Schöpf-Schulz-Passarge syndrome (SSPS)

Identity

Other names	Keratosis palmoplantaris with cystic eyelids, hypodontia, and hypotrichosis.
	Eccrine tumours with ectodermal dysplasia.
Atlas_Id	10138
Genes implicated in	WNT10A
Note	SSPS is an eponymous form of ectodermal dysplasia first described in 1971 by Erwin Schöpf, Johann Schulz and Eberhard Passarge in a report of two sisters with eyelid cysts, hypodontia, hypotrichosis, palmoplantar hyperkeratosis and nail dystrophy.
Inheritance	Autosomal recessive. Fewer than 100 cases of SSPS have been reported. Heterozygous carriers may show some ectodermal anomalies (predominantly hair/nails in females, teeth in males).

Clinics

Phenotype and clinics	SSPS is characterized by eyelid cysts (apocrine hidrocystomas), palmoplantar keratoderma, hypodontia, hyperhidrosis, hypotrichosis and onychodystrophy, as well as other, often variable, ectodermal developmental anomalies (Schöpf et al., 1971; Monk et al., 1992). SSPS shows clinical overlap with odonto-onycho-dermal dysplasia (OODD), but the eyelid cysts are a typical sign of SSPS. Some features may not present until adulthood and diagnosis can be delayed (Granger et al., 2012). The presence of ectodermal abnormalities in some carriers can lead to confusion in the mode of inheritance (Craigen et al., 1997).
Neoplastic risk	The neoplastic risk in SSPS is controversial. Some authors consider that SSPS can be associated with an increased risk of benign as well as malignant skin tumours (Monk et al., 1992). Reports include an increased incidence of benign adnexal tumours, such as eyelid hidrocystomas or eccrine syringofibroadenomas (Starink, 1997), and possibly a higher risk of malignant skin tumours such as squamous cell carcinoma, basal cell carcinoma and eccrine porocarcinoma (Bohring et al., 2009; Monk et al., 1992; Starink, 1997).
Treatment	There is no effective treatment for SSPS. Hyperhidrosis of the palms may respond partially to tap water iontophoresis (although use of anti-cholinergics may induce excessive systemic side-effects such as dry mouth, dizziness and drowsiness). Systemic retinoids can exacerbate skin peeling, although low doses may help some individuals. The apocrine hidrocystomas can be improved by electrocautery. Regular skin examination to detect non-melanoma skin cancer may be advisable. Regular dental care/surgery is indicated in most cases. Hair/nail cosmesis may help some individuals. Psychological support should be offered, as necessary.
Evolution	Many of the features of ectodermal dysplasia only manifest or worsen during adulthood. In some individuals with SSPS, the apocrine hidrocystomas tend to become larger and more numerous with age.
Prognosis	Life expectancy is normal ; the main challenge is the symptomatic management of whichever ectodermal pathologies cause the patient the most concern.

Genes involved and Proteins

Gene Name	WNT10A (Wnt family member 10A)
Location	2q35
Note	WNT10A is a key signalling molecule that regulates cell-cell interactions and which is involved in multiple developmental processes in embryogenesis. In adult tissues it inhibits the β-catenin degradation complex and is involved in hair follicle and tooth morphogenesis (Logan and Nusse, 2004).

Mutations

Note

Mutations in WNT10A underlie SSPS, OODD and some cases of hypohidrotic ectodermal dysplasia. Thus far, 16 different WNT10A mutations have been reported. These include six nonsense mutations (p.Trp9X, p.Cys107X, p.Arg128X, p.Glu233X, p.Arg248X, and p.Cys376X), nine missense mutations (p.Ile116Thr, p.Arg128Gln, p.Ala131Thr, p.Ala131Val, p.His143Tyr, p.Val145Met, p.Phe228Ile, p.Gly266Cys, and p.Arg360Cys) and one frameshift mutation (p.Glu52fsX29) (Adaimy et al., 2007; Bohring et al., 2009; Nagy et al., 2010; Wedgeworth et al., 2011; van Geel et al., 2010; Catori et al., 2011; Cluzeau et al., 2011; Petrof et al., 2011; Granger et al., 2012). Of note, cases classified clinically as SSPS or OODD may harbour the same WNT10A gene mutation(s). The two most frequently observed mutations are p.Cys107X and p.Phe228Ile. Moreover, homozygous or compound heterozygous mutations involving p.Cys107X have been found in both SSPS and OODD, demonstrating that these two disorders are indeed allelic and that the precise phenotypic consequences are influenced by more than just this particular mutation in WNT10A alone. There is no genotype-phenotype correlation with regard to neoplastic risk.

