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Nelson's syndrome
Nelson's syndrome is the rapid enlargement of a pituitary adenoma that occurs
after the removal of both adrenal glands
Pathophysiology:
Removal of both adrenal glands, or bilateral adrenalectomy, is
an operation for Cushing's syndrome. Removal of both adrenals eliminates production
of cortisol, and the lack of cortisol's negative feedback can allow any preexisting pituitary
adenoma to grow unchecked. Continued growth can cause mass effects due to physical
compression of brain tissue, along with increased production of adrenocorticotrophic
hormone(ACTH) and melanocyte stimulating hormone (MSH).
Clinical Presentation:
The common signs and symptoms include muscle weakness and
skin hyperpigmentation due to excess MSH. Nelson's syndrome is now rare because
bilateral adrenalectomy is now only used in extreme circumstances.
Management:
Pituitary surgery is performed in some cases. The risk can also be minimized by
pituitary irradiation.
Kallmann syndrome
Kallmann syndrome is a hypogonadism (decreased functioning of the glands that
produce sex hormones) caused by a deficiency of gonadotropin-releasing
hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also
called hypothalamic hypogonadism, familial hypogonadism with anosmia,
and hypogonadotropic hypogonadism, reflecting its disease mechanism.
Kallmann syndrome is a form of tertiary hypogonadism, reflecting that the
primary cause of the defect in sex-hormone production lies within the hypothalamus
rather than a defect of the pituitary (secondary hypogonadism), testes or ovaries (primary
hypogonadism).
Kallmann syndrome was described in 1944 by Franz Josef Kallmann, a GermanAmericangeneticist. However, others, such as the Spanish doctor Aureliano Maestre de
San Juan in 1856, had noticed a correlation between anosmia and hypogonadism.
Clinical Features:
Kallmann syndrome's characteristics:
Hypogonadotropic hypogonadism (a lack of the pituitary hormones LH and FSH)
Congenital (present from birth) anosmia (complete inability to smell) or hyposmia
(decreased ability to smell)
Normal stature
It can occasionally be associated with optic problems, such as colour blindness or
optic atrophy, nerve deafness, cleft palate,cryptorchidism, renal agenesis, and mirror
movement disorder. However, it is not clear how, if at all, these other problems have the
same cause as the hypogonadism and anosmia.
Males present with delayed puberty and may have micropenis (although
congenital micropenis is not present in most male KS cases).
Females present with delayed puberty (i.e., primary amenorrhea) and lack
of secondary sex characteristics, such as breast development.
A fraction of cases may present with post-pubertal onset, which results in a
phenotypically normal penis in men with subsequent testicular atrophy and loss of some
secondary sex traits. These men generally present with sexual impairment and low libido.
In women, late-onset Kallmann Syndrome can result in secondary
amenorrhea. Anosmia may or may not be present in these individuals.
Physical findings associated with hypogonadism include eunuchoidal skeletal
proportions.
A low ratio, less than 1:1 in adults, of the upper body segment (crown to pubis) to
the lower body segment (pubis to heels) is present only in patients with classic Kallmann
syndrome or idiopathic hypogonadotropic hypogonadism.
Similarly, an arm span greater than height by more than 5 cm is observed only in
patients with congenital Kallmann syndrome or idiopathic hypogonadotropic
hypogonadism.
Height for age is normal in these patients, distinguishing them during adolescence
from individuals with constitutional delay in growth and development because
adolescents in the latter group tend to be short for chronological age.
Absence of terminal facial hair and decreased body hair is observed in men with
Kallmann syndrome or who have congenital idiopathic hypogonadotropic hypogonadism.
Men with adult-onset idiopathic hypogonadotropic hypogonadism may report decreased
shaving frequency. In addition, lack of temporal hair recession (male-type baldness) is
noted in men with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.
High-pitched voice is present only in men with Kallmann syndrome or congenital
idiopathic hypogonadotropic hypogonadism.
Lack of breast development is observed in women with Kallmann syndrome or
congenital idiopathic hypogonadotropic hypogonadism. Women with long-standing
hypothalamic amenorrhea may experience a decrease in breast size.
Gynecomastia is observed only rarely in men with classic Kallmann syndrome or
idiopathic hypogonadotropic hypogonadism at the time of diagnosis, but it may occur as
an adverse effect of androgen replacement therapy in these patients.
Muscle mass is decreased, muscle strength is diminished, and fat is distributed
over the hips and chest, particularly in men with Kallmann syndrome or congenital
idiopathic hypogonadotropic hypogonadism.
Axillary and pubic terminal hair may be scantly present in these patients (with the
exception of patients with X-linked idiopathic hypogonadotropic hypogonadism and
AHC) because of circulating adrenal androgens. Males with Kallmann syndrome or
congenital idiopathic hypogonadotropic hypogonadism lack terminal hair growth along
the midline towards the umbilicus.
Men with Kallmann syndrome or congenital idiopathic hypogonadotropic
hypogonadism have prepubertal testes (<4 mL) and lack scrotal pigmentation.
Some patients (previously known as fertile eunuchs) experience some testicular
growth in association with partial GnRH deficiency.
Testicular volumes in patients with adult-onset idiopathic hypogonadotropic
hypogonadism are either within the normal range or mildly decreased (10-15 mL).
Cryptorchidism is present in a minority of men with classic Kallmann syndrome
or idiopathic hypogonadotropic hypogonadism.
Males with classic Kallmann syndrome or idiopathic hypogonadotropic
hypogonadism have small penises (<8 cm long in adults). In addition, prostate size is
decreased, particularly in men with classic Kallmann syndrome or idiopathic
hypogonadotropic hypogonadism.
In women, the vaginal mucosa has a deep red color because of the lack of
squamous epithelial differentiation.
All patients with Kallmann syndrome by definition have anosmia or severe
hyposmia.
Formal smell testing can be carried out by administering the Smell Identification
Test (SIT, Sensonics, Haddon Heights, NJ), which is a standardized, multiple choice test
that includes 40 scratch-and-sniff panels, each with 4 possible answers.
Alternatively, the sense of smell can be evaluated by using serial dilutions of
multiple odorants such as dimethyl sulfide, menthone, acetic acid, exaltolide, amyl
acetate, cineole, and pm-carbinol (Olfacto Laboratories, El Cerrito, Calif), according to
the protocol of Rosen and Rogol.
A small percentage of patients with Kallmann syndrome experience color
blindness, as assessed by Ishihara plate testing. In addition, sensorineural hearing loss has
been reported in some Kallmann syndrome patients.
Some patients with X-linked Kallmann syndrome and a contiguous gene
syndrome may have ichthyosis.
Cleft lip, cleft palate, or high (arched) palate has been reported in 6-22% of
patients with Kallmann syndrome. Short metacarpals and pes cavus also have been
reported in a minority of Kallmann syndrome patients.
Cardiovascular findings are present in some patients with Kallmann syndrome
who have congenital heart disease (including ASD, VSD, Ebstein anomaly, transposition
of the great vessels, right aortic arch, atrioventricular block, right bundle-branch block,
and WPW syndrome). A detailed discussion of these findings is beyond the scope of this
review.
Neuropsychiatric findings that exist in a minority of patients with Kallmann
syndrome or idiopathic hypogonadotropic hypogonadism include abnormal eye
movements (including gaze-evoked horizontal nystagmus, abnormal pursuit, and
saccades), synkinesia (mirror movements of the opposite upper extremity), paraplegia,
cerebellar ataxia, and learning disability (secondary to mental retardation). Synkinesia
has been reported only in X-linked Kallmann syndrome patients.
Conditions associated with primary adrenocortical insufficiency are present in
males with X-linked idiopathic hypogonadotropic hypogonadism and AHC. A detailed
discussion of these conditions is beyond the scope of this review.
Early-onset obesity is present in patients with idiopathic hypogonadotropic
hypogonadism and mutations of either the leptin gene or the leptin receptor gene
Sheehan's syndrome
Sheehan syndrome, also known as postpartum hypopituitarism or postpartum
pituitary necrosis, is hypopituitarism (decreased functioning of the pituitary gland),
caused by necrosisdue to blood loss and hypovolemic shock during and after childbirth.
Causes:
It is a rare complication of pregnancy, usually occurring after excessive blood
loss. The presence of disseminated intravascular coagulation(i.e., in amniotic fluid
embolism or HELLP syndrome) also appears to be a factor in its development.
