Abstracts in Developmental Medicine

ABSTRACTS IN DEVELOPMENTAL MEDICINE
Ned Rapp, MD, AADMD Co-editor, Abstracts in DEVELOPMENTAL HEALTHCARE PROJECT

Summaries and Reviews of Adult Medical and Dental Developmental Disabilities

Rett syndrome:Long term clinical follow up experience over four decades

Hagberg Bengt

J Child Neurol (2005); 20:722-727

Rett syndrome is the result of different mutations at the MECP2 gene at the distal tip of the long arm of the X chromosome(at Xq28). This results in a group of various phenotypes. Rett syndrome ranges from a young girl with a borderline IQ and some difficulty with manual dexterity to a middle aged individual with severe muscular atrophy and an IQ in the 45-60 range(Rett syndrome survivors include a women who survived until age 71). The cases presented below describe three adults with severe manifestations of Rett syndrome.

Patient 1

With the exception of a seizure like episode at 6 months, the patient deveveloped normally until the age of 1.5 years in at which time she developed “hand wringing” and was unable to grasp objects as effectively as before. At age 19, she was diagnosed with Rett syndrome based on clinical criteria (the MECP2 gene was not found until the late 1990’s) based on appraxia, delayed development and aggressive behavior with a high kyphosis and a modest left convex scoliosis. At age 47, she was a very small women(with a height of 134 cm and weight of 50 kgm . She had thin distorted feet which were very short( 34cm). She was able to walk with assistance but had difficulty with balance. She had extremely thin legs.Rather than typical hand stereotypies with hand wringing,, she had “finger snapping” stereotypies and was unable to use her hands. Her feet were small and demonstrated dystonic positioning with a downward fixed position of the right toe. She was able to walk but only inside in her bare feet

Patient 2

This patient developed normally until age 1.25 years except she never learned to creep on her knees . There were very subtle signs of motor deterioration. At age 1.75 years, she started to show signs of regression with hand clapping,,deceleration of head growth, autistic traits and stopped walking completely. At age 23, the diagnosis of Rett syndrome was made. At age 44, she was noted to have a very small head, and a distended abdomen. Her feet were bluish, sweaty, cold and small (23 cm). She had extreme dystonia with right side dominance. She was subject to paroxysmal laughing attacks and paroxysmal night screaming.

Patient 3

This patients neonatal and perinatal history were normal. She could play with toys, sit up, walk with support and say single words. At one and one half years she had stopped using her hands completely and at age two and one half her head growth decelerated markedly. At this age, she stopped creeping and talking and had screaming spells. Meaningful contact with her parents ceased and she was said to be in her “own world”.She had truncal ataxia, slight hypotonia, intention tremor of her hands as well as stereotypic movement patterns. Over the next three decades she developed a severe dystonic -atrophic syndrome, contractures and collapse scoliosis. She died at age 36 as a deformed , emaciated ,growth retarded,individual. Throughout adult life, she maintained good eye contact and maintained a good memory , particularly for familiar items in her childhood and was able to recognize her parents and personal assistants.

REVIEW

The most important contribution of this article is to point out the most distinctive features of Rett syndrome in adulthood. The most important differences are as follows : 1.) Contractures and frozen, stiff joints are seen in adults with Rett syndrome. In many types of ID/DD contractures exist and it is possible to mistake this syndrome for cerebral palsy. 2.) Hand wringing may not be as evident in adults with Rett syndrome because of the frequent presence of frozen stiff metacarpal and interphalangeal joints although the hands are often clasped 3.)The feet are often small, bluish and dystonic 4,) Seizure activity often diminishes markedly after age 40(although the EEG is invariably abnormal after two years of age) 5.) Eye contact is often well preserved in adulthood 6.) There is remarkable preservation of memory, usually, but not exclusively for childhood events. Because of the relatively recent discovery and use of the MECP2 gene as a diagnostic tool (which began in the late 90’s)and the absence of “typical” hand wringing in the adult with Rett syndrome, the diagnoses is not considered in some adults. Although there is now data that very subtle developmental delay occurs as early as 6 months, usually the parents will notice marked regression between I and 2 years. Therefore, in evaluating a patient suspected of having Rett syndrome, the childhood history between birth and two years is crucial

Summaries and Reviews of Adult Developmental Medicine and Dentistry

Systematic review: Safety and efficacy of antiviral chemoprophylaxis against pandemic and seasonal influenza.

