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At a glance

Genetic disorder with defective transport for L-tryptophan resulting in blue urine.

Synonyms

Familial Hypercalcemia and Indicanuria; Drummond Syndrome; Familial Hypercalcemia with Nephrocalcinosis and Indicanuria; Tryptophan Malabsorption Syndrome.

Incidence

Extremely rare with a frequency of 1:1117 consecutive patients studied for detection of inborn errors of metabolism.

Genetic inheritance

Either autosomal recessive or X-linked recessive inheritance.

Pathophysiology

It is caused by a deficiency of a substrate-specific intestinal membrane transport system for L-tryptophan. The defect is located in the brush-border membrane of epithelial cells in the small intestine and kidney tubules, similar to Hartnup Disease, Diaminopentanuria, Iminoglycinuria, and Lysine Malabsorption Syndrome.

Diagnosis

Blue discoloration of the diapers starting in early infancy is the result of bacterial degradation of tryptophan, producing indigo-blue (indigotin) by enzymatic conversion of indolic compounds in the urine. The discoloration of the diaper intensifies for several hours if left standing.

Clinical aspects

Hypercalcemia and nephrocalcinosis are associated with failure to thrive; recurrent unexplained fever; respiratory and urinary tract infections; irritability; and episodic diarrhea and vomiting, alternating with episodes of constipation. Blood urea nitrogen is typically increased. Severe and prolonged hypercalcemia is frequent and appears to occur as a consequence of high intake of vitamin D. Lowering its dose leads to significant improvement of symptoms, but the blue discoloration of the urine persists. Kidney biopsies reveal extensive cortical and medullary nephrocalcinosis with periglomerular fibrosis and interstitial infiltration with inflammatory cells. The multiple foci of calcium depositions are associated with granuloma formation. Stool tryptophan levels are moderately increased in these patients, but show a striking increase far beyond normal following the administration of an oral tryptophan load. Increased amounts of tryptophan derivatives (indole-3-acetic acid, indole lactic acid) are also found in the urine and presumably the result of bacterial degradation in the colon with increased absorption from the intestinal lumen. Interestingly, no such increase is seen after an intravenous tryptophan loading dose. Renal clearance of tryptophan is considered normal. In addition, serum calcium concentration increases (which however is also observed in some of the control patients) as does urinary phosphate excretion following the oral tryptophan loading. However, it should be noted that phosphate clearance and tubular phosphate reabsorption are persistently low and excretion increased even without a tryptophan challenge, which has been interpreted as secondary hyperparathyroidism. In contrast, the tryptophan plasma concentration after an oral loading dose is significantly lower than in normal subjects. Other clinical features described may include ocular abnormalities, such as microcornea, hypoplasia of the optic disc, abnormal eye movements, and osteosclerosis (which was reversible once vitamin D intake was reduced). The indoluria may look similar to the one in seen in Hartnup Syndrome. In one report, a blue-greenish stool discoloration ...

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