Symptoms:
Most common initial symptoms of Sheehan's syndrome
are agalactorrhea (absence of lactation) and/or difficulties with lactation. Many women
also report amenorrhea or oligomenorrhea after delivery. In some cases, a woman with
Sheehan syndrome might be relatively asymptomatic, and the diagnosis is not made until
years later, with features of hypopituitarism. Such features include secondary
yhypothyroidism with tiredness, intolerance to cold, constipation, weight gain, hair
loss and slowed thinking, as well as a slowed heart rateand low blood pressure. Another
such feature is secondary adrenal insufficiency, which, in the rather chronic case is
similar to Addison's disease with symptoms including fatigue, weight
loss, hypoglycemia (low blood sugar levels), anemia and hyponatremia (low sodium
levels). Such a woman may, however, become acutely exacerbated when her body is
stressed by, for example, a severe infection or surgery years after her delivery, a
condition equivalent with an Addisonian crisis. Gonadotropin deficiency will often
cause amenorrhea, oligomenorrhea, hot flashes, or decreased libido.[1] Growth hormone
deficiency causes many vague symptoms including fatigue and decreased muscle mass.
Uncommonly, Sheehan syndrome may also appear acutely after delivery, mainly
by hyponatremia. There are several possible mechanisms by which hypopituitarism can
result in hyponatremia, including decreased free-water clearance by hypothyroidism,
direct syndrome of inappropriate antidiuretic hormone (ADH) hypersecretion, decreased
free-water clearance by glucocorticoid deficiency (independent of ADH). The potassium
level inthese situations is normal, because adrenal production of aldosterone is not
dependent on the pituitary. There have also been cases with acute hypoglycemia.
Pathophysiology:
Hypertrophy and hyperplasia of lactotrophs during pregnancy results in the
enlargement of the anterior pituitary, without a corresponding increase in blood supply.
Secondly, the anterior pituitary is supplied by a low pressure portal venous
system.
These vulnerabilities, when affected by major hemorrhage or hypotension during
the peripartum period, can result in ischaemia of the affected pituitary regions leading
to necrosis.
The posterior pituitary is usually not affected due to its direct arterial supply.
Empty sella syndrome
Empty sella syndrome is a condition in which the pituitary gland shrinks or
becomes flattened.
Causes, incidence, and risk factors:
The pituitary gland is a small gland located at the base of the brain. It sits in a
saddle-like compartment in the skull called the "sella turcica," which in Latin means
"Turkish saddle."
When the pituitary gland shrinks or becomes flattened, it cannot be seen
on MRI scans, giving the appearance of an "empty sella." This is referred to as empty
sella syndrome.
The pituitary makes several hormones that control the other glands in the body,
including the:
Adrenal glands
Ovaries
Testicles
Thyroid
Primary empty sella syndrome occurs when a hole in the membrane covering the
pituitary gland allows fluid in, which presses on the pituitary.
Secondary empty sella syndrome occurs when the sella is empty because the
pituitary gland has been damaged by:
A tumor
Radiation therapy
Surgery
Empty sella syndrome may be seen in a condition called pseudotumor cerebri.
This is a condition seen most commonly in obese women.
Symptoms
Often, there are no symptoms or loss of pituitary function.
Patients with empty sella syndrome may have symptoms caused by a partial or
complete loss of pituitary gland function. For more information, see hypopituitarism.
Symptoms include:
Erectile dysfunction (impotence)
Headaches
Irregular or absent menstruation
Low sexual desire (low libido)
Nipple discharge
Signs and tests:
Primary empty sella syndrome is most often discovered during radiological
imaging of the brain. Pituitary function is usually normal.
The health care provider may test pituitary gland function to make sure that the
gland is working normally.
Sometimes tests for high pressure in the brain will be done, such as:
Examination of the retina by an ophthalmologist
Lumbar puncture (spinal tap)
The hormone prolactin is a little high in a small percentage of patients, which may
interfere with the normal function of the testicles or ovaries.
Prognosis:
Primary empty sella syndrome does not cause health problems, and it does not
affect life expectancy.
Complications:
Complications of primary empty sella syndrome include mild hyperprolactinemia.
Complications of secondary empty sella syndrome are related to the cause of
pituitary gland disease or to the effects of too little pituitary hormone.
Forbes-Albright syndrome
Forbes-Albright syndrome is characterized by pituitary tumor in a patient without
acromegaly, which secretes excessive amounts of prolactin (PRL) and produces
persistent lactation. A pituitary adenoma which secretes PROLACTIN, leading to
HYPERPROLACTINEMIA. Clinical manifestations include AMENORRHEA;
GALACTORRHEA; IMPOTENCE; HEADACHE; visual disturbances; and
CEREBROSPINAL FLUID RHINORRHEA.
Symptoms of Forbes-Albright syndrome:
The list of signs and symptoms mentioned in various sources for Forbes-Albright
syndrome includes the 14 symptoms listed below:
Increased prolactin secretion
Enlarged pituitary gland
Galactorrhea
Absence of menstruation
Lack of ovulation
Altered pattern of body hair in females
Decreased libido
Female obesity
Oily skin
Enlarged male breasts
Milk-secreting male breasts
Impotence
Decreased sperm
Low level of gonadotropins
Complications list for Forbes-Albright syndrome:
The list of complications that have been mentioned in various sources for ForbesAlbright syndrome includes:
Dyspareunia
Optic nerve disorder
Gynaecomastia
Female infertility
Amenorrhoea
Galactorrhoea-Hyperprolactinaemia
Pituitary tumour
Diagnosis:
The diagnosis is often one of exclusion found during the workup of delayed
puberty. The presence of anosmia with delayed puberty should suggest Kallmann
syndrome.
Pathophysiology:
Under normal conditions, GnRH travels from the hypothalamus to the pituitary
gland via the hypophyseal portal system, where it triggers production and release
of gonadotropins (LH and FSH) from the gonadotropes. When GnRH is low, the pituitary
does not create the normal amount of gonadotropins. The gonadotropins normally
increase the production of gonadal steroids; so, when they are low, these steroids will be
low as well.
Kallmann syndrome
In Kallmann syndrome, the GnRH neurons do not migrate properly from
the olfactory placode to the hypothalamus during development. The olfactory bulbs also
fail to form or have hypoplasia, leading to anosmia or hyposmia.
Management:
Treatment is directed at restoring the deficient hormones—hormone therapy (HT).
Males are administered human chorionic gonadotropin(hCG) or testosterone. Females are
treated with estrogen and progestins.
Klinefelter syndrome
Klinefelter syndrome, 47, XXY, or XXY syndrome is a condition in which human
males have an extra X chromosome. While females have an XX chromosomal makeup,
and males an XY, affected individuals have at least two X chromosomes and at least
one Y chromosome. Because of the extra chromosome, individuals with the condition are
usually referred to as "XXY Males", or "47, XXY Males".
In humans, Klinefelter syndrome is the most common sex chromosome disorder
in males and the second most common condition caused by the presence of extra
chromosomes. The condition exists in roughly 1 out of every 1,000 males. One in every
500 males has an extra X chromosome but does not have the syndrome. Other mammals
also have the XXY syndrome, including mice.
The principal effects are development of small testicles and reduced fertility. A
variety of other physical and behavioral differences and problems are common, though
severity varies and many boys and men with the condition have few detectable
symptoms.
Signs and symptoms
Affected males are almost always effectively infertile, although advanced
reproductive assistance is sometimes possible. Some degree of language learning
impairment may be present, and neuropsychological testing often reveals deficits
in executive functions. In adults, possible characteristics vary widely and include little to
no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body
type with some degree of gynecomastia (increased breast tissue). Gynecomastia is present
to some extent in about a third of affected individuals, a slightly higher percentage than in
the XY population. About 10% of XXY males have gynecomastia noticeable enough that
they may choose to have cosmetic surgery.
The term hypogonadism in XXY symptoms is often misinterpreted to mean
"small testicles" or "small penis". In fact, it means decreased testicular
hormone/endocrine function. Because of this (primary) hypogonadism, individuals will
often have a low serum testosterone level but high serum follicle-stimulating
hormone (FSH) and luteinizing hormone (LH) levels. Despite this misunderstanding of
the term, however, it is true that XXY men also have microorchidism (i.e. small
testicles).
The more severe end of the spectrum of symptom expression is also associated
with an increased risk of germ cell tumors, male breast cancer, and osteoporosis, risks
shared to varying degrees with females. Additionally, medical literature shows some
individual case studies of Klinefelter syndrome coexisting with other disorders, such
as pulmonary disease, varicose veins,diabetes mellitus, and rheumatoid arthritis, but
possible correlations between Klinefelter and these other conditions are not well
characterized or understood.[citation needed]
In contrast to these potentially increased risks, it is currently thought that rare Xlinked recessiveconditions occur less frequently in XXY males than in normal XY males,
since these conditions are transmitted by genes on the X chromosome, and people with
two X chromosomes are typically onlycarriers rather than affected by these X-linked
recessive conditions.
