Journal ofMedical Genetics, 1980, 17, 212-215

Ichthyosis, hepatosplenomegaly, and cerebellardegeneration in a sibshipP S HARPER, R MARKS, P J DYKES, AND I D YOUNG

From the Department of Medicine, University Hospital of Wales, Cardiff

SUMMARY A sibship is described in which at least two brothers suffer from a unique disordercharacterised by ichthyosis, hepatosplenomegaly, and late onset cerebellar ataxia. The clinicalfeatures and investigations are described. No metabolic abnormality has been found so far.

Ichthyosis, ataxia, and hepatosplenomegaly mayeach occur independently in several hereditarydisorders. This report describes a sibship where allthree have occurred in at least two brothers, andpossibly in a third, who is now dead. A fourthbrother has only ichthyosis. We suggest that thisclinical triad is unique and represents a new diseaseentity.

Case reports

The family tree is shown in fig 1. The findings in theproband, I.1, are described in detail. Other relevantfamily information follows.

CASE I. 1This retired steelworker, born in 1911, has had dryskin since childhood, but was otherwise well untilthe age of 62 years, when he noted slurring of speechand unsteadiness of gait. Both balance and speechhave slowly deteriorated, so that he now walks andtalks with difficulty. He also admits to impairedmemory for recent events. There is no history ofdrug ingestion or other serious illness.Received for publication 10 October 1979

IV

FIG 1 Family pedigree. Shaded subjects show thefullsyndrome. H.2 shows only ichthlyosis. FIG 2

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At recent examination he was plethoric (fig 2) withdry ichthyotic skin most marked on extensor sur-faces with flexural sparing (fig 3). His hands showedmarked accentuation of the creases (fig 4). Firmhepatosplenomegaly was present with no otherstigmata of liver disease. Mentally he showed mildeuphoria with evidence of early dementia. Ataxia ofboth trunk and limb movements and dysarthria werepresent. There was impairment of upward conjugategaze but no nystagmus was present and no fundalchanges were noted. Reflexes were sluggish withbilateral extensor plantar responses. Power andsensation were normal.

Plethoric dry facial skin observed in I.1

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Ichthyosis, hepatosplenomegaly, and cerebellar degeneration in a sibship

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FIG 3 Loft er limib ichthyosis in ILL

: ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.;.FIG 4 Accentuation ofpalmar creases in 11

CASE 11.2This subject, born in 1913, has a long history of mildichthyosis with marked hyperkeratosis of palms andsoles (fig 5), but is otherwise symptom free. Nohepatosplenomegaly or neurological abnormalitieswere found on examination.

CASE 11.3This ex-coal miner, born in 1915, with a similar lifelong history of dry skin affecting mainly the legs andtrunk, had a rectal carcinoma removed at the age of51. One year later, he noticed slurring of speechfollowed by unsteadiness of gait. These have pro-gressed. Recent examination confirmed the presenceof severe cerebellar ataxia with dysarthria, hepato-splenomegaly, mild euphoria with early signs ofdementia, and impairment of upward gaze. Skin wasdry and ichthyotic as in11.1.

FIG 5 Marked hyperkeratotic changes on feet in 11.2.

CASE II.4This fourth brother died of cerebral haemorrhageaged 58 years. His hospital notes describe facialplethora with hepatosplenomegaly and ataxia.Mentally he was said to be very slow with slurredspeech. No necropsy studies were performed.The seven offspring of these brothers have been

examined and all are free of any signs of the disease.The parents of these brothers I.1 and 1.2 died aged 81and 87 years, respectively, with no evidence ofprogressive neurological disease. They were un-related.

Investigations

In members II.1 and II.3 the following were normal:routine haematological tests including serum ironand B12 and routine biochemical tests including liverfunction tests, calcium, phosphate, uric acid, bloodand urine amino-acids, blood copper and caerulo-plasmin, thyroid function, serum immunoglobulins,and creatine kinase. Biopsies of liver, bone marrow,and sural nerve were also normal with no evidence ofstorage abnormality. Wasserman reaction and auto-immune antibody screens were negative. Nophytanic acid or 5, 8, 11, eicosatrienoic acid wasdetected in the plasma.The following blood liver and fibroblast enzymes

were assayed at the Galton Laboratory inLondon and were normal; N acetyl hexosaminidase,ac-mannosidase, ao-galactosidase, ,-galactosidase,

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0c-glucosidase, adenosine deaminase, malate dehydro-genase, phosphogluconate dehydrogenase, phospho-glucomutase, glyoxylase, and acid phosphatase.Fibroblast steroid sulphatase levels were also normal(assayed by PJD in Cardiff).

In IL.1 fasting lipids showed raised serum trigly-cerides of 2-5 mmol/l (normal range 0 8 to 2*0mmol/l) with normal cholesterol. Electrophoresisshowed a raised pre-,-lipoprotein level. In I1.3fasting lipids were normal.CT scan in I1.1 showed dilated lateral ventricles.

In 11.3 cerebellar atrophy was noted. Formalpsychometric testing in I1.3 showed impaired visual-motor integration, perception of form, and shortterm recall. Nerve conduction velocity was normal.The dermatological aspects of this family,

including results of histopathology, histochemistry,and electron microscopy on skin biopsies from I1.1and I.3 have been reported elsewhere.' Briefly,marked hyperkeratosis was noted with an increasednumber of desmosomal complexes in the granularcell layer and adjoining corneal cells. These findingsare not typical ofany type of ichthyosis yet described.

Discussion

DIAGNOSTIC ASPECTS

The clinical features in this sibship strongly suggesta hereditary disorder, although we have been unableto find any specific metabolic abnormality. Thepresence of hepatosplenomegaly in the affectedsubjects suggests a storage abnormality, despite thenormal findings in liver, bone marrow, and suralnerve. Although central nervous system involvementwas initially limited clinically to the cerebellum,there is now evidence of a more generalised cerebralinvolvement with ophthalmoplegia, dementia, anddilatation of the lateral ventricles on CT scan.

In attempting to classify this disorder several welldefined differential diagnoses must be considered.Skin changes are found in many genetic disordersshowing multisystem involvement, such as Hartnup'sdisease where an intermittent photosensitive rashaccompanies episodes of cerebellar ataxia.2 Severalsyndromes are recognised in which ichthyosis occurswith neurological signs including spasticity,3 oligo-phrenia,4 and polyneuritis with ataxia.5 Giroux andBarbeau6 have described a French Canadian familywhere a childhood papulosquamous ichthyosiformeruption preceding the onset of ataxia in later yearsshowed autosomal dominant inheritance. They wereunable to trace any records of a similar disorder.The cerebellar ataxias comprise a large and poorly

defined group of disorders showing marked clinicaland genetic heterogeneity. Schimke7 concluded that

P S Harper, R Marks, P J Dykes, and I D Young

at least 40 different syndromes showed cerebellarataxia as a predominant feature, with inheritancebeing either autosomal dominant or recessive or Xlinked recessive. External ophthalmoplegia has beendescribed in some of these families.8 Paralysis ofupward conjugate gaze is found in at least one formof olivopontocerebellar atrophy with onset in lateadult life,9 and Neville et al 10 have described verticalophthalmoplegia in association with neurovisceralinvolvement.

In none of these reports do the clinical featurescorrespond sufficiently with those in the subjects ofthis report to suggest an identical disorder. Thisfactor, coupled with the previously undescribedultrastructural findings in the skin, prompts us tosuggest that these brothers suffer from a uniquehereditary disease.

GENETIC ASPECTSThe family pedigree is clearly consistent with eitherautosomal or X linked recessive inheritance and inthe absence ofaffected male descendants in the femaleline it is impossible to distinguish between these.The occurrence of skin changes in an otherwise

normal brother (II.2) could be explained by thepresence of two discrete disorders segregating in thesibship, such as an X linked ichthyosis and an auto-somal recessive storage disorder. Shapiro et allhave recently shown that steroid sulphatase levelsare abnormal in X linked ichthyosis. In these brothersthis enzyme is present in normal quantities. It wouldbe a remarkable coincidence iftwo discrete previouslyundescribed disorders were present in this family andwe therefore favour the explanation that thesebrothers show variable manifestations of an uniden-tified pleiotropic metabolic defect, analogous to themultisystem involvement seen in Refsum's disease5or the Sj6gren-Larsson syndrome.3

We thank Dr C E C Wells of the University Hospitalof Wales for referring the family, Dr A J Franks ofLeeds General Infirmary for reporting on the suralnerve biopsies, and Dr Dallas Swallow of theGalton Laboratory, London for performing theenzyme assays.

This paper was presented at the Clinical GeneticsSociety in Oxford, April 1979.

References1 Dykes PJ, Marks R, Harper PS. A syndrome of ichthyosis,hepatosplenomegaly and cerebellar degeneration. Br JDermatol 1979;100:585-90.

2 Baron DN, Dent CE, Harris H, Hart EW, Jepson JB.Hereditary pellagra-like skin rash with temporary cere-bellar ataxia, constant renal amino-aciduria and otherbizarre biochemical features. Lancet 1956;2:421-8.

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Ichthyosis, hepatosplenomegaly, and cerebellar degeneration in a sibship3 Sjdgren T, Larsson T. Oligophrenia in combination withcongenital ichthyosis and spastic disorders. A clinical andgenetic study. Acta Psychiatr Scand (Suppl) 1957;113:1-112.

4 Passwell JH, Goodman RM, Ziprkowski M, Cohen BE.Congenital ichthyosis, mental retardation, dwarfism andrenal impairment: a new syndrome. Clin Genet 1975;8:59-65.

5 Refsum S, Salomonsen L, Skatvedt M. Heredopathiaatactica polyneuritiformis in children. J Pediatr 1949; 35:335-43.

6 Giroux JM, Barbeau A. Erythrokeratodermia with ataxia.Arch Dermatol 1972;106:183-8.

7 Schimke RN. Adult-onset hereditary cerebellar ataxia andneurosensory deafness. Clin Genet 1974 ;6 :416-21.

8 Stephens J, Hoover ML, Denst J. On familial ataxia,neural amyotrophy, and their association with progressiveexternal ophthalmoplegia. Brain 1958;81:556-66.

9 Konigsmark BW, Weiner LP. The olivopontocerebellaratrophies: a review. Medicine (Baltimore) 1970;49:227-41.

10 Neville BGR, Lake BD, Stephens R, Sanders MD. Aneurovisceral storage disease with vertical supranuclearophthalmoplegia, and its relationship to Niemann-Pickdisease. Brain 1973;96:97-120.Shapiro LJ, Weiss R, Buxmann MM, Vidgoff J, DimondRL, Roller JA, Wells RS. Enzymatic basis of typicalX-linked ichthyosis. Lancet 1978; 2:756-7.

Requests for reprints to Dr P S Harper, Section ofMedical Genetics, Department of Medicine, Uni-versity Hospital of Wales, Heath Park, Cardiff CF44XW.

Addendum

Since submitting this paper, patient II.1 died sud-denly at home. Necropsy findings were as follows.The lungs showed evidence of acute broncho-pneumonia and pulmonary oedema with hyper-tensive changes in the pulmonary arteries. The heartweighed 500 g and showed right ventricular hyper-trophy. Atheroma was noted in the coronary arteries

and distal descending aorta. The liver showed evi-dence of chronic passive congestion. The spleenweighed 1000 g and contained large histiocytic cellsscattered diffusely throughout (fig 6). Some of thesecells showed cytoplasmic vacuoles. No abnormalityof this or any other type was noted in bone marrow,testis, thyroid, kidney, or brain, nor were grosschanges noted in cerebellum or spinal cord. Furtherneuropathological studies are in progress.We wish to thank Dr J N Dearnaley of Nevill

Hall Hospital, Abergavenny, for supplying detailsof necropsy findings.trP;4 P

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FIG 6 Section of spleen showing foamy histiocytes.

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