ARTICLE
Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption
during pregnancy [1, 2]. Three grades (I-III) of this polydystrophy syndrome
of malformations can be distinguished in children [3]. The fetal alcohol
effects (FAE) is a mild form, in which the clinical signs are not diagnostic
in the child. There may, however, be evidence of cerebral dysfunctions
and disturbed behavior [4].
The intrauterine exposure of alcohol is the first recognised, the most
frequent, and quantitatively the most significant teratogenic noxa for
the unborn child. In the United States, the incidence of recognisable
FAS is approximately 1:700, in combination with alcohol-related neurodevelopment
disorder (ARND) the ratio is in the region of 1:100 [5, 6]. In Germany,
the incidence is approximately 1:300 to 1:600 and in France 1:200 to 1:250
[3, 7]. These data do not include the abortive forms of FAS or children
with FAE. In comparison to FAS, the incidence of Morbus Down is approximately
1:700 [8].
Children affected by FAS may also present to the dermatologist with
skin diseases. Explanations and active treatments may be demanded by the
parents or the adoptive parents. For this reason and to reduce alcohol-related
diseases during pregnancy, knowledge of the clinical features and the
ability to diagnose FAS should also be required of dermatologists [9,
10]. Further physical and psychological support for the affected children
and their parents is the most important aim in the treatment.
In adults, cutaneous diseases may be signs of alcohol abuse (Table
I) [11-20]. Women of childbearing age and with evidence of alcohol
abuse may have one or even more of these signs. Apart from the history,
these signs in young women should also alert the dermatologist to the
possible risk of FAS or FAE.
Pathogenesis of FAS
The pathogenesis of FAS is only partly understood. Alcohol consumed
by the pregnant woman reaches the fetal blood circulation after approximately
one hour [21]. Evidence of the activity of alcohol dehydrogenase, the
main enzyme of alcohol reduction in the human body, can be found in the
embryo from the eighth week of gestation [22]. Alcohol and its metabolite
acetaldehyde are toxic for placentar cells and for mitotic cell substances
during histo-, embryo- and fetogenesis. All cells, particularly those
with increased metabolism, may be affected. Reduced growth and volume
of the cells are caused by disturbances of the cellular metabolism such
as reduced availability of aminoacids, less permeable cell barriers, hypoxia
of the cells, disturbances of the cell migration, and reduced activity
of enzymes (Na+, K+-ATPase, CA2+-ATPase,
acetylcholine-esterase, 5'-nucleotidase) [23-25]. These effects serve
to explain the clinical manifestations of children with FAS and their
physical, mental, intellectual and social development [23, 26, 27].
Basis of the diagnosis
of FAS
Due to the importance of the diagnosis, FAS should not be diagnosed
at a glance, even if this would be suggested by the very typical clinical
features of grade II or III of FAS (Fig.
1). Almost identical clinical features and dysmorphism in children
can be found in different aetiologies, e.g. chromosomal anomalies
such as Dubowitz syndrome or complex malformation syndromes such as Cornelia-de-Lange
syndrome or Smith-Lemli-Opitz syndrome [28-30]. Particularly in mildly
affected children (grade I) and in those with FAE, the spectrum of the
clinical features is neither characteristic nor very distinctive. Thus
the diagnosis of FAS must rely on three criteria [1-5, 7]:
1. The history of maternal alcohol disease;
2. The clinical status and the dysmorphias of the child;
3. The mental, psycho-social and behavior-related development of the
child.
Maternal alcohol disease
The maternal history is invariably significant for the diagnosis of
FAS. Occasionally this history must rely on information from a third-party.
Especially in mildly affected children (FAE and grade I), when the typical
changes are not visible or characteristic, FAS must be diagnosed on the
basis of the maternal history and/or the evidence of a third party.
Apart from the dermatological diseases (Table
I), further clinical signs in the mothers can also point to the
possibility of alcohol disease: foetor ex ore, tremor, poor coordination,
reddish and/or yellowish conjunctiva, slurred speech, neglected appearance
and behavior indicative of alcohol abuse.
In the pathogenesis of FAS, the mother's tolerance of alcohol and to
a certain extent, also that of the child, might prove to be more important
than the absolute daily intake of alcohol. According to Jellinek, the
phase of maternal alcohol disease (prodromal, critical and chronic phase)
has an influence on the pathogenesis [31, 32]. It is important to establish
whether the mother drank only occasionally or habitually during the pregnancy
[3, 29]. However, a parallel between the alcohol intake of the mother
during the pregnancy and the mental retardation of the child is more likely
than a parallel between the alcohol intake and the severity of the dysmorphia
[4, 5, 23, 24, 32-35]. An increased vulnerability to alcohol-related birth
defects is also reported in the offspring of mothers over 30 years of
age [36].
The history of the mother will also help to evaluate the role of medicines,
nicotine, and other drugs as well as severe illness during pregnancy [4,
20, 29, 37].
Clinical features of the
fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE)
No single clinical feature is specific for FAS. Diagnosis of FAS requires
the presence of more than one malformation.
Dermatological features of FAS and FAE
Dermatological features (Table
II) are epicanthal folds, a short upturned nose, a nasolabial
fold, a thin upper lip, a flat philtrum (Figs.
1 and 2),
abnormal palmar creases (Figs.
3 and 4),
reduced subcutaneous fat-tissue and fovea coccygea [1-3, 7, 23].
The features of hair-spread at the neck, hirsutism of the forehead,
synophrys, hypertelorism, ptosis, blepharophimosis, antimongoloide lid-axis,
cleft palate, dysplastic low-set ears, brachy- and clinodactylia V, camptodactylia,
plane line-relief of the hand, hypoplasia of phalangeals and the nails
(Fig. 5), malformations
of the genitalia, weakness of connective tissue, displacement of nipples,
umbilical- inguinal- and/or hiatushernia, hemangioma and spina bifida
are uncommon (Table II)
[1-3, 7, 23, 38].