There are many variances within the XXY population, just as in the most
common 46, XY population. While it is possible to characterise 47, XXY males with
certain body types, that in itself should not be the method of identification as to whether
or not someone has 47,XXY. The only reliable method of identification
is karyotype testing.
Diagnosis:
A karyotype is used to confirm the diagnosis. In this procedure, a small blood
sample is drawn. White blood cells are then separated from the sample, mixed with tissue
culture medium, incubated, and checked for chromosomal abnormalities, such as an extra
X chromosome.
Diagnosis can also be made prenatally via chorionic villus
sampling or amniocentesis, tests in which fetal tissue is extracted and the fetal DNA is
examined for genetic abnormalities. A 2002 literature review of elective abortion rates
found that approximately 50% of pregnancies in the United States with a diagnosis of
Klinefelter syndrome were terminated.
Cause:
The extra X chromosome is retained because of a nondisjunction event
during meiosis I(gametogenesis). Nondisjunction occurs with when homologous
chromosomes, in the case the X and Y sex chromosomes, fail to separate, producing a
sperm with an X and a Y chromosome. Fertilizing a normal (X) egg produces an XXY
offspring. The XXY chromosome arrangement is one of the most common genetic
variations from the XY karyotype, occurring in about 1 in 500 live male births.
Another mechanism for retaining the extra X chromosome is through a
nondisjunction event duringmeiosis II in the female. Nondisjunction will occur when
sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An
XX egg is produced which, when fertilized with a Y sperm, yields XXY offspring.
In mammals with more than one X chromosome, the genes on all but one X
chromosome are not expressed; this is known as X inactivation. This happens in XXY
males as well as normal XX females. However, in XXY males, a few genes located in
the pseudoautosomal regions of their X chromosomes, have corresponding genes on their
Y chromosome and are capable of being expressed. These triploid genes in XXY males
may be responsible for symptoms associated with Klinefelter syndrome.[citation needed]
Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is one of the most common
female endocrine disorders affecting approximately 5%-10% of women of reproductive
age (12–45 years old) and is thought to be one of the leading causes of female
subfertility.
The principal features are obesity, anovulation (resulting in
irregular menstruation) oramenorrhea, acne, and excessive amounts or effects
of androgenic (masculinizing) hormones. The symptoms and severity of the syndrome
vary greatly among women. While the causes are unknown, insulin resistance, diabetes,
and obesity are all strongly correlated with PCOS
Other names for this syndrome include polycystic ovarian syndrome (also PCOS),
polycystic ovary disease (PCOD), functional ovarian hyperandrogenism, Stein-Leventhal
syndrome(original name, not used in modern literature), ovarian
hyperthecosis and sclerocystic ovary syndrome.
igns and symptoms
Common symptoms of PCOS include:
Menstrual disorders - mostly oligomenorrhea or amenorrhea but other types of
menstrual disorders may also occur.
Infertility, generally resulting from chronic anovulation (lack of ovulation).
Hirsutism — symptoms of hyperandrogenism, such as acne
or hypermenorrheaApproximately three-fourths of patients with PCOS (by the diagnostic
criteria of NIH/NICHD 1990) have evidence of hyperandrogenemia.
Metabolic syndrome, characterised by central obesity, insulin resistance and other
symptoms.
PCOS can present in any age during the reproductive years. Due to its often vague
presentation it can take years to reach a diagnosis.
Serum insulin, insulin resistance and homocysteine levels are significantly higher
in subjects having PCOS.
Diagnosis:
Not all women with PCOS have polycystic ovaries (PCO), nor do all women with
ovarian cysts have PCOS; although a pelvic ultrasound is a major diagnostic tool, it is not
the only one. The diagnosis is straightforward using the Rotterdam criteria, even when
the syndrome is associated with a wide range of symptoms.
Standard diagnostic assessments:
History-taking, specifically for menstrual pattern, obesity, hirsutism, and the
absence of breast development. A clinical prediction rulefound that these four questions
can diagnose PCOS with a sensitivity of 77.1% (95% confidence interval [CI] 62.7%–
88.0%) and aspecificity of 93.8% (95% CI 82.8%–98.7%).
Gynecologic ultrasonography, specifically looking for small ovarian follicles.
These are believed to be the result of disturbed ovarian function with failed ovulation,
reflected by the infrequent or absent menstruation that is typical of the condition. In
normal menstrual cycle, one egg is released from a dominant follicle - essentially a cyst
that bursts to release the egg. After ovulation the follicle remnant is transformed into
a progesterone producing corpus luteum, which shrinks and disappears after
approximately 12–14 days. In PCOS, there is a so called "follicular arrest", i.e., several
follicles develop to a size of 5–7 mm, but not further. No single follicle reach the
preovulatory size (16 mm or more). According to the Rotterdam criteria, 12 or more
small follicles should be seen in an ovary on ultrasound examination. The follicles may
be oriented in the periphery, giving the appearance of a 'string of pearls'. The numerous
follicles contribute to the increased size of the ovaries, that is, 1.5 to 3 times larger than
normal.
Laparoscopic examination may reveal a thickened, smooth, pearl-white outer
surface of the ovary. (This would usually be an incidental finding if laparoscopy were
performed for some other reason, as it would not be routine to examine the ovaries in this
way to confirm a diagnosis of PCOS).
Serum (blood) levels of androgens (male hormones),
including androstenedione, testosterone and Dehydroepiandrosterone sulfate may be
elevated. The free testosterone level is thought to be the best measure, with ~60% of
PCOS patients demonstrating supranormal levels. The Free androgen index of the ratio of
testosterone to sex hormone-binding globulin (SHBG) is high, is meant to be a predictor
of free testosterone, but is a poor parameter for this and is no better than testosterone
alone as a marker for PCOS, possibly because FAI is correlated with the degree of
obesity.
Some other blood tests are suggestive but not diagnostic. The ratio of LH
(Luteinizing hormone) to FSH (Follicle stimulating hormone) is greater than 1:1, as
tested on Day 3 of the menstrual cycle. The pattern is not very specific and was present in
less than 50% in one study. There are often low levels of sex hormone binding globulin,
particularly among obese women.
Fasting insulin level or GTT with insulin levels (also called IGTT). Elevated
insulin levels have been helpful to predict response to medication and may indicate
women who will need higher dosages of metformin or the use of a second medication to
significantly lower insulin levels. Elevated blood sugar and insulin values do not predict
who responds to an insulin-lowering medication, low-glycemic diet, and exercise. Many
women with normal levels may benefit from combination therapy. A hypoglycemic
response in which the two-hour insulin level is higher and the blood sugar lower than
fasting is consistent with insulin resistance. A mathematical derivation known as the
HOMAI, calculated from the fasting values in glucose and insulin concentrations, allows
a direct and moderately accurate measure of insulin sensitivity (glucose-level x insulinlevel/22.5).
Glucose tolerance testing (GTT) instead of fasting glucose can increase diagnosis
of increased glucose tolerance and frank diabetes among patients with PCOS according to
a prospective controlled trial. While fasting glucose levels may remain within normal
limits, oral glucose tests revealed that up to 38% of asymptomatic women with PCOS
(versus 8.5% in the general population) actually had impaired glucose tolerance, 7.5% of
those with frank diabetes according to ADA guidelines.
Pathogenesis:
Polycystic ovaries develop when the ovaries are stimulated to produce excessive
amounts of male hormones (androgens), particularly testosterone, either through the
release of excessive luteinizing hormone (LH) by the anterior pituitary gland or through
high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries are
sensitive to this stimulus.
The syndrome acquired its most widely used name due to the common sign on
ultrasound examination of multiple (poly) ovarian cysts. These "cysts" are actually
immature follicles, not cysts ("polyfollicular ovary syndrome" would have been a more
accurate name). The follicles have developed from primordial follicles, but the
development has stopped ("arrested") at an early antral stage due to the disturbed ovarian
function. The follicles may be oriented along the ovarian periphery, appearing as a 'string
of pearls' on ultrasound examination. The condition was first described in 1935 by Dr.
Stein and Dr. Leventhal, hence its original name of Stein-Leventhal syndrome.