Khazeni N, Bravata D, Holti Jon-Eric, Uyeki TM, Stave CD and Gould MK.

Ann Intern Med.2009;151-163(Review-79 references)

This study examined and compared the prophylactic effect of neuraminidase inhibitors (specifically zanumivir(Tamiflu) and oseltamivir (Relenza) given for an extended period of time(>4wks with a range of 28-42 days) after which patients were tested for various influenza A viruses.(including H1N1).The study was controlled, randomized and doubling, It was considered important to do a comparative study since increasing oseltamivir resistance has been noted. Studies that were included were done in the period from 1999 to 2007 and documented the occurrence of both symptomatic and asymptomatic influenza in seven different studies. Asymptomatic and symptomatic influenza were detected by nasal and pharyngeal swabs and in some cases serum specimen as well as symptoms. Five studies tested the specimen obtained for H1N1, one study tested the specimen only for other influenza A viruses and one study simply monitored outcome (and therefore was only able to determine whether the patient developed symptomatic influenza without determining the viral source). The studies were double blind, controlled and randomized. The dose in the two groups was oseltamivir 75mgm per day(one study administered oseltamivir 75mgm bid) and zanumivir 10mgm od There were 7021 patients . The age range was 28.8 to 81.2 years. Three studies excluded subjects who had been vaccinated with trivalent inactivated vaccine (neuraminidase inhibitors were not given to individuals immunized with live attenuated inactive vaccine so these results do not apply to this subgroup). Three studies excluded people who excluded people who had been vaccinated, three included a mix of individuals who had been vaccinated and with those who had not been vaccinated and one included only individuals who had been vaccinated The results showed no difference between the groups where more than 50% had been vaccinated and groups less than 50% had been vaccinated. None of the subjects had any major medical problems, although one study included an elderly population from a nursing home. There were no intellectually disabled patients in the study population. Of the viral studies that tested for H1N1 influenza (5 of 7 did), all tested for the virus during each study’s influenza season.

RESULTS

Extended duration treatment with neuraminidase inhibitors showed that both types of inhibitors decreased the risk for symptomatic influenza(with no significant difference between the two inhibitors) compared to placebo but there was no significant difference in preventing asymptomatic influenza compared to placebo. The inhibitors decreased the risk of contacting symptomatic influenza (RR 0.26, 95% Cl=0.18-0.37). The article states that all the subjects were immunocompetent. The placebo groups did not differ significantly as to risk profile . Higher dose oseltamivir (75 mgm bid )produced a higher incidence of of nausea and vomiting than than the lower dose(75mgm od). It should be noted , however, that zanumivir has been reported to increase the incidence of bronchospasm in patients with chronic lung disease(these patients were not included in the study) and is administered in a powdered aerosol form and may be difficult for non-cooperative patients to take. Four studies described adverse events but there was no difference between the chemoprophylaxis and placebo groups as far as adverse events other than an increase in nausea and vomiting from oseltamivir in four studies( RR 1.48(Cl 1.66 to 2.3 ) Immunocomprimised individuals were not included in this study, so guidelines for this group cannot be determined based on this study.

