Ectopia

Homocystinuria Usually a failure of cystathionine synthase (Fig. 40-2 reaction 6). Rarely associated with aberrant vitamin B12 metabolism (Fig. 40-2) Thromboembolic diathesis, marfanoid habitus, ectopia lentis. Mental retardation is frequent. Diet low in methionine Vitamin B6 in pyridoxine-responsive syndromes Vitamin B12 in responsive syndromes Anticlotting agents... 

About half of individuals who do not respond to pyridoxine will sustain ectopia lentisbj age 5-10 years. Indeed, the diagnosis commonly is made by an ophthalmologist. The median IQ score for B6 responsive and nonresponsive patients is 78 and 56 respectively. Some children present at 1-2 years with psychomotor retardation, convulsions (=20% of cases) and psychiatric difficulties such as depression and personality disorders (=50% of cases). 

Accumulation of homocysteine and reduced transsulfation of various compounds leads to abnormalities in connective tissue structures that cause altered blood vessel wall structure, loss of skeletal bone density (osteoporosis), dislocated optic lens (ectopia lentis), and increased risk of blood clots. 

Ectopia lentis (with downward dislocation) is a characteristic finding of this disease, which may also lead to cardiovascular manifestations and mental retardation. 

The answer is A. The constellation of symptoms exhibited by this patient is characteristic of homocystinuria. The impairment of her cognitive function could be attributed to many conditions, but the key findings are ectopia lentis with downward lens dislocation and osteoporosis in a female of this age. Homocystinuria is produced by inherited deficiency of one of the enzymes in the pathway of Met conversion to Cys. The most common form is cystathionine P-synthase deficiency, which results in accumulation of all upstream components of the pathway, including homocysteine, which is responsible for the toxic effects, and Met, which becomes elevated in the blood. Cystathionine and cysteine, which are both downstream of the block in the pathway caused by cystathionine P Synthase deficiency, would be decreased. Metabolic pathways for lactate and urea are not involved in this disease mechanism. 

Characteristic ocuiar features of Marfan syndrome, such as ectopia lentis (upward iens disiocation instead of downward disiocation as in homocystinuria) and myopia, arise from the effects of defective fibriiiin in the eiastic fibers of the iens. 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Ectopia lentis may occur as part of the syndrome of homocystinuria and Marfen s syndrome. Dilate these patients with caution with a weak mydriatic due to the risk of angle closure. Place the patient in a supine position during the fundus assessment.After the examination, confirm that the crystalline lens remains behind the iris and then mydriasis can be reversed by using a miotic, such as 0.5% dapiprazole. 

Mental retardation, seizures, ectopia lensis, dysmorphic features, muscle tone abnormalities... 

Deficiencies of methionine adenosyltransferase, cystathionine 8-synthase, and cystathionine )/-lyase have been described. The first leads to hypermethioninemia but no other clinical abnormality. The second leads to hypermethioninemia, hyperhomocysteinemia, and homo-cystinuria. The disorder is transmitted as an autosomal recessive trait. Its clinical manifestations may include skeletal abnormalities, mental retardation, ectopia lentis (lens dislocation), malar flush, and susceptibility to arterial and venous thromboembolism. Some patients show reduction in plasma methionine and homocysteine concentrations and in urinary homocysteine excretion after large doses of pyridoxine. Homocystinuria can also result from a deficiency of cobalamin (vitamin B12) or folate metabolism. The third, an autosomal recessive trait, leads to cystathioninuria and no other characteristic clinical abnormality. 

Patients with this most common form of homocystinuria show evidence of involvement of the eye, the skeletal system, the vascular system, and the brain. It is important to note that individuals with cystathionine P-synthase deficiency do not manifest any abnormalities at birth and that the affected pregnancies are uneventful. Thus, this disorder, as opposed to the more rare remethylation defect variants of homocystinuria (described below), is not usually part of the differential diagnosis of the catastrophically ill newborn. Ectopia lentis does not usually appear before the age of 3 years, but most patients have some manifestations by the age of 10. The initial recognition of ocular abnormahties may be an observation by parent or physician that the iris shakes, when the head is moved rapidly. While a predilection for... 

