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that the natural course of their disease was altered by anymedication" and felt that the group provided control datafor a transplant programme. Dickson et al used the Coxproportional hazards model and examined forty-fivepotential prognostic variables. Variables included in theirfinal model were limited to those that were statisticallysignificant (p<0-01) in both the forward and backward

stepwise variable selection procedures. Initially they foundten variables to be important in determining survival-serum bilirubin and albumin concentrations, age, urinarycopper excretion, prothrombin time, serum aspartateaminotransferase, histological stage, excoriations, hirsutism,and xanthelasma. They were not satisfied by this attemptbecause measurement of urinary copper is not readilyavailable and histological staging requires a liver biopsy.They also dropped excoriation, hirsutism, and xanthelasmaand developed a second model with five variables- oedema,log bilirubin, log albumin, log prothrombin time, and age.

Interactions between the five variables were not thoughtto be troublesome and, with the exception of oedema, thevariables exerted their effects consistently in the period offollow-up. The researchers also applied the model to 106Mayo Clinic patients who refused to enter the trials and toEuropean data.7 The results were satisfactory and they wenton to develop a "final Mayo" model based on all 418 Mayopatients. The Mayo model seems to be useful for predictingsurvival and thus for indicating when a liver transplantshould be entertained, but can this or any other model beused to assess any benefit to be gained from transplantation?The 418 Mayo control patients were studied between

1974 and 1984. Eligibility criteria included not takingimmunosuppressive or anti-inflammatory drugs at time ofentry to the trial. 19 controls underwent liver

transplantations and were presumably censored at thatpoint. The 161 patients in the transplant group received atransplant between 1980 and 1987 in other centres. 132 weretransplanted because of poor liver function, and theremainder because of repeated, massive upper

gastrointestinal bleeding; 40 had more than one

transplantation. Transplanted patients had higher bilirubinvalues, lower albumin concentrations, and longerprothrombin times. Not surprisingly, only 76% of thetransplanted patients were alive after 1 year compared withover 90% of the "historical" control group. The

transplanted patients were manifestly different from thecontrols and therefore their expected survival was

computed. The actual survival was better than expected: themodel predicted that only 45 % would be alive at 1 year.Markus et al admit that patients in Pittsburgh and Dallas

may be different from those in Rochester-they may havebeen at less risk because of careful screening or at more riskowing to the selection of severely ill patients for

transplantation. Some of the transplanted group were somuch more ill than the controls that extrapolation of theMayo model was required. Moreover, the Mayo modelincorrectly predicted good survival for the patients withupper gastrointestinal bleeding. The effect of computingfrom the time of transplantation, and not from the date ofpresentation, is unclear. It would also be interesting to knowwhat happened to Pittsburgh and Dallas patients who didnot receive a transplant.The Dutch workers noted that a disadvantage of the

Christensen and Mayo models for prediction of survivalwithout transplantation was their derivation from a patientpopulation with early disease. The necessary extrapolation

to more severe disease could introduce inaccuracies and theAZG model was devised with this in mind. Nevertheless,the 5-year survival probabilities without transplantationwere similar with the three models 19 Christensen; 0-29AZG; 0-29 Mayo. The jury may not yet have reached a firmdecision about liver transplantation but in the absence ofrandomised controlled trials the progressive refinement ofprognostic models should aid the difficult task of patientselection.

1. Markus BH, Dickson ER, Grambsch PM, et al. Efficacy of livertransplantation in patients with primary biliary cirrhosis. N Engl J Med1989; 320: 1709-13.

2. Chapman RW, Forman D, Peto R, Smallwood R. Lancet 1989; 335:32-35.

3. Dickson ER, Grambsch PM, Fleming TR, Fischer LD, Langworthy A.Prognosis in primary biliary cirrhosis: model for decision making.Hepatology 1989; 10: 1-7.

4. Cox DR. Regression models and life-tables (with discussion). J R StatSoc (B) 1972; 34: 187-202.

5. Christensen E. Multivariate survival analysis using Cox’s regressionmodel. Hepatology 1987; 7: 1346-58.

6. Neuberger J, Altman DG, Christensen E, et al. Use of a prognostic indexin evaluation of liver transplantation for primary biliary cirrhosis.Transplantation 1986; 41: 713-16.

