Case Report

Oral sequelaeof chronic defects: case report of a child with glycogenstorage diseasetype lb

Nancy Dougherty, DMDMary Ann Gataletto, DMD

complex group of enzymereactions is respon- tion presently are inconclusive. Various etiologies of sible for the breakdownof the large glycogen include abnormal maturation of neutro- A moleculeinto glucose, whichis used by the body phil precursors and reduced release of from to maintain blood sugar and provide energy. The glyco- the .It is unclear whether either of these is gen storage diseases are a group of inherited disorders responsible for the neutropenia seen in GSDtype lb. involving deficiencies of one or more of the enzymes The importance of transport of glucose into neutrophils necessary to store and metabolize glycogen. Glycogen for chemotaxis has been demonstrated, and this might storage disease (GSD)exists in a variety of forms, each well2 be the etiology for the neutrophil dysfunction. involving different enzyme systems of the glycogen The purpose of this paper is to present, via a report metabolic pathway. of a patient with GSDtype lb, the short- and long-term GSDtype lb is caused by a lack of glucose-6-phos- effects of a chronic neutrophil defect on the phatase (G6P) translocase. This prevents the transport periodontium and . of G6Pacross the .1 As a result, glycogen cannot be metabolized into glucose and is Casereport deposited in the liver. The modeof genetic transmis- Medicalhistory sion of GSDtype lb is autosomal recessive. It is ex- The patient was an African-American male diag- tremely rare, with an estimated incidence of less than 1 nosed with GSDtype lb at 3 months of age. Presenting in 1,000,000.1 symptomsupon admission to the hospital were diar- This disorder affects patients in a numberof ways. rhea, dehydration, failure to thrive and a massively Clinical features include hypoglycemia, hepatomegaly, enlarged liver. A liver biopsy, demonstrating fatty in- growth retardation, delayed puberty, bleeding diathesis filtrate and a glycogen content greater than 10%. Sub- secondary to platelet dysfunction, and enlarged kid- sequent enzymetests established the diagnosis. neys. Hypoglycemiain children is defined as a blood Numerous systemic problems, some related and glucose level < 40 mg/dl.2In GSDtype lb, the level of someunrelated to GSD,complicated the patient’s medi- blood glucose may characteristically be < 15 mg/dl, cal treatment. Developmentally,he functioned at a level which is profoundly low.1 This hypoglycemia results of mild mental retardation, with IQ scores ranging from from the inability of the body to metabolize glycogen 50-60 at ages 6 and 9. This mayhave been secondary to into glucose. Hepatomegalyis secondary to deposition chronic severe hypoglycemiaduring crucial periods of of excessive glycogen in the liver. Glycogen also is brain development. deposited within the proximal tubular cells of the kid- In addition to seizures precipitated by hypoglycemia, neys, which causes enlargement of these organs. 3 The the patient had a history of central seizures. etiology of the platelet dysfunction is unclear. Two Phenobarbital was used to control the central seizures. theories include metabolic disturbances in the liver To prevent the hypoglycemia,the patient required fre- and reduced activity of glucose-6-phosphatase in the quent feedings of glucose or starch. He was capable of platelets2 themselves. eating solid foods, but at age 6, in an attempt to better Neutropenia, neutrophil dysfunction, and the result- regulate his blood sugar levels, he began to receive most ing inability to combatinfection are additional impor- of his feedings via a nasogastric tube connected to a tant features of GSDtype lb. These are of special inter- pumpthat delivered a nutritional solution 24 hr per day. est to the dentist, as they are the underlying causes of Throughout his life, the patient was plagued with the early, severe periodontal breakdownand frequent neutropenia. Neutrophil levels ranged from less than oral-4 ulcerations seen in patients with this disease2 100 to 1000 cells/mmL At age 14, after developing Causes of the neutropenia and neutrophil dysfunc- intermittent abdominalpain, occasional diarrhea, loss

224American Academy of PediatricDentistry PediatricDentistry - 17:3,1995 of appetite, and weight loss, the patient was diagnosed with Crohn's disease, a chronic ulceration of the gas- trointestinal system. The diagnosis was made by barium enema and CT scan. Daily prednisone was used in an attempt to control this condition. In late adolescence, the patient developed a cardiomyopathy. Although the etiology was never de- finitively determined, his physicians presumed it was a complication of the CSD type lb. This condition un- fortunately continued to progress and led to his death at age 21 from a presumptive congestive heart failure and pulmonary edema. The family refused an autopsy. Dental history In 1975, at 4 years old, the patient was referred by Fig 1. Periapical radiograph of the maxillary primary his primary care physician to our clinic for routine incisors at age 4. dental care. The diagnosis of GSD type lb was well established prior to this time and was made known to the dental clinic by the patient's physician. Clinical examination at that time showed a com- plete primary dentition, except for a missing maxillary left primary central incisor. The remaining maxillary primary central incisor displayed great mobility (Fig 1). There was no known history of trauma to the teeth. The finding of bone loss, however, was compatible with the patient's chronic neutropenic condition. The tooth was extracted at that visit because of pain. Radio- graphs taken several months later show the extensive bone loss not only in the maxillary incisor region, but also the mandibular incisor region (Fig 2). Poor compliance with scheduled appointments greatly hindered routine dental treatment. The family tended to bring the child in only when there was a perceived emergency. After a 1 Yz-year absence from the clinic, the patient presented at age 6 with an aphthous-like ulcer on the lower labial mucosa (Fig 3). A bland diet was recom- mended, along with palliative topical application of Kaopectate® (The Upjohn Co, Kalamazoo, MI) and Benadryl® (Parke-Davis, Morris Plains, NJ). An oral Fig 2. Periapical radiographs of the maxillary and mandibular primary incisors showing extensive alveolar exam also revealed generalized marginal inflamma- resorption. tion of the gingiva. The mandibular anterior primary dentition showed minimal root resorption, but dis- played great mobility secondary to alveolar bone loss. The patient was seen again 6 months later, at which time the chief complaint was discomfort in the maxil- lary left primary molar region. Oral examination showed extreme mobility of the maxillary left first pri- mary molar with almost complete resorption of the adjacent buccal alveolar bone (Fig 4). Due to the marked mobility of this tooth, along with the maxillary pri- mary lateral incisors and the four mandibular primary incisors, the decision was made to schedule extrac- tions. Antibiotic prophylaxis was deemed necessary due to the patient's inability to withstand . Treatment was canceled because he was hospitalized Fig 3. Clinical view of the mandibular incisor region at with a staphylococcal infection. The patient did not age 5 '/>. Notice ulceration on labial mucosa and gingival l present to the dental clinic again for 2 /2 years. recession.

Pediatric Dentistry-17:3,1995 American Academy of Pediatric Dentistry 225 Fig 4. Radiographic and clinical views of maxillary left first primary molar at age 6. Notice the extensive alveolar and gingival recession.

Fig 5. Periapical radiographs of the maxillary and mandibular primary molar regions at age 8 '/;. Notice the alveolar resorption.

At age 8 '/2, clinical and radiographic examinations already displayed some mobility. At this point, he was revealed generalized alveolar bone loss with class III scheduled for extraction of the remaining primary den- mobility of all remaining primary teeth (Fig 5). The tition. Several factors influenced the decision to per- mandibular permanent central incisors and all of the form the procedure in the hospital under general anes- first permanent molars had erupted at this time and thesia. First, the patient's level of cooperation for dental

226 American Academy of Pediatric Dentistry Pediatric Dentistry - 17:3,1995 Fig 6. Panoramic radiograph at age 12 demonstrating numerous lost teeth and alveolar bone loss. treatment had gradually deteriorated. Also, due to the in a pediatric patient and the recurrent oral bleeding diathesis secondary to platelet dysfunction, ulcerations. provision for possible blood transfusion was necessary. Neutropenia is considered to be an absolute neutro- Intravenous antibiotic coverage was provided due to phil count below 1800 cells/mm3. Some African-Ameri- his inability to combat bacterial infection. The patient cans, however, may have a count as low as 1200 cells/ was kept in the hospital several days after surgery to mm3 without being symptomatic.10-" The patient in continue the antibiotic therapy and for observation. this paper was chronically in the extremely severe to The patient continued to be seen over the next 6 years on a fairly regular basis. A number of the visits were of an emergency nature due to the TABLE. CONDITIONS EXHIBITING NEUTROPHIL DISORDERS frequent and very painful recurrence of oral ul- WITH ORAL MANIFESTATIONS cerations. The patient's progressive periodontal Neutrophil disease was followed through routine scheduled Condition Disorder Oral Manifestation appointments. An attempt was made to manage the problem with aggressive scaling and addi- Chediak-Higashi II chemotaxis Severe periodontal tional oral hygiene instruction. Despite these mea- disease II phagocytosis disease, ulcerations sures, chronic gingival and rapid Papillon-Lefevre II chemotaxis Severe periodontal alveolar bone loss continued. During this time, syndrome disease numerous teeth were lost due to lack of bony Infantile genetic Neutropenia Gingival inflam- support (Fig 6). mation, ulcerations When the patient was 14, the decision was made to extract his remaining dentition and fab- Cyclic neutropenia Neutropenia Gingival inflam- ricate full dentures. The extractions were done mation, ulcerations in the hospital under general anesthesia, again Benign chronic Neutropenia Gingival inflam- with antibiotic coverage and provisions made neutropenia mation, ulcerations for possible blood transfusion. The patient, how- Down syndrome II chemotaxis ever, never wore the dentures on a consistent basis due to continued frequent oral ulcerations. Diabetes mellitus II chemotaxis Periodontal disease He continued to be followed in this clinic, Job's syndrome (hyper- •U- chemotaxis Gingival inflam- primarily for emergency visits, until shortly be- immunoglobulin E) mation, ulcerations fore his death. Chronic granulo- •11 cell killing Gingival inflam- Discussion matous disease mation, ulcerations This case history demonstrates the devastat- Juvenile periodontitis •II chemotaxis Periodontal disease ing and even life-threatening implications of Crohn's disease Neutropenia Ulcerations CSD type lb. •II chemotaxis The features of most relevance to the dental CSD type lb Neutropenia Severe periodontal practitioner, as mentioned in the introduction, JI chemotaxis disease, ulcerations are the severe, rapidly progressing periodontal

Pediatric Dentistry -17:3,1995 American Academy of Pediatric Dentistry 227 moderate neutropenic range, with levels varying from This patient’s opportunity for optimumdental treat- less than 100 to 1000 cells/mm3. Although neutrophil ment was compromised in a number of ways. First, function tests never were done on this patient, neutro- there was difficulty in keeping regularly scheduled phil dysfunction -- specifically defective chemotaxis appointments, which was due in large part to the -- is a reported feature of GSDtype lb, and it was patient’s illness. The patient was also reluctant to de- presumedthat the patient also had this problem.1, 5 vote muchtime or care to oral hygiene at home, despite Manyauthors have cited neutropenia and/or neu- repeated instruction from the dental staff. Wedo not trophil dysfunction as important etiologic factors in feel that his developmental level was responsible for periodontal disease and oral ulcerations.2, 4, 7-11 Several the difficulty with homecare, as he was easily capable conditions in which this relationship has been well of performing muchmore difficult tasks, such as in- established are listed in the Table. serting his ownnasogastric tube on a daily basis. In a patient presenting with progressive periodon- The patient was frequently on antibiotics for vari- tal disease and/or recurrent oral ulcerations who ous staphylococcal infections, with no noticeable effect does not have a previously established medical diag- on the oral ulcerations or periodontal disease. nosis, these diseases could serve as a basis for a differ- Although chlorhexidine gluconate is not approved ential diagnosis. or proven as a treatment for periodontitis, a practitio- Given the relentless nature of this patient’s peri- ner treating a patient with GSDType lb today might odontal disease together with the established diagno- consider it as an adjunct to good home care to help sis of GSDtype lb, it is reasonable to assume that the minimize gingival inflammation and bleeding. This quantitative and qualitative neutrophil disorders were was not an option for us at the time before this patient responsible for the problemrather than other possibili- lost his teeth, as chlorhexidene had not yet been ap- ties such as osteoporosis and malabsorption syndrome. proved for oral use in the United States. The same applies to the mucosal ulcerations. Non-neu- Dentures were fabricated very carefully for this pa- trophil related etiologies for oral ulcerations could in- tient, with the realization that the prostheses might clude trauma due to convulsive disorders, uremia, and intensify his oral ulcerations. As a young adolescent, . However, this patient’s seizures were very however, the patient and his family had great concerns well controlled and he was never shown to be uremic about his appearance and self-esteem. After numerous or anemic. His medical history points to neutrophil requests from the patient, dentures were fabricated with problems as being the most likely etiology for his mu- the caveat that he should present to the dental clinic cosal ulcerations. should any problems develop. As it was, the dentures It also has been speculated that the need for frequent were rarely worn due to continued mucosal ulceration. high-carbohydrate meals in patients with GSDtype lb might exacerbate the poor periodontal condition. 9 Our Conclusions patient, however, received this nourishment through a Severe chronic gingival inflammation and periodon- nasogastric tube and did not consume meals by mouth tal disease are rare in children who are otherwise regularly. Despite this, his periodontal decline contin- healthy. In prepubertal patients, the disease entity most ued rapidly and unabated, which we feel eliminates frequently associated with gingival tissue is a marginal carbohydrate intake as an important etiologic factor. gingivitis13 without accompanyingalveolar bone loss. The diagnosis at age 14 of Crohn’s disease suggests This patient presented to the dental clinic with an that the oral ulcerations were not an isolated entity, but established diagnosis. There may be instances, how- were actually a manifestation of Crohn’s disease. This ever, when oral lesions are an important diagnostic is not inconsistent with the patient’s neutropenic con- sign in an otherwise undiagnosed systemic disease. dition, however, as inflammation of the gastrointesti- This is especially true in entities such as cyclic nal tract (which can include Crohn’s disease) has been neutropenia and acute agranulocytosis. noted to be a complication of neutropenia and neutro- The point is that severe oral mucosal inflammation, phil2,13 dysfunction2 alveolar bone loss, and chronic oral ulcerations in chil- If and when a diagnosis of a neutrophil disorder is dren should not be assumed to be due solely to local made, then the question is: to what extent can aggres- factors. Onceall local etiologies are taken into account, sive dental treatment, both clinically and at home,alle- any one of these warrants referral to a physician for viate the periodontal and oral mucosal problems com- further investigation of possible systemic factors. monlyseen in these patients? The prognosis is correlated Although the effectiveness of aggressive oral treat- closely with the extent of neutrophil impairment. A ment measures in patients with neutrophil disorders person with periodic and/or cyclic neutropenia could may depend on the patient’s level of neutrophil im- gain muchbetter control over his oral health than a pairment, every patient deserves the implementation person whose cells are chronically in the neutropenic of a strictly monitored oral hygiene program in an range. The same holds true for neutrophil function. effort to preserve the dentition for as long as possible, The effectiveness of antibiotics to prevent periodontal as well as to minimize discomfort caused by mucosal disease and mucosal ulcerations in neutropenic pa- ulcerations and periodontal disease. tients is also of a highly speculative natured. 7 228 AmericanAcademy of PediatricDentistry PediatricDentistry - 17:3,1995 The authors thank Dr. Harold Diner, director emeritus, Special 6. Greenberg MS:Neutrophil dysfunction syndromes. In: In- Care Dental Unit, Childrens’ Evaluation and Rehabilitation Cen- ternal Medicine for Dentistry, 2nd Ed. Rose LF, Kaye D, ter, Albert Einstein Collegeof Medicine,for his assistance in the Eds. Philadelphia: CVMosby Co, 1990, pp 364-65. preparation of this manuscript. 7. Barrett AP, BuckleyDJ, Katelaris CH:Oral complicationsin type 1B glycogen storage disease. Oral Surg Oral MedOral Dr. Doughertyis assistant professor, departments of dentistry Pathol 69:174-76, 1990. and pediatrics, Albert Einstein Collegeof Medicine.Dr. Gataletto 8. CharonJA, MergenhagenSE, Gallin Jh and oral was assistant professor, departmentsof dentistry and pediatrics, ulceration in patients with neutrophil dysfunction. J Oral Albert Einstein College of Medicine whenthe manuscript was Pathol 14:150-55,1985. prepared. 9. Van Dyke TE, Levine MJ, Genco RJ: Neutrophil function and oral disease. J Oral Pathol 14:95-120,1985. 1. BeaudetAL: The glycogen storage diseases. In: Harrison’s 10. VanDyke TE et al: The Papillon-Lef6vre syndrome:neutro- Principles of Internal Medicine,11th Ed. BraunwaldE et al, phil dysfunction with severe periodontal disease. Clin Eds. NewYork: McGraw-Hill,1987, pp 1643-49. ImmunolImmunopathol 31:419-29, 1984. 2. AmbrusoD, McCabeER, Anderson D, Beaudet A, Ballas 11. GencoRJ, Van DykeTE, Levine MJ, Nelson RD, Wilson ME: LM,Brandt IK, BrownB, ColemanR, Dunger DB, Falletta Molecularfactors influencing neutrophil defects in peri- JM, et al.: Infectious and bleeding complicationsin patients odontal disease. J Dent Res 65:1379-91,1986. with glycogenosis Ib. AmJ Dis Child 139:691-97,1985. 12. AmentME, Ochs HD: Gastrointestinal manifestations of 3. Sidbury JB Jr: The glycogenoses. In: Pediatrics, 15th Ed. chronic granulomatousdisease. N Engl J Med288:382-87, Barnett H, Ed. NewYork: Appleton-Century-Crofts, 1972, 1973. pp 367-70. 13. Geelhoed GW,Kane MA,Dale DC, Wells SA: Colon ulcer- 4. Barrett AP: Neutropeniculceration: a distinctive clinical ation and perforation in cyclic neutropenia. J Pediatr Surg entity. J Perio- donto158:51-55,1987. 8:379-82,1973. 5. AbrahmJL: Qualitative and quantitative neutrophil disor- 14. Baer PN, BenjaminSD: Periodontal Disease in Children and ders. In: Internal Medicinefor Dentistry, 2nd Ed. Rose LF, Adolescents. Philadelphia: JB Lippincott Co, 1974, pp 17- Kaye D, Eds. Philadelphia: CVMosby Co, 1990, pp 310-15. 25, 183-212.

