summarizes some of the genetic syndromes associated with cutaneous
manifestations. Some of these syndromes are rare and usually appear early in
life .These syndromes are included in this
text on belief that one time or one-day some of these syndromes may
be faced during medical practice. It would be hard for the physician
at that time to be confused in front of his patient having nothing
to do or to tell.
is referred to a group of diseases which are due to genetically
abnormality which is present at or before birth, is not
necessarily genetically determined.
defect: may be as a result of an infection from the mother or an
abnormality in the development, which is not genetically related.
inherited disorders are congenital;
they may not become apparent until late childhood or even old age.
manifestations of the genotype are referred to as the phenotype.
tend to appear when the organ or tissue concerned first reaches its
full functional development.
skin disorders such as atopic eczema and psoriasis are
manifestations of abnormal constitutional states of genetic origin.
about genetic theory is essential for the understanding the terms or
syndromes to be discussed.
characteristics are transmitted from one generation to the next by
chromosomes, composed of double helix strands of deoxyribonucleic
acid (DNA). A gene is a sequence of bases in DNA that codes for one
position of the gene on the chromosome is known as its locus.
the 46 chromosomes are present in homologous pairs and thus there
are two copies of every gene, one maternal and the other paternal in
origin. It is the same in males except for the difference in the sex
chromosome pair X and Y. Alternative genes at a single locus are
individual with two different alleles at a particular locus is heterozygous
for that gene; where both alleles are identical; the individual
is homozygous for that gene.
Types of Genes
gene: capable of
exerting its full effect when it is present on only one member of
the chromosome pair (heterozygous state).
gene: the gene is
present at both corresponding loci (homozygous state) before it can
exert its full effect.
borne on chromosomes other than the sex chromosomes (X and Y) are
known as autosomal.
controlled by genes borne on the X or Y-chromosomes are sex-linked.
The Y chromosome is much smaller than the X chromosome.
inheritance is the
only one of significance in clinical practice. The great majority,
perhaps all, sex-linked genes are exclusive to the X chromosome.
replication of DNA is completely accurate, but errors or mutations
can occur at random.
may occur as a result of point substitution of a single nucleotide
base or by insertion or deletion of one or two base pairs.
mutation occurs in a somatic cell, (somatic mutation), only the
descendants of that cell are affected and there will be no
transmission of the abnormality to further generations.
mutations occurring in the gametes or their precursors can be
transmitted to offspring.
Linkage and Diseases Association
residing on the same chromosome remain linked in transmission so
long as the chromosome remains intact, but during reduction division
or meiosis such linkages may be disrupted if crossing-over occurs.
two genes are situated on a chromosome, the less likely they are to
be separated by crossing-over and the more likely they are to be
gene loci are said to be linked and it is possible to demonstrate
genetic linkage in a family using appropriate genetic markers, if
different alleles are present at each of the two loci.
alleles occur together, the case is in linkage disequilibrium, which
may result from recent mutation or of a particular combination.
counseling depends upon the recurrence risk to parents of having an
affected child. Both parents should be investigated thoroughly.
abnormal character is determined by an autosomal dominant gene and
one parent is affected, 50% of the offspring will be affected.
fail to understand that the risk remains constant for every
pregnancy, and that an affected first child does not guarantee a
normal second child. If the parents of an affected child have no
manifestations of genetic abnormality, the recurrence risk is likely
to be small, as the child would have the genetic disorder as a fresh
recessive disorders are homozygous for the mutant gene. The
recurrence risk for the carrier parents is 1 in 4, but offspring
risk for those who are affected is small. Most recessive conditions
are rare and it is unlikely that the affected person will marry
are glycoproteins on the cell surface of most nucleated human cells.
These differ from person to person and uniquely fingerprint to each
person‘s cells. These fingerprints allow a person‘s immune
system to be recognized if a given cell is its own.
importance of the HLA antigens is of prime importance in matching
donors and recipients in the transplantation of human tissues.
region is located on the short arm of chromosome 6, referred to as
the major histocompatibility complex (MHC). A person inherits HLA
antigens as a set; one set (haplotype) from each parent. There are
at least 4 or 5 genetic loci that produce HLA antigens termed A, B,
C, D and DR and their gene products are called HLA-A, -B, -C, -D and
has multiple allelic determinants (polymorphism). Each allele at
each locus controls an antigen that is identified by a number placed
after the letter of that series, e.g. HLA-A1, HLA-B5.
association of an HLA antigen with a given disease means that there
is a higher incidence of that antigen in a group of patients with
the disease than in a group of people without the disease.
agent may have a similar configuration to the HLA antigen, so that
the agent is then not attacked by the body‘s defense system.