7. Christensen E, Neuberger J, Crowe J, et al. Beneficial effect of

azathioprine and prediction of prognosis in primary biliary cirrhosis:final results of an international trial. Gastroenterology 1985; 89:1084-91.

PRENATAL TREATMENT OF CONGENITALADRENAL HYPERPLASIA

Congenital adrenal hyperplasia due to 21-hydroxylasedeficiency is an autosomal recessive disorder with anincidence of about 1 in 12 000 in white populations.!Reduced cortisol production in utero leads to increasedcorticotropin secretion, which in turn promotes fetal adrenalsynthesis of large quantities of androgenic steroids-mainlydehydroepiandrosterone, a precursor of testosterone.

Consequently almost all affected female infants are virilisedwith ambiguous genitalia and require extensivereconstructive surgery. Several groups have explored thepossibility of preventing such virilisation by givinghydrocortisone or dexamethasone to the mother duringpregnancy to suppress the fetal adrenals; dexamethasone ispreferred because of its resistance to placental degradation.The introduction of reliable first-trimester prenataldiagnosis, made possible by molecular analysis of DNAfrom chorionic villi,2 lent support to this approach becausetreatment could be targeted to mothers of female fetusesknown to be affected.

Pang and colleagues3 lately presented a detailed account oftheir attempts to prevent virilisation in an affected infant andalso summarised the experience of others. Essentially,maternal dexamethasone therapy started early in the firsttrimester has prevented virilisation in only a third of affectedfemale fetuses. Slightly over half the remaining infants haveshown mild or partial virilisation (usually labial fusion withor without clitoromegaly), and in the rest the treatmentappears to have had little effect. The success of this approachlargely correlates with the degree of suppression of the fetalpituitary-adrenal axis as gauged by assay of maternaloestriol, although very low levels do not necessarilyguarantee a satisfactory outcome.Why has this novel and non-invasive approach to

intrauterine therapy met with only limited success?The rationale underlying maternal dexamethasone

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administration is that the fetal pituitary-adrenal axismatures by 9 weeks’ gestation, when differentiation of theexternal genitalia is believed to begin, and that no otherendogenous or exogenous factors play a major part insteroidogenesis or genital development. The variable resultsachieved suggest that not all of these assumptions areentirely valid. Intrafamilial variation in degree of virilisationin affected female infants4 supports the notion that other

genetic and/or environmental factors, such as individualdifferences in maternal or placental processing of

dexamethasone, may be important.Despite the disappointing outcome in some of the first

cases to be treated, Pang and colleagues conclude thatprenatal therapy for congenital adrenal hyperplasia is

justified. No teratogenic effects have been observed nor hassuppression of fetal growth. Adverse maternal side-effectssuch as excessive weight gain and facial hirsutism are seldomreported, although compliance has not always been

confirmed, and it would clearly be unwise to administer thistreatment to any pregnant woman with a history ofhypertension or hyperglycaemia. Without this therapy,David and Forests noted that 49 of 50 affected female babies

required genital reconstruction, so even if only a third oftreated infants were spared surgery that alone would seem tovindicate these attempts. Treatment should probably beginas early as the fifth week of gestation and be closely followedby chorion villus sampling for specific diagnosis and fetalsexing. Regular monitoring of maternal hormonal statusduring pregnancy is highly desirable and there is a strongcase for multicentre studies such as the one underway inFrance.6 At a time when proposals for embryo manipulationand gene therapy regularly make the headlines, prenataltreatment of congenital adrenal hyperplasia seems a

pleasingly simple method of paving the way for more radicaland innovative treatment strategies.

1. Pang S, Wallace MA, Hofman L, et al. Worldwide experience in newbornscreening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 1988; 81: 866-74.

2. Strachan T, Sinnott PJ, Smeaton I, Dyer PA, Harris R. Prenataldiagnosis of congenital adrenal hyperplasia. Lancet 1987; ii: 1272-73.

3. Pang S, Pollack MS, Marshall RN, Immken L. Prenatal treatment ofcongenital adrenal hyperplasia due to 21-hydroxylase deficiency.N Engl J Med 1990; 322: 111-15.

