ARTICLE
The syndrome of focal dermal hypoplasia (FDH) was first described by
Goltz et al. in 1962 [1]. It is a multisystem malformation syndrome
with manifestation in organs of ecto- or mesodermal origin. The disease
predominantly affects skin and bone with a typical linear pattern following
the lines of Blaschko but a variety of additional anomalies are
frequently reported (Table I).
Goltz syndrome seems to follow an X-linked dominant mode of inheritance
with in utero lethality in hemizygous males. Friedman et al.
1988 [2] observed an affected girl presenting with a distal deletion of
the X-chromosome with a breakpoint in Xp22.31 and proposed that the FDH
gene is located near this region. Zuffardi et al. 1989 [3] described
a Goltz like syndrome in a girl with a deletion in 9q32-pter. About
95% of the patients present as sporadic cases [4] suggesting a high rate
of new mutations. More than 200 affected individuals have meanwhile been
reported including 30 affected males [5]. These affected males
always represented the first case in the family. Their survival might
be due to new, non-lethal autosomal mutations or a mosaic status of the
lethal X-linked gene following half chromatid mutation in the gamete or
an early somatic (post-zygotic) mutation [6, 7]. Father to daughter transmission
has been reported in at least three cases [8-10] and could result from
paternal germ cell mosaicism. However, in such cases of father to daughter
transmission a possible autosomal dominant mutation and thus heterogeneity
of the disorder should be borne in mind.
We report on a newborn female with symptoms compatible with Goltz syndrome
and additional, atypical malformations including thoraco-gastroschisis,
diaphragmatic hernia, aortic arch anomaly, spina bifida occulta and partial
aplasia of the corpus callosum. Possible pathogenetic mechanisms responsible
for the phenotypic expression and variability in Goltz syndrome are discussed.
Case report
Pregnancy and birth
The girl was the first child born to young, healthy, non-consanguineous
parents with no microsymptoms of Goltz syndrome but a hairy patch upon
the lumbar spine in the father, suggesting spina bifida occulta. There
was no family history of miscarriage or skin disease. Ultrasound examination
in the 33rd week of gestation revealed intrauterine growth retardation,
an omphalocele, a diaphragmatic defect and limb anomalies. There was no
depletion of amniotic fluid. Chromosome analysis by chorionic villus sampling
(CVS) showed a normal female karyotype (46, XX). Because of the malformations,
Caesarean section was performed at the 38th week. Birth weight was 2,015
g (< 3rd PC*), length 45 cm (= 10th PC) and occipito-frontal head circumference
30 cm (< 3rd PC). Apgar score was 3/5/6/ and the child died shortly
after delivery as a result of irreversible respiratory insufficiency caused
by severe lung hypoplasia.
External and autopsy findings
The child displayed multiple malformations (Fig.
1) including Goltz syndrome's typical asymmetric, circumscribed
and depressed, yellowish or erythematous skin lesions of focal dermal
hypoplasia. The cutaneous changes were predominantly found on the face
and at the limbs following the Blaschko lines and the left side
of the body was more severely affected than the right side. Histologically
(Fig. 2) the lesions showed
atrophic thinning of the epidermis and corium with depletion of the stratum
spinosum and loss of hair follicles, apocrine and holocrine tissue. Compared
to normal skin, the dermal collageneous bundles in affected areas were
completely disorganized and fragmented and elastic fibres were practically
absent. Spread of inflammatory cells and vascular proliferation and telangiectasias
into the papillary dermis indicated the presence of a reactive process.
Ectopic fat lobules were found in some areas within the corium or touching
the atrophic epidermis only separated by a thin strand of connective
tissue. Occasionally, ectopic fat tissue prolapsed and organized pseudopapillomatous
structures were seen at the skin surface (Fig.
3).
Limb malformations were present and were more
severe on the left side. The severity of the limb defects seemed to correspond
to the local severity of the skin affection. The girl had a split left
hand with defects of the 3rd and 4th digital ray including the 3rd and
4th metacarpal and with compensatory hyperplasia of a single postaxial
finger ray (Fig. 4). The
left lower limb was only rudimentarily developed with a distal circular
constriction and defect of the forefoot and with four rudimentary toe
buds (Figs. 5 and
6). The right hand had a hypoplastic first ray with a small,
proximally set thumb. The right foot was clefted as a result of a defect
of the fourth digital ray and there was complete cutaneous syndactyly
between the first and second toe. X-rays revealed additional brachymeso-
and brachytelephalangy of the existing fingers, hypoplasia of the right
radius and first metacarpal of the right hand, absence of the left fibula
and a single metatarsal and phalangeal bone of the left foot. Furthermore,
the child showed a defect of the medial two thirds of the right clavicle,
a shortening of the left clavicle and left sided absence of the 12th rib.