Alternatively, the agent might differ only slightly from the HLA
antigen, so those antibodies are produced which attack both the
infective agent and the cells, which contain the HLA antigen, thus
inducing autoimmune damage.
antigen may be close to another gene on the same chromosome which
produces a disease, either directly (e.g. due to an enzyme
deficiency) or indirectly due to an effect on the immune response,
which may be either abnormally enhanced, leading to autoimmunity or
abnormally decreased leading to infection.
chemicals, including drugs and toxins, bind to the cell surface
before they are taken into the cytoplasm. Since HLA antigens are
present on the cell surface, they could modify the binding of these
potentially toxic substances.
association between HLA and a particular disease is not absolute.
disorders may be due to abnormalities of chromosome number or
structure. They may involve autosomes or sex chromosomes.
Approximately 7.5% of all conceptions have a chromosomal disorder,
but most of these are spontaneously aborted.
abnormalities generally cause multiple congenital malformations.
Children with more than one physical abnormality, should undergo
chromosomal analysis as part of their investigation.
disorders are incurable but can be reliably detected by prenatal
or chorionic villus sampling should be offered to women whose
pregnancies are at increased risk, namely, women in their
mid-thirties or older and couples with an affected child.
Manifestations of Chromosomal Disorders
manifestations of different autosomal defect syndromes are discussed
It is the
most common autosomal abnormality, characterized by bluish black
macules of various sizes and shapes occurring on the sacral region
of the newborn, mostly in orientals. Mongolian spots usually
disappear during childhood.
syndrome accounts for about one-third of all moderate and severe
mental handicap in children of school age.
result from trisome of chromosome 21 in which the extra chromosome
is derived by non-dysfunction at meiosis usually from the mother.
child has the normal number of 46 chromosomes but one of the
clinically normal parents carries a translocation of part of
appearance is diagnostic and is characterized by the following:
flat face with small ears .
eyes with slanting pulpebral fissures and epicanthic folds.
eyelids with short and sparse eyelashes.
iris with hypopigmented spots (Brush field spots).
are stumpy and the joint ligaments are lax.
are short and cone-shaped and are sometimes webbed.
finger is often curved.
- At birth
the skin is normal.
- In early
childhood it is soft and velvety.
- Between the
ages of 5 and 10 years, it becomes increasingly dry and less
xerosis at the age of 15.
lichenifecation showing dry skin surface.
follicular papular eruption of the presternal and interscapular
infections, angular cheilitis, chronic blepharitis and a purulent
nasal discharge are common.
are often red.
circulation is poor, acrocyanosis is frequent and livedo reticularis
is often conspicuous throughout the year, on the thighs, buttocks
features include a single flexion crease on the fifth finger, and an
increased incidence of ulnar loops on the fingers.
and thickening of the lips.
is scrotal in almost all cases.
perforans and syringomata occur more often than in normal subjects.
The hair may
be normal, but is often fine and may be hypopigmented.
are hypoplastic and late to erupt.
are stumpy and the joint ligaments are lax. The fingers are short
and cone-shaped and are sometimes webbed. The little finger is often
retardation is a serious complication. The IQ is usually less than
malformations are present, death during infancy is common.
