LYMPHEDEMA HEREDITARY SYNDROMES
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=====================================================
Related Terms: MILROY'S SYNDROME,
MEIGE
LYMPHEDEMA SYNDROME,
LYMPHEDEMA PRAECOX,
YELLOW NAIL SYNDROME, STEWART-TREVES SYNDROME,
HENNEKAM
LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME,
TURNER
SYNDROME,
KLIPPEL-TRENAUNAY-WEBER
SYNDROME, NOONAN'S SYNDROME,
LYMPHEDEMA-DISTICHIASIS
SYNDROME,
LYMPHEDEMA-CHOLESTASIS
SYNDROME,
LYMPHEDEMA,
MICROCEPHALY, CHORIORETINOPATHY SYNDROME, LYMPHEDEMA-HYPOPARATHYROIDISM SYNDROME,
LYMPHEDEMA-HYPOPARATHYROIDISM
SYNDROME,
LYMPHEDEMA,
CONGENITAL RECESSIVE SYNDROME,
LYMPHEDEMA AND
PTOSIS SYNDROME,
HYPOTRICHOSIS-LYMPHEDEMA-TELANGIECTASIA
SYNDROME, ECTODERMAL
DYSPLASIA, ANHIDROTIC, WITH IMMUNODEFICIENCY, OSTEOPETROSIS, AND
LYMPHEDEMA;
OLEDAID, LYMPHEDEMA
AND CEREBRAL ARTERIOVENOUS ANOMALY
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Syndromes
associated with hereditary lymphedema
MILROY'S
SYNDROME
See also: Nonne-Milroy lymphedema, Milroy's Disease, Primary congenital
hereditary lymphedema,
hereditary lymphedema I
Milroy's Syndrome is an old term used to describe hereditary
congenital
lymphedema. It is a congenital familial primary lymphedema which
results from
veritical autosomal inheritance of a single gene. The gene has been
identified
as
VEGFR3. The condition usually presents itself at birth with
the swelling of
one or even both legs.
If the condition is unilateral (single leg), the other leg may continue
in the
latency stage for years before expressing itself. The same is indicated
for
arm
lymphedema.
It is the rarest of the inherited lymphedema, accounting for
approximately 2% of
hereditary lymphedemas.
Hereditary lymphedema was first described by Nonne in 1891, however in
1892 Dr.
William F. Milroy described a missionary who had returned from work in
India who
had swollen legs his entire life. His mother likewise was afflicted
with
the same condition. Milroy had also, previously studied the 250 year
history of
a family and had been able to identify 22 persons with this condition
through 6
generations. He was also able to pinpoint when the condition entered
the family
through a marriage in 1768.
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MEIGE
LYMPHEDEMA SYNDROME
See also:Praecox
Meige Syndrome, Nonne-Milroy-Meige Syndrome,
Meige's lymphedema, Hereditary lymphedema
II, familial lymphedema praecox
Named after French physician Dr. Henri Meige who first described
hereditary
lymphedema in 1891. This form of lymphedema which usually presents
itself at or
during puberty is the most common of the hereditary lymphedemas,
account for
65-80% of all diagnosed cases.
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YELLOW NAIL
SYNDROME
Yellow nail syndrome is a very rare disorder often associated
with lymphedema of
the lower extremities. It is also associated with lung disorders. Other
associated indications are rhinosinusitis,
pleural
effusions, bronchiectasis.
The syndrome is characterized by yellow nails that lack a cuticle, grow
slowly
and are loose or detached. The nails also become dystrophic with
longitudinal or
transverse ridging.
There is no treatment or cure specifically for the resolution of the
condition.
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STEWART-TREVES
SYNDROME
See also: lymphangiosarcoma
Stewart-Treves
Syndrome is a rare, aggressive and
cutaneous
angiosarcoma
often
associated with long standing lymphedema.
Most cases arise from lymphedema induced by a radical mastectomy in
breast
cancer patients. Although there has also been significant reports
regarding
development from Milroy lymphedema and in idiopathic, congenital,
traumatic, or
filarial lymphedema.
The three main indications for the development of Stewart Treves in a
lymphedemous limb appear to be radiation, extensive fibrosis and
recurrent or
chronic infection.
The sarcoma first appears as a bruised area or a purplish discoloration
in an
extremity. It progresses to an ulcer with crusting and finally to an
extensive
necrosis involving the skin and subcutaneous tissue. It metastasizes
widely and
there is no effective therapy.
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HENNEKAM
LYMPHANGIECTASIA-LYMPHEDEMA
SYNDROME
Classified as a developmental disorder of the lymphatics. First
described by
Dutch physician R.C.M. Hennekam in 1989. Characteristics include
Intestinal or
pleural
lymphangiectasia was accompanied by the usual hypoproteinemia,
hypogammaglobulinemia,
and
lymphocytopenia.
Facial anomalies included flat face,
flat nasal bridge, hypertelorism, epicanthal folds, small mouth, tooth
anomalies, and ear defects. Complications involve severe lymphedema
cellulitis
and erysipelas
There is no specific treatment for the condition, only management of
the
complications.
