2):501–509 inhibition of phosphomannose F-1-P: fructose-1-phosphate isomerase secondary to F-1-P HFI: hereditary fructose 11. Da Lozzo P, Magnolato A, Del Rizzo I, accumulation. Some patients with HFI intolerance Sirchia F, Bruno I, Barbi E. When long- lasting food selectivity leads to an have been initially misdiagnosed with unusual genetic diagnosis: a case type 1 congenital disorders of report. 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Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 146, number 2, August 2020 7 Pitfalls in the Diagnosis of Hereditary Fructose Intolerance Alexander Y. Kim, Joel J. Hughes, Angela Pipitone Dempsey, Krista Sondergaard Schatz, Tao Wang and Meral Gunay-Aygun Pediatrics originally published online July 24, 2020;

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Downloaded from www.aappublications.org/news by guest on September 23, 2021 Pitfalls in the Diagnosis of Hereditary Fructose Intolerance Alexander Y. Kim, Joel J. Hughes, Angela Pipitone Dempsey, Krista Sondergaard Schatz, Tao Wang and Meral Gunay-Aygun Pediatrics originally published online July 24, 2020;

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