The Skin in Genetically-Controlled Metabolic Disorders P

Review Article J Med Genet: first published as 10.1136/jmg.10.2.101 on 1 June 1973. Downloaded from Journal of Medical Genetics (1973). 10, 101. The Skin in Genetically-controlled Metabolic Disorders P. C. H. NEWBOLD Department of Medicine, Cambridge University Medical School, Hills Road, Cambridge CB2 2QL Diseased nature oftentimes breaks forth however, it may lead to difficulty in assessing intelli- In strange eruptions.-Henry IV, part 1, III, i. gence, which is within normal range in 50% of The skin is now commonly accepted as a mirror patients. There is suggestive evidence of a re- of internal disease, but as with other looking-glasses, lationship between subnormal folate levels and low the evidence offered may be selected or ignored. intelligence (Carey et al, 1968), and studies have The epidermis is an interesting structure, especially shown increased turnover of folate coenzymes and rich in tyrosine, phenylalanine, tryptophan, and resulting folate depletion in these patients (Carey et histidine, when compared with the corium (Roth- al, 1968; Butterworth, Krumdieck, and Baugh, man, 1965). Tyrosinaemia and histidinaemia do 1971). There is also a high incidence of an organic not include cutaneous manifestations, but culture of brain syndrome following intracranial vascular skin fibroblasts is a helpful diagnostic tool for study- thromboses (Dunn, Perry, and Dolman, 1966), ing metabolic defects such as citrullinaemia, cysti- copyright. nosis, and maple-syrup urine disease (Scriver, 1969). Most of the conditions now to be described are rare, but if these metabolic diseases were common, there could be no human race as we know it. Homocystinuria http://jmg.bmj.com/ This most informative anomaly was discovered during a study of mentally retarded patients in Ire- land (Carson and Neill, 1962). The disease is so variable that many asymptomatic cases must be missed, but the incidence is about one in every 40,000 live births. There are two major variants of the disease, one responsive to vitamin B6 and the other not (Gerritsen and Waisman, 1972). In on September 26, 2021 by guest. Protected both, lack of the enzyme cystathionine synthase leads to accumulation of homocystine (Mudd et al, 1964), although it is likely that this is partially off- set by remethylation of homocysteine to methionine (Carey, Fennelly, and Fitzgerald, 1968). Fig. 1 summarizes the major clinical aspects of homocystinuria. As McKusick (1971) has pointed out, the lens dislocation is acquired and progressive, and therefore may not always be present. If present, Received 30 November 1972. FIG. 1 101 102 P. C. H. Newbold J Med Genet: first published as 10.1136/jmg.10.2.101 on 1 June 1973. Downloaded from which may also be related to the high mortality Down's syndrome, and the Rothmund-Thomson after anaesthesia (Cusworth and Dent, 1969). The syndrome (Meara, 1958; Smith et al, 1962; Korting, importance of cystathionine, which is one of the 1966), so it is far from diagnostic, except ofa dermal- major free amino acids in the brain, has not yet been epidermal interaction. Other points of distinction assessed and may be crucial in intelligence (Perry, from homocystinuria are that the inheritance is 1968). It has been shown that the raised blood autosomal dominant, and that no enzyme deficiency levels of homocystine increase platelet stickiness has been found. There seems to be decreased (McDonald et al, 1964), and it may be relevant that cross-linkage of collagen secondary to a defect such the abnormal methionine metabolism of homocys- as lack of amine oxidase required to form aldehydes tinaemia predisposes to atheroma (McCully and (Grant and Prockop, 1972). Similar changes are Ragsdale, 1970). These chemical abnormalities seen with lathyrism, and after 3-amino-propioni- lead to the vascular lesions which produce arterial trile, as well as with penicillamine used in the treat- and venous thromboses, as well as the malar flush, ment of scleroderma (Harris and Sjoerdsma, 1966). and the livedo reticularis of trunk and limbs which are significant cutaneous markers. In addition, there is reduction in the colour of skin, hair, and eyes Hartnup Disease and the hair is thin, sparse, and unusually fragile. This is another interesting rarity, also fairly re- Abnormal skin creases and nail-fold capillaries have cently described (Baron et al, 1956) and of wide been noted, together with telangiectases around scars fascination. Again variability of expression is (Price, Vickers, and Brooker, 1968). There are seen, and episodes of involvement are intermittent, many unsolved problems in this disease. In some and decrease in number and severity with age patients elevated levels of methionine and homocys- (Jepson, 1972). Cerebellar ataxia may be associ- tine have been found in the aqueous humour ated with infections, or be worse when the rash is (Curtius, Martenet, and Anders, 1968), and in one worse. Headaches are common, and some patients case normal activity of cystathionine synthase was have fainting