Finger and toe nails were dystrophic.
Facial features included frontal bossing, hypertelorism, deep set eyes,
downturned palpebral fissures, prominent, asymmetric, anteverted nostrils,
macrostomia, micrognathia, and posteriorly rotated, low set and extremely
large and dysplastic ears. The sternal bone was cleft, and a thoraco-gastroschisis
of 7.0 x 7.5 cm extended caudally from the level of the 6th rib to the
upper border of the umbilical ring with eventeration of part of the liver
and the pericardium. A lumbar spina bifida occulta was covered by hairy
skin.
Autopsy revealed a large, postero-lateral diaphragmatic defect with
herniation of most of the liver and the colon into the left thoracic cavity
resulting in severe lung hypoplasia and dextroposition of a hypertrophic
heart. There was an atypical, left-sided origin of the right subclavian
artery (arteria lusoria) and a defect of the left umbilical artery. The
kidneys appeared small with mild hydronephrosis and the uterus was bicornuate.
CNS examination revealed a partial agenesis of the corpus callosum and
bilateral microphthalmos most severe on the right. Both eyes showed
fundus coloboma. The anterior chamber was completely occluded on the right
and hypoplastic on the left, and the iris, the ciliar body and cornea
were affected through fibrotic changes and unspecific infiltrations of
predominantly histiocytes and plasma cells most probably representing
irritative or regressive changes.
Discussion
Our case represents a very severe manifestation of Goltz syndrome (FDH)
with characteristic features such as focal dermal hypoplasia, limb malformations,
asymmetric microphthalmia and additionally, a large defect of the ventral
abdominal wall, diaphragmatic hernia, spina bifida and partial agenesis
of the corpus callosum. A diaphragmatic defect in association with FDH
has been described once before [11]. Defects of the corpus callosum have
been reported in at least 2 patients with features of FDH [2, 12]. Microcephaly,
facial clefts, neural tube defects, omphalocele, extrophy of bladder,
diastasis recti or cleft sternum have been reported in single cases [13-15],
but a thoraco-gastroschisis as it presents in our case has, to our knowledge,
not been reported previously.
Several reports on Goltz syndrome patients [11, 16], as well as our
own case, show that skin lesions, limb and other malformations in Goltz
syndrome may affect either side of the body more profoundly than the other
and that severe effects frequently present in circumscribed body
areas or developmental fields. The focal or linear mode of skin involvement
as related to the lines of Blaschko is characteristic also for the type
of skin involvement in other X-linked dominant diseases as e.g.
incontinentia pigmenti or X-linked dominant chondrodysplasia punctata.
A functional mosaicism due to the early, randomized X-inactivation could
possibly explain this phenomenon [6, 17-19].
Besides the clearly regressive changes involving the skin and eyes,
the malformations of our case although being genetically determined
and thus inherent have a disruptive character**. Opitz [13] suggested
that the pathogenesis of these anomalies involved an element of atypical
apoptosis or of necrosis with subsequent healing. A locally disturbing
factor could possibly be represented by an abnormal, maybe toxic gene
product. The distribution and severity of the defects would then depend
on the distribution of cells with an active mutated X-chromosome, the
field of activity of the mutated gene product and the temporal onset of
gene activity during development. Early expression of the mutated gene
would have a teratogenic effect, which means disruption during organogenesis
through cell reduction in organ blastemas or during cell migration leading
to true malformations. Expression after termination of organogenesis would
cause inhibition of growth of organs and regressive changes and scarring.
The fact that the atrophic skin lesions still show progressive activity
at birth and in postnatal life but later decrease or disappear could be
explained by the disadvantaging of those proliferating cells in which
the mutant X-chromosome is active and the normal X-chromosome is inactivated
causing skewed X-inactivation in time.
An interesting example of disruption in the present case is the ring
constriction with distal swelling and rudimentary distal development of
the left forefoot (Fig. 5).