COMMENT

The peak of the H1N1 epidemic has yet to occur, but the question of the efficacy of neuraminidase inhibitors or their appropriateness for prophylaxis in the intellectually disabled cannot be answered with assurance because there are no equally thorough, double blind, control studies in the ID/DD population and this group of patients are free of significant medical problems. Nonetheless the article demonstrates that oseltamivir and zanumivivir are efficacious for prophylaxis of HINI flu in a group of relatively young patients who are for the most part healthy, although the study includes a group of elderly healthy nursing home residents It should be stressed, that this is a prophylactic study and does not apply to patients who already have symptoms. As of this time, the H1N1 outbreak is not of pandemic proportions, but the production and delivery of the vaccine has been slower than anticipated. The antiviral medications may be of some use for prophylaxis in the ID/DD population since there are patients with pre-existing medical problems who are more likely to develop complications from H1N1 infection. The fact that oseltamivir causes a small increase in nausea and vomiting (RR=1.48) must be weighed against the value of treatment with oseltamivir since many of these patients, particularly those with a history of aspiration or frequent reflux, are the ones who would be the most adversely affected by influenza but other than this effect, there were no significant difference in adverse effects between either of the medications and placebo or the two medications. Patients who aspirate may also have bronchoconstriction and zanumivir has been known to increase bronchoconstriction in patients with chronic obstructive lung disease. The value of this paper is that it provides a baseline of efficacy and adverse effects among normals in the absence of literature concerning the ID/DD population. In any circumstances one would be wise to consult the website of the American Academy of Developmental Medicine and Dentististry (http://www.AADMD.org) for guidelines in the ID/DD population as well as the relevant CDC website (http://www.cdc.gov/h1n1flu/)

Summaries and Reviews of Adult Developmental Medicine and Dentistry

Multisystem Study of 29 Older Adults with Williams Syndrome

Cherniske Elizabeth, Carpenter Thomas Klaiman Cheryl, Young Eytan, Bregman Joel, Insogna Karl,Schultz Robert T and Pober Barbara R

American Journal of Medical Genetics (2004);131A:255-264.

Williams syndrome is a multisystem congenital disease caused by a submicroscopic deletion at chromosome 7q11.23. In some cases Williams syndrome presents differently in adulthood and there are signs of accelerated aging in some patients with Williams Syndrome . The current study consisted of adults with Williams syndrome over 30 recruited through the the Genetics Clinic at Yale New Haven Medical Center The average age of the patients was 38.8 with an age range of 30-51. Seventeen of the 20 patients had an elastin deletion in the WS critical region confirmed by FISH analysis.The other three patients were not tested by FISH analysis for financial reasons but the diagnosis was clinically confirmed by one of the authors (BOP). The clinical findings among this group are described in the following portion of this review.

1.) Body weight. Four of the 30 patients were found to be obese and nine of the 30 patients were considered overweight BMI criteria for these these categories were not given. Seven had >30% body fat and five had body fat in the 20-30% range. The patients with excess body fat , were often pear shaped, with the fat deposited in a central location. Sixty-five percent of the entire group had a BMI greater than 65%.

2.) Visual problems. All 20 subjects had some sort of visual problem. Six had a history of strabismus while 7 had it currently, 6 had had hyperopia, 6 had myopia, 4 had presbyopia, 4 had cataracts and one had conjunctivitis

3.) Audiologic testing. Seventy-five percent had high frequency sensorineural hearing loss.

4.) Dental Hygeine Nine of the twenty patients had poor dental hygiene which included halitosis, dental caries, dental extractions and gum recession.

5.) Cardiovascular Thirteen of the fourteen who were evaluated for cardiovascular abnormalities. Thirteen had supravalvular stenosis, 3 had pulmonic stenosis , 2 had mitral regurgitation. 2 had a bicuspid aortic valve, 1 had mital valve prolapse and 1 had a ventricular septal defect. Twelve had hypertension. Nine patients had a history of a stroke . Ten underwent Doppler ultrasound of their descending aorta, renal arteries and mesenteric arteries. Four had isolated branch stenosis of either the SMA or celiac axis while a fifth had SMA tortuosity probably caused by isolated SMA origin stenosis Nine patients underwent a Doppler examination of the carotid arteries (only one had a bruit and his Doppler was normal). Eight of the nine patients had a normal Doppler study of the carotid arteries, while one had possible hypoplasia of the left internal carotid artery.