To be noted

It is also noteworthy that individuals who are heterozygous for WNT10A mutations may show some clinical abnormalities. Hair, nail, teeth and skin abnormalities may all occur in heterozygotes; this probably accounts for the initial difficulties in classifying SSPS/OODD as either autosomal dominant or autosomal recessive disorders (the latter is correct). The mutation p.Phe228Ile appears to have a population frequency of ~0,5% and it has been estimated that approximately half of all individuals who are heterozygous for this missense mutation will manifest some form of ectodermal defects (Bohring et al., 2009). This equates to ~1 in 400 of the general population displaying some clinical anomaly affecting hair, teeth, nails, sweat glands, or a combination thereof, as a direct consequence of this WNT10A gene sequence variant.

Bibliography

Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia.

Adaimy L, Chouery E, Megarbane H, Mroueh S, Delague V, Nicolas E, Belguith H, de Mazancourt P, Megarbane A.

Am J Hum Genet. 2007 Oct;81(4):821-8. Epub 2007 Aug 9.

PMID 17847007

WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes.

Bohring A, Stamm T, Spaich C, Haase C, Spree K, Hehr U, Hoffmann M, Ledig S, Sel S, Wieacker P, Ropke A.

Am J Hum Genet. 2009 Jul;85(1):97-105. Epub 2009 Jun 25.

PMID 19559398

Two families confirm Schopf-Schulz-Passarge syndrome as a discrete entity within the WNT10A phenotypic spectrum.

Castori M, Castiglia D, Brancati F, Foglio M, Heath S, Floriddia G, Madonna S, Fischer J, Zambruno G.

Clin Genet. 2011 Jan;79(1):92-5. doi: 10.1111/j.1399-0004.2010.01513.x.

PMID 21143469

Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.

Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, Bal E, Chassaing N, Vincent MC, Viot G, Clauss F, Maniere MC, Toupenay S, Le Merrer M, Lyonnet S, Cormier-Daire V, Amiel J, Faivre L, de Prost Y, Munnich A, Bonnefont JP, Bodemer C, Smahi A.

Hum Mutat. 2011 Jan;32(1):70-2.

PMID 20979233

Schopf-Schulz-Passarge syndrome with an unusual pattern of inheritance.

Craigen WJ, Levy ML, Lewis RA.

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Late diagnosis of ectodermal dysplasia syndrome.

Granger RH, Marshman G, Liu L, McGrath JA.

Australas J Dermatol. 2012 Jun 4. doi: 10.1111/j.1440-0960.2012.00895.x. [Epub ahead of print]

PMID 22670871

The Wnt signaling pathway in development and disease.

Logan CY, Nusse R.

Annu Rev Cell Dev Biol. 2004;20:781-810. (REVIEW)

PMID 15473860

Schopf-Schulz-Passarge syndrome.

Monk BE, Pieris S, Soni V.

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PMID 1637691

Schopf-Schulz-Passarge syndrome resulting from a homozygous nonsense mutation in WNT10A.

Nagy N, Wedgeworth E, Hamada T, White JM, Hashimoto T, McGrath JA.

J Dermatol Sci. 2010 Jun;58(3):220-2. Epub 2010 Mar 23.

PMID 20418069

Schopf-Schulz-Passarge syndrome resulting from a homozygous nonsense mutation, p.Cys107X, in WNT10A.

Petrof G, Fong K, Lai-Cheong JE, Cockayne SE, McGrath JA.

Australas J Dermatol. 2011 Aug;52(3):224-6. doi: 10.1111/j.1440-0960.2011.00788.x. Epub 2011 Jun 29.

PMID 21834823

Syndrome of cystic eyelids, palmo-plantar keratosis, hypodontia and hypotrichosis as a possible autosomal recessive trait.

Schopf E, Schulz HJ, Passarge E.

Birth Defects Orig Artic Ser. 1971 Jun;7(8):219-21.

PMID 4281327

Eccrine syringofibroadenoma: multiple lesions representing a new cutaneous marker of the Schopf syndrome, and solitary nonhereditary tumors.

Starink TM.

J Am Acad Dermatol. 1997 Apr;36(4):569-76. (REVIEW)

PMID 9092743

Phenotypic variability associated with WNT10A nonsense mutations.

Van Geel M, Gattas M, Kesler Y, Tong P, Yan H, Tran K, Steijlen PM, Murrell DF, Van Steensel MA.

Br J Dermatol. 2010 Jun;162(6):1403-6. doi: 10.1111/j.1365-2133.2010.09703.x. Epub 2010 Feb 15.

PMID 20163410

Intra-familial variability of ectodermal defects associated with WNT10A mutations.

Wedgeworth EK, Nagy N, White JM, Pembroke AC, McGrath JA.

Acta Derm Venereol. 2011 May;91(3):346-7.

PMID 21279306

Citation

This paper should be referenced as such :

McGrath, JA

Schè_pf-Schulz-Passarge syndrome (SSPS)

Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):940-942.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/SchopfSchulzPassargeID10138.html

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