SURFING THE WEB FOR INFORMATION ON GENETIC AND HORMONE DISORDERS
John A. Phillips III, MD
David T. Karzon, Professor of Pediatrics
Professor of Medicine and Biochemistry
Vanderbilt University School of Medicine
Nashville, TN
New findings are reported at an ever increasing rate in a growing variety of journals. Access to current information on clinical and laboratory findings, and who performs genetic tests, cannot be found in a single journal or text. Electronic databases are now providing medical professionals rapid access to a bulk of current information and data. These electronic databases can be searched in an interactive way for symptoms and signs that permit generation of differential diagnoses which will often include rare or recently discovered disorders and which professionals probably have never encountered. This access enables these professionals to more frequently diagnose cases and be aware of subtleties which differentiate alternative diagnoses. These are reasons to use electronic databases. This article attempts to enlighten interested professionals on how to accomplish surfing the Web for information about genetic and hormonal disorders.

ON-LINE MENDELIAN INHERITANCE IN MAN (OMIM)1 - Electronic Database:

OMIM is maintained by the National Center for Biotechnology Information or NCBI. It is available without charge at the Web address (http://www3.ncbi.nlm.nih.gov/Omim). It is updated daily. In March 1999, 10,227 entries were included. A wealth of information is contained about the history, signs, symptoms, diagnosis, management, and research findings in these 10,227 disorders, as are detailed gene and disease focused maps. Access through "hyperlinks" to a variety of Web sites is another important strength. These hyperlinks include MEDLINE, The Alliance of Genetic Support Groups, The Cardiff Human Gene Mutation Database (HGMD), and databases on genes that cause retinal diseases, mitochondrial diseases, and a variety of other locus specific databases. The utility of using these databases and their hyperlinks in clinical applications will be subsequently discussed.

FREQUENTLY USED TERMS RELATED TO THE WEB 2

Knowing the definitions of terms that will be helpful in using the Web is essential as a first step in surfing the net.

E-mail: An acronym for electronic mail. The use of a network to send and receive messages.

HTML: Acronym for Hyper Text Markup Language which enables authors to insert hyperlinks. Clicking a hyperlink displays another HTML document. Therefore, in a hypertext system one can navigate by clicking hyperlinks, which produces a display of another document which also contains hyperlinks.

Http: The Internet standard supporting exchange of information on the World Wide Web (WWW). Http enables the embedding of hyperlinks in Web documents. Http defines the process by which a Web client uses a Web browser program to originate a request for information and send it to a Web server which is a program designed to respond to Http requests and provides the desired information.

Hypertext: A computer text form that allows readers to click on hyperlinks to display another document which may also contain hyperlinks to other documents.

Internet: The world wide system of linked computer networks that facilitates data communication services such as remote log on, file transfer, e-mail, the World Wide Web, and news groups. The Internet assigns every connected computer a unique Internet address so that any two connected computers can locate each other on a network and exchange data.

Log on/Log off: The processes of establishing and terminating a connection with a network or computer.

Netscape Communicator: A package including a popular Web browser called Netscape Navigator that is available for Microsoft Windows, Macintosh computers, and a variety of Unix workstations.

Online information service: America Online (AOL) is a for profit firm that makes current news, stock quotes, and other information available to subscribers over standard telephone lines.

Surfing the net: Exploring the Web by following a series of links of interest to the surfer.

URL: Acronym for Uniform Resource Locator. On the WWW, URL’s are a string of characters that precisely identifies an Internet's resource types and locations. The following fictitious URL identifies a WWW document (http://www.genetic.edu). 1) (http://) indicates the domain name of the computer on which it is stored, and 2) (www.genetic.edu), fully describes the document’s location. In addresses, small letters (www and http) are used. In abbreviations not pertaining to addresses, capital letters may be used (WWW and Http and HTTP).

Web (World Wide Web or WWW): A global hypertext system that uses the Internet linked computer network to facilitate data communication.

Web browser: A program that runs on an Internet connected computer and provides access to the WWW.

Web server: A program that accepts Http formatted requests for information. The server processes these requests and sends the requested document.