Further clinical features of FAS and FAE
Additional clinical features of greater significance for FAS and FAE
are intrauterine growth deficiency (98%/4 points in the score system of
Majewski [3 and see below]), antenatal developmental delay (89%/up to
8 points), dysmorphia of head and face (microcephaly (84%/4 points) and
micrognathia (63%/2 points)) and extremities (41%/2 points) (Figs.
1 and 2)
[1-3, 7, 23]. Less significant clinical features include a high palate
(25%/2 points), malformation of the eyes (25%/0 points), a missing cupido
arch (20%/0 points), anomalies in the teeth (16%/0 points) and other parts
of the skeleton (< 10%/0 points).
A score-system was proposed by Majewski (Table
III) [3]. A corresponding grading of severity (degree I-III) is
based on the clinical features of the affected child [31]. However, these
score systems should not be taken as a diagnostic score, since other syndromes
(e.g. Dubowitz syndrome, Cornelia-de-Lange-Lange syndrome) could
incorrectly be considered as a FAS [28-30].
In the follow-up the clinical features change: Lemoine et al.
and Spohr et al. were able to demonstrate that in contrast
to the findings at birth the nose and chin become hypertrophic
[33, 39]. Changes may also occur in the lips, philtrum and eyes. The typical
features in the face (Fig. 1)
may regress, with the result that FAS is no longer clearly recognisable
in adolescence and adulthood. The general hypotrophy of the body improves,
whereas the microcephaly persists [40, 41]. At the age of three years
the typical physiognomy of FAS can be blurred and diagnosis becomes more
difficult [40, 41]. For this reason, use of the Majewski score system
is only feasible in the first three years of life (Table
III) [3].
The psycho-social, behavior-related
and mental development of the child
The brain reacts as the most sensitive of all organs to the neurotropic
substance of alcohol and its metabolites during pregnancy [7, 23, 26,
39, 41, 42]. There exists no FAS-specific behavioral pattern, but hyperactivity
does not occur as frequently in other syndromes as in the FAS [3, 4, 39,
41, 43]. Due to the disturbing nature and noisiness of hyperactivity and
particularly because of the lack of sensitivity in general social behavior,
the child is often avoided by other children. This behavior can be easily
judged in the medical investigation: offered several toys, the child will
frequently change his focus. Recognition of the disturbed behavior requires
observation only and does not require any specific test. The parents often
report an increased readiness to take risks and a lack of fear in the
child. Children were observed with abnormal eating behavior such as rapid
eating without preference or looking for food in trash cans.
The behavior of the children (e.g., hyperactivity, hyperexcitability,
slight mental-intellectual developmental disorders, increased readiness
to take risks) could indicate disturbance of the brain by alcohol at FAE
and the mildest forms of FAS. These children have limited disorders of
the cerebral functions and behavior without morphological changes [41,
43].
The formal thought disturbances are characterised by blocked, troublesome,
"viscous" thinking. The children have difficulties in abstract, mathematical,
complex and logical thinking. Associational thinking, in contrast, is
unaffected.
Approximately 90% of the children underachieve [26, 39, 40]. In follow-up
studies, no child with FAS was able to attend University and most of the
children were attending schools for the handicapped [39, 40]. Spohr et
al. demonstrated that even supporting therapy does not increase the
intelligence quotient [39]. Nevertheless some children have made clear
progress in their mental development in foster- and adoptive-families,
suggesting that the initial social deprivation might also be an important
factor in the development of mental and intellectual disorders.
The importance of the diagnosis
The early diagnosis of FAS is important for a number of reasons:
1. Although there is as yet no specific therapy for FAS, an early adequate
treatment and support of the affected children is important, independent
of the severity of the condition [4, 7, 32, 33, 39, 44].
2. Stressful and invasive diagnostic procedures can be avoided.
3. The alcohol disease of the mother is often recognised due to FAS
in the child.
4. Before and during further pregnancies the danger of a birth of a
further child with FAS or FAE can be reduced or even prevented by reduction
of alcohol consumption or by complete abstention [24, 35].
5. For foster- and adoptive-families information on FAS or FAE in an
affected child is important as manifestations of possible mental developmental
disorders often appear in the infant-age [33, 39].
6. Prophylactically, the diagnosis is important, since the affected
children have an increased risk of developing an alcohol disease themselves
[24, 35].
7. Certain cutaneous diseases could be significantly affected by alcohol
abuse. These might occur early and are distinct from the well known stigmata
of established liver disease due to alcohol. Immunological (humoral and
cellular) functions are impaired and changes in the cutaneous vasculature
are induced by the alcohol [11-20].
CONCLUSION
The diagnosis of FAS is based on a combination of the history of the
maternal alcohol disease, the clinical status, the dysmorphias, the mental,
psycho-social and behavior-related development of the child. The FAS cannot
be diagnosed in the absence of alcohol disease in the mother or if disturbances
of mental, psycho-social and/or behavior-related development of the child
are present without other features. In the interest of the child, the
diagnosis has to be proved. Apart from the medical care and surgical treatment
of associated disorders, support at an early stage of the mental development
of the child is of great importance. Furthermore, the medical, social
and psycholocigal care of the mother is essential.
In dermatology knowledge about the pathomechanism and the clinical features
of FAS is also important for its prevention in unborn children and for
the recognition and support of the affected children. Women of childbearing
age with dermatological signs of possible alcohol abuse should alert the
dermatologist to the possible danger of FAS in the child.
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