attacks without ataxia. Mental found in the lens, whereas brain and liver were de- changes are like those of pellagra, and although ficient (Gaull and Gaitonde, 1966). Despite the some cases are of low intelligence, one patient is factors which have been found to increase clotting, known to be the president of a bank (Jepson, 1972). copyright. many patients have no thromboses, and L-homo- The rash is most common in summer, and involves cystine activates Hageman factor (Gerritsen and exposed areas of face, neck, and limbs. It may be Waisman, 1972). Unusual sulphur compounds red, dry, and scaly, but sometimes can be exudative. have been found in the urine, including S-adenosyl Fig. 2 summarizes the clinical aspects of the disease. homocysteine and homolanthionine, and further The precise nature of the defect is still not decided, study may reveal as yet unknown metabolic path- but there is reduced activity of the pathway from ways (Perry, 1968). tryptophan to nicotinamide. So the rash and other http://jmg.bmj.com/ features are pellagra-like for the excellent reason that they reflect nicotinamide deficiency. Inheritance Marfan's Syndrome is probably autosomal recessive, but this is open to In homocystinuria there is generalized osteo- question as some heterozygotes seem to be far from porosis, long thin limbs, pectus excavatum, and flat normal. However, the sine qua non of the disease feet producing a picture very like that of Marfan's is the specific amino aciduria (Milne, Asatoor, and syndrome. The latter three features are also found Loughbridge, 1961). The pattern is important as on September 26, 2021 by guest. Protected in Marfan's syndrome, whereas osteoporosis is rare. the total amounts excreted vary so greatly. There In addition, the dislocation of the lens is congenital is increased output of alanine, serine, threonine, as- and upwards (McKusick, 1971), and secondary eye paragine, glutamine, valine, leucine, isoleucine, changes are frequent. Weakness of the aortic phenylalanine, tyrosine, tryptophan, histidine, and media produces aneurysms and aortic regurgitation, citrulline. The transport defect involved has been but there is no thrombotic tendency. Skin in- intensively studied, and one fruit of this work has volvement is a very minor feature of the syndrome, been knowledge of the transport of amino acids in but striae distensae have been reported especially the gastrointestinal tract and in the kidneys (Milne, over the thighs, chest and shoulders (McKusick, 1964). This is a beautiful demonstration of how 1971). Elastosis perforans serpiginosa of Miescher investigation of a rare disease can add greatly to has also been seen, but this condition has also been knowledge of normality. Many of these patients found with cutis laxa, the Ehlers-Danlos syndrome, have high urinary excretion of indican, reduced by pseudoxanthoma elasticum, osteogenesis imperfecta, antibiotics. In the blue-diaper syndrome, the The Skin in Genetically-controlled Metabolic Disorders 103 J Med Genet: first published as 10.1136/jmg.10.2.101 on 1 June 1973. Downloaded from very early to reduce brain damage (Murphy, HARTNUP DI SEA SE 1958). PSYCHIATRIC CHANGES When diet with normal levels of phenylalanine is re- CEREBELLAR ATAXIA sumed, facial eczema may appear within 24 hours. There has also been a report of scleroderma-like skin and muscle indurations in a child of 5 years (Jablonska, Stachow, and Suffczynska, 1967). However, many other skin lesions have been found to have the same incidence in a control group SPECIFIC A (Braun-Falco and Geissler, 1964). /:/j : \ \ \ RRASH PELLAGRA-LIKE ; \V| \ l S lPhotosensitivity) Hair Abnormalities Changes in homocystinuria and phenylketonuria have been mentioned above. Hair fragility is also seen with arginino-succinic aciduria (Rauschkolb, MUSCLE PAINS Freeman, and Farrell, 1968), in which the unusual WEAKNESS anomaly of monilethrix has also been reported (Mader and Rose, 1969). Monilethrix may be due to a dominant gene with incomplete penetrance, it is often accompanied by keratosis pilaris, and there may be some overlap with trichorrhexis nodosa. It has also been described, together with pili torti, in the kinky-hair syndrome, with severe mental deficiency (Aguilar et al, 1966a and b; O'Brien et al, FIG. 2 1966). Gross changes in free -SH- groups in the hair keratin cause the kinks, and this seems to be due to a lack of et colour is due to indigotin, an oxidation product of copper (Danks al, 1972). Copper deficiency also explains the changes in the elastic indican. There is a defect in the intestinal trans- copyright. port of tryptophan, features like Hartnup disease, fibres of arterial walls, the scorbutic bone changes, and the neonatal and hypercalcaemia (Drummond et al, 1964). This hypothermia. If treatment with acetate is started disease also suggests an unrecognized link between cupric rapidly, it may be possible amino-acid metabolism and homoeostasis of calcium to avert brain damage (Danks et al, 1972). There and phosphate.

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