This is the
second most common multiple malformation syndrome. It occurs in
about 1 per 3000 live births, 95% of affected fetuses abort
dysfunction at either the first or second meiotic division results
in the extra copy of chromosome 18. Rarely, a parental translocation
mosaicism is seen with a milder phenotype.
comprises severe mental deficiency with a characteristic skull shape
and a small chin. Other general features are:
hands with overlapping index and fifth fingers.
feet and short sternum.
of the heart, kidneys and other organs are frequent.
include cutis laxa of the neck, hypertrichosis of the forehead and
back. Capillary hemangiomas.
show a distinctive low-arch dermal ridge pattern.
cent die within a month. Only 10% survive beyond the first year and
these infants show profound developmental delay.
characteristic features of the syndrome are:
including microphthalmia or anophthalmia.
palate, cleft lip and low-set ears.
defects and a variety of other visceral abnormalities.
more than 6 months is unusual.
hemangiomas, especially that of the forehead, hyperconvex nails and
localized defects of the scalp.
of the neck has also been reported.
prints shows distal palmer axial triradii.
frequency of Turner‘s syndrome is 1 per 2500 of female births. In
some 80% of cases there are 45 chromosomes with an XO sex chromosome
complement. Such cases are chromatin-negative buccal smears. It is
assumed that the missing chromosome was lost before or at
fertilization. The incidence 45X is increased in the offspring of
Most of the
remaining 20% of cases are chromatin-positive. Some have 46
chromosomes but with part deletion of one X chromosome.
have shown mosaicism of various types, XX/XO or XXX/XO.
posterior hairline margin.
the frontal area of the scalp.
carrying angle of the elbow.
syndrome occurs in both sexes as pheno-type and resembles Turner‘s
syndrome. This is considered by others as “ the male type
Turner‘s syndrome “ but the karyotype is normal (46XY or 46XX).
Most cases are sporadic, but autosomal dominant inheritance has been
syndrome is most common in males.
show characteristic association of hypertelorism, blepharoptosis,
epicanthic folds and a small chin.
stature and have a broad, short neck that may be webbed. Skeletal
defects are frequent.
in the back and the hair is coarse, light colored and curly with a
low posterior hairline
hypertrichosis may occur on the cheeks or shoulders. Pubic hair is
scanty in the male and beard growth is poor.
defects and pulmonary stenosis are often present.
may be normal but some degree of mental retardation is usual.
In 70% of
males the testes are undescended.
of the feet and legs is common and more severe than in Turner‘s
coaractation of the aorta and its prevalence in males.
to Turner‘s syndrome, short stature and infertility are not
with cutaneous manifestations as that of Noonan‘s syndrome.
diagnosis of Noonan‘s syndrome must be suspected in all patients
labeled as Turner‘s syndrome if they are of normal height,
mentally retarded, have a cardiac-valve defect or with normal
syndrome is a problem of male sex differentiation; it is frequently
an XXY sex chromosome pattern.
syndrome affects male births and is characterized by:
Fig. 252a. KlineFilter's syndrome
Fig. 252b. KlineFilter's syndrome &Icthyosis
patients are tall and obese.
there may be a low frontal hair line, sparse body hair and absent or
very few hair on the pubic, axillary and beard areas.
of the fifth digit of both hands.
acrocyanosis, vascular angiomas, peripheral vascular disease and
occur in about one third of the patients.
Osteoporosis, leg ulcers, obesity, psychiatric disorders and
taurodontism (vertical enlargement of the molar pulp chamber).
association of gynecomastia with small testes and otherwise
apparently normal genitalia should suggest the diagnosis, which is
supported by finding an increased urinary excretion of
diagnosis is confirmed by chromosome studies.
replacement therapy will improve secondary sexual characteristics,
but not the infertility.
syndrome is a congenital dysplasia characterized by cutaneous,
nervous system, muscles and bones manifestations.
skin manifestations include café au lait macules.
lait macules are flat and round with several dark brown spots. When
there is six or more of these macules of a size of at least 1.5-cm
in diameter, the diagnosis of neurofibromatosis is established.
lait spots are the first features of the disease to appear in all
children. Bronzing of the skin pigmented hairy nevi; axillary
freckling and sacral hypertrichosis are other manifestations of the
Fig. 252. Neurofibromatosis
(cafe au lait macules & cysts)
Fig. 253. Neurofibromatosis
neurofibromas occur along peripheral nerves which are soft and
cystic, pedunculated, most numerous on the trunk and limbs. Hundreds
may be present, ranging from a few millimeters to several
centimeters in diameter.
type of the disease is characterized by the occurrence of acoustic
neuromas, usually bilateral, as well as meningiomas and other tumors
of the nervous system.
