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CLINICAL REPORT

Focal Dermal Hypoplasia WithoutFocal Dermal Hypoplasia

Silvina N. Contreras-Capetillo,1* Maria Paola Lombardi,2 Doris Pinto-Escalante,1 andRaoul C. Hennekam2,3

1Departamento de Genetica, Centro de Investigaciones Regionales Dr. Hideyo Noguchi, Merida, Yucatan, Mexico2Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, The Netherlands3Department of Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands

Manuscript Received: 14 May 2013; Manuscript Accepted: 6 October 2013

How to Cite this Article:Contreras-Capetillo SN, Lombardi MP,

Pinto-Escalante D, Hennekam RC. 2014.

Focal dermal hypoplasia without focal

dermal hypoplasia.

Am J Med Genet Part A 164A:778–781.

Focal dermal hypoplasia (FDH;Goltz–Gorlin syndrome) is anX-

linked dominant disorder affectingmainly tissues of ectodermal

and mesodermal origin. The phenotype is characterized by

hypoplastic linear skin lesions, eye malformations, hair and

teeth anomalies, and multiple limbs malformations. The disor-

der is caused by PORCNmutations. Here we describe a mother

and daughter with FDH in whom a c.938T>G in PORCN was

detected. Neither of the two had FDH, but otherwise the pheno-

typewas classical. Focal skin hypoplasia is a hallmark of FDHbut

the present family indicates that FDH should also be considered

in absence of this skin manifestation. � 2013 Wiley Periodicals, Inc.

Key words: Goltz–Gorlin syndrome; focal dermal hypoplasia;

PORCN; variability

�Correspondence to:

Silvina N. Contreras-Capetillo, M.D., Centro Regional de Investigaciones

“Dr. Hideyo Noguchi”, Universidad Autonoma de Yucatan. Calle 96 s/n

x Av. Jacinto Canek y calle 47 Paseo de Las Fuentes. C.P. 97225, Merida,

Yucatan, Mexico. E-mail: silvina.contreras@uady.mx

Article first published online in Wiley Online Library

(wileyonlinelibrary.com): 19 December 2013

DOI 10.1002/ajmg.a.36341

INTRODUCTION

Focal dermal hypoplasia (FDH; OMIM #305600) or Goltz–Gorlin

Syndrome is an infrequently reported X-linked dominant disorder

[Goltz et al., 1962]. About 250 patients have been reported, most are

females and few are (usually mosaic) males, 95% of the cases are

sporadic and 5% are familial [Goltz, 1990; Hennekam et al., 2010].

FDHaffectsmainly tissues of ectodermal andmesodermal origin. The

main skin sign is a linear FDH, often going along with linear hyper-

pigmentations or hypopigmentations and fat herniations. Multiple

papillomas around the orifices, and telangiectasias have also been

reported [Kore-Eda et al., 1995]. Skin manifestations can be highly

variable and be present at birth or develop with age, although dermal

hypoplasia is usually evident from birth. Other FDH characteristics

are craniofacial signs (microcephaly, sparse hair, microphthalmia,

colobomaof iris or retina, lacrimal duct anomalies, cleft lip andpalate,

and prominent ears), dental anomalies (small teeth, hypodontia,

and enamel defects) and skeletal anomalies (syndactyly, absent digits,

ectrodactyly and polydactyly, in any combination). A host of other

manifestations has been published [Hennekam et al., 2010].

In 2007, mutations in PORCN, located at Xp11.23 and encoding

the human homolog of Drosophila melanogaster porcupine, were

found to cause FDH[Grzeschik et al., 2007;Wang et al., 2007].Over

100 PORCN variants are known [Lombardi et al., 2011].

2013 Wiley Periodicals, Inc.

Here we report on a mother and daughter with a PORCN

mutation and a phenotype which was classical for FDH, but

who did not have the main dermal manifestation, that is, FDH.

CLINICAL REPORT

The proband was born at term after an uneventful pregnancy to

nonconsanguineous Mexican parents who had experienced two

earlier spontaneous miscarriages. At birth weight, length and OFC

were normal. Multiple anomalies of face and distal limbs and a

giant omphalocele were evident. She followed a normal cognitive

development. At 5 years all bodyparameterswere found tobe below

the 3rd centile. Physical examination (Fig. 1) showed sparse hair,

facial asymmetry, right microphthalmia and coloboma, irregular

vermilion of upper and lower lip, dental misalignment and thin,

prominent ears. She had syndactyly and brachydactyly of second

to third fingers bilaterally, absent third fingernail, clinodactyly

of the fifth fingers and ectrodactyly of her right foot. Her skin

showed slightly hyperpigmented lines following Blaschko’s lines

but no dermal hypoplasia or fat herniations. She had a bifid

sternum, underdeveloped labia majora and absent labia minora.