A majority of patients with PCOS have insulin resistance and/or are obese. Their
elevated insulin levels contribute to or cause the abnormalities seen in the hypothalamicpituitary-ovarian axis that lead to PCOS.
PCOS is characterized by a complex set of symptoms, and the cause cannot be
determined for all patients. In many cases it is characterised by a complex positive
feedback loop of insulin resistance and hyperandrogensim. In most cases it can not be
determined which (if any) of those two should be regarded causative. Experimental
treatment with either antiandrogens or insulin sensitizing agents improves both
hyperandrogenism and insulin resistance. PCOS is also likely to have a genetic
predisposition, and further research into this possibility is taking place. A few specific
genetic defects are known accounting only for a small fraction of cases, the rest may be
due to the combination of several factors.
Adipose tissue possesses aromatase, an enzyme that converts androstenedione to
estrone and testosterone to estradiol. The excess of adipose tissue in obese patients
creates the paradox of having both excess androgens (which are responsible for hirsutism
and virilization) and estrogens (which inhibits FSH via negative feedback).[18]
Hyperinsulinemia increases GnRH pulse frequency, LH over FSH dominance,
increased ovarian androgen production, decreased follicular maturation, and
decreased SHBG binding; all these steps contribute to the development of PCOS. Insulin
resistance is a common finding among patients of normal weight as well as those
overweight patients.
PCOS may be associated with chronic inflammation, with several investigators
correlating inflammatory mediators with anovulation and other PCOS symptoms.[19][20]
One study in the United Kingdom concluded that the risk of PCOS development
was shown to be higher in lesbian women than in heterosexuals. It should be noted
however that all the participants in this study were referred after infertility was
discovered or highly suspected and conclusion made is purely conjecture. Until further
studies have been conducted and the research collaborated there is no assumption that
female homosexuality will increase the occurrence of PCOS.
It has previously been suggested that the excessive androgen production in PCOS
could be caused by a decreased serum level of IGFBP-1, in turn increasing the level of
free IGF-I which stimulates ovarian androgen production., but recent data concludes this
mechanism to be unlikely.
Management:
Medical treatment of PCOS is tailored to the patient's goals. Broadly, these may
be considered under four categories:
Lowering of insulin levels
Restoration of fertility
Treatment of hirsutism or acne
Restoration of regular menstruation, and prevention of endometrial hyperplasia
and endometrial cancer
Prognosis:
Women with PCOS are at risk for the following:
Endometrial hyperplasia and endometrial cancer (cancer of the uterine lining) are
possible, due to overaccumulation of uterine lining, and also lack
of progesterone resulting in prolonged stimulation of uterine cells by estrogen. It is not
clear if this risk is directly due to the syndrome or from the associated
obesity, hyperinsulinemia, and hyperandrogenism
Insulin resistance/Type II diabetes. A review published in 2010 concluded that
women with PCOS had an elevated prevalence of insulin resistance and type II diabetes,
also when controlling for body mass index (BMI).
High blood pressure
Depression/Depression with Anxiety
Dyslipidemia - disorders of lipid metabolism — cholesterol and triglycerides.
PCOS patients show decreased removal of atherosclerosis-inducing remnants, seemingly
independent on insulin resistance/Type II diabetes.
Cardiovascular disease
Strokes
Weight gain
Miscarriage
Acanthosis nigricans (patches of darkened skin under the arms, in the groin area,
on the back of the neck)
Autoimmune thyroiditis
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the
blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce
cortisol oradrenocorticotropic hormone (ACTH) or CRH.
Cushing's disease refers to one specific cause of the syndrome, a tumor (adenoma)
in thepituitary gland that produces large amounts of ACTH, which in turn elevates
cortisol. It is the most common cause of Cushing's syndrome, responsible for 70% of
cases
This pathology was described by Harvey Cushing in 1932. The syndrome is also
called Itsenko-Cushing syndrome, hyperadrenocorticism or hypercorticism)
Cushing's syndrome is not confined to humans and is also a relatively common
condition in domestic dogs and horses.
Signs and symptoms:
Symptoms include rapid weight gain, particularly of the trunk and face with
sparing of the limbs (central obesity). A common sign is the growth of fat pads along the
collar bone and on the back of the neck (buffalo hump) and a round face often referred to
as a "moon face". Other symptoms include hyperhidrosis (excess
sweating), telangiectasia (dilation of capillaries), thinning of the skin (which causes easy
bruising and dryness, particularly the hands) and other mucous membranes, purple or
red striae (the weight gain in Cushing's syndrome stretches the skin, which is thin and
weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts,
proximal muscle weakness (hips, shoulders), and hirsutism (facial male-pattern hair
growth), baldness and/or cause hair to become extremely dry and brittle. In rare cases,
Cushing's can cause hypercalcemia, which can lead to skin necrosis. The excess cortisol
may also affect other endocrine systems and cause, for example, insomnia,
inhibited aromatase,
reduced libido, impotence, amenorrhoea/oligomenorrhea and infertility due to elevations
inandrogens. Patients frequently suffer various psychological disturbances, ranging
from euphoria to psychosis. Depression and anxiety are also common.
Other striking and distressing skin changes that may appear in Cushing's
syndrome include facial acne, susceptibility to
superficialdermatophyte and malassezia infections, and the characteristic purplish,
atrophic striae on the abdomen.:500
Other signs include polyuria (and accompanying polydipsia),
persistent hypertension (due to cortisol's enhancement of epinephrine's vasoconstrictive
effect) and insulin resistance (especially common in ectopic ACTH production), leading
to hyperglycemia (high blood sugar) and insulin resistance which can lead to diabetes
mellitus. Insulin resistance is accompanied by skin changes such as acanthosis
nigricansin the axilla and around the neck, as well as skin tags in the axilla. Untreated
Cushing's syndrome can lead to heart disease and increasedmortality. Cushing's
syndrome due to excess ACTH may also result in hyperpigmentation,This is due to
Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from
Pro-opiomelanocortin (POMC). Cortisol can also exhibit mineralcorticoid activity in high
concentrations, worsening the hypertension and leading to hypokalemia (common in
ectopic ACTH secretion). Furthermore, gastrointestinaldisturbances, opportunistic
infections and impaired wound healing (cortisol is a stress hormone, so it depresses the
immune and inflammatory responses). Osteoporosis is also an issue in Cushing's
syndrome since, as mentioned before, cortisol evokes a stress-like response.
Consequently, the body's maintenance of bone (and other tissues) becomes secondary to
maintenance of the false stress response. Additionally, Cushing's may cause sore and
aching joints, particularly in the hip, shoulders, and lower back.
Cause:
There are several possible causes of Cushing's syndrome.
Exogenous vs. endogenous
Hormones that come from outside the body are called exogenous; hormones that
come from within the body are called endogenous.
The most common cause of Cushing's syndrome is exogenous administration
of glucocorticoids prescribed by a health care practitioner to treat other diseases
(called iatrogenic Cushing's syndrome). This can be an effect of steroid treatment of a
variety of disorders such asasthma and rheumatoid arthritis, or
in immunosuppression after an organ transplant. Administration of synthetic ACTH is
also possible, but ACTH is less often prescribed due to cost and lesser utility. Although
rare, Cushing's syndrome can also be due to the use of medroxyprogesterone.
Endogenous Cushing's syndrome results from some derangement of the body's
own system of secreting cortisol. Normally, ACTH is released from the pituitary
gland when necessary to stimulate the release of cortisol from the adrenal glands.
(Exogenous Cushing’s syndrome)
In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also
known as Cushing's disease and is responsible for 70% of endogenous Cushing's
syndrome.
In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors,
hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia.
Finally, tumors outside the normal pituitary-adrenal system can produce ACTH
that affects the adrenal glands. This final etiology is
calledectopic or paraneoplastic Cushing's syndrome and is seen in diseases like small
cell lung cancer.
Pseudo-cushing's syndrome
Elevated levels of total cortisol can also be due to estrogen found in oral
contraceptive pills that contain a mixture of estrogen and progesterone. Estrogen can
cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to
be elevated. However, the total free cortisol, which is the active hormone in the body, as
measured by a 24 hour urine collection for urinary free cortisol, is normal.
Pathophysiology:
The hypothalamus is in the brain and the pituitary gland sits just below it. The
paraventricular nucleus (PVN) of the hypothalamus releasescorticotropin-releasing
hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin
(ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release
of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called
thezona fasciculata in response to ACTH. Elevated levels of cortisol exert negative
feedback on the pituitary, which decreases the amount of ACTH released from the
pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol of any etiology.
