Brilish Jowntil of Dermatology 1997; 157: 1 14-118.

The scleroatrophic syndrome of Huriez

G.M.KAVANAGH. REJARDINE.* R.D.PEACHEY.t J.C.MURRAY4 ANDD. DE BERKERfUuiversity Dfi>iinn!C!it oj Dcnuiilohgtj. The Roiiid Infinunnj ol l-.diiiburcili MHS Tnisl. Lmiriston Hiiikhiui. Lmiriston Place.

Edinburgh EH3 9YW. Svolkmd. UK.

"* Department ofClinUal Genetks. Institute of Child llpiillh, Hristol. U.K.

^Universitfi Depiirtnie)it of Dernmtoioi^ij. Bristol Royal liifinmirii. Bristol. U.K.

^Depart me lit of Pediatrics, liniversitii of I own Collecic oj Meiliiine. U.S.A.

Accepted lor pubiication 9 January 1997

S u m m a r y We have examined 14 of 28 members of a ibur-}^eneration family. 10 of whom demonstraled theclinical features of the scleroatrophic syndrome of Hnriez. a cancer-prone dermatosis. Severalmemhers of this family demonstrated additional features, previously unrecorded in this syndrome,including poikiloderma-like changes on the nose, flexion contractures of the little linger, a distinctivelittle linger nodule, and telangiectasia on the lips. Genetic linkage was excluded to distal chromosome4q (LOU score —4- 399 at 6 = 0001). This concurs with the recent reappraisal study of one of the twooriginal families described by Huriez. in which no evidence of linkage between this syndrome and theMNSs erythrocytic system (mapped to 4q28-q51) was found. This is the Hrsl report of a family fromthe U.K. with this syndrome.

In 1968. Huriez described a unique inherited sclero-atrophic syndrome characterized by a triad of theclinicopathological manifestations: (i) diffuse sclero-atrophy of the hands; (ii) ridging or hypoplasia ofthe nails; and (iii) lamellar keratoderma of the handsand. to a lesser extent, the soles.' The inheritancepattern was consistent with an autosomal dominantdisorder. Although earlier studies suggested linkagewith the MNSs blood group.- the recent reappraisalstudy has negated this.' The development of an aggres-sive squamous cell carcinoma ISCC) on involved skinwas reported in six of 42 affected members in twofamilies described by Huriez. Hamm and colleaguesrecently reported the lirst family from Germany affectedwith this syndrome.^ Immunohistochemical and ultra-structural studies of their index case revealed an absenceof Langerhans cells in involved skin. The authors sug-gested that this might account for the tendency ofscleroatrophic skin to undergo malignant change.

Report of the index case

A 29-year-old district nurse presented to Ihe dermatol-ogy department with worsening hand dermatitis. Shehad suffered from mild eczema since infancy. In addi-tion, her hands had apparently been small since birth,with abnormal linger and toenails which did not requirecutting. There was a notable absence of sweating on the

extremities and she usually applied make-up to camou-llage an 'odd' appearance of the skin on her nose.Several members of her family (which originates fromDurham) were thought to have similar features to agreater or lesser extent. Her sister (age 22] died of ametastatic SCC which developed on scleroatrophic skinon the finger. Her aunt also had a SCC. which appa-rently arose from scleroatrophic skin on the hand,excised at 45 years. She later developed a bowel carci-noma. Another aunt died at 52 years of a subarachnoidhaemorrhage.

Physical examination revealed a striking tapering ofthe fingers, which were also disproportionately small. Apatchy reticulate erythema was noted on the dorsa ofthe hands and feet, with dry. hyperkeratotic patchesover the metacarpal phalangea! (MCP) joints and sclero-atrophy of the skin on her lingers (Fig. 1). The palmarsurface was dry. scaly and mildly hyperkeratotic. withaccentuation of the major palmar creases. Numerouspunctate pits, but no keratotic plugs were evident overthe thenar and hypothenar eminences (Fig. 2). A local-ized keratoderma. predominantly over pressure sites, wasfound on examination of the soles (Fig. i). Fingernails,and to a lesser extent toenails. were hypoplastic withridging and distal splitting. A poikiloderma-like appear-ance was noted on the end of her nose, which wasslightly asymmetrical (Fig. 4). There was no evidence ofeczema or any abnormality of the hair, teeth or palate.

114 ? British Association ol"Dermatologists

SCLEROATROPHIC SYNDROME OF HUKIE'Z 115

Figure 1. RelaUvcly short lapered lingers witli :i dry. luul. and shinyappt-ariiiict' of the overlying skin. \ote the palcliy hyperkeratosis overthe melacarpal phiilaiigeiil joints and pale, and somewhat atrophicskin with ixx-isioniil leliiiigiectnsia on ihe proximiil area of the hands.