are present in 5-10% of cases, as papillomatous tumors of palate,
buccal mucous membrane, tongue and lips, or as macroglossia, which
is usually unilateral.
nodules (melanocytic pigmented iris hamartomas) appear as
dome-shaped lesions found superficially around the iris on slit-lamp
be a symptom of neurofibromatosis. The presence of large numbers of
mast cells in the skin in this condition, and the response of the
itching to antihistamines suggest that histamine is the cause of
neurofibromatosa is a similar diffuse neurofibromatosis of nerve
trunks associated with overgrowth of the subcutaneous tissue and of
the skin, which is wrinkled and pendulous and may produce gross
may also involve the viscera and blood vessels.
occurs in 2% of cases, and the early onset leading to
cardio-respiratory disease, unless aggressive surgery is performed.
when present is the result of a congenital defect of the renal
involving the tibia or radius.
stature and macrocephaly.
handicap occurs in one third of cases and physical development may
and headaches are also common.
puberty, Acromegaly, Addison‘s disease, hyperparathyroidism,
and phaeochromocytoma of the adrenal.
occur in children.
of the lower urinary tract may give rise to urinary symptoms.
occurs due to dysfunction of the colonic musculature.
Gastrointestinal lesions may also cause recurrent hemorrhage or
common solitary intracranial tumor is an optic nerve glioma.
Astrocytomas and Schwannomas also occur. Tumors may arise in
peripheral nerves and within the spinal cord. Intracranial tumors
may cause epilepsy, but fits may occur in the absence of any
demonstrable focal lesion.
sarcomatous changes may accompany the disease.
change may occur simultaneously in several lesions. Enlargement or
pain should suggest the possibility of malignant change, but rapid
enlargement may follow hemorrhage.
malignant diseases associated with neurofibromatosis include
Wilms‘ tumor, rhabdomyosarcoma, leukemia and retinoblastoma.
of the disease varies considerably. Characteristically café au lait
spots are present either at birth or, more commonly, develop in
neurofibromas appear usually during childhood and increase rapidly
in number at puberty. However, lesions may be present at birth and
become progressively more extensive. Although early onset and rapid
progression before puberty usually indicate a poor prognosis,
minimal cutaneous involvement in the young child does not
necessarily imply a favorable course, although many cases remain
involvement of the urinary or gastrointestinal tract or of the
central nervous system carries a poor prognosis. Very rarely, the
disease may be so extensive at birth to endanger life.
induces rapid progression of existing lesions and the development of
new ones besides hypertension.
neurofibromas are clinically and histologically distinctive.
lait spots, usually are the earliest manifestations in children.
These are present in 10-20% of normal individuals and in about 35%
of patients with Albright syndrome.
If six or
more café au lait lesions are present, the possibility of
neurofibromatosis is high, and if these are associated with axillary
freckling the diagnosis is almost certain.
should be thoroughly investigated.
follow-up with routine checks every 6-12 months is advisable.
counseling is important. First-degree relatives (e.g. siblings and
offspring) who have no stigmata of the disease are unlikely to carry
the gene and the risk for their offspring is minimal.
should be thoroughly investigated, to include an IQ assessment,
electroencephalography, audiography, slit-lamp ocular examination,
radiological skeletal survey, cranial CT scan and 24-h Urinary
disfiguring lesions can be excised if not too diffuse.
also indicated when an increase in size and pain suggests possible
We used CO2
laser for excision of cystic lesions of neurofibromas in a young
female using topical Emla cream as local anaesthetics. The patient
tolerated the procedure well and was satisfied with the result.
condition was originally considered to be part of the spectrum of
Von Recklinghausen‘s disease, but it is now recognized as a
separate entity, because of its distinct genetic basis and natural
lait spots and cutaneous neurofibromas may be seen, but are usually
few in numbers and much less common than in NF-1.
sclerosis is a complex genetic disorder transmitted as an autosomal
dominant gene. The syndrome is characterized by triad: epilepsy,
mental deficiency and adenoma sebaceous.
characteristic skin lesions are angiofibromas in the form of
- sized yellowish red, translucent, discrete, waxy papules situated
symmetrically on the face.
tuberous sclerosis and neurofibromatosis have certain features in
common and may coexist, they are genetically distinct.