6.) Gastrintestinal A history of “any gastrointestinal” problem was present in 15/20 patients. Eight patients had a history of abdominal pain, 5 had a history of gastroesophogeal reflux and 5 had a history of constipation Four had a history of diarrhea and in another 4 had a history of both diarrhea and constipation. Two had diverticulosis, three had diverticulitis and 3 had a combination of diverticulosis and diverticulitis. Half of the patients with with diverticulitis or diverticulosis had a history of constipation.

7.) Genitourinary Half of the patients had a history of urinary frequency, and two had a history of incontinence. Four patients had a history of urinary tract infections and one of the female patients had bladder spasm, bladder diverticuli and interstitial cystitis. Renal function was assessed in 18 patient by means of BUN and creatinine determinations and found to be normal in all patients. An ultrasound exam was performed in 13 patients. Four had bladder diverticuli and one had a history of medullary nephrocalcinosis.

8.) Endocrine Only one patient had hypercalcemia (two had a history of hypercalcemia.) Twelve of twenty had a history of osteopenia or osteoporosis using femoral neck T score cutoffs .One patient had hypothyroidism with elevated anti-thyroid antibodies. Four additional patients had an elevated TSH level suggesting subclinical hypothyroidism. Regarding diabetes. two had been diagnosed with adult onset diabetes prior to study participation. Of the remaining patients, 6/17 demonstrated silent diabetes based on blood sugar levels, impaired glucose tolerance was found in 9/17and normal glucose tolerance in only 2/17

9.) Musculoskeletal Four of twenty subjects had scoliosis, six had lordosis and two had both. Almost all the subjects had decreased range of motion of the hamstrings and/or heelcords.All patients had some contractures.

10.) Integument Grey hair was confirmed on physical exam on 19/20 patients. The average age of onset was 35.Dry skin was present in two of the patients

11.) Central Nervous System The mean brain size of the group was found to be one standard deviation below normative data. Neurologial exam revealed upper extremity deep tendon reflexes in half of the subjects while lower extremity deep tendon reflexes were increased in 13/19. Clonus was present in half. A fine resting tremor was present in eight and an intention tremor was present in 15.

12.) Cognitive Borderline intelligence (IQ 70—80),was present in 3 patients, mild mental retardation (50-69) in 14 and moderate mental retardation (IQ <50)in 3.

13.) Psychiatric Thirteen of 20 patients were diagnosed as having moderate to severe anziety . Additional diagnosis were depression in 2 patients, manic depressive disorder in 1,panic disorder in 1, obsessive compulsive disorder in 1 and sexual impulse disorder in 1.

Review

The child with Williams syndrome presents in most (but not all) with delayed development usually including problems with spatial ability, behavioral difficulties ,distinctive facial features and a heart murmur usually due to supraaortic stenosis(as well as murmurs due to other cardiac problems) and is often said to be “hypersocial” and approachable. The patients facial dysmorphology is characterized by short palpebral fissures, epicanthal folds, a depressed nasal bridge and a long philtrum. The child with Williams syndrome frequently has hypercalcemia.as well and is not obese The adult with Williams syndrome may present with distinctive facial features(often with a longer neck) and a cardiac murmur, and he often moderately or severely obese. Typically, he has anxiety or depression and is not “hypersocial”. Hypercalcemia may be present but is far less likely than in children with Williams syndrome. He may also have signs of early aging –prematurely grey hair, dry skin, severe contractures and osteopenia or osteoporosis and is at very high risk of having diabetes or impaired glucose tolerance. He may also have diverticulosis or diverticulitis or signs of renovascular disease or mesenteric artery insufficiency. Hypertension is very common in adults with Williams syndrome so the blood pressure should be monitored frequently.