Figure 2. Scaling and hyperkeratosis of the palmar surface, withaceentuation of the palmar creases and multiple small pits over theIhenar and hypothenar eminences.

Figure J. Palchy plantar keraloderma. mainly over pressure sites.

The following investigalions were normal or negative:full blood count, antinuciear antibody. Ro and La anti-bodies, microscopy and culture of skin scrapings formycological examination. Karyotype was 4f) XX. Noevidence was found to suggest cibnormai chromosomefragility on analysis of blood, and sister chromatidexchange frequencies were within normal limits. Herblood group phenotypc was M -I- N -1- S -(- s-.

Hand X-rays were normal. Finger pulp impressions,taken on plastic dental silicone, demonstrated a com-plete absence of sweat pores (normal range f>0()-7()0/cm" on the palms),^ A skin biopsy of the dorsal surfaceof the hand showed mild orthokeratosis. with a tibroticpapillary dermis. Ati clastin stain demotistrated scantyelastic tissue. Prominent blood vessels were noted in thepapillary and reticular dermis. Sweat glands were notidentified and no inflammatory infiltrate was seen. Thepossibility of" the acrogeric type of Ehlers-Danlos syn-drome (EDS) was raised, and so cultured fibroblasts fromthis patient were studied. A slight reduction in type 1 1 1collagen WHS found when estimated quantitatively byNorthern blot analysis.

1997 British Association of Dermalologisls. Brilish jotirmil oj Denmnologii. 1 i7. 114-1 IS

l l f ) G.M.KAVANAGH ct al

Figure 4. Poikiloderma-like changes on the nose (index easel: note also

the leliinglectJisia on the lips.

Linkage analysis

Fourteen of 28 family members were examined. Bloodsamples were obtained from 12 members and lym-phocyte DNA was extracted by a phenol/chloroform

Tigure S. Flexion contracturc iil' the little linger,

tncthod. Three cytosine adetiosiiie repeat polymorph-isms which have been mapped to the region of MNSswere selected and DNA typing was performed by stan-dard polymerase chain reaction techniques.*' Two-pointLOD scores were calculated using the MLINK progratnfrom the LINKAGE package (who also makes this ver-sion 5-1).' Autosomal domincint Inheritance with fullpenetrance was assumed,

Ten patients showed Huriez' triad and some had addi-tioiiiil cliniciil features (summarized in Table 1). Theseincluded a poikiioderma-like appearance on the nose.frequently accompanied by telangiectasia on the lips:flexion contracture of the liltle linger (Fig. 5); a hyper-keratotic nodule at the base of the little linger: anddlstitictive nail chatigcs already described by two of theauthors (D. de B. and G.K.. Fig. 6).' The family pedigreeis shown in Fig. 7. and the results of the linkage analysisare showti in Table 2. Linkage of the disease to each ofthe three markers was excluded.

Table 1. Clinical features ol the 11) afft'ctcd family memhcrs who were exainincd —, absent: + , present: + + , prominent

Patient

II. 1

II. 311. h

in . 5

111,7

III.S

111,12

IV.l

IV, 2

IV. 3

Sex

M

FF

M

F

F

F

M

M

F

Age(year.s)

75

70

fii45

46

J9

29

21

15

211

Sclcroalrophy

hands

-1-

+++++

+

+++++

Keratoderma

palms and soles

+-l-l-

+++

+

++-i-

-t-+

Hypoplasia

nails

-1-1--l-l-

++--1-

-l-l-

++-1-

-1-•f

Contract ure

little finger

4-

-l-l-

+++

+

---—

Poikilodenna

nose

-1-

++

-+

-

--—

Hypo hydros ishands and Teet

-1--1-

++-

+

+--—

Additional

fea lures

palmar

nodule

palmar

nodule

British Association of Dermatologists, BritJsJi joiinml oj Dcnniiwlogi), U 7 , 1 1 4 - 1 1 8

SCLEROATROPHIC SYNDROME OF HURIEZ 117

Figure 6. Note prominence of the lunula. elongation of theapparent leiiconychia and longitudinal fissures.

Discussion

The characteristic genodermatosis described by Huriez.found to affect 42 of 132 members in two unrelatedFrench families from northern France, has now been

reported in seven families.' ''^ '^ The distinctive triadand mode of inheritance seen in the family presentedhere was consistent with the Huriez syndrome. Thepoikiloderma-like changes on the nose, contracture ofthe little finger and distinctive palmar nodule have notpreviously been reported. Interestingly, although sunexposure is thought to act as a cofactor in precipitatingneoplastic change, SCCs have not been reported on thenose. Details of previously reported families have recentlybeen summarized by Hamtn ct id. who also discussed thedifferential diagnosis, The poikiloderma-like changes onthe nose raised additional possibilities in our family.