characteristic features of the syndrome are:
are found in 60-70% of cases. Lesions of four types are
may rarely be present at birth or develop in infancy but usually
appear between the ages of 3 and 10 and sometimes later. They
often become more extensive at puberty and then remain unchanged.
papules: 1-10 mm in diameter, firm, discrete, red brown extend
from the nasolabial furrows to the cheeks and chin and are
occasionally found in the ears. They may be numerous and
conspicuous and very rarely may form large, cauliflower-like
patch is an irregularly thickened, slightly elevated, soft,
skin-colored plaque, usually in the lumbosacral region.
macules: 1-3 cm in length, ovoid or ash leaf-shaped most
easily detectable by examination under Wood‘s light which are
frequently present on the trunk or limbs. These are a valuable
physical sign which may be found at birth or in early infancy some years before other signs of the disease
suggest the correct diagnosis in infants with convulsions.
cutaneous manifestations include:
fibromatous plaques, especially on the forehead and scalp.
pedunculated fibromas may appear around the neck, axillae and
papillomatosis on the gingiva and on other parts of the mouth and
tumors are occasionally present on the gums, palate and are rarely
found on the tongue, larynx or pharynx.
commonly occur in the tooth enamel in adult patients, and these
pits, though less obvious in the deciduous teeth, have been used as
an early diagnostic sign in children with tuberous sclerosis.
fibromas and Koenen‘s periungual tumors appear as small degitate
protruding asymptomatic tumors.
may appear early in infancy.
deficiency is usually seen early during infancy.
symptoms, including schizophrenia.
osteoporosis of the long bones and skull with pseudocysts mainly in
in the form of hamartomas.
tumors as rhabdomyoma.
changes are rare and seldom cause symptoms but if they are
extensive, they may cause increasing dyspnea and recurrent
usually hamartomatous colonic polyps.
should be considered in the investigation of patients with tuberous
and other metabolic disturbances may be present, most frequently
reported are pituitary-adrenal dysfunction, thyroid disorders and
localized gigantism and diffuse cutaneous reticulohistiocytosis.
is seen on plain skull X-ray in about 50% of patients. These are not
usually apparent until later childhood or adult life.
CT scan appearance of tuberous sclerosis consists of calcified
periventricular nodules that project into the lateral ventricles.
is more sensitive in the detection of parenchymal lesions. The
periventricular lesions may not be seen initially and can progress
to calcified lesions with time.
lesions of the phalanges and irregular thickening of the cortex of
metatarsals, vertebrae, pelvis or long bones are not uncommon.
There may be
irregular reticulation of the lung-fields, not radiologically
distinguishable from other types of interstitial fibrosis.
treatment is available.
treatment of the affected organs.
bullosa (EB) is a rare chronic skin diseases characterized by
formation of bullae elicited by friction or trauma to the skin due
to separation at the dermo-epidermal junction.
bullosa is either a genetic dominantly transmitted disease or
This is a
dominantly recessive type, characterized by formation of bullae
mainly on the palms and soles elicited by friction or trauma. The
lesions become apparent when the child starts to crawl or walk,
where the bullae appear after minor trauma or friction.
rupture of the bullae takes long time without scarring.
or buccal mucosa are not affected.
measures are the main line of treatment, which includes minimizing
friction or trauma by using loose or open shoes, and avoiding trauma.
is helpful in severe cases.
potent fluorinated steroids cream for skin lesions.
be considered in such type of treatment because of possibility of
absorption of the concentrated steroids, hence, the skin is abraded
that enhances more absorption leading to unwanted side effects.
reported the success of oral sodium citrate 2gms three times daily.
Fig. 254 Epidermolysis bullosa
dominant epidermolysis bullosa
epidermolysis bullosa is a dystrophic bullous disease begins in
infancy and early childhood affecting mainly the joints and limbs.
Fig. 255. Epidermolysis Bullosa
255. Epidermolysis Bullosa
are precipitated by friction and trauma where bullae appear due to
subepidermal splitting. The lesion has a chronic course healing by
membranes and hair are not affected .
sign is usually positive and the bullae are flaccid where the fluid
in the bulla can be moved few centimeters.