Also, related to Turner Syndrome.
******
Homburger
and
Petermann (1949) described a disorder, which they called
'familial
idiopathic dysproteinemia,' characterized by edema of the legs, with
ulcers in
the males and 'functional vascular changes' in the females;
dysproteinemia of
variable type, sometimes discernible only by electrophoresis; a number
of
congenital malformations; and a high incidence of stillbirths. Persons
in 3
generations were affected and male-to-male transmission occurred.
Subsequently
these patients were found to have intestinal loss of protein,
presumably because
of lymphangiectasia (Waldmann
et al., 1961; Waldmann
and Schwab, 1965). Murphy
(1972) gave clinical follow-up. Lymphopenia due to
exaggerated intestinal
loss is also a feature. Double vortex pilorum ('hair whorl') and
usually
prominent 'floating ribs' (ribs 11 and 12) were present. Parfitt
(1966) described 3 sibs (2 females, 1 male) affected out of
5. All had
neonatal edema. The small bowel showed dilated lymphatic spaces and
partial
villous atrophy. Cottom
et al. (1961) reported neonatal
hypoproteinemia in 2 sibs, and other
probable cases are known. See also hereditary lymphedema I (153100)
and protein-losing enteropathy (226300).
Patients with intestinal lymphangiectasia have hypogammaglobulinemia,
lymphocytopenia, skin anergy and impaired allograft rejection.
Peripheral blood
lymphocytes show impaired in vitro blastic transformation (Weiden
et al., 1972). This is attributable to depletion of
lymphocytes necessary
for transformation. The situation is comparable to experimental
thoracic duct
drainage. 
Victor A. McKusick : 6/2/1986
joanna :
3/18/2004
carol : 11/19/2003
mimadm : 11/6/1994
davew : 8/2/1994
warfield : 3/1/1994
supermim : 3/16/1992
carol : 6/13/1990
supermim : 3/20/1990
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=152800
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TURNER
SYNDROME
Named after Dr. Henry Turner who was one of the first to describe its
features
in the 1930's. An internist at the University of Oklahoma, he first
identified a
common set of traits or physical features in seven of his patients in
an article
published in 1938. This is a chromosomal condition caused when one of
the two x
chromosomes normally found in females is missing or incomplete.
However, the
actual chromosomal deficiency was not identified until 1959.
The condition is diagnosed, or confirmed by a blood test called a
kerotype. The
test analyzes the chromosomal composition of the individual. Another
unique
feature of Turner Syndrome is that is occurs only in females.
Characteristics include short stature, lack of ovarian development,
webbed neck
and/or arms, low hairline at the base of the neck. Other reported signs
include
cardio-vascular difficulties, kidney and thyroid problems, and
scoliosis.
Another complication of Turner Syndrome is lymphedema.
Because this is a chromosomal based disorder there is no cure. There
are
treatments however that can lesson the symptoms. These include growth
hormone,
estrogen replacement therapy.
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Klippel-Trenaunay-Weber
Syndrome
First described by French physicians Klippel and Trenaunay in 1900,
this
syndrome is characterized by port-wine stain (capillary hemangioma),
varicose
veins and bony and soft tissue hypertrophy involving an
extremity. Please
note that there is still much on-going debate as to whether or not this
is a
hereditary condition.
Other features involve lymphedema or lymphatic obstruction, cellulitis,
chronic
venous insufficiency, stasis dermatitis, poor wound healing,
ulceration,
thrombosis, and emboli.
Treatment is varied for the different symptoms present. Compression
garments are
used to control the lymphedema, prophylactic antibiotics are of course,
used to
treat the cellulitis and
lymphangitis spells. Orthopedic procedures are
available for the limb hypertrophy and wound treatment is sometimes
necessary
for ulcerations.
Other treatments for the symptoms or complications include lasers for
the hemangiomas,
and surgical intervention for the vascular anomalies may be called
for.
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NOONAN'S
SYNDROME
A familial condition similar to both Turner Syndrome. It is different
however, in
that here is no comromosomal defect as is involved with Turner and
unlike
Noonan's, this condition can affect both sexes.
Though an early description of the syndrome is credited to a Russian
medical
student, Koblinsky, at the Russian/Estonian University at Dorpat, the
condition
is named after an American cardiologist, Jacquline A. Noonan. She and
pediatrician Dorothy Ehmke conducted an extensive clinical study of 833
children
with congenital heart disease. Their findings were published and
reported to the
Midwest Society of Pediatric Research held in Cincinnati in 1962.
Cardiac abnormalities occur in 50% of patients: these include pulmonary
valve
stenosis, thick and dysplastic pulmonary valves, right heart anomalies
and left
ventricular cardiomyopathy.
Symptoms of the disorder include not only heart indications but
valvular
pulmonary stenosis, short stature, hypertelorism and skeletal
anomalies, and, in
boys, retention testis.
