Sjogren-Larsson two with · incontinentia pigmenti onhistological studies. Sylvester (1969),...
Transcript of Sjogren-Larsson two with · incontinentia pigmenti onhistological studies. Sylvester (1969),...
Journal ofNeurology, Neurosurgery, and Psychiatry, 1974, 37, 1306-1315
Sjogren-Larsson syndrome in two sibs withperipheral nerve involvement and bisalbuminaemia
MARIA MAIA
From the Department of Neurology, Hospital St'. Antonio, Porto, Portugal
SYNOPSIS Two sibs are described with Sjogren-Larsson syndrome. Another sib died in early lifewith signs which appear to be indicative of the same condition. In the two cases studied we havedocumented signs of peripheral nerve involvement (not previously reported in the literature) whichpoint towards a pathological process acting on ectodermal structures to a greater extent than haspreviously been considered.
Ichthyosis, spastic tetraparesis, and mentalretardation were first described as a syndrome bySjogren (1956) and Sjogren and Larsson (1957)reporting on 33 patients from a Northern area inSweden. This genetic and statistical studyenabled those authors to postulate an auto-somal recessive entity the mutation of which hadoccurred about 600 years earlier. Very soonsimilar cases were published from different partsof the world (Blumel et al., 1958; Link andRoldan, 1958; Richards, 1960; Baar et al., 1960;Zaleski, 1962; Heijer and Reed, 1965; Selmano-witz and Porter, 1967). Gomes da Costa andMenano (1963) were the first to report fromPortugal on such an entity-a male child whopresented at 15 days to a paediatric departmentin Lisbon as a 'collodion baby'. One sister withsimilar skin lesions died at the age of 19 daysand the family tree shows that their grandfatherswere half brothers.The ichthyosis, as in Rud's syndrome, is of
congenital type (Wells and Kerr, 1965): theflexor surfaces are the site of predilection, theface is usually involved, and ectropion is veryoften present. In addition to the increased plate-like hyperkeratosis, there is erythema. Histologyshows marked hyperkeratosis, the granular layeris increased, and perivascular infiltrates arepresent in the clinically evident areas of erythema(Schnyder, 1970), features which differentiatethis type of ichthyosis from the other types.No biochemical abnormality has been so far
described in the Sjogren-Larsson syndrome,including the results of analysis of cutaneouslipids (Selmanowitz and Porter, 1967).
This report deals with two cases in a sibship.They have severe alterations in the peripheralnerves, lesions not previously reported in theliterature. An interesting aspect of the conditionis bisalbuminaemia, an asymptomatic dominantcharacteristic found in some of the members ofthe same family.
CASE 1
A female patient aged 20 years was born normallybut with all skin covered by a severe erythema. Onthe second day of life scales began to appear andhave become progressively thicker ever since. Whenshe was about 2 years old her fourth and fifthfingers started forced flexion and, according to thefamily, the terminal phalanges were spontaneouslyexpelled soon after. She began walking at 3 yearsof age and talking still later. No diseases werecontracted in childhood and, apart from her skintrouble, she did well until the age of 7 years when herwalking started to be difficult. At about the sametime her toes became deformed and twisted. Thewalking got progressively worse but she was able toattend school on her own for four years: she couldnot, however, learn to read or write. She men-struated at 15 and periods have been normal eversince. At 7 years she started to wear glasses andthese have already had to be changed three timesbecause her vision has deteriorated.On examination the patient's skin was seen to be
covered in scales all over her body, not sparing306
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FIG. 1. Case 1.