Web site: A set of related documents making up a hypertext presentation on the WWW. A Web site usually has a welcome or home page that serves as the initial document.

 

GENERATING DIFFERENTIAL DIAGNOSES FOR A DYSMORPHIC NEWBORN

A newborn baby is suspected of having some form of dwarfism. Ventriculomegaly and short limbs, as detected by fetal ultrasound, were noted at 20 weeks gestation. Chromosome studies from amniocentesis revealed a 46, XY pattern without any abnormalities noted. The fetal head size at 30 weeks gestation as noted on ultrasound was stated to be 35 weeks. The ventriculomegaly had resolved, and the limb lengths were those expected at 29 weeks. Physical examination detected macrocephaly, macroglossia, downward slanting palpebral fissures, cataracts, and syndactyly of the second and third fingers. Blood [glucose] was 28 mg/%; therefore, low.

The attending neonatologist believes the baby "looks funny" and wants to know if you, the consultant physician, think the baby has a syndrome. He wants to know if the infant has this syndrome, how to confirm it, and what is the expected prognosis?

You as the consultant physician are unaware of this constellation of clinical findings and/or what syndrome might be present but must solve the problem. A keyword search is desirable. Since the WWW might contain helpful information, one needs to initiate a search beginning with the OMIM database. The computer in the nursery is turned on and you or the operator open Netscape Communicator, America Online, or whatever Web browser the computer has, and type in the OMIM URL or address - http://www3.ncbi.nlm.nih.gov/Omim. The OMIM homepage appears on the computer screen and you click on "Search the OMIM Database," and then enter "macrocephaly" as a search term and press the "enter" key. Eighty-one disorders in OMIM have macrocephaly listed. This is too many items to consider, so you repeat the search using "cataract" as a finding, and 183 matching entries appear. This number of disorders is impossible to consider, so you search by using "syndactyly." The search produces 168 matching entries--again too many. A decision is then made to find out how many disorders have both macrocephaly and cataract by typing both macrocephaly and cataract in (macrocephaly AND cataract) as a search string. Only seven entries are listed as having both of these findings. These are 1) #109400 Basal Cell Nevus Syndrome; BCNS; 2) #30700 Hydrocephalus Due to Congenital Stenosis of Aqueduct of Sylvius, HSAS1, HSAS, HYCX; 3) #301050 Alport Syndrome, X-Linked, ATS; 4) #156550 Kniest Dysplasia; 5) *231680 Glutaricaciduria IIA; 6) #312870 Simpson Dysmorphia Syndrome, SDYS; and 7) *#231675 Glutaricaciduria IIC. The entry numbers are in hypertext (color) on the screen, and clicking on the number will open each corresponding entry. To further focus, you add "syndactyly" and enter - macrocephaly AND cataracts AND syndactyly - as a search string. Only one OMIM entry is listed for all three of these findings - #312870 Simpson Dysmorphia Syndrome, SDYS.

You have participated in a remarkable accomplishment. In less than two minutes, a large electronic database of genetic disorders was searched and a successive series progressively refined differential diagnoses was generated. Opening the matching file (#312870 SDYS) by clicking your mouse on it, the first page of information appears on the screen for review (Figure 1). The clinical synopsis under Table of Contents or complete text of this entry can then be reviewed. Figure 1 is only the first of seven pages of information on SDYS. Note in the Figure that the Database Links below the Table of Contents provide immediate access to other databases including MEDLINE. The diagnosis needs to be confirmed, and the HELIX database is a directory of laboratories that provide testing for genetic disorders (see list of selected Web sites below). You register with HELIX and are given a password for professional users. This is used first to access and search the HELIX database for SDS or SDYS or the Simpson-Golabi-Behmel Syndrome, and secondly to find matching labs that provide either clinical or research testing for this disorder. In a matter of a very few minutes, you have generated a working diagnosis (SDYS) and obtained information concerning the pathogenesis, mode of inheritance, the findings associated with SDYS, and access to a lab that can help confirm the working diagnosis. Obviously after expending just a few minutes one feels much better prepared to talk with the neonatologist and the baby’s parents who are waiting for your opinion.