Skin manifestations present as transient lymphedema, in the dorsal
hands during
infancy and progresses to stasis in adulthood. Scalp findings include
low
posterior neck hairline and coarse curly hair. Scanty pubic, axillary,
and beard
hair growth has been noted. Nails show short and wide dystrophic
changes.
************
| NOONAN SYNDROME 1; NS1 |
Alternative titles; symbols
NOONAN SYNDROMEA number sign
(#) is used with this entry because of evidence that one form
of Noonan syndrome, that which maps to 12q24.1, is due to mutations in
PTPN11 (176876),
a gene encoding the nonreceptor protein tyrosine phosphatase SHP2,
which
contains 2 Src homology-2 (SH2) domains (Tartaglia
et al., 2001). Tartaglia
et al. (2001) found that mutations in the PTPN11 gene
accounted for about
half the patients studied. Mutations in the neurofibromin gene (NF1; 162200),
which is the site of mutations causing classic neurofibromatosis type
I, have
been found in neurofibromatosis-Noonan syndrome (NFNS; 601321).
Noonan
syndrome is a dysmorphic syndrome characterized by hypertelorism, a
downward eyeslant, and low-set posteriorly rotated ears (Shah
et al., 1999). Other features include short stature, a short
neck with
webbing or redundancy of skin, cardiac anomalies, epicanthic folds,
deafness,
motor delay, and a bleeding diathesis.
The disorder
now known as Noonan syndrome bears similarities to the disorder
described by Turner
(1938) and shown by Ford
et al. (1959) to have its basis in a 45,X chromosomal
aberration. (With
considerable justification, Ullrich's name is combined with that of
Turner as
the designation for the 45,X syndrome. Ullrich described the disorder 8
years
before Turner. Wiedemann
and Glatzl (1991) provided a follow-up of Ullrich's original
patient with
Ullrich-Turner syndrome and demonstrated that the restudy in 1987, when
the
patient was 66 years old, confirmed the 45,X chromosome constitution.)
Noonan
(1968) reported 19 cases of whom 17 had pulmonary stenosis
and 2 had patent
ductus arteriosus (see 607411).
Twelve were males and 7 were females. Deformity of the sternum with
precocious
closure of sutures was a frequent feature. Kaplan
et al. (1968) described 2 brothers with elevated alkaline
phosphatase
levels, one of whom also had malignant schwannoma of the forearm. Nora
and Sinha (1968) observed mother-to-offspring transmission in
3 families; in
1 family, transmission was through 3 generations. They suggested
X-linked
dominant inheritance of either a single mutant gene or a submicroscopic
deletion. Among 95 male patients with pulmonary stenosis, Celermajer
et al. (1968) found the Turner phenotype in 8. In 5 of these,
karyotyping
was performed. In 4 the chromosomes were normal. In one an extra
acrocentric
chromosome was present.
Abdel-Salam
and Temtamy (1969) reported 2 affected sibs from a
first-cousin marriage. A
deceased female sib may have been affected also. They suggested
autosomal
recessive inheritance. Baird
and De Jong (1972) described 7 cases in 3 generations. One
affected woman
had 5 affected children (out of 6) with 2 different husbands. Seizures
and
anomalous upper lateral incisors may have been coincidental. Diekmann
et al. (1967) described 2 brothers and a sister, with normal
and unrelated
parents, who had somatic characteristics of the Noonan syndrome,
particularly
pterygium colli and deformed sternum, and had myocardiopathy leading to
death at
ages 12 and 10 in two of them. Migeon
and Whitehouse (1967) described 2 families, each with 2 sibs
with somatic
features of the Turner syndrome. In 1 family, 2 brothers had webbing of
the
neck, coarctation of the aorta, and cryptorchidism. In the second, a
brother and
sister were affected.
Simpson
et
al. (1969) reported experiences suggesting that rubella
embryopathy may
result in the Turner phenotype, thereby accounting for either the male
Turner
syndrome or the female pseudo-Turner syndrome. A particularly
convincing
pedigree for autosomal dominant inheritance was reported by Bolton
et al. (1974), who found the condition in a man and 4 sons
(in a sibship of
10). Four of the 5 affected persons had pulmonic stenosis.
Father-to-son
transmission was reported by Qazi
et al. (1974).
Koretzky
et
al. (1969) described an unusual type of pulmonary valvular
dysplasia which
showed a familial tendency with either affected parent and offspring or
affected
sibs. Although some relatives had pulmonary valvular stenosis of the
standard
dome-shaped variety, the valvular dysplasia in others was characterized
by the
presence of three distinct cusps and no commissural fusion. The
obstructive
mechanism was related to markedly thickened, immobile cusps, with
disorganized
myxomatous tissue. Other features were retarded growth, abnormal facies
(triangular face, hypertelorism, low-set ears and ptosis of the
eyelids),
absence of ejection click, and unusually marked right axis deviation by
electrocardiogram. It now seems clear that the patients of Koretzky
et al. (1969) had the Noonan syndrome.