778

FIG. 1. Manifestation of FDH in the proband. A: Facial asymmetry. B: Hyperpigmented lines following Blaschko lines. C: Syndactyly and nails

defect. D: Right foot ectrodactyly.

CONTRERAS-CAPETILLO ET AL. 779

Chromosome analysis showed a normal female karyotype (46,XX).

Excretory urography showed vesicoureteral reflux, and a full

skeletal survey demonstrated osteopathia striata (Fig. 2).

Her mother was found to have unilateral microphthalmia and

coloboma, irregular vermillion of the upper and lower lip, thin ears,

and abortive ectrodactyly of the right hand (Fig. 3). She had linear

hyperpigmented skin lesions on her legs, but no dermal hypoplasia

or fat herniation.

Molecular analysis showed a single nucleotide change, c.938T>G

(p.Leu313Arg) in PORCN in both proband and her mother.

This mutation has not been reported previously. In silico analysis

with four prediction programs (SIFT, Polyphen 2, Align GVGD and

MutationTaster) predicts this change to be pathogenic. In addition

Leu313isconservedacrossspeciesdowntoamphibians.Thismutation

isnot found inmore than10,000 control alleles of EuropeanAmerican

andAfricanAmericandescent (ESP6500SI-V2,ExomeVariant Server,

NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL:

http://evs.gs.washington.edu/EVS/) May, 2013 accessed). X inactiva-

tion ratios were 50:50 in the mother and 65:35 in the daughter.

FIG. 2. Osteopathia striata in the proband (arrow).

DISCUSSION

FDH can be clinically diagnosed based on the multisystem

anomalies which are widely variable and of which the skin

FIG. 3. Mild FDH phenotype in the mother. A: Right eye microphthalmia. B: Linear hyperpigmented skin lesions. C: Abortive ectrodactyly. D:

Partial syndactyly.

780 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

findings are paramount. Dermal hypoplasia with fat

herniations are the commonest cutaneous lesions, and a mildly

affected skin is unusual in FDH [Maas et al., 2009]. All

patients reported in literature had true dermal hypoplasia

except one, molecularly unproven patient in whom only

hypo-/hyperpigmentations of the skin were reported [Ayme

and Fraser, 1982].

In the present patients the facial and skeletalmanifestations were

strong clues for FDH despite the absence of the dermal hypoplasia.

The skin was involved however, showing in the hypo-/hyperpig-

mentations following Blaschko lines, and there were also hair and

nail abnormalities, which makes it unlikely that absence of the

mutation in tissues derived from the ectoderm explains the lack of

dermal hypoplasia.

FDH is an X-linked dominantly inherited disorder, which

usually occurs in sporadic patients but in 5% more than a single

individual in a family is affected. Intrafamilial variability has shown

that a diagnosis in an individual may go unrecognized until the

birth of amore severely affected child [Ruiz-Maldonado et al., 1974;

Temple et al., 1990; Maas et al., 2009]. Lyonization has been

suggested to explain the clinical variability of FDH [Grzeschik

et al., 2007]. In the present family random X inactivation was

observed in both mother and daughter. Maas et al. [2009], sug-

gested that other, as yet undetermined factors like environmental,

epigenetic ormodifying genes are of importance in determining the

FDHphenotype. It remains uncertain whether the unusual presen-

tation in this family can depend in part on the particular PORCN

mutation that was found. This PORCN mutation has not been

reported previously. In a recent overview of PORCN mutations

there was a single FDH patient without FDH [Lombardi et al.,

2011], and at present the LOVD database contains an additional

individual with a PORCNmutation in whom no FDH was found.

These PORCN mutations were c.787T>G and c.845þ1G>C,

respectively. This may indicate the presence of skin hypoplasia is

not depending on the nature or site of the PORCN mutation.

Including the present patients, four of the 121 individuals with

a PORCN mutation in whom sufficient clinical information is

available, do not have a FDH.

We conclude that the present family shows that the variability of

FDH is even larger than anticipated, and that it can also occur

without dermal hypoplasia. This denotes that the indication to

initiate molecular analysis of PORCN in children with only limited

CONTRERAS-CAPETILLO ET AL. 781

manifestations of FDH should be wide, also in the absence of the

name-giving skin manifestation.

ACKNOWLEDGMENTS

We are grateful to the family for their participation in this study.

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