One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of
the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and
negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be
very low. Cushing's disease refers only to hypercortisolism secondary to excess
production of ACTH from a corticotrophic pituitary adenoma. This causes the blood
ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels
remain high because a tumor causes the pituitary to be unresponsive to negative feedback
from high cortisol levels.
Cushing's Syndrome was also the first autoimmune disease identified in humans.
Diagnosis:
When Cushing's syndrome is suspected, either a dexamethasone suppression
test (administration of dexamethasone and frequent determination of cortisol and ACTH
level), or a 24-hour urinary measurement for cortisol offer equal detection rates.
Dexamethasone is aglucocorticoid and simulates the effects of cortisol,
including negative feedback on the pituitary gland. When dexamethasone is administered
and a blood sample is tested, high cortisol would be indicative of Cushing's syndrome
because there is an ectopic source of cortisol or ACTH (e.g.: adrenal adenoma) that is not
inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is
sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late night
levels of salivary cortisol are high in Cushingoid patients. Other pituitary hormone levels
may need to be ascertained. Performing a physical examination to determine any visual
field defect may be necessary if a pituitary lesion is suspected, which may compress
the optic chiasm causing typical bitemporal hemianopia.
When any of these tests are positive, CT scanning of the adrenal gland
and MRI of the pituitary gland are performed to detect the presence of any adrenal or
pituitary adenomas or incidentalomas (the incidental discovery of harmless
lesions). Scintigraphy of the adrenal gland withiodocholesterol scan is occasionally
necessary. Very rarely, determining the ACTH levels in various veins in the body by
venous catheterization, working towards the pituitary (petrosal sinus sampling) is
necessary.
Mnemonic
C - Central obesity, Cervical fat pads, Collagen fibre weakness, Comedones (acne)
U - Urinary free cortisol and glucose increase
S - Striae, Suppressed immunity
H - Hypercortisolism, Hypertension, Hyperglycaemia, Hirsutism
I - Iatrogenic (Increased administration of corticosteroids)
N - Noniatrogenic (Neoplasms)
G - Glucose intolerance, Growth retardation
Wolfram syndrome
Wolfram syndrome also called DIDMOAD
(Diabetes Insipidus, Diabetes Mellitus, OpticAtrophy, and Deafness), is a rare genetic
disorder, causing diabetes mellitus, optic atrophy, anddeafness as well as various other
possible disorders.
Causes:
It is thought to be caused by both a malfunction of the mitochondria and
of myelination, the latter in effect similar to multiple sclerosis. It may have autosomal
recessive or dominant or mitochondrial inheritance depending on the genes involved.
Three genetic forms have been described: Wolfram Syndrome 1 (WFS1),
Wolfram Syndrome 2 (WFS2)[5] and a possible mitochondrial syndrome.
WFS1
The WFS1 or wolframin gene provides instructions for making the wolframin
protein. The WFS1 gene is active in cells throughout the body, with strong activity in the
heart, brain, lungs, inner ear, and pancreas. The pancreas provides enzymes that help
digest food, and it also produces the hormone insulin. Insulin controls how much glucose
(a type of sugar) is passed from the blood into cells for conversion to energy.
Other disorders - caused by mutations in the WFS1 gene
Mutations in the WFS1 gene cause Wolfram syndrome, which is also known by
the acronym DIDMOAD. This syndrome is characterised by childhood-onset diabetes
mellitus (DM), which results from the improper control of glucose due to the lack of
insulin; a gradual loss of vision caused by optic atrophy (OA), in which the nerve that
connects the eye to the brain wastes away; and deafness (D). This syndrome can
sometimes cause diabetes insipidus (DI), a condition in which the kidneys cannot
conserve water. Other complications that affect the bladder and nervous system may also
occur.
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Introduction
The serum sodium concentration is regulated by the balance of water intake, renal
filtration and reabsorption of sodium, and antidiuretic hormone (ADH) – mediated water
conservation by the collecting duct. Water balance is normally mediated by thirst, the
secretion of antidiuretic hormone (also known as vasopressin), the feedback mechanisms
of the renin-angiotensin-aldosterone system, and renal handling of filtered sodium and
water. Disorders in any one of these components of sodium balance can result in
hyponatremia.
ADH is secreted by supraoptic and paraventricular nuclei in the hypothalamus
and transmitted via the neuronal axons to the posterior pituitary where it is secreted. It is
released when a decrease in the effective circulatory volume is sensed by vascular
baroreceptors primarily located in the large arterial vessels. The key action of ADH in the
kidney is to trigger the insertion of aquaporin-2 into the principal cells of the collecting
duct. Aquaporins' selective permeability allows water reabsorption and consequently
urine concentration.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was
initially described by Leaf and Mamby. They demonstrated a direct relationship between
excessive vasopressin and fall in serum sodium concentration without any change in
urine osmolality or flow rate.
Pathophysiology:
The key to the pathophysiology, signs, symptoms, and treatment of SIADH is to
understand that the hyponatremiais a result of excess water and not a serum sodium
deficiency. SIADH consists of hyponatremia, inappropriately elevated urine osmolality
(>200 mOsm/kg), excessive urine sodium (UNa >30 mEq/L), and decreased serum
osmolality. These findings occur in the absence of diuretic therapy; in the presence of
euvolemia without edema; in the setting of otherwise normal cardiac, renal, adrenal,
hepatic, and thyroid function; and in absence of factors known to stimulate ADH
secretion such as severe pain, hypotension, and stress.
In SIADH, the inappropriately elevated level of vasopressin enhances the
reabsorption of water, thus concentrating the urine. It is the excess free water absorption
that causes hyponatremia.
Two scenarios can occur in which vasopressin secretion will be not be correlated with the
serum osmolality. First, a decrease in the effective circulatory volume may be falsely
sensed by the large arterial baroreceptors in conditions such as cirrhosis, nephrotic
syndrome, and congestive heart failure. In these cases, the stimulus for ADH secretion
overrides osmotic signals, which are conveying a hypoosmotic state. ADH secretion
ensues despite hypoosmolality resulting in hyponatremia. In contrast to patients with
SIADH, these patients appear hypervolemic.
Second, inappropriate ADH secretion occurs when there is dysregulation of cells
secreting vasopressin or in the feedback mechanisms responsible for its release. A variety
of ADH-secreting tumors both inside and outside the pituitary have been associated with
SIADH, as well as certain CNS disorders, pulmonary disorders, and medications
(see Differentials).
A distinction should be made between the SIADH and the clinical syndrome of
euvolemic hyponatremia. A mutation of the ADH receptor can make it more responsive
to ADH and can result in the same clinical picture of hyponatremia, concentrated urine
output, and decreased serum osmolality but with normal ADH secretion.
Clinical Findings:
In general, increased ADH causes water retention and extracellular fluid volume
expansion without edema or hypertension, owing tonatriuresis (the excretion of sodium
by the kidneys). The water retention and sodium loss both cause hyponatremia, which is a
key feature in SIADH. Hyponatremia and concentrated urine (UOsm >300 mOsm) are
seen, as well as no signs of edema or dehydration. When hyponatremia is severe (sodium
<120 mOsm), or acute in onset, symptoms of cerebral edema become prominent
(irritability, confusion, seizures, and coma).
Diagnosis:
Laboratory findings in diagnosis of SIADH includeHyponatremia <135 mEq/L, and POsm <270 mOsm/kg. Hyponatremia is often
treated pharmaceutically through the use of vasopressin receptor antagonists, which
include the phase III drug lixivaptan.
Other findings includeUrine sodium concentration >20 mEq/L (inappropriate natriuresis). Urine sodium
concentration may be normal reflecting dietary intake.
Maintained hypervolemia
Suppression of renin-angiotensin system
No equal concentration of atrial natriuretic peptide
Low blood urea nitrogen (BUN)
Normal serum creatinine
Low uric acid
Low albumin
Normal Acid-Base, K+ balance
Normal Adrenal, Thyroid function
Causes:
Some common causes of SIADH include:
Meningitis
Head injury
Subarachnoid hemorrhage
Cancers
Lung cancer (especially small-cell lung cancer, as well as other small-cell
malignancies of other organs)
Infections
Brain abscess
Pneumonia
Lung abscess
Drugs
Chlorpropamide
Clofibrate
Phenothiazine
Cyclophosphamide
Carbamazepine
Selective serotonin reuptake inhibitors (SSRIs, a class of antidepressants)
Methylenedioxymethamphetamine (MDMA, commonly called Ecstasy. SIADH
due to taking ecstasy was cited as a factor in the death of Leah Betts)
Oxytocin
Vincristine
Hypothyroidism
Management:
Management of SIADH includes:
Treating underlying causes when possible.