While the poikiloderma observed in the Rothmund-Thompson syndrome is maxitnal on the face and otherexposed areas, the absence of other features of thissyndrome (cataract formation, alopecia, hypogonadismand small stature) exclude this diagnosis.'^ Patientswith xeroderma pigmentosum also demonstrate poikilo-derma, maximal iti but not confined to light-exposedsites, and a propensity to form keratoses and cutaneousmalignancies, but scleroatrophy and keratoderma arenot present. ^

The features of Werner's syndrome include sclero-derma-Iike changes of the distal extremities, but addi-tional characteristic abnormalities are usually found(cataracts, alopecia, bird-like fades and a high-pitchedvoice), with onset in late adolescence."' Hereditarysclerosing poikiloderma was also considered, as the"shiny, scotch-grained leather" appearance of the sclero-tic change in the skin of the paltns and soles in thecondition described by Weary et al. was reminiscent ofthe changes seen in our family.'' This was also inheritedas an autosomal dominant trait, but differed signifi-cantly in its widespread involvetnent, the presence ofhyperkeratotic and sclerotic bands in the flexures, andassociation with Hnger clubbing.

Figure 7. Pedigree ol the family. Closedcircles (fcmalesi and squares (males)represent affected members. The asterixindicates the I'emale who died at 12 years ofa metastatic squamous cell carcinoma{SCO. and another family memher whoalso had an SCC in scleroatrophic skin, hutdied of a bowel carcinoma.

II

III

IV 1 110 11

I13

O5

iy97 British Association of Dermatologists, Brilish jminuil of Denimtolafjy. 1 57, 114- l lH

118 (^.M.KAVANACH cl al.

ECFMH54

OOOl 0-)

-4 - i 99 - 1 -

- 5 4 2 6 -()•

Recombination fraction

:)5 {)-l 0-2

870 - 0 5 9 2 - 0 ' 1 ) T 5S72 - 0 407 -()'()65

m0- i

-IHI58lH)2fi

0 4

-OOlt)OU-.0'014

0-5

D

(1

0

Tdble 2. Two poinl \A)D scores va. tiiiirkcrsECK \\\] 54 ittiLi FCA

Finally, the acrogeric type of KDS was considered. Thisheterogeneous syndrome may be inherited in an auto-somal dominatit or recessive mode and is associatedwitii total or partial collagen type HI deficiency.'"• Incontrast to the cccymotic group of liDS patients whoproduce reduced amotints of collageti type HI. theacrogeric group retaiti this protein intracellularly. andfail to secrete it. Thinning of the skin on acral sitesincluding the face, hands and feet is reminiscent ofour patients, in conjunction with the history of sub-arachnoid haemorrhage [the feature which accountsfor the lethality of EDS type IV). hut the presence ofHuriez* distinctive triad in the patients we descriherender this an extremely unlikely possibility. The resultswe have obtained exclude the disease gene in this l'atnilyfrom the short segment of distal ciironiosonie 4q withodds of greater than 1 ().{)()(): 1. the locus has yet to bedetermined.

Acknowledgments

We would like to thank Dr Mike Pope ((Genetics Depart-ment. Cambridge) who kitidly analysed lihrobiasts fromthe index case, and Dr I'cter Lutit (Department ofClinical (Genetics. Bristol), for his initial assessmentand opinion on the index case.

References

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2 Hurioz C. Deniinatii \1, Agache I* cl nl. (.iciiodermatose sclero-atropbiante et kertilodermique des exlreniitics. Aim Deniutto!Siiphihfir 1969: 96: 135-46.

3 Delaportc \'.. N'Cuyen-Mailfer C, Janin A cl iiL Keratoderrna with

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9 Lambert I), t^lanehc fl. Chapuis [L. Lu gen(idermalo,se sclero-alrophianie d keralodcrniiquc ties extremites. Aim Demi \cnerco}1977: 104: 654-7.

10 h'ischt'r S, La gcnodcrmatose scleroatrophianle el keralodermiquedej- extremities (au sujet de trois n{)uvfaiLx cas familiauxl. AimDerm Vencreol 197H: lOS: 1079-82.

11 Sliaw M. I'ormenti E. df Kaminsky AR el iil. (.ScnodermalosisesrleralroiliiiJile y iiueralodt'rmii-a de las extramid;ides frecuente-iiK-nlf dfgeiifnitiva. Med Ciil Ihert' Ijit Am 1978: 5-6; 291-f>.

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14 Borg E, Cbuang T-Y, Cripp.s 1), Rotbmund Thompson syndromt', /Am Aciid Dcrmiilo! 1987: 17: 552-8,

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© 1997 British Associalion of Dermatologists. British lowiinl n} DcnnatLihnjij, 1 37, 114- 1 IS