scalp or face (Fig. 1); the trunk and the flexion areas
were the most involved (Figs 2 and 3); the palms andsoles showed a keratoderma, and no dermatoglyphicpattern could be seen. The two last fingers had no
terminal phalanx and the left middle finger was in
deformed flexion (Fig. 4). Her feet were still moredeformed (Figs 5 and 6), being short, turned out-
wards and with atrophic and grotesque toes. The
radiograph (Figs 7 and 8), besides showing areas of
circumscribed osteoporosis, demonstrates that someof the phalanges had just disappeared.Walking was still possible without help but was
slow and of clearly spastic type. There was a tetra-paresis with brisk reflexes and bilateral ankle clonus.The cutaneoplantar responses, when present wereslightly extensor. The muscles in arms and legsseemed to be atrophic but this was difficult to deter-mine because of the severe skin changes. Superficialsensation for touch, pin-prick, and temperature wascompletely normal. Two simultaneous stimuli showedno abnormality. Vibration sense and articularlocalization were also preserved. No signs of ataxiaor incoordination could be elicited. There was nocranial nerve involvement and the fundi, apart fromher high myopic disturbances, were normal withoutsigns of macular pigmentation.Her face was very extraordinary, mainly because
of her ectropion (Fig. 9). In spite of her strikingappearance and her IQ (37 on the Terman-Merrilltest), she was rather sweet tempered.The results of haemoglobin, white blood count,
urea, and glucose tolerance test were normal.Serological tests for syphilis were negative. Urinalysisshowed slight protein but urea clearance and phenol-sulphonphthalein excretion were normal. Bloodprotein was increased (98 g/l.); on electrophoresisbisalbuminaemia was present. The CSF was normalwith 0 39 albumin and 4 cells. CSF electrophoresiscould not be performed as, unfortunately, thecentrifuge tube broke during the procedure. No LEcells were found in peripheral blood and the anti-nuclear factor was negative.The EEG showed discrete slow waves over the
right temporal areas. There was a slight bilateralventricular dilatation and a discrete cortical atrophyof the cerebral cortex in the pneumoencephalogram(Fig. 10) with a normal posterior fossa.On EMG (performed on quadriceps, tibial anterior
and extensor digitorium brevis muscles) no spon-taneous activity was seen. The recruitment patternappeared moderately reduced on volition. With aconcentric needle electrode in extensor digitorumbrevis no action potential could be obtained stimu-lating the lateral popliteal nerve at the fibular neck.Dr Canijo's comment was 'inconclusive results'.
Skin biopsy (Fig. 11) showed marked hyper-keratosis with granular layer increased and peri-vascular inflltrates with lymphocytes and histiocytes.On biopsy, the sural nerve showed variations andpartial destruction of axons with vacuolization andfragmentation of myelin (Fig. 12).
CASE 2
Case 2 was a brother of case 1. He presented at 17
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FIG. 2. Case 1. Scaling on back.
FIG. 3. Case 1. Scaling on thighs and back ofknees.
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FIG. 4. Case 1. Deformities of hands.
FIGS 5 (left) and 6 (right). Case 1. Deformities offeet.
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FIGS 7 (left) and 8 (right). Case 1. Radiographs of hands andfeet.
years of age, with a history of slowly progressiveimpairment in walking for the last three years.On examination we observed a rather abnormal
posture with a tendency to keep the head in slightflexion; there was a discrete dorsal scoliosis with alumbar hyperlordosis. His gait was markedly spasticwith very brisk knee reflexes. Ankle jerks were justpresent with bilateral extensor responses. There wasan internal strabismus of the right eye with a slightimpairment of abduction of both eyes. Fundi werenormal. All modes of sensation were normal, as they
were in his sister. No ataxia or incoordination couldbe detected. The skin appeared normal with nolesions of ichthyotic type and nothing abnormal wasobserved on general examination.Radiography of the cervical area and examination
of the CSF were normal. The EEG showed an alpharhythm of 8 Hz with brief slower waves on thefronto-temporal regions which increased slightlyduring hyperventilation. His IQ (Terman-Merrill)was 52.The EMG of the lateral rectus muscles, bilaterally,
FIG. 9. Case 1.
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FIG. 10. Case 1. Pneumoencephalogram.
FIG. 1 1. Case 1. Skin biopsy, x 60.FIG. 12. Case 1. Sural nerve. Luxol fast blue
staining, x 320.
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Maria Maia''mII_IIIF..A--l 110I leW.
2J~~~~~~~~~~~~~~~ii .r. .............*... ,44%R .|l
FIG 13 Case 2. Skin biopsy, x 80.
wasnormal. Quadriceps, tibialis anteriorand extensordigitorum brevis muscles showed no spontaneousactivity with concentric needle electrode. On con-traction there was a moderately reduced recruitmentpattern due to a reduction in the number of units.The conduction velocity in the lateral poplitealnerve in the left side was 37 m/s (lower limit ofnormal) with a distal latency of 7 5 ms (upper limitof normal). These signs were suggestive of neuro-pathy in Dr Canijo's opinion.
Skin biopsy showed (Fig. 13) a slight but definitehyperkeratosis with an irregular increase of thegranular layer and discrete perivascular infiltration.Histological examination of sural nerve showedvacuolization of myelin sheaths with partial tume-faction of axons (sausage appearance) (Figs 14 and15).
GENETICS (Fig. 16)
Our patients IV2 (case 1) and IV3 (case 2) had a sibIV1 with skin lesions similar to her sister who diedwhen she was 3 months old. The youngest sib IV4,
FIG. 14. Case 2. Sural nerve biopsy. Luxol fast bluestaining, x 320.