Long-term fluid restriction of 1,200–1,800 mL/day[2] to increase serum sodium.
Intravenous saline - For very symptomatic patients (severe confusion,
convulsions, or coma) hypertonic saline (5%) 200-300 ml IV in 3-4 h should be given.
Drugs
Conn Syndrome
Introduction:
Conn syndrome is characterized by increased aldosterone secretion from the
adrenal glands, suppressed plasma renin activity (PRA), hypertension, and hypokalemia.
It was first described in 1955 by JW Conn in a patient who, as in the image below, had an
aldosterone-producing adenoma (ie, Conn syndrome). Later, many other cases of adrenal
hyperplasia with increased aldosterone secretion were described, and now the term
primary hyperaldosteronism is used to describe Conn syndrome and other etiologies of
primary hypersecretion of aldosterone (eg, adrenal hyperplasia). Currently, primary
hyperaldosteronism, especially Conn syndrome, seems to be the most common form of
secondary hypertension.
Primary hyperaldosteronism has many causes, including adrenal hyperplasia and
adrenalcarcinoma. When it occurs due to a solitary aldosterone-secreting adrenal
adenoma (a type of benign tumor), it is known as Conn's syndrome. In practice, however,
the terms are often used interchangeably, regardless of the underlying physiology.
Conn's syndrome is an Aldosterone-Producing Adenoma (APA).
Causes:
The syndrome is due to:
bilateral idiopathic adrenal hyperplasia 70 %
unilateral idiopathic adrenal hyperplasia 20 %
aldosterone-secreting adrenal adenoma (benign tumor, < 5%)
rare forms, including disorders of the renin-angiotensin system
Signs, symptoms and findings:
Aldosterone enhances exchange of sodium for potassium in the kidney so
increased aldosteronism will lead to hypernatremia andhypokalemia. Once the potassium
has been significantly reduced by aldosterone, a sodium/hydrogen pump in
the nephron becomes more active leading to increased excretion of hydrogen ions and
further exacerbating the hypernatremia. The hydrogen ions that are exchanged for sodium
are generated by carbonic anhydrase in the renal tubule epithelium causing increased
production of bicarbonate. The increased bicarbonate and the excreted hydrogen combine
to generate a metabolic alkalosis. The high pH of the blood makes calcium less available
to the tissues and causes symptoms of hypocalcemia (low calcium levels).
The sodium retention leads to plasma volume expansion and elevated blood
pressure. The increased blood pressure will lead to increasedglomerular filtration rate and
cause a decrease in renin release from the granular cells of the juxtaglomerular
apparatus in the kidney. If there is a primary hyperaldosteronism the decreased renin (and
subsequent decreased angiotensin II) will not lead to a decrease in aldosterone levels (a
very helpful clinical tool in diagnosis of primary hyperaldosteronism).
Aside from high blood pressure manifestations of muscle cramps (due to
hyperexcitability of neurons secondary to hypocalcemia), muscle weakness (due to
hypoexcitability of skeletal muscles secondary to hypokalemia), and headaches (due to
hypokalemia or high blood pressure) may be seen.
Secondary hyperaldosteronism is often related to decreased cardiac output which
is associated with elevated renin levels.
Diagnosis:
Measuring aldosterone alone is not considered adequate to diagnose primary
hyperaldosteronism. Rather, both renin and aldosterone are measured, and the ratio is
diagnostic.
Usually, renin levels are suppressed, leading to a very low renin-aldosterone ratio
(<0.0005). This test is confounded by antihypertensive drugs, which have to be stopped
up to 6 weeks.
If plasma levels of renin and aldosterone suggest hyperaldosteronism, CT
scanning can confirm the presence of an adrenal adenoma. If the clinical presentation
primarily involves hypertension and elevated levels of catecholamines, CT or MRI
scanning can confirm a tumor on the adrenal medulla, typically an aldosteronoma.
Hyperaldosteronism can be mimicked by Liddle syndrome, and by ingestion
of licorice and other foods containing glycyrrhizin. In one case report, hypertension
and quadriparesis resulted from intoxication with a non-alcoholic pastis (an aniseflavored aperitif containingglycyrrhizinic acid).
Shy-Drager syndrome
Also called as Neurologic orthostatic hypotension; Shy-McGee-Drager syndrome;
Parkinson's plus syndrome; MSA-P; MSA-C, Multiple system atrophy
Multiple system atrophy (MSA) is a rare condition that causes symptoms similar
to Parkinson's disease. However, patients with MSA have more widespread damage to
the part of the nervous system that controls important functions such as heart rate, blood
pressure, and sweating.
Causes, incidence, and risk factors:
The cause is unknown. MSA develops gradually and is most often diagnosed in
men older than 60.
Symptoms:
MSA damages the nervous system, which can cause the following symptoms:
Changes in facial expression
"Mask" appearance to face
May be unable to close mouth
Reduced ability to show facial expressions
Staring
Difficulty chewing or swallowing (occasionally)
Disrupted sleep patterns (especially during rapid eye movement (REM) sleep late
at night)
Dizziness or fainting when standing up or after standing still
Frequent falls
Impotence
Loss of control over bowels or bladder
Loss of fine motor skills
Difficulty eating
Difficulty with any activity that requires small movements
Writing that is small and hard to read
Loss of sweating in any part of the body
Mild decline in mental function (may occur)
Movement difficulties
Loss of balance
Shuffling
Walking pattern (gait) changes
Muscle aches and pains (myalgia)
Muscle rigidity
Difficulty bending arms or legs
Stiffness
Nausea and problems with digestion
Posture difficulties: may be unstable, stooped, or slumped over
Slow movements
Difficulty beginning to walk or starting any voluntary movement
Freezing of movement when the movement is stopped, unable to start moving
again
Small steps followed by the need to run to keep balance
Tremors
May become severe enough to interfere with activities
May be worse when tired, excited, or stressed
May occur at rest or at any time
May occur with any action, such as holding a cup or other eating utensils
Finger-thumb rubbing (pill rolling tremor)
Vision changes, decreased or blurred vision
Voice and speech changes
Difficulty speaking
Monotone
Slow speaking
Voice is low volume
Other symptoms that may occur with this disease:
Confusion
Dementia
Depression
Sleep-related breathing difficulties, especially sleep apnea or a blockage in the air
passage that leads to a harsh vibrating sound
Signs and tests:
The health care provider may perform the following:
Blood pressure measurement, lying and standing
Eye examination
Nerve and muscle (neuromuscular) examination
There are no specific tests to confirm this disease. A neurologist can make the
diagnosis based on:
History of symptoms
Findings during a physical examination
Ruling out other causes of symptoms
Testing to help confirm the diagnosis may include:
MRI of head
Plasma norepinephrine levels
Urine examination for norepinephrine breakdown products (urine catecholamines)
Prognosis:
The outcome is poor. Loss of mental and physical functions slowly get worse. .
Early death is likely. The typical survival time from the time of diagnosis is 7 to 9 years.
Complications:
Progressive loss of ability to walk or care for self
Difficulty performing daily activities
Injuries from falls/fainting
Side effects of medications
Milk-alkali syndrome
Milk-alkali syndrome is an acquired condition in which there are high levels of
calcium (hypercalcemia) and a shift in the body's acid/base balance towards alkaline
(metabolic alkalosis).
Causes, incidence, and risk factors:
Milk-alkali syndrome is caused by excessive consumption of milk (which is high
in calcium) and certain antacids, especially calcium carbonate or sodium
bicarbonate (baking soda), over a long period of time.
Calcium deposits in the kidneys and in other tissues can occur in milk-alkali
syndrome. Consumption of excessive amounts of vitamin D, which is usually added to
milk bought at the supermarket, can worsen this condition.
In the past, milk-alkali syndrome was often a side effect of treating peptic
ulcer disease with antacids containing calcium. It is rarely seen today, because newer,
better medications are available for treating ulcers. A more common scenario today is
when someone takes too much calcium carbonate in an attempt to prevent osteoporosis.
This syndrome has been reported in persons who take as little as 2 grams of calcium per
day.
Symptoms:
The condition usually has no symptoms (asymptomatic). When symptoms do
occur, they are often related to complications, such as kidney problems.
