Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 3-3

Three-Year-Old Girl



The patient is a 3-year-old Caucasian female presenting with a 1-year history of intermittent vomiting, increasing in frequency during the past 2 weeks. During the past year the patient has had nonbloody, nonbilious emesis approximately one time per day. The emesis is not associated with eating, nor does it occur at a specific time of the day. Occasionally, she wakes from sleep with emesis. She complains of photophobia and a sensation that there is a foreign body in her eyes. Her mother states that she seems to urinate more than other children. She denies abdominal pain, diarrhea, and rashes. Her mother denies noticing any lethargy, change in appetite, change in behavior, change in balance, or change in vision.

On the day prior to admission, her primary care physician began treatment with cefixime for presumed sinusitis after the patient had 3 days of cold symptoms and fever to 38.8°C.


The patient’s medical history is significant for failure to thrive since birth. She has always been below the 5th percentile for weight and height. Her family history is significant for a mother with Graves disease and two maternal cousins on dialysis for unknown reasons.


T 36.8°C; RR 24/min; HR 118/min; BP 98/55 mmHg

Weight 11.1 kg (<5th percentile); Height 86 cm (<5th percentile)

Physical examination revealed a thin pale female in no acute distress. She had moist mucous membranes and a small amount of clear nasal discharge. Her optic discs were not able to be visualized. Her neck was supple with full range of motion. Cardiovascular and pulmonary examinations were normal. Her abdomen was soft, nontender, and nondistended without any masses, hepatomegaly, or splenomegaly. She had no rashes, petechiae, or purpura. Cranial nerves 2-12 were intact. She had normal speech, gait, and reflexes.


Laboratory evaluation revealed a normal complete blood count. Serum chemistries were as follows: sodium, 128 mmol/L; potassium, 2.0 mmol/L; chloride, 105 mmol/L; bicarbonate, 21 mEq/L; blood urea nitrogen (BUN), 37 mg/dL; creatinine, 2.2 mg/dL; glucose, 89 mg/dL; calcium, 7.9 mg/dL; phosphorus, 3.1 mg/dL; and magnesium, 2.0 mg/dL. Liver function tests were normal. Urinalysis showed a specific gravity of 1.010, pH of 6.5, trace blood, 3+ protein, 1+ glucose, and hyaline casts. Urine electrolytes were as follows: sodium 38 mmol/L, potassium 22 mmol/L, and chloride 37 mmol/L. A chest radiograph was normal as was an ECG. A renal ultrasound displayed small echo-genic kidneys. A brain MRI was normal.


The patient received an intravenous bolus of normal saline and was admitted to the hospital with a diagnosis of renal failure of unknown etiology. Her electrolytes slowly normalized throughout hospitalization after IV and oral supplementations. While in the hospital, she underwent an ophthalmologic slit-lamp evaluation which provided a diagnosis (see Figure 3-7).


FIGURE 3-7. Retinal examination of patient with similar findings. (Reproduced, with permission, from Oppenheim RA, Mathers WD. The eye in endocrinology. In: Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. Philadelphia: Lippincott Williams and Wilkins; 2001:1968.)



This patient displayed signs and symptoms of Fanconi syndrome (Table 3-5), a generalized dysfunction of the proximal renal tubule resulting in an excessive loss of amino acids, glucose, bicarbonate, uric acid, and phosphate into the urine. Fanconi syndrome can be hereditary or acquired. Hereditary causes of Fanconi syndrome include cystinosis, Lowe syndrome (oculocerebrorenal syndrome), galactosemia, hereditary fructose intolerance, tyrosinemia, Wilson disease, Dent disease, Fanconi-Bickel syndrome, glycogen storage disease, mitochondrial disorders, and Alport syndrome. Acquired causes of Fanconi syndrome include nephrotic syndrome, Sjögren syndrome, renal vein thrombosis, cancer, or damage from drugs (Azathioprine, Gentamycin, Tetracycline) or heavy metals (lead, mercury, and cadmium).

TABLE 3-5. Signs and symptoms of Fanconi syndrome.



The diagnosis of Fanconi syndrome is made by documenting excessive loss of amino acids, glucose, phosphate, and bicarbonate in the urine in the absence of high plasma concentrations. Once Fanconi syndrome has been diagnosed, further testing can be performed to determine the specific etiology. In a newborn or infant, testing should be done as clinically indicated for tyrosinemia (urine succinylacetone), galactosemia (erythrocyte galactose-1-phosphate uridyltransferase), hereditary fructose intolerance (urinary reducing substances), and Lowe syndrome. In a child with a history suspicious for heavy metal ingestion, serum levels can be obtained.