African-Americanchildren with cancer fare as well as Caucasianchildren with equal access to treatment

PREVIOUSSURVIVAL RATE GAP HAS DISAPPEARED children with newly diagnosed malignancies treated from January 1962 through June 1992 at St. Jude ith equal access to effective contemporary treat Wm Children’s Research Hospital, in Memphis, Tenn. ent, African-American children with cancer These patients were accepted for treatment regard- fare as well as Caucasian children when treated at a less of their financial status. pediatric oncology research center, according to an The researchers found that in the early stage of the article in a recent Journal of the American Medical study period, black children had a poorer survival Association. rate than white children In the later stages of the Ching-Hon Pui, MD, from the Departments of study period, there were no significant differences in -Oncology, Biostatistics, and Pathology treatment outcomes. and Laboratory Medicine, St. Jude Children’s Research The authors believe that a number of conditions Hospital, Memphis, Tenn., and colleagues conducted need to exist if there is to be equal treatment out- a study to determine whether there is a racial differ- comes among children. ence in prognosis among childhood cancers. They write: "The first condition is effective, inten- The researchers found: "We have shown that con- sive, risk-directed therapy, which increasingly over- temporary anticancer treatment can equally benefit rides the importance of other prognostic factors in black children who, as a group, are economically many childhood cancers -- particularly acute lym- disadvantaged compared with white children in our phoblastic leukemia. The second is treatment in fa- referral area. cilities equipped to provide the sophisticated sup- "It is conceivable that socioeconomic factors could portive care that is essential to the safe and timely affect the outcome of children with cancer, as has delivery of these therapies and, hence, to improved been demonstrated in studies of adult mortality for cure rates. major disease categories. However, all of the patients "Finally, there is the issue of access to care. While we studied were treated without regard to insurance not a factor in our study population, unequal access status or ability to pay, negating unequal access to to care may well explain, at least in part, the growing care as a potential factor in treatment outcome." gap in mortality rates between relatively advantaged The study included 798 black and 4,507 white and disadvantaged adults."

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