The enzyme performs a crucial step in the breakdown of the glycosaminoglycan heparan sulfate which is found in the extra-cellular matrix and on cell surface glycoproteins. Although undegraded heparan sulfate is the primary stored substrate, glycolipids such as gangliosides are also stored despite no genetic defect in the enzymes associated with their breakdown.

MPS-III A has an incidence of approximately 1 in 115 000 live births. Higher rates are found in certain populations such as the Ashkenazi jews. It is a rare disease.

Natural History and Diagnosis

It should be noted that MPS-III A, B, C and D are considered to be clinically indistinguishable, although mutations in different genes are responsible for each disease. The following discussion is therefore applicable to all four conditions.

The disease manifests in young children. Affected infants are apparently normal, although some mild facial dysmorphism may be noticeable. The stiff joints, hirsuitism and coarse hair typical of other mucopolysaccharidoses are usually not present until late in the disease. The child often develops normally initially. Acquisition of speech is often slow and incomplete. The disease then progresses to increasing behavioural disturbance including temper tantrums, hyperactivity, destructiveness, aggressive behaviour, pica and sleep disturbance. As affected children have normal muscle strength and mobility, the behavioural disturbances are very difficult to manage. The disordered sleep in particular presents a significant problem to carers. In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures. Death eventually results from inanition. The life-span of an affected child does not usually extend beyond late teens to early twenties.

Although the clinical features of the disease are mainly neurological, patients may also develop diarrhoea, carious teeth, and an enlarged liver and spleen. There is a broad range of clinical severity. The disease may very rarely present later in life as a psychotic episode.

The diagnosis may be confirmed by assay of enzyme levels in tissue samples and gene sequencing. Prenatal diagnosis is possible.

Treatment

Treatment remains largely supportive. The behavioural disturbances of MPS-III respond poorly to medication. If an early diagnsosis is made, bone marrow replacement may be beneficial. Although the missing enzyme can be manufactured and given intravenously, it cannot penetrate the blood-brain barrier and therefore cannot treat the neurological manifestations of the disease.

Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system. Several promising therapies are in development. Gene therapy is under investigation for MPS-III in animal models. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the brain blood-brain barrier, stabilisation of abnormal but active enzyme to prevent its degradation, and implantation of stem cells strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis.

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Getting comfortable with pediatric, adolescent gynecology - Expert Opinion
From OB/GYN News, 10/15/02 by Bruce Jancin

BIG SKY, MONT. -- With the American College of Obstetricians and Gynecologists gearing up for a major campaign to encourage members to incorporate pediatric and adolescent gynecology into their practices, here are some clinical tips regarding this area.

The tips were offered by Dr. Joseph S. Sanfilippo at an ob.gyn. update sponsored by the Geisinger Health System.

* Physical examination of a child. Don't use the dorsolithotomy position that's standard in adults. Instead have the child assume a frog-leg position, he pointed out.

After finishing this segment, have her turn over and assume the knee-chest position, take a deep breath, and then bear down to induce a Valsalva response.

"You can probably see the cervix. And even if you can't, that's okay, because the lower one-third of the vagina is where virtually all the vulvovaginitides will occur in this age group, said Dr. Sanfilippo, professor of ob.gyn. at the University of Pittsburgh.

* Document Tanner stage in your record. It looks much more professional should you eventually refer the patient to, say, a plastic surgeon for definitive treatment of a breast abnormality Tanner Stage 1 is a nipple with no palpable underlying breast tissue, typical of preadolescence. Stage 2 features a breast bud. In stage 3, the contour of the areola is not separated from that of the breast. In stage 4, the areola and nipple form a secondary mound. Stage 5 is a mature adult breast.

* Polythelia. This congenital condition, which is marked by extra breast nipples located along the milk line from midclavicle to labia, affects 2% of the population. In the great majority of cases, it's best left alone. When the condition is too physically irritating, plastic surgery is the solution.

* Breast hypoplasia. This is typical in patients with Turner's syndrome or other causes of gonadal dysgenesis secondary to lack of endogenous estrogen. In replacing estrogen in these Tanner stage 1 patients, do so physiologically using 0.3 mg of conjugated equine estrogen for a minimum of 6 months before increasing the dose to 0.625 mg/day.

* Asymmetric breast development. There is no medical therapy for this common condition, which can be psychologically disruptive when the asymmetry is marked. Sewing padding into the bra is a good interim solution until breast development is completed at around age 18.

"Age 18 is probably when you should pick up the phone and make that referral to the plastic surgeon for some form of augmentation. Insurers pay for this surgery because it's for a medical problem," Dr. Sanfilippo continued.

* Virginal hypertrophy. This is a familial condition in which an adolescent's breasts can enlarge up to 30-50 pounds each. Reductive mammoplasty is the only therapy.

* Labial adhesions. These defects are a common reason for parents to bring a child in. The etiology is believed to be a perineal hygiene problem in which Escherichia coli from the rectal area cause nonspecific vulvitis. Pooling of urine in the vagina can occur, so it's always a good idea to ask about urinary tract infection.

Treatment consists of education about wiping fecal material posteriorly after a bowel movement, using sitz baths, and showing the parent how to do a fingertip application of estrogen cream to the labia once daily for 10 days.

After the labia separate, use of A & D ointment is helpful. Parents need to understand that this condition will recur until their girl reaches puberty, when changes in vaginal pH will end the problem.

"I have them come back once after separation, because I've got to be sure in my mind that there's no transverse septum or other problem, but that's optional," the ob.gyn. said.

* Provide "belt-and-suspenders" birth control. The 1 million teen pregnancies per year in the United States, 40% of which end in abortion, constitute a national disgrace, particularly when one considers that teen pregnancy rates in The Netherlands and Sweden are only one-fifth those here despite an equal prevalence of teen sexual activity, Dr. Sanfilippo noted.

That's why he has turned to what he calls belt-and-suspenders birth control in adolescents. He not only provides a prescription for OCs, he also explains the importance of insisting that her male partner uses a condom to protect her from STDs.

"And I take that one step further. We're now giving all the teenagers a second prescription for Plan B or another form of emergency contraception. It takes just a few minutes to talk about that-and let me tell you, it can make a difference," he commented.

* Selecting an OG. For adolescents, Dr. Sanfilippo favors OCs that contain third-generation progestins because of their peripheral actions, which include occupying the androgen receptor without turning it on and converting testosterone to dihydrotestosterone.

For an adolescent with acne or oily skin, he'll pick a less androgenic norgestimate-containing OC, while for a patient with endometriosis, he'll opt for an OC with a progestin at the more androgenic end of the spectrum, such as norgestrel.

* Abnormal uterine bleeding. In 19% of affected adolescents, this is the first manifestation of von Willebrand's disease or another coagulopathy.

Once this has been ruled out, the young patient with heavy irregular bleeding and a hemoglobin level greater than 12 g/dL can be sent home with a menstrual calendar to return in 3 months.

If at that point her hemoglobin level is less than 10 g/dL and she's bleeding acutely a highly effective therapy is one 35-[micro]g OC every 6 hours for 2 days, then one pill per day for 3 days, followed by twice a day for 2 days, and one per day thereafter until the 21-pill pack is completed. This quickly causes endometrial proliferation and seals off the arterioles.

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