 

GENERATING A DIFFERENTIAL DIAGNOSES FOR A FAMILY HAVING UNUSUAL ENDOCRINE PROBLEMS

A 15 month old male is referred to you by his pediatrician who suspects he has growth hormone deficiency (GHD). The child weighed 3.2 kg. at full term following an uncomplicated pregnancy, labor and vaginal delivery. The height SDS is now -3.2, and the length since 5 months has become progressively retarded. The child is proportionate and the height and weight are commensurate with each other. The extremities appear normal in length, and no kyphosis, limitation of joint motion or dysmorphic features are present. His bone age is delayed greater than -2 SD. You see no skeletal abnormalities. A [serum thyroxin] is abnormally low, but the electrolytes, glucose, urea nitrogen, bicarb and anion gap, calcium, and phosphorus, and urine pH are all within normal limits. A 16 year old full sister reportedly received GH for presumed panhypopituitarism. The blood tests on the 15 month old reveal low serum levels of gonadotropins and thyroxin. Combined pituitary hormone deficiency is logical, as there is failure of response to GHRH, TRH, and LHRH, and the MRI study reveals a hypocellular pituitary.

A keyword search is valuable. Since the WWW may contain some information on familial hormone deficiencies, a search of the OMIM database is indicated. To do this, one logs on to the OMIM Home Page by entering the URL - http://www3.ncbi.nlm.nih.gov/Omim/. Then one clicks on "Search the OMIM Database" with the mouse and enters "gh and thyroid" as a search term. Note gh is used as a search term rather than growth hormone because the latter is two words. Use of gh gives 36 hits while growth AND hormone gives 271 hits. Using gh AND thyroid seven disorders appear on the screen (Figure 2). The first entry, (173110 POU DOMAIN, CLASS 1, TRANSCRIPTION FACTOR 1; POU1F1) is about the PIT1 transcription factor and includes an interesting paragraph

"Mutations of the POU1F1 gene in the human and Pit1 in the mouse are responsible for deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone, while the production of ACTH, LH, and FSH are preserved. In contrast, patients with combined pituitary hormone deficiency due to homozygosity or compound heterozygosity for inactivating mutations of PROP1 (601538) cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously (Wu et al, 1998)4."

The case under consideration seems to fit the findings reported for PROP1 mutations so it is appropriate to review the article by Wu et al., 1998. On the Web, you can obtain a copy of the abstract by clicking the mouse on either of the following: 1) the Wu et al., 1998 hypertext at the end of the paragraph cited above, 2) the Wu et al., 1998 hypertext in either the PIT1 (173110) or PROP1 (601538) entries, and then click on the PubMed ID (9462743) that follows the reference that appears. You will then see the abstract of the reference on your screen and you can print it. Since this is a PubMed document you can also save it as a file on your computer as shown at the bottom of the page or you can order a complete copy through Lonesome Doc as shown at the top. Alternatively, you can obtain copies of articles by clicking on MEDLINE under "Database Links" that are just below the TABLE OF CONTENTS of each entry (Figure 1). If you do a PubMed search for "gh AND thyroid AND gonadotropin AND familial" you will immediately find eight related articles, the first three of which contain information that you may find helpful in your further evaluation and treatment of your new patient (Figure 3). As in the first case, you can carry out a HELIX search to find a lab that can carry out molecular analysis of the PROP1 gene.

Now there is a working diagnosis (PROP1 defects), information on the pathogenesis, mode of inheritance, the findings associated with the disorder, and a way to find a lab that helps confirm the working diagnosis. Obviously, after this you feel better prepared to talk with your patient’s parents and to answer their questions.

SELECTED WEB SITES THAT CONTAIN INFORMATION ON GROWTH AND HORMONE DISORDERS.

Summaries of disorders for professionals, educators, and individuals

MEDLINE PubMed and Internet Grateful Med: Provides access to a cornucopia of scientific and medical publications in a searchable format (http://www.nlm.nih.gov/databases/freemedl.html).

American Diabetes Association (http://www.diabetes.org) - For professionals and laity.http://www.childrenwithdiabetes.com - the online community for kids, families and adults.

Helix (http://healthