Journal of Neurology, Neurosurgery, and Psychiatry, 1980, 43, 962-966

Disordered pigmentation, spastic paraparesis andperipheral neuropathy in three siblings: a newneurocutaneous syndromeA ABDALLAT, S M DAVIS, J FARRAGE, AND W I McDONALD

From the King Hussein Medical Centre, Amman, Jordan and the National Hospitals,Queen Square and Maida Vale, London.

SUMMARY Three siblings in a Jordanian family presented with a distinctive syndrome consistingof disordered skin and hair pigmentation, progressive spastic paraparesis and peripheral neuropathy.Sural nerve biopsy revealed axonal degeneration and skin biopsy showed abnormal epidermalpigmentation. Skin fibroblast repair studies were normal. No underlying biochemical defect hasbeen found in this previously undescribed neurocutaneous syndrome.

Many syndromes in which disorders of the skinare assodiated with abnormalities of the nervoussystem have been described.' 2 We have seenrecently a family in which several membersshowed a distinctive association of abnormal skinand hair pigmentation and progressive gait dis-order which seems not to have been describedpreviously.

Case report

Case IA 21-year-old Jordanian civil servant wasreferred for investigation of abnormal skin and hairpigmentation and a progressive gait disorder. He haddiffusely depigmented hair and skin at birth. Fromthe age of 6 months patchy pigmentation deve-loped, particularly in exposed regions of the skin.His hair also developed irregular pigmentation atthe same time. At 6 years of age, his mother be-came aware that he had difficulty running and thathe fell frequently. He gradually developed progres-sive difficulty in walking with noticeable weaknessand stiffness in the legs. He was still walking at theage of 21 years but required the use of a walkingaid or an assistant. He had no sensory symptoms.His intellectual and secondary sexual developmentwas normal. He had no visual disturbance or deaf-ness. His general health was excellent. The patientwas the third child of a sibship of ten (fig 1).A 17-year-old brother and a 9-year-old sister(cases 2 and 3) had been brought to medical

Address for reprint requests: Prof WI McDonald, Institute of Neur-ology, The National Hospital, Queen Square, London WCI.

Accepted 10 July 1980

attention with identical problems to those of thepropositus. The patient's parents are first cousins.The patient was intellectually normal and of

average height. Scalp, eyebrow, eyelash and pubichair were all irregularly depigmented. Patchy areasof pigmentation and "freckling" were present in theskin with other regions of hypopigmentation (figs2 and 3). The skin texture was normal and there wereno scars, telangiectasia, or skin tumours. There wasno abnormal pigmentation in the buccal mucosa,palms of the hands or soles of the feet. The patienthad a spastic gait with bilateral foot drop. Therewas no muscle wasting. The reflexes in the upperlimbs were sluggish, but pathologically brisk in thelower limbs with extensor plantar responses. Therewas a peripheral "stocking" sensory reduction inthe lower limbs to temperature, pin prick and lighttouch to the upper calf level. Vibration sense wasabsent at the ankles and knees but present at thehips. Joint position sense was normal. The peri-pheral nerves were not palpably enlarged. There wasno scoliosis. Both cardiological and general examina-tions were normal.Normal investigations included blood urea and

electrolytes, full blood count, serum lipids, serumVitamin B12, renal function tests, liver functiontests, uric acid, immunoglobulin profile, syphiliticserology (negative), urinary aminoacid screen andCSF analysis. Chest, skull and spinal X-rays wereall normal. A cerebral CT scan was normal and anEEG showed a mild posterior slow wave excess.Psychometry was normal.Nerve conduction studies revealed normal motor

and sensory values (median and ulnar nerves) inthe upper limbs. The lateral popliteal motor con-duction velocity was normal (45 m/s) although themixed nerve action poitential was small (2 uV). Thesural nerve sensory action potentials were absent

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Disordered pigmentation, spastic paraparesis and peripheral neuropathy in three siblings

PEDIGREE : A.T. ( 1980 )

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I~~Z00Fig 1 Pedigree of the present family.

Fig 2 Case 1, showing abnormal skin and hairpigmnentation. Note the contrast between dark andlight hair in the eyebrows and eyelashes.

bilaterally. Sampling in tibialis anterior did notreveal any evidence of denervation. There was agrossly diminished pattern of normal units firing at

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low rates consistent with an upper motor neuronelesion. Sural nerve fascicular biopsy (Prof PKThomas) revealed a mild depopulation of myelinatednerve fibres, with relative preservation of those oflarger calibre. Tihere was no definite evidence ofregenerative activity, demyelination or hypertrophicchange. The connective tissue and vasa nervorumboth appeared normal. The appearances were thoseof an axonal neuropathy.

Skin biopsy (Dr GAK Missen) revealed a normaldermis. The epidermis was mildly acanthotic. Therewas striking variability in the degree of basal pigmen-tation, from areas of heavy pigmentation to regionsof hypopigmentation (fig 4). There was no evidenceof premalignancy or malignancy. DNA repair syn-thesis in tthe patient's cultured skin fibroblasts,irradiated by germicidal UV-light (254 nm), wasnormal (Dr FB Gianelli).

Case 2The 17-year-old brother of Case 1 (fig 5)was found to have an identical disorder, withslightly less gait disability than the propositus. Thedevelopment of the dermatological and neurologicalfeatures in the patient paralleled those of his oldersibling. Nerve conduction studies also showed a mildsensory neuropathy in the lower limbs.

Case 3A 9-year-old sister was also affected. As expected,both dermatological and neurological abnormalitieswere less marked than in her older brothers. Nerve

conduction studies again showed mild lower limbsensory neuropathy.

Other relativesTwo paternal aunts and a fourth sibling had abnor-mal facial skin "freckling" (fig 1). The remainderof the body skin and hair pigmentation was normal.They had no neurological abnormalities. Nerve con-duction studies were performed on all three andwere normal. This type of facial freckling is veryrare in Jordan and it is likely that in the presentfamily it is pathological and represents the heterozy-gous manifestation of the disease.

Discussion

The three patients reported here have a neuro-cutaneous disorder of which we have been un-able to find any previous description. Theexpression of an identical syndrome in threesiblings with unaffected consanguinous parentsis consistent with an autosomal recessive modeof inheritance.2 The other three relatives withdermatological abnormalities confined to abnor-mal facial skin pigmentation, and no neuro-logical abnormalities probably represent theheterozygous expression of the disorder.The dermatological h.allmark is disordered pig-

mentation, both hypopigmentation and hyperpig-mentation, of skin and hair. The neurological

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Fig 4 Section of the skin showing patchy depigmentation (arrow) in the melanocytes and cells of thestratum basale. (Masson-Fontana technique.)

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Disorcdered pig.nentation, spastic paraparesis anid peripheral neiuropathy in three siblinigs

Fig S Ca.se 2, showing .5imilar cutaneou.s features.

picture is that of a progressive spastic para-paresis with peripheral neuropathy. A few of thelarge number of neurocutaneous diseases pre-viously reported merit brief discussion in relationto our patients. Hypopigmentation occurs in a

variety of neurocutaneous syndromes. Crosset al3 described an autosomal recessive conditionin three siblings in a genetic isolate. Cutaneoushypopigmentation, mental retardation and severeocular abnormalities were present at birth,followed by spasticity and athetoid movementsin infancy. WaardenbergX described an autoso-mal dominant condition consisting of neuraldeafness, facial congenital abnormalities and awhite forelock. The Chediak-Higashi syndrome5is an autosomal recessive dise!ase with partialoculocutaneous albinism, neutropenia and in-creased susceptibility to pyogenic infections, re-

lated to defective neutrophil function. Tissueinfiltration with mononuclear cells may produceneurological abnormalities, particularly peri-pheral neuropathy.5 The clinical picture in ourpatients is clearly different from that of all these