This defect is similar to those seen in the amniotic rupture sequence
which is supposed to be based on disruption following ischemia. In the
absence of amniotic bands and in association with the focal skin lesions
it supports Streeter's view that constricting limb defects may well be
due to focal deficiencies in fetal tissues and are not necessarily caused
by constricting bands [20].
Friedman et al. 1988 [2] proposed a provisional
deletion mapping of the mutated FDH-gene to Xp22.31. Naritomi et al.
1992 [21] stressed similarities of clinical and cytogenetic findings in
the Goltz and Aicardi syndrome, the latter being characterized by agenesis
of the corpus callosum, microcephaly, microphthalmia, chorioretinal anomalies
and costovertebral defects. They suggested that the two disorders might
be contiguous in the region Xp22.31. Happle et al. 1993 [22] made
a preliminary delineation of an entity of patients with microphthalmia,
dermal aplasia in the head and neck and sclerocornea for which they chose
the term MIDAS syndrome. The two cases of Aicardi syndrome reported by
Naritomi et al. [21] were thought to show simultaneously the malformations
of MIDAS-syndrome and on the basis of reported cytogenetic findings
in the two syndromes the authors proposed the existence of a contiguous
gene in Xp22.3 comprising both Aicardi and MIDAS syndrome. However, owing
to differences in clinical findings the authors recommended a diagnostic
distinction between the MIDAS and the Goltz syndromes.
Based on fluorescence in situ-hybridization (FISH) studies of
the short arm of the X-chromosome in 3 patients with variable features
of MIDAS syndrome Lindsay et al. 1994 [23] suggested that MIDAS,
Aicardi and Goltz syndromes are due to involvement of the same gene or
genes and as we believe that the different patterns of X-inactivation
are responsible for the phenotypic differences in these three disorders.
This view was opposed by Mücke et al. 1994 [24] because no
reports of alternating MIDAS and Goltz syndromes (FDH) within the same
family have been published. Furthermore, limb defects and herniation of
fatty tissue have not been reported in the Aicardi and MIDAS syndromes.
Bearing in mind a pathogenesis involving disruption, one should be careful
of syndromologically classifying patients on the basis of phenotypical
features alone. Presence of e.g. microphthalmia or callosal defects
in the above mentioned syndromes may be a product of different pathogenetic
pathways which are not necessarily caused by the same gene defects. Definition
of a contiguous gene syndrome at Xp22.3 comprising MIDAS, Aicardi and
Goltz syndromes should thus await further DNA studies.
* Percentile, distribution of normal standards and deviations for age
dependent body weight, height and head circumference within a population,
50th PC generally representing the peak of a gauss' distribution curve,
standard deviations of below 3rd PC and above 97th PC being considered
abnormal.
** According to a valid classification of developmental disorders "primary
malformations and dysplasias" that are genetically determined and thus
inherent are distinguished from "secondary malformations or disruptions"
resulting from an exogenously or endogenously induced disturbance of an
initially intrinsically normal developmental process [27].
REFERENCES
1. Goltz RW, Peterson WC, Gorlin RJ, Ravitis HG. Focal dermal hypoplasia.
Arch Dermatol 1962; 86: 708-17.
2. Friedman PA, Rao KW, Teplin SW, Aylsworth AS. Provisional deletion
mapping of the focal dermal hypoplasia (FDH) gene to Xp22.31. Am J
Hum Genet 1988; 43: A50.
3. Zuffardi O, Caiulo A, Maraschio P, Tupler R, Bianchi E, Amisano P,
Beluffi G, Moratti R, Liguri G. Regional assignment of the loci for adenylate
kinase to 9q32 and for alpha (1)-acid glycoprotein to 9q31-q32. A locus
for Goltz syndrome in region 9q32-qter? Hum Genet 1989; 82: 17-9.
4. Wettke-Schäfer R, Kantner G. X-linked dominant inherited diseases
with lethality in hemizygous males. Hum Genet 1990; 64: 1-23.
5. Goltz RW. Focal dermal hypoplasia syndrome: an update. Arch Dermatol
1992; 128: 1108-11.
6. Happle R. Lethal genes surviving by mosaicism: a possible explanation
for sporadic birth defects involving the skin. J Am Acad Dermatol
1987; 16: 899-906.