Symptoms include:
Back, middle of the body, and loin pain (related to kidney stones)
Excessive urination
Fatigue
Nausea
Other problems that can result from kidney failure
Signs and tests:
Calcium deposits within the tissue of the kidney (nephrocalcinosis) may be seen
on:
X-rays
Computed tomography (CT scans)
Ultrasound
Other tests used to make a diagnosis:
Electrolyte levels
Kidney function blood tests
Blood gas
Blood calcium level
Treatment
Treatment involves reducing or eliminating milk and other forms of calcium such
as in antacids. If severe kidney failure has occurred, the damage may be permanent.
Expectations (prognosis)
This condition is often reversible if kidney function remains normal. Severe
prolonged cases may lead to permanent kidney failure requiring dialysis.
Complications
The most common complications include:
Calcium deposits in tissues (calcinosis)
Kidney failure
Kidney stones
Kearns–Sayre syndrome
Kearns–Sayre syndrome (abbreviated KSS) also known as oculocraniosomatic
disease orOculocraniosomatic neuromuscular disease with ragged red fibers is
a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more
severe syndromic variant of chronic progressive external ophthalmoplegia (abbreviated
CPEO), a syndrome that is characterized by isolated involvement of the muscles
controlling eyelid movement (levator palpebrae, orbicularis oculi), and those controlling
eye movement (extra-ocular muscles). This results in ptosis and ophthalmoplegia
respectively. KSS involves a triad of the already described CPEO, as well as bilateral
pigmentary retinopathy, and cardiac conduction abnormalities. Other areas of
involvement can include cerebellar ataxia, proximal muscle weakness, deafness,diabetes
mellitus, growth hormone deficiency, hypoparathyroidism, or other endocrinopathies. In
both of these diseases, muscle involvement may begin unilateral but always develops into
a bilateral deficit, and the course is progressive.
Signs and Symptoms:
Individuals with KSS present initially in a similar way to those with typical
CPEO. Onset is in the first and second decades of life. The first symptom of this disease
is a unilateral ptosis, or difficulty opening the eyelids, that gradually progresses to a
bilateral ptosis. As the ptosis worsens, the individual commonly extends their neck,
elevating their chin in an attempt to prevent the eyelids from occluding the visual axis.
Along with the insidious development of ptosis, eye movements eventually become
limited causing a person to rely more on turning the head side to side or up and down to
view objects in the peripheral visual field. Pigmentary retinopathy: KSS results in a
pigmentation of theretina, primarily in the posterior fundus. The appearance is described
as a "salt-and-pepper" appearance. There is diffuse depigmentation of the retinal pigment
epithelium with the greatest effect occurring at the macula. This is in contrast to retinitis
pigmentosa where the pigmentation is peripheral. The appearance of the retina in KSS is
similar to that seen in myotonic dystrophy type 1 (abbreviated DM1). Modest nightblindness can be seen in patients with KSS. Visual acuity loss is usually mild and only
occurs in 40-50% of patients. Cardiac conduction abnormalities: most often occurs years
after the development of ptosis and ophthalmoplegia. Atrioventricular(abbreviated "AV")
block is the most common cardiac conduction deficit. This often progresses to a Thirddegree atrioventricular block, which is a complete blockage of the electrical conduction
from the atrium to the ventrical. Symptoms of heart block include syncope, exercise
intolerance, and bradycardia.Other: As characterized in Kearns' original publication in
1965 and in later publications, inconsistent features of KSS that may occur are weakness
of facial, pharyngeal, trunk, and extremity muscles, hearing loss, small stature,
electroencephalographic changes, cerebellar ataxia and elevated levels of cerebrospinal
fluid protein.
Genetics:
KSS is the result of deletions in mitochondrial DNA (mtDNA) that cause a
particular phenotype. mtDNA is transmitted exclusively from the mother's
ovum. Mitochondrial DNA is composed of 37 genes found in the single
circular chromosome measuring 16,569 base pairs in length. Among these, 13 genes
encode proteins of the electron transport chain (abbreviated "ETC"), 22 encode transfer
RNA (tRNA), and two encode the large and small subunits that form ribosomal
RNA (rRNA). The 13 proteins involved in the ETC of the mitochondrion are necessary
for oxidative phosphorylation. Mutations in these proteins results in impaired energy
production by mitochondria. This cellular energy deficit manifests most readily in tissues
that rely heavily upon aerobic metabolism such as the brain, skeletal and cardiac muscles,
sensory organs, and kidneys. This is one factor involved in the presentation of
mitochondrial diseases.
There are other factors involved in the manifestation of a mitochondrial disease besides
the size and location of a mutation. Mitochondria replicate during each cell division
during gestation and throughout life. Because the mutation in mitochondrial disease most
often occurs early in gestation in these diseases and only occurs in one parent
mitochondria, only those mitochondria in the mutated lineage are defective. This results
in an uneven distribution of dysfunctional mitochondria within each cell, and among
different tissues of the body. This describes the term heteroplasmic which is
characteristic of mitochondrial diseases including KSS. The distribution of mutated
mtDNA in each cell, tissue, and organ, is dependent on when and where the mutation
occurs. This may explain why two patients with an identical mutation in mtDNA can
present with entirely different phenotypes and in turn different syndromes. A publication
in 1992 by Fischel-Ghodsian et al. identified the same 4,977-bp deletion in mtDNA in
two patients presenting with two entirely different diseases. One of the patients had
characteristic KSS, while the other patient had a very different disease known as Pearson
marrow pancreas syndrome. Complicating the matter, in some cases Pearson's syndrome
has been shown to progress into KSS later in life
Prader–Willi syndrome
Prader–Willi syndrome (abbreviated PWS) is a rare genetic disorder in which
seven genes (or some subset thereof) on chromosome 15 (q 11-13) are deleted or
unexpressed (chromosome 15q partial deletion) on the paternal chromosome.
The incidence of PWS is between 1 in 25,000 and 1 in 10,000 live births. The
paternal origin of the genetic material that is affected in the syndrome is important
because the particular region of chromosome 15 involved is subject to parent of
origin imprinting, meaning that for a number of genes in this region only one copy of the
gene is expressed while the other is silenced through imprinting. For the genes affected in
PWS it is the paternal copy that is usually expressed, while the maternal copy is silenced.
This means that while most people have a single working copy of these genes, people
with PWS have no working copy. PWS has the sister syndrome Angelman syndrome in
which maternally derived genetic material is affected in the same genetic region.
Clinical features and signs:
In utero:
Reduced fetal movement
Frequent abnormal fetal position
Occasional polyhydramnios (excessive amniotic fluid)
At birth:
Often breech or caesarean births
Lethargy
Hypotonia
Feeding difficulties (due to poor muscle tone affecting sucking reflex)
Difficulties establishing respiration
Hypogonadism
Infancy:
Failure to thrive (continued feeding difficulties)
Delayed milestones/intellectual delay
Excessive sleeping
Strabismus
Scoliosis (often not detected at birth)
Childhood:
Speech delay
Poor physical coordination
Hyperphagia (over-eating) from age 2 – 8 years. Note change from feeding
difficulties in infancy
Excessive weight gain
Sleep disorders
Scoliosis
Adolescence:
Delayed puberty
Short stature
Obesity
Extreme flexibility
Adulthood:
Infertility (males and females)
Hypogonadism
Sparse pubic hair
Obesity
Hypotonia
Learning disabilities/borderline intellectual functioning (but some cases of
average intelligence)
Prone to diabetes mellitus
Extreme flexibility
General physical appearance (adults)
Prominent nasal bridge
Small hands and feet with tapering of fingers
Soft skin, which is easily bruised
Excess fat, especially in the central portion of the body
High, narrow forehead
Almond-shaped eyes with thin, down-turned lids
Light skin and hair relative to other family members
Lack of complete sexual development
Frequent skin picking
Striae
Delayed motor development
Behavioral:
Prader–Willi syndrome is also frequently associated with an extreme and
insatiable appetite, often resulting in morbid obesity. There is currently no consensus as
to the cause for this particular symptom, although genetic abnormalities in chromosome
15 disrupt the normal functioning of the hypothalamus.[3] Given that the hypothalamus
regulates many basic processes, including appetite, there may well be a link. However, no
organic defect of the hypothalamus has been discovered on post mortem investigation.[3]
Prader–Willi syndrome patients have high ghrelin levels, which are thought to
directly contribute to the increased appetite, hyperphagia, and obesity seen in this
syndrome. Cassidy states the need for a clear delineation of behavioural expectations, the
reinforcement of behavioural limits and the establishment of regular routines.[21]
The main mental health difficulties experienced by people with PWS include
compulsive behaviour (usually manifested in skin-picking) and anxiety.[4][7] Psychiatric
symptoms, for example, hallucinations, paranoia and depression have been described in
some cases[4] and affect approximately 5–10% of young adults.[3] Psychiatric and
behavioural problems are the most common cause of hospitalization.