diseases.Abnormal pigmentation also occurs in Xero-

derma Pigmentosum. This is an autosomal reces-sive disease in which neurological abnormalitiesoccur in 15-20'%, of cases.'} De Sanctis and Cac-chione' originally described the association ofXeroderma Pigmentosum with mental deficiency,microcephaly, dwarfism and genital hypoplasia.A wide range of neurological abnormalities hassubsequently been reported, including cerebellarataxia, choreoathetosis, spasticity and peripheralneuropathy.8 9 However, the dermatologicalfeatures are different from those of our patients.The lack of early acute sun sensitivity and oftelangiectasia, keratoses or skin tumours even inour oldest patient aged 21 years make the clini-cal diagnosis highly unlikely. Defective DNArepair rate of cultured skin fibroblasts after ultra-violet DNA repair in our patient (case 1) wasnormal. We conclude that our patients did nothave Xeroderma Pigmentosum.

Spastic paraparesis also occurs in relation toa dermatosis in the autosomal recessive Sjogren-Larsson syndrome.1' T,he clinical picture is how-ever quite different from that of our patients,congenital icfhthyosis and mental retardationbeing associated with spastic paraparesis.

Straightforward screening failed to revealevidence of the metabolic abnormality in ourpatients. As in the case of other neurocutaneoussyndromes, the mechanism of the linkage be-tween the neurological and dermatologicaldefects is obscure.

We are grateful to a number of colleagues whogave us expert advice: Dr M Barraitser, Dr JVDiengdoh, Dr A Gale, Dr FB Giannelli, ProfRW Gilliatt, Mr B Jay, Dr GAK Missen, Mr DTaylor, Prof PK Thomas, Dr RS Wells, and DrRG Willison. We thank Miss Teresa Claph,amfor her secretarial assistance.

References

I Adams RD. Neurocutaneous diseases, Ch. 123,In: Fitzpatrick TB, ed. Dermatology in GeneralMedicine, 2nd ed. New York: McGraw-Hill,1979.

2 McKusick VA. Mendelian Inheritance in Man,5th ed. Baltimore: Johns Hopkins UniversityPress, 1978.

3 Cross HE, McKusick VA, Breen WA. A nexxoculocerebral syndrome with hypopigmentation.J Pediatr 1967; 70:398-406.

4 Waardenberg PJ. A new syndrome combiningdevelopmental anomalies of the eyelids, eyebrowksand nose root with pigmentary defects of the

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iris and head hair and with congenital deafness.Am J Hum Genet 1951; 3:195-253.

5 Wolff SM, Dale DC, Clark RA, Root RK,Kimball HR. The Chediak-Higashi syndrome:studies of host defences. Ann Intern Med 1972;76(2):293-306.

6 Aita JA. Miscellaneous neurocutaneous diseases.In: Vinken PJ, Bruyn GW, eds. Handbook ofClinical Neurology. Amsterdam: North-HollandPublishing Company, 1972; 14:788.

7 De Sanctis C, Cacchione A. L'Idioza xeroder-mica. Riv speriment freniatr med legale alienment 1932; 56:269-92.

8 Robbins JH, Kraemer KH, Lutzner MA, FestoffBW, Coon HG. Xeroderma Pigmentosum. Aninherited disease with sun sensitivity, multiple

cutaneous neoplasms and abnormal DNA repair.Ann Intern Med 1974; 80(2):221-48.

9 Thrush DC, Holti G, Bradley WG, CampbellMJ, Walton JN. Neurological manifestations ofxeroderma pigmentosum in two siblings. J NeurolSci 1974; 22:91-104.

10 Pawsey SA, Magnus IA, Ramsay CA, BensonPF, Giannelli F. Clinical, genetic and DNArepair studies on a consecutive series of patientswith xeroderma pigmentosum. Q J Med 1979;48(190):179-210.

11 Sjogren T, Larsson T. Oligophrenia in con-

junction with congenital icthyosis and spasticdisorders. A clinical and genetic study. ActaPsychiatr Scand 1957; Suppl 113, 1.

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