11 years old, is entirely normal on clinical examina-tion and doing well at secondary school.We have then a sibship of four with three affected
members. Their parents are first cousins and entirelynormal on clinical examination. Bisalbuminaemia ispresent in the propositus IV2, in her mother III20, andin her normal sister IV4. The condition is indicatedin Figure 16 by a ringed line. Protein electro-phoresis was performed in those cases marked by adotted line.
Three deaf-mutes (1114, III5, III21) and two caseswith 'foot deformities' (116 and 11117) were alsoreferred.
DISCUSSION
According to Richards' extensive review (1972),about 100 cases of Sjogren-Larsson syndromehave been traced and 60 examined in theliterature. No cases have hitherto been describedwith peripheral nerve involvement, but no nervebiopsy has so far been carried out.A biopsy was carried out in case 2 because the
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Sjogren-Larsson syndrome in two sibs with peripheral nerve involvement and bisalbuminaemia 1313
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FIG. 1 5. Case;
discrepancy between the knee and ankle jerksmade us wonder if a peripheral component couldbe present. A rather strange feature was that,although the histological pictures were stronglyindicative of severe nerve involvement, none ofthe patients showed any sensory changes onclnical examination. The only clinical signs ofsuch involvement were the severe bone changes incase 1, which we believe are trophic distur-bances. Of the 14 cases examined by Sjogrenand Larsson, nine were said to have muscularatrophy in the legs, although none of them hadany deformities or signs of motor neurone diseaseon electromyography (performed in two cases).Richards (1972) talks about irregularities in thelength of the fingers and toes but does not giveany details. The same author quotes Timpany'spersonal communication (1962) but again withoutgoing further. Franceschetti et al. (1963) reporton a peculiar case with bone lesions but theseseem to be more dysplasic changes than trophicones. This case, oddly enough, shows signs ofincontinentia pigmenti on histological studies.
Sylvester (1969), reporting on a case thatcame to necropsy, did not examine the peri-pheral nerves. In the brain he found no macro-
2. Sural nervebiopsyx Luxolfast blue scopic disturbance in the cortex but on histologystaining, x 800.
ILKEY: SJOGREN LARSSON SYNDROME IVa
C FEET DEFORMITIES
© BISALBUMINAEMIA
DEAF MUTES
,' SERUM ELECTROPHORESIS PERFORMED
FIG. 16. Family tree. Case 1: IV2. Case 2: IV3.
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there was diffuse cell loss, particularly poverty ofBetz cells in the motor cortex. It was, however,the white matter which showed mainly diffuseand widespread myelin loss. With the presentfindings at peripheral level, we may assume thatthe pathological process, whatever it might be inSjogren-Larsson syndrome, affects both myelinin CNS and peripheral nerves as well as the skin.The disturbances in the skin manifest themselvesat birth, and the peripheral nerve involvement,as suggested by the clinical history in case 1,appears very early. This may explain, bearing inmind the extraordinary adaptative capacity ofthe nervous system, the absence of sensorydisturbances in our patients.From the point of view of genetics, our cases
fit an autosomal recessive inheritance pattern.Case 2, however, shows the congenital ichthyoticlesions only on histological study. We mustremember that, of the 33 cases reported bySjogren and Larsson, five of them who did nothave ichthyosis were excluded for genetic andstatistical analysis. Our results show the impor-tance of doing skin biopsy on such a case.
Bearing in mind that two relatives were said tohave had 'foot deformities', we could argue(in a family with a higher coefficient ofinbreedingthan the usual population) for another recessivecharacteristic. However, as we did not see theother cases, we cannot be sure of what sort ofabnormalities they had and we believe, aspointed out above, that we are dealing withtrophic disturbances secondary to peripheralnerve lesion.
In relation to bisalbuminaemia and quotingWeitkamp et al. (1967), at least 19 unrelatedfamilies have been so far described with such acondition. The pattern does not fit any definedentity. For instance, it has been found in normalpeople (Sandor et al., 1965), in some members ofa family with goitre and deafness as well as thehealthy ones (Fraser et al., 1959), and in apeculiar condition which presented as 'bluehands' (Franglen et al., 1960). It has thereforebeen considered as an asymptomatic autosomaldominant characteristic. Tarnoky et al. (1970)found eight types of albumin in eight unrelatedfamilies and we may assume that, with moresophisticated techniques, more knowledge willbe gained.
I am much indebted to Dr Corino Andrade for hisadvice and stimulating help. I should like to thankDr Pereira Guedes for the histological studies, DrCanijo for the EMG, Dr Pinho Costa for thebiochemical studies and help with the text, and DrL. Wagner for the photographs.
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