Mendez
and
Opitz (1985) stated that the Watson syndrome (193520)
and the LEOPARD syndrome (151100)
'are essentially indistinguishable from the Noonan syndrome.' Witt
et al. (1987) reviewed the occurrence of lymphedema in Noonan
syndrome. When
it does occur, it opens the possibility of prenatal diagnosis by
imaging methods
or by AFP level. Noonan syndrome was one of the causes found for
posterior
cervical hygroma in a series of previable fetuses studied by Kalousek
and Seller (1987). The authors found, furthermore, that 45,X
Turner syndrome
lethal in the fetal period showed a constant association of 3 defects,
posterior
cervical cystic hygroma, generalized subcutaneous edema, and preductal
aortic
coarctation.
Evans
et al.
(1991) found a large cutaneous lymphangioma of the right
cheek and
amegakaryocytic thrombocytopenia in a male infant with Noonan syndrome.
Donnenfeld
et al. (1991) presented a case of Noonan syndrome in which
posterior nuchal
cystic hygroma was diagnosed at 13 to 14 weeks of gestation by
ultrasonography.
The hygroma had regressed by the time of birth leaving nuchal skin fold
redundancy and pterygium colli. On the basis of studies of genital
tract
function in 11 adult males with Noonan syndrome, Elsawi
et al. (1994) concluded that bilateral testicular maldescent
was a main
factor in contributing to impairment of fertility. Four of the 11 men
had
fathered children.
Thrombocytopenia
occurs in some cases of the Noonan syndrome (Goldstein,
1979). Partial deficiency of factor XI was described by Kitchens
and Alexander (1983). Out of 9 patients with Noonan syndrome,
de
Haan et al. (1988) found 4 with partial deficiency of factor
XI (30-65% of
normal). They reviewed the other reports of bleeding tendency
associated with
thrombocytopenia or with abnormal platelet function. Witt
et al. (1988) described bleeding diathesis in 19 patients
with Noonan
syndrome. Several different defects were identified in the coagulation
and
platelet systems, occurring singly or in combination; for example, 2
patients
had factor XI deficiency, 3 had presumptive von Willebrand disease, and
1 had
thrombocytopenia. In 5 of the patients an unusually pungent odor of
urine and
sweat was noted by parents. One of these patients was reported by Humbert
et al. (1970) as a case of trimethylaminuria (136131)
and another patient was suspected of having this condition. Sharland
et al. (1990) also described a variety of coagulation factor
deficiencies.
The most common abnormality was a partial factor XI deficiency in the
heterozygote range, found in 21 of 31 patients. Of 72 patients studied
(37 male,
35 female, mean age 11.4 years) by Sharland
et al. (1992), 47 (65%) had a history of abnormal bruising or
bleeding. In
29 patients (40%), prolonged activated partial thromboplastin time was
found. In
36 patients (50%) specific abnormalities were found in the intrinsic
pathway of
coagulation, i.e., partial deficiency of factor XI:C, XII:C, and
VIII:C.
Multiple abnormalities among these 36 patients included combined
deficiencies of
factors XI and XII (4 patients), of factors XI and VIII (4 patients),
and of
factors VIII, XI, and XII (1 patient). In 5 families, similar
coagulation-factor
deficiencies were present in first-degree relatives. Sharland
et al. (1992) suggested that because of the involvement of
several factors,
either singly or in combination, there are likely to be regulatory
factors that
control the intrinsic (contact activation) system; that these factors
are under
chromosomal genetic control; and that abnormalities of this regulation
occur in
Noonan syndrome.
Allanson
et
al. (1985) studied the changes in facial appearance with age.
They pointed
out that the manifestations may be subtle in adults. Ranke
et al. (1988) analyzed the clinical features of 144 patients
from 2 West
German centers. The size at birth was normal in both sexes. In both
males and
females, the mean height followed along the 3rd percentile until
puberty, but
decreased transiently due to an approximately 2-year delay in onset of
puberty.
Final height approaches the lower limits of normal at the end of the
second
decade of life. The mean adult height was 162.5 cm in males and 152.7
cm in
females, respectively. Allanson
(1987) provided a useful review. The fetal primidone
syndrome, occurring in
the offspring of mothers taking this anticonvulsant, closely simulates
the
Noonan syndrome. Baraitser
and Patton (1986) reported 4 unrelated children (2 boys, 2
girls) with a
Noonan-like syndrome associated with sparse hair as a conspicuous
feature.
Leichtman
(1996) reported a family suggesting that cardiofaciocutaneous
syndrome (CFC;
115150)
is a variable expression of Noonan syndrome. He described a 4-year-old
girl who
had all of the manifestations of CFC syndrome (characteristic facial
and cardiac
anomalies, developmental delay, hypotrichosis, eczematic eruption with
resistance to treatment), whose mother had typical characteristics of
Noonan
syndrome. Lorenzetti
and Fryns (1996) reported a 13-year-old boy with Noonan
syndrome and
retinitis pigmentosa. Because similar eye defects are found in CFC
syndrome, the
authors suggested that CFC and Noonan syndromes might be variable
manifestations
of the same entity. However, Neri
and Zollino (1996) noted distinctions between the patient
reported by Lorenzetti
and Fryns (1996) and CFC syndrome, and stated that similarity
of eye defects
is not enough to conclude that CFC and Noonan syndromes are the same
condition.