7. Temple IK, Mac Dowall P, Baraitser M, Atherton DJ. Focal dermal hypoplasia
(Goltz syndrome). J Med Genet 1990; 27: 180-7.
8. Burgdorf WH, Dick GF, Soderberg HD, Goltz RW. Focal dermal hypoplasia
in a father and daughter. J Am Acad Dermatol 1981; 4: 273-7.
9. Gorski JL. Father-to-daughter transmission of focal dermal hypoplasia
associated with nonrandom X-inactivation: support for X-linked inheritance
and paternal X-chromosome mosaicism. Am J Med Genet 1991; 40: 332-7.
10. Mahé A, Corturier J, Mathe C, Lebras F, Bruet A, Fendler
J. Minimal focal dermal hypoplasia in a man: a case of father to daughter
transmission. J Am Acad Dermatol 1991; 25: 879-81.
11. Kunze J, Heyne K, Wiedemann H.-R. Diaphragmatic hernia in a female
newborn with focal dermal hypoplasia and marked asymmetric malformations
(Goltz-Gorlin syndrome). Eur J Pediatr 1979; 131: 213-8.
12. Baughman FA, Worchester DD. Agenesis of corpus callosum in a case
of focal dermal hypoplasia. Mt Sinai J Med 1970; 37: 702-9.
13. Opitz JM. Pathogenetic analysis of certain developmental and genetic
ectodermal defects. Birth defects. Original Article Series 1988;
24 (2): 75-102.
14. Almeida L, Anyane-Yeboa K, Grossman M, Rosen T. Myelomeningocele,
Arnold-Chiari anomaly and hydrocephalus in focal dermal hypoplasia. Am
J Med Genet 1988; 30: 917-23.
15. Irvine AD, Stewart FJ, Bingham EA, Nevin NC, Boston VE. Focal dermal
hypoplasia (Goltz syndrome) associated with intestinal malrotation and
mediastinal dextroposition. Am J Med Genet 1996; 62: 213-5.
16. Leisti J, Hallman M. Focal dermal hypoplasia with marked asymmetry.
Birth defects. Original Article Series; XIII (3C). The National
Foundation 1977. New York: March of Dimes, AR LISS Inc., 242.
17 Happle R, Lenz W. Striation of long bones in focal dermal hypoplasia:
manifestation of functional mosaicism? Br J Dermatol 1977; 96:
133-8.
18. Happle R. Lyonization and the lines of Blaschko. Hum Genet
1985; 70: 200-6.
19. Happle R. Cutaneous manifestation of lethal genes. Hum Genet
1986; 72: 280.
20. Streeter GL. Focal deficiencies in fetal tissues and their relation
to intrauterine amputations. Contrib Embryol 1930; 22: 1-44.
21. Naritomi K, Izumikawa Y, Nagataki S, Fukushima Y, Wakui K, Niikawa
N, Hirayama K. Combined Goltz and Aicardi syndromes in a terminal Xp deletion:
are they a contiguous syndrome? Am J Med Genet 1992; 43: 839-43.
22. Happle R, Daniëls O, Koopman RJJ. MIDAS syndrome (microphthalmia,
dermal aplasia, and sclerocornea): an X-linked phenotype distinct from
Goltz syndrome. Am J Med Genet 1993; 47: 710-3.
23. Lindsay EA, Grillo A, Ferrero GB, Roth EJ, Magenis E, Grompe M,
Hultén M, Gould C, Baldini A, Zoghbi HY, Ballabio A. Microphthalmia
with linear skin defects (MLS) syndrome: clinical, cytogenetic and molecular
characterization. Am J Med Genet 1994; 49: 229-34.
24. Mücke J, Happle R, Theile H. MIDAS syndrome respectively MLS
syndrome: a separate entity rather than a particular lyonization pattern
of the gene causing Goltz syndrome. Am J Med Genet 1994; 57: 117-8.
25. Hall EH, Terezhalmy GT. Focal dermal hypoplasia syndrome, case report
and literature review. J Am Acad Dermatol 1983; 9: 443-51.
26. Kilmer SL, Grix AW, Isseroff RR. Focal dermal hypoplasia: four cases
with widely varying presentations. J Am Acad Dermatol 1993; 28:
839-43.
27. Opitz JM, Gilbert EF. Pathogenetic analysis of congenital anomalies
in humans. Pathobiol Ann 1982; 12: 301-49.
|
Version imprimable