4. Sinnott PJ, Dyer PA, Price DA, Harris R, Strachan T. 21-hydroxylasedeficiency families with HLA identical affected and unaffected sibs.J Med Genet 1989; 26: 10-17.

5. David M, Forest MG. Prenatal treatment of congenital adrenal

hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr 1984;105: 799-803.

6. Forest MG, B&eacute;tuel H, David M. Prenatal treatment in congenital adrenalhyperplasia due to 21-hydroxylase deficiency: update 88 of the Frenchmulticentric study. Endocr Res 1989; 15: 277-301.

CYSTIC HYGROMA

Cystic hygroma, a rare developmental anomaly of thelymphatic system, is characterised by the formation of amultilocular cystic mass of variable size. Such lesions wereformerly distinguished from other forms of lymphangiomain various classifications, but the terms are now usedsynonymously as variations of a single entity. Mostlymphangiomas occur in the head and neck; other sitesinclude the mediastinum, shoulder and axilla, arm, chestwall, abdomen, inguinal region, and leg. About 50% arepresent at birth; about 80% will be detected before the age oftwo years; and a few cases manifest in adulthood.

Sabin2 showed that the lymphatic system arises from fiveprimitive sacs developed from the venous system.Lymphangiomas are caused by a growth anomaly or arrestin normal development whereby the lymphatic sacs fail toreunite with the venous system or the peripheral lymphaticvessels fail to flow into the sacs.3 These sequestrations oflymphatic tissue form cysts, from which endothelial fibrillarmembranes sprout, penetrate into surrounding normaltissue, and subsequently canalise to produce more cysts.4Lymphangiomas are composed of dilated endothelium-lined channels, which vary from capillary-sized lymphoidspaces to very large cysts several centimetres in diameter.Spaces of different size are often found within a single lesion.Cyst expansion seems to be determined by the nature of thesurrounding tissues: large cysts develop in the neck, whereexpansion is possible; smaller ones in the floor of mouth; andvery small spaces within the tongue. The hygroma infiltratesaround and engulfs adjacent normal structures such asvessels and nerves, and destroys the normal planes ofdissection, making surgery extremely difficult. Lymphnodes may be incorporated within parts of the hygroma, andsometimes there are mixed lesions containinghaemangiomatous elements.

The most common presenting feature is a mass in theneck, often noticed at birth, and sometimes of huge size. It isusually lobulated, fluctuant, and attached to the deep tissuesbut not to the skin; it may be firm in places where lymphnodes are incorporated. Hygromas transilluminate brightlythereby distinguishing them from other neck masses. Theremay be airway obstruction or dysphagia if cysts extend intothe floor of mouth, tongue, hypopharynx, larynx, or

mediastinum. Sudden enlargement can occur at any timedue to infection (usually from the upper respiratory tract) orhaemorrhage into the cysts. Magnetic resonance imaging orcomputed tomography of the neck and chest is essential toexclude mediastinal extension, and very helpful in

delineating the involvement of neighbouring structures inthe neck. 3

Treatments used in the past have included repeatedaspiration, injection of sclerosing agents, and radiotherapy,but all are associated with dangerous complications andnone is very effective. Surgical excision is the treatment ofchoice,3,5,6 although it can be a formidable undertaking witha significant mortality and morbidity, the risks increasingwith the size of the hygroma. Mortality is 2-6% in mostseries,3 and permanent nerve paralysis occurs in 12-33 % ofcases.3,5 Spontaneous regression of cystic hygromas is notedoccasionally.5,7

Surgery should not be unduly delayed since enlargementof the hygroma and scarring from infection increase thedifficulty of excision. With large lesions complete removal isoften precluded because of involvement of major nerves andvessels; in cases residual cysts should be opened andlow-pressure suction drainage applied to preventaccumulation of cyst fluid. Resection is especially difficultwith lesions of the suprahyoid portion of the neck and theface and impossible when there is involvement of the floor ofmouth, tongue, and larynx. Laryngeal hygroma usuallyrequires a tracheostomy; eventual restoration of the airway issometimes achieved by vapourisation of the supraglotticcysts endoscopically with a carbon dioxide laser. The laser isalso useful for removing the haemorrhagic lymphatic blebsthat form on the surface of the tongue, but the blebs recurand treatment needs to be repeated. Occasionally massive