Laurence-Moon-Biedl-Bardet Syndrome
Also called as Laurence-Moon-Biedl syndrome and Laurence-Moon-BiedlBardet, Bardet–Biedl syndrome is a ciliopathic human genetic disorder that
produces many effects and affects many body systems. It is characterized principally
by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism,
and renal failure in some cases
Summary of the syndrome:
"Bardet–Biedl syndrome is a pleiotropic disorder with variable expressivity and a
wide range of clinical variability observed both within and between families. The main
clinical features are rod–cone dystrophy, with childhood-onset visual loss preceded by
night blindness; postaxialpolydactyly; truncal obesity that manifests during infancy and
remains problematic throughout adulthood; specific learning difficulties;
malehypogenitalism and complex female genitourinary malformations;
and renal dysfunction, a major cause of morbidity and mortality. There is a wide range of
secondary features that are sometimes associated with BBS" including
Speech disorder/delay
Strabismus/cataracts/astigmatism
"Brachydactyly/syndactyly of both the hands and feet is common, as is partial
syndactyl (most usually between the second and third toes)"
"Developmental delay: Many children with BBS are delayed in reaching major
developmental milestones including gross motor skills, fine motor skills, and
psychosocial skills (interactive play/ability to recognize social cues)"
Polyuria/polydipsia (nephrogenic diabetes insipidus)
Ataxia/poor coordination/imbalance
Mild hypertonia (especially lower limbs)
Diabetes mellitus
Dental crowding/hypodontia/small dental roots; high-arched palate
Cardiovascular anomalies
Hepatic involvement
Anosmia
Auditory deficiencies
Hirschsprung disease
Pathophysiology:
The detailed biochemical mechanism that leads to BBS is still unclear. At this
moment, twelve genes that are responsible for the disease when mutated, have been
cloned.[citation needed]
The gene products encoded by these BBS genes, called BBS proteins, are located
in the basal body and cilia of the cell.
Using the round worm C. elegans as a model system, biologists found that BBS
proteins are involved in a process called Intraflagellar transport (IFT), a bi-directional
transportation activity within the cilia along the long axis of the ciliary shaft that is
essential for the formation and maintenance of cilia. Recent biochemical analysis of
human BBS proteins revealed that BBS proteins are assembled into a multiple protein
complex, called "BBSome". BBSome is proposed to be responsible for transporting
intracellular vesicles to the base of the cilia and to play an important role in the ciliary
function. Since abnormalities of cilia are known to be related to a wide range of disease
symptoms including those commonly seen in BBS patients, it is now widely accepted that
mutated BBS genes affect normal cilia functions, which, in turns, causes BBS.[citation
needed]
Genes involved include:
BBsome: BBS1, BBS2, BBS4, BBS5, BBS7, TTC8/BBS8, BBS9
chaperone: BBS6, BBS10, BBS12
Other: ARL6/BBS3, TRIM32/BBS11
Waterhouse-Friderichsen syndrome
It is a malignant form of cerebrospinal meningitis
Multiple species of bacteria can be associated with the condition:
Meningococcus is another term for the bacterial species Neisseria meningitidis,
blood infection with which usually underlies WFS. While many infectious agents can
infect the adrenals, an acute, selective infection is usually Meningococcus.
WFS can also be caused by Streptococcus pneumoniae infections, a common
bacterial pathogen typically associated with meningitis in the adult and elderly
population.
Mycobacterium tuberculosis could also cause WFS. Tubercular invasion of the
adrenal glands could cause hemorrhagic destruction of the glands and cause
mineralocorticoid deficiency.
Staphylococcus aureus has recently also been implicated in pediatric WFS.
It can also be associated with Haemophilus influenzae.
Cytomegalovirus can cause adrenal insufficiency, especially in the
immunocompromised.
The list of signs and symptoms mentioned in various sources includes the 10
symptoms listed below:
Fever
Collapse
Coma
Cyanosis
Petechiae on the skin
Confusion
Altered mental status
Photophobia
Seizures
Papilloedema
Complications and sequelae of Waterhouse-Friderichsen syndrome from the
Diseases Database include:
Adrenal cortex insufficiency
The infection leads to massive hemorrhage into one or (usually) both adrenal
glands.[1] It is characterized by overwhelming bacterial infection meningococcemia, low
blood pressure and shock, disseminated intravascular coagulation (DIC) with
widespread purpura, and rapidly developing adrenocortical insufficiency.
Von Graefe's sign
Von Graefe's sign (lid lag sign) is the immobility or lagging of the upper eyelid on
downward rotation of the eye, indicating exophthalmicgoiter
Joffroy's sign
Joffroy's sign is a clinical sign in which there is a lack of wrinkling of the
forehead when a patient looks up with the head bent forwards. It occurs in patients
with exophthalmos in Graves disease.
Stellwag's sign
Stellwag's sign is a sign of infrequent or incomplete blinking associated
with exophthalmos or Graves orbitopathy. It is accompanied byDalrymple's sign, which
is a retraction of the upper eyelids resulting in an apparent widening of
the palpebral opening.
Dalrymple's sign
Dalrymple's sign is a widened palpebral (eyelid) opening, or eyelid spasm, seen
in thyrotoxicosis (as seen in Graves' disease, exophthalmicGoitre and other hyperthyroid
conditions), causing abnormal wideness of the palpebral fissure. As a result of the
retraction of the upper eyelid, the white of the sclera is visible at the upper margin of
the cornea in direct outward stare.
Chvostek sign
The Chvostek sign (also Weiss sign) is one of the signs of tetany seen
in hypocalcemia. It refers to an abnormal reaction to the stimulation of the facial nerve.
When the facial nerve is tapped at the angle of the jaw (i.e. masseter muscle), the facial
muscles on the same side of the face will contract momentarily (typically a twitch of the
nose or lips) because of hypocalcemia (ie from hypoparathyroidism,
pseudohypoparathyroidism, hypovitaminosis D) with resultant hyperexcitability of
nerves. Though classically described in hypocalcemia, this sign may also be encountered
in respiratory alkalosis, such as that seen in hyperventilation, which actually causes
decreased serum Ca2+with a normal calcium level due to a shift of Ca2+ from the blood
to albumin which has become more negative in the alkalotic state.
Chvostek's sign may also be present in hypomagnesemia, frequently seen in
alcoholics, persons with diarrhea, patients taking aminoglycosides or diuretics, because
hypomagnesemia can cause hypocalcemia. Magnesium is a cofactor for Adenylate
Cyclase. The reaction that Adenylate Cyclase catalyzes is the conversion of ATP to 3',5'cyclic AMP. The 3',5'-cyclic AMP (cAMP) is required for Parathyroid hormone
activation.
Type 1a Pseudohypoparathyroidism is clinically manifest by bone resorption with
blunting of the fourth and fifth knuckles of the hand, most notable when the dorsum of
the hand is viewed in flexed position. This presentation is known as 'knuckle knuckle
dimple dimple' sign. This is as opposed to Turner syndrome which is characterized by
blunting of only the fourth knuckle, and Down's syndrome, which is associated with a
hypoplastic middle phalynx.
Trousseau sign
Trousseau sign is the name of two distinct phenomena observed in clinical
medicine. Both are attributed to Armand Trousseau:

Trousseau sign of latent tetany

Trousseau sign of malignancy
Trousseau sign of latent tetany is a medical sign observed in patients with
low calcium.[1] This sign may become positive before other gross manifestations
of hypocalcemia such ashyperreflexia and tetany, but is generally believed to be more
sensitive (94%) than the Chvostek sign (29%) for hypocalcemia. To elicit the sign,
a blood pressure cuff is placed around the arm and inflated to a pressure greater than
the systolic blood pressure and held in place for 3 minutes. This will occlude the brachial
artery. In the absence of blood flow, the patient's hypocalcemia and subsequent
neuromuscular irritability will induce spasm of the muscles of the hand and forearm. The
wrist andmetacarpophalangeal joints flex, the DIP and PIP joints extend, and the
fingers adduct. The sign is also known as main d'accoucheur (French for "hand of
the obstetrician") because it supposedly resembles the position of an obstetrician's hand
in delivering a baby.
The Trousseau sign of malignancy is a medical sign found in certain cancers that
is associated with venous thrombosis[1] andhypercoagulability. It is also referred to
as Trousseau syndrome[2] and is distinct from the Trousseau sign of latent tetany.