This patient had serum and urinary findings consistent with Fanconi syndrome. An ophthalmologic evaluation revealed crystals in the cornea consistent with cystine deposits (Figure 3-7). Subsequently, an elevated leukocyte cystine level was obtained confirming the diagnosis of cystinosis.


Cystinosis is a rare autosomal recessive lysosomal storage disorder that occurs in approximately 1 in 200 000 live births in North America. The carrier frequency is approximately 1 in 225 people. The disease predominately affects individuals of European descent; however, there have been reported cases in most ethnicities. Cystinosis results from a deletion or mutation of the CTNS gene on chromosome 17p13 which encodes for the cystine transport protein, cystinosin. As a result of this defect, intracellular cystine accumulates in almost all body cells and tissues.


Three forms of cystinosis exist and differ based on severity of symptoms and age of onset. Infantile or nephropathic cystinosis is the most common form and presents between 3 and 18 months of age. Patients develop symptoms of Fanconi syndrome including dehydration, electrolyte imbalance, failure to thrive, and rickets. With time, patients develop tubulointerstitial and glomerular disease leading to chronic renal failure. Infants with nephrogenic cystinosis are unable to sweat, and subsequently have frequent episodes of fever and flushing. Characteristic corneal crystals become evident by 1 year of age and may cause photophobia or eye irritation. Fifteen percent of patients develop corneal ulcerations; however, visual acuity is not usually affected until 10 years of age. Patients with infantile cystinosis may develop hypothyroidism in the first decade of life secondary to accumulation of cystine crystals in the thyroid follicles. Without therapy, all patients develop end-stage renal disease by 10 years of life.

The second type of cystinosis is juvenile cystinosis. Patients with this form of the disease present in adolescence with proteinuria and chronic renal failure but do not have Fanconi syndrome. These patients have slower progression to end-stage renal disease and do not display failure to thrive.

The third type of cystinosis is ocular nonnephropathic cystinosis. These patients present in adulthood with photophobia. They do not have Fanconi syndrome, nephropathy, or retinal depigmentation. Adults with this form of cystinosis have intracellular cystine levels that are only moderately increased (30-50 times normal), as compared to infants with cystinosis who have intracellular cystine levels that are 100-1000 times normal. In ocular cystinosis, cystine crystals only accumulate in the cornea, bone marrow, leukocytes, and skin fibroblasts.


Cystinosis should be considered in any infant presenting with Fanconi syndrome and failure to thrive.

Urine studies. Findings are consistent with Fanconi syndrome including proteinuria, glucosuria, aminoaciduria, and phosphaturia.

Leukocyte cystine content. Leukocytes from peripheral blood can be tested to evaluate for an elevated cystine level.

Ophthalmologic examination. Corneal crystals are usually apparent on ocular slit lamp examination in patients older than 1 year of age.

Skin biopsy. Skin fibroblasts can also be tested to evaluate for an elevated level of accumulated cystine. This test is usually unnecessary, as blood can be sent to obtain the same information.

Prenatal testing. Prenatal diagnosis can be established by demonstrating increased levels of cystine in cultured amniotic cells or in a chorionic villus sample.


In the early stages of the disease, management is aimed at correcting electrolyte abnormalities resulting from Fanconi syndrome and improving growth. Patients often require oral supplementation of bicarbonate, potassium, phosphorus, and 1,25-dihydroxyvitamin D. They may also require enteral nutritional supplementation. As renal failure progresses, patients require a renal transplant. Fanconi syndrome does not recur in the transplanted kidney; however, cystine continues to accumulate in nonrenal tissues. As a result, patients may develop decreased visual acuity, corneal ulceration, retinal degeneration, pancreatic exocrine insufficiency, diabetes mellitus, hypothyroidism, delayed sexual maturation, infertility, and pulmonary disease. Patients who survive into late adulthood may develop progressive neurologic and muscular problems as cystine crystals accumulate in both the brain and muscle.

In addition to electrolyte replacement and renal transplant to manage the Fanconi syndrome, all patients should receive oral cysteamine therapy. Cysteamine enters the lysosome and reacts with cystine to form a compound that is able to be transported outside of the lysosome, thus reducing the amount of intracellular cystine. Oral cysteamine is helpful at any stage of the disease, but is most effective when initiated early. If cysteamine is started before 2 years of age, renal failure is slowed and growth is improved. Cysteamine should be continued even after renal transplant to help reduce cystine levels in nonrenal tissues. Cysteamine can be given in an intraocular topical formation to help prevent ocular complications.


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