Early feeding
difficulties are common in Noonan syndrome but often go
unrecognized. Shah
et al. (1999) studied a consecutive series of children with
Noonan syndrome
whose diagnosis had been confirmed by a clinical geneticist. Sixteen
had poor
feeding (poor suck or refusal to take solids or liquids) and symptoms
of
gastrointestinal dysfunction (vomiting, constipation, abdominal pain,
and
bloating). All 16 had required nasogastric tube feeding. Seven of the
25 had
foregut dysmotility and gastroesophageal reflux. In 4 of these,
electrogastrography and antroduodenal manometry demonstrated immature
gastric
motility reminiscent of that of a preterm infant of 32 to 35 weeks'
gestation.
Other children had less severe forms of gastric dysmotility. The
authors
highlighted the importance of recognizing this common, treatable
feature of
Noonan syndrome.
Lemire
(2002) described a father, son, and daughter with an
apparently autosomal
dominant disorder characterized by craniofacial anomalies, coarctation
of the
aorta, hypertrophic cardiomyopathy, and other structural heart defects
with
normal psychomotor development. Some clinical features such as webbed
neck,
low-set ears, low posterior hairline, and widely spaced nipples
suggested Noonan
syndrome. Alternatively, a previously unrecognized disorder was
considered. The
paternal age at the father's birth was 50 years. The father presented
at age 13
years when postductal coarctation of the aorta was discovered during
routine
physical examination. Preoperative evaluation showed hypertrophied
interventricular septum with pulmonic stenosis and bicuspid aortic
valve in
addition to the aortic coarctation. At age 22 years, echocardiogram
showed
marked systolic thickening of interventricular septum and posterior
wall of the
left ventricle and concentric left ventricular hypertrophy. He later
developed
atrial flutter and congestive heart failure. His son was recognized at
birth to
have 2 small ventricular septal defects, mildly hypoplastic aortic
arch, and
coarctation of the aorta. The coarctation was repaired at age 14 days
and
bilateral inguinal hernias at age 5 weeks. At age 9 months, he was
found to have
congestive heart failure due to a restrictive cardiomyopathy. At age 10
months,
studies confirmed the presence of spongy myocardium with much impaired
diastolic
function. He died of early acute graft failure at age 14 months after
heart
transplantation. Autopsy showed restrictive cardiomyopathy with
generalized
myocardium hypertrophy. The daughter was found at birth to have a small
ventricular septal defect, small patent ductus arteriosus, aneurysm of
the
atrial septum, and coarctation of the aorta. Cardiomyopathy was
suspected on the
basis of excessive thickening of the lower two-thirds of the
interventricular
septum and of the free wall of the right ventricle. Coarctation of the
aorta was
repaired surgically at age 19 days. At age 10.5 months, she was noted
to have
plagiocephaly, facial asymmetry with left side smaller than the right,
webbed
neck, asymmetric chest with widely spaced nipples, and edema of the
dorsum of
the feet. At age 2 years, bicuspid aortic valve and diffuse concentric
hypertrophy of the left ventricle were noted.
Juvenile myelomonocytic leukemia (JMML; 607785) has been observed in some cases of Noonan syndrome (Bader-Meunier et al., 1997; Fukuda et al., 1997; Choong et al., 1999).
Holder-Espinasse
and Winter (2003) described a 6-year-old girl with clinical
features of
Noonan syndrome, short stature, and headache who was noted to have
Arnold-Chiari
malformation (207950)
on MRI. They cited 3 previous reports of Noonan syndrome and Chiari
malformation
and/or syringomelia (Peiris
and Ball, 1982; Gabrielli
et al., 1990; Colli
et al., 2001). Holder-Espinasse
and Winter (2003) concluded that Chiari malformation should
be considered
part of the Noonan syndrome spectrum and that brain and cervical spine
MRI
should be required in patients with Noonan syndrome, particularly if
headaches
or neurologic symptoms are present.
For a comprehensive review of Turner syndrome, including clinical management, see Ranke and Saenger (2001).
Noonan
et
al. (2003) reported their findings in 73 adults over 21 years
of age with
Noonan syndrome. In 30%, adult height was in the normal range between
the 10th
and 90th percentiles. More than half of the females and nearly 40% of
males had
an adult height below the third percentile. The presence or severity of
heart
disease was not a factor, and none of the adults with normal height had
been
treated with growth hormone. Serial measurements of height over many
years
through childhood to adulthood were available in only a few patients,
but their
pattern of growth suggested that catch up may occur in late
adolescence. The
possible benefit of growth hormone therapy could not be evaluated.
Kondoh et al. (2003) described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a 3-month-old Japanese patient with Noonan syndrome and a de novo missense mutation in the PTPN11 gene (176876.0007).