Ectopia lends is often the first sign recognized in an undiagnosed patient and is usually present between 5 and 10 years of age [6,7]. Classically, the lens dislocates downwards, in contrast to Marfan syndrome, a condition often considered in the differential diagnosis of homocystinuria, where the lens classically dislocates upwards. Exceptions occur. Other eye findings may include retinal detachment, optic atrophy, and cataracts. 

Ectopia lends (dislocated lens), myopia, glaucoma, retinal detachment, optic atrophy, and cataracts... 

The data by Mudd et al. also demonstrated that ectopia lends occurred by age 6 years in 50 % of patients with Bg-unresponsive homocystinuria and by age 10 years in Bg-responsive disease [24]. Eighty-six percent of patients with homocystinuria were ascertained on the basis of ectopia lends. Finally, the time to event curves demonstrated a 50 % occurrence of radiographic spinal osteoporosis by approximately age 16 years. 

Anomalies of renal position and rotation are well demonstrated by the high resolution anatomic images. Horseshoe and ectopic kidneys can be easily separated from the background and overlying tissues. Pelvic kidneys in particular, which often are significantly smaller than the normally positioned kidney, are well demonstrated with MR urography (Fig. 1.2.13). Hypoplastic kidneys associated with ureteric ectopia and supernumerary kidneys, which have been difficult to demonstrate with other imaging modalities, can usually be demonstrated even if there is minimal renal function. 

Crossed renal ectopia is the second most common fusion anomaly after horseshoe kidney, with an incidence of 1 in 7,000 autopsies (Abeshouse and Bhisitkul 1959). The crossed ectopic kidney lies on the opposite side from the ureteral insertion of the bladder. There are four varieties of renal crossed ectopia (Fig. 4.4) (McDonald and McClellan 1957 Abeshouse and Bhisitkul 1959). Crossed renal ectopia with fusion occurs in 85%,... 

Fig. 4.4a-d. Four types of crossed renal ectopia a with fusion b without fusion c solitary d bilateral... 

Fig. 4.5a-f. Six types of crossed renal ectopia with fusion a unilateral fused kidney, superior ectopia b sigmoid or S-shaped kidney c lump kidney d L-shaped kidney e disk kidney f unilateral fused kidney, inferior ectopia... 

Crossed renal ectopia occurs with fusion in 85%, without fusion in less than 10%. MRI is the best diagnostic imaging. VUR is the most common associated abnormality. 

Fig. 4.6a,b. Crossed renal ectopia in a 14-year-old girl a leftsided kidneys with correct position of the ureterovesical junctions on US crossed ectopia with fusion is suspected b VCU bilateral VUR grade III... 

Abeshouse BS, Bhisitkul I (1959) Crossed renal ectopia with and without fusion. Urol Int 9 63-91 Boatman DL, Kolln CP, Flocks RH (1972) Congenital anomalies associated with horseshoe kidney. J Urol 107 205-207 Buntley D (1976) Malignancy associated with horseshoe kidney. Urology 8 146-148 Campbell MF (1930) Renal ectopy. J Urol 24 187-198 Campbell MF (1970) Anomalies of the kidney. In Campbell MF, Harrison JH (eds) Urology, vol 2,3rd edn. Saunders, Philadelphia, pp 1416-1486... 

Glenn JF (1959) Analysis of 51 patients with horseshoe kidney. N Engl J Med 261 684-687 Kakei H, Kondo A, Ogisu BI, Mitsuya H (1976) Crossed ectopia of solitary kidney a report of two cases and a review of the literature. Urol Int 31 470-475 Kissane JM (1983) Congenital malformations. In Heptinstall RH (ed) Pathology of the kidney, vol 1, 3rd edn. Little, Brown, Boston, pp 83-140... 

Lippe B, Geffner ME, Dietrich RB, Boechat MI, Kangarloo H (1988) Renal malformation in patients with Turner s syndrome imaging in 141 patients. Pediatrics 82 852-856 Malek RS, Kelalis PP, Burke EC (1971) Ectopic kidney in children and frequency of association with other malformations. Mayo Clin Proc 46 461-467 McDonald JH, McClellan DS (1957) Crossed renal ectopia. Am J Surg 93 995-1002... 

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