Using a number
of probes at the neurofibromatosis type I locus in the study
of 11 families with Noonan syndrome in 2 or 3 generations, Sharland
et al. (1992) excluded proximal 17q as the location of the
gene. Studying
six 2-generation families with classic Noonan syndrome, Flintoff
et al. (1993) could find no evidence of linkage of this
disorder to NF1 on
17q or to NF2 (101000)
on 22q. Edman
Ahlbom et al. (1995) likewise could find no evidence of
linkage between NF1
and Noonan syndrome with cafe-au-lait spots.
By means of a
genomewide linkage analysis in a large Dutch kindred with
autosomal dominant Noonan syndrome, Jamieson
et al. (1994) localized the gene to chromosome 12; maximum
lod = 4.04 at
theta = 0.0. Linkage analysis using chromosome 12 markers in 20
smaller,
2-generation families gave a maximum lod of 2.89 at theta = 0.07, but
haplotype
analysis showed nonlinkage in 1 family. These data suggested that a
gene for
Noonan syndrome is located in the 12q22-qter region between markers
D12S84 and
D12S366. Clinical studies in this kindred were reported by van
der Burgt et al. (1994).
Brady
et al.
(1997) further analyzed the 3-generation Dutch family studied
by Jamieson
et al. (1994) using newly isolated CA-repeat markers derived
from the
interval between D12S84 and D12S366. In this way they were able to
reduce the
localization to an interval bounded by markers D12S105 and NOS1 (163731),
which has been mapped to 12q24.2-q24.31.
Legius
et
al. (1998) performed linkage analysis in a 4-generation
Belgian family with
Noonan syndrome in some individuals and CFC syndrome in others.
Clinical and
linkage data in this family indicated that the 2 syndromes result from
variable
expression of the same genetic defect. They found a maximum lod score
of 4.43 at
zero recombination for marker D12S84 in 12q24. A crossover in this
pedigree
narrowed the candidate gene region to a 5-cM interval between D12S84
and
D12S1341. A remarkable feature of the family studied by Legius
et al. (1998) was the presence of 3 dizygotic twins in the
offspring of 2
affected females. A dizygotic twin pair was observed in the offspring
of an
affected female in the family in which linkage was studied by Jamieson
et al. (1994). It is possible that an increased frequency of
dizygotic
twinning is associated with NS1/CFC linked to 12q24. The fragile X
syndrome (309550)
is another mendelian disorder with a possibly increased frequency of
dizygotic
twinning (Partington
et al., 1996; Schwartz
et al., 1994).
In a study of candidate genes, Ion et al. (2000) excluded the genes EPS8 (600206) and DCN (125255) from the critical region by FISH analysis. They also excluded the MYL2 (160781) and RPL6 (603703) genes by mutation analysis.
Robin
et al.
(1995) described 6 patients with Noonan syndrome who
underwent molecular
evaluation for submicroscopic deletion of chromosome 22q11. None of
these
patients presented with conotruncal heart defects. Evidence for 22q11
hemizygosity was demonstrated in only 1 patient. This patient had
Noonan-like
manifestations without clinical manifestations of DiGeorge (188400)
or velocardiofacial (192430)
syndromes. Digilio
et al. (1996) studied 4 patients with Noonan syndrome and
tetralogy of
Fallot. Chromosome analysis was normal in all 4 patients. DNA analysis
showed no
hemizygosity for the 22q11 region in any of the patients.
Butler
et
al. (2000) used metacarpophalangeal pattern profile (MCPP)
analysis to
evaluate 15 individuals with Noonan syndrome. Discriminant analysis
resulted in
the correct classification of 93% of Noonan syndrome patients based on
2 MCPP
variables (metacarpal 1 and middle phalanx 3). The authors suggested
that MCPP
analysis may be useful as a diagnostic tool in screening subjects for
Noonan
syndrome.
MacFarlane
et al. (2001) reported growth data from the first 3 years of
a multicenter
study examining the efficacy and safety of recombinant human GH in 23
children
with Noonan syndrome. Sixteen male and 7 female patients (aged 9.3 +/-
2.6 years
at onset of GH therapy, mean +/- SD; range 4.8-13.7) were each assessed
at 1, 2,
and 3 years after starting treatment. Comparisons were made with a
group of 8
subjects (6 males and 2 females, aged 9.0 +/- 4.1 years; range
4.1-14.8) with
Noonan syndrome and not treated with recombinant GH, and measured over
the same
period. All treated subjects underwent annual cardiac assessment.
Height SD
score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9
+/- 0.9
three years later. This corresponded to an increase in height from
116.1 +/-
13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4 +/- 1.7
cm/year in
the year before treatment to 8.4 +/- 1.7, 6.2 +/- 1.7, and 5.8 +/- 1.8
during
the first, second, and third years of GH treatment, respectively.
Height
acceleration was not significant during the second or third years when
pubertal
subjects were excluded. The authors concluded that the increase in
growth rate
in Noonan syndrome resulting from 1 year of GH therapy seems to be
maintained
during the second year, although height velocity shows a less
significant
increase over pretherapy values. Possible abnormal anabolic effects of
recombinant GH on myocardial thickness were not confirmed, and no
treated
patient developed features of hypertrophic cardiomyopathy.
Kirk
et al.
(2001) presented data on 66 Noonan syndrome patients (54
males) treated with
growth hormone. Treatment improved height velocity in the short term,
but
longer-term therapy resulted in a waning of effect. The study indicated
that
final height is not substantially improved in most patients.
After germline
mutations in PTPN11 (176876)
were demonstrated in the Noonan syndrome, Tartaglia
et al. (2003) investigated defects in PTPN11 in myeloid
disorders including
cases of juvenile myelomonocytic leukemia (JMML; 607785)
in children with Noonan syndrome. Specific mutations in PTPN11
associated with
isolated JMML occurred as somatic changes and had never been observed
as
germline defects, leading Tartaglia
et al. (2003) to speculate that these molecular defects are
stronger and
associated with embryonic lethality. Conversely, most mutations in
PTPN11
associated with Noonan syndrome, which were sufficient to perturb
developmental
processes, were not fully leukemogenic, suggesting a milder
gain-of-function
effect.
In 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, Schollen et al. (2003) identified a missense mutation in the PTPN11 gene (176876.0018). The mutation was not found in 7 unaffected relatives or 3 spouses.
Musante
et
al. (2003) screened the PTPN11 gene for mutations in 96
familial or sporadic
Noonan syndrome patients and identified 15 missense mutations in 32
patients
(33%). No obvious clinical differences were detected between subgroups
of
patients with mutations in different PTPN11 domains. Analysis of the
clinical
features of their patients revealed that several patients with facial
abnormalities thought to be pathognomonic for NS did not have a
mutation in the
PTPN11 gene. Widely varying phenotypes among the 64 patients without
PTPN11
mutations indicated further genetic heterogeneity. Musante
et al. (2003) also screened 5 sporadic patients with CFC
syndrome and found
no mutations in the PTPN11 gene.
Cole
(1980)
pointed out that the blacksmith in the famous painting 'Among Those
Left' by
Ivan Le Lorraine Albright appears to have had Noonan syndrome. The
contour of
the sternum, the low-set ears, and the short stature are suggestive.
Genetic
confirmation was provided by studies of a great-grandson with general
features
of the Noonan syndrome and cardiac abnormalities consistent with that
diagnosis
(pulmonic stenosis and regurgitation, abnormal architecture of the left
ventricular musculature). Opitz
and Pallister (1979) reproduced the first published
illustration of the
Noonan syndrome by Kobylinski
(1883), and Opitz
(1985) republished the photograph of Rickey E., the first
patient with 'her'
syndrome studied at the State University of Iowa by Jacqueline A.
Noonan.
Alslev and Reinwein (1958); Char et al. (1972); Duncan et al. (1981); Fisher et al. (1982); Golabi et al. (1985); Hall et al. (1982); Levy et al. (1970); Linde et al. (1973); Miller and Motulsky (1978); Nora et al. (1974); Pierini and Pierini (1979); Sharland et al. (1992); Wiedemann (1991); Witt et al. (1985)
Marla J. F.
O'Neill - updated : 5/12/2004
Marla J. F. O'Neill - updated : 4/2/2004
Natalie E. Krasikov - updated : 3/29/2004
Siobhan M. Dolan - updated : 2/19/2004
Victor A. McKusick - updated : 1/14/2004
Victor A. McKusick - updated : 5/15/2003
Victor A. McKusick - updated : 5/13/2003
Cassandra L. Kniffin - updated : 1/9/2003
Victor A. McKusick - updated : 11/27/2002
Victor A. McKusick - updated : 11/12/2001
Victor A. McKusick - updated : 8/6/2001
John A. Phillips, III - updated : 7/10/2001
Michael J. Wright - updated : 5/21/2001
Sonja A. Rasmussen - updated : 10/12/2000
Paul Brennan - updated : 4/10/2000
Victor A. McKusick - updated : 4/30/1998
Victor A. McKusick - updated : 12/19/1997
Iosif W. Lurie - updated : 1/8/1997
Iosif W. Lurie - updated : 9/12/1996
Victor A. McKusick : 6/2/1986
carol : 5/13/2004
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163950
---------------------------------------------------------
LYMPHEDEMA-DISTICHIASIS
SYNDROME
Gene Map Locus: 16q24.3
Genetics: Mutation in the forkhead family
transcription factor gene MFH1
(FOX2; 602402). Related disorders with overlapping features include
hereditary
lymphedema II. (Meige Syndrome); lymphedema with ptosis and lymphedema
with
yellow nail syndrome.
Description: Expressed as the characteristic
"double-row" of
eye lashes. Usually not detected or observed until a complication such
as
corneal irritation or ulceration brings it to the attention of the
patient or
physician.
Related genetic features (lymphedema): Cardiac
defects, cleft-palate,
spinal extradural cysts and photofobia.
*****
| DISTICHIASIS |
Alternative titles; symbols
EYELASHES, TWO ROWS OFFox
(1962)
reviewed the heredity of this anomaly. Dominant pedigrees were
presented by Erdmann
(1904) and by Cockayne
(1933). Blatt
(1924) traced double rows of eyelashes through 3 generations.
See
tristichiasis (190800).
(The terms 'districhiasis' and 'tristrichiasis' refer to 2 or 3 hairs
per
follicle. Much confusion exists, however, and 'distichiasis' and
'districhiasis'
are often used interchangeably to mean 'two rows of eyelashes.') In 3
generations of a family, Pico
(1957) found 11 persons with congenital ectropion of whom 8
also had
distichiasis. Two persons had distichiasis alone. Histologic study in 2
showed
absence of Meibomian glands and replacement of the dense collagenous
tissue of
the tarsal plates by loose areolar tissue. The observation by Szily
(1923) suggested recessive inheritance. Maumenee
(1982) questioned the existence of mendelian distichiasis
except as part of
the syndrome of lymphedema with distichiasis (153400).
Study of a family with both distichiasis and atypical serum
cholinesterase
indicated that the 2 traits are not closely linked (Shammas
et al., 1976).
Howard
and
Wilson (1993) used the term pseudodistichiasis for the double
row of
eyelashes seen in association with anhidrotic ectodermal dysplasia (305100).
They pointed out that the double row of eyelashes should not be
confused with
the misdirection of normal lashes referred to as trichiasis. A similar
but
distinct eyelash anomaly was reported in association with the Setleis
forceps
marks syndrome (227260)
by Frederick and
Robb (1992). In true distichiasis, a second row of eyelashes
merges from the
meibomian gland orifices; in pseudodistichiasis, the double row of
eyelashes
exit anterior to the meibomian orifices.
Victor A. McKusick : 6/4/1986
alopez :
3/18/2004
davew : 6/27/1994
mimadm : 6/25/1994
warfield : 4/8/1994
carol : 3/30/1994
carol : 7/22/1993
supermim : 3/16/1992
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126300
---------------------------------------------------------
LYMPHEDEMA-CHOLESTASIS SYNDROME
Gene Map Locus: 15q
Related terms:
Aagenaes
syndrome,
Cholestasis
Syndrome-Lymphedema
Complication associated with primary hereditary lymphedema. First study
of this
condition took place in 2 Norwegian families with recurrent cholestasis
and
lymphedema. Patients experienced jaundice soon after birth and edema of
the legs
was caused by hypoplasia of the lymphatics. Liver histology showed
giant cell
transformation in infancy and some fibrosis or cirrhosis in later
childhood.
Extremely rare disorder with limited clinical studies available.
---------------------------------------------------------
LYMPHEDEMA,
MICROCEPHALY, CHORIORETINOPATHY SYNDROME
Genetics: Autosomal recessive; indication of
X-linkage.
Description: Retinal fold with microcephaly and
microphthalmos, included.
Other indications observed in this disorder include: congenital
lymphedema and/ora
delay in the maturation of the lymphatic system, lymphedema nails
(usually in the
toes), coarseness of the hair follicles over the dorsum of the hands
and feet.
While normal intelligence was the more common pattern, there also have
been unusually
high incidences of slow learning, mental retardation or attention
deficit disorder. Psychomotor development is normal.
The most extensive clinical study was involving 5 members of a Chinese
family,
involving 4 generations, giving clear indications of familial (male)
transmission (Leung 1985).
******
| MICROCEPHALY WITH CHORIORETINOPATHY |
Alternative titles; symbols
CHORIORETINAL DYSPLASIA-MICROCEPHALY-MENTAL RETARDATION SYNDROME, AUTOSOMAL DOMINANT FORMMicrocephaly
with chorioretinopathy (of a type that suggests congenital
infection) occurs as an autosomal recessive (251270);
in addition, autosomal dominant inheritance with variable expressivity
has been
reported by Alzial
et al. (1980) and by Tenconi
et al. (1981). Warburg
and Heuer (1983) presented the cases of 2 brothers and their
mother who had
the combination of microcephaly and lacunar depigmentation of the
retina.
Microcephaly was slight and the foreheads were bulging. Mental
retardation was
also mild. A 5-year follow-up demonstrated that visual function was
stable (Warburg
and Heuer, 1994). Manning
et al. (1990) reported the electroretinographic findings in
members of a
possible third family. Male-to-male transmission was observed for the
first time
in a family reported by Sadler
and Robinson (1993); also see Robinson
and Sadler (1993). A father and 2 sons were affected.
Polycystic kidney
disease was segregating in the family, apparently independently of the
microcephaly syndrome. Hordijk
et al. (1996) described a father and son with this syndrome.
In addition to
the usual manifestations, both had microcornea and overgrowth of the
conjunctiva
over the corneoscleral junction. The father had microphthalmia, and his
son was
severely mentally retarded. Microphthalmia, microcornea, and severe
mental
retardation had not been reported in other families with the autosomal
dominant
form of the syndrome.
This disorder may be identical to the lymphedema, microcephaly, chorioretinopathy syndrome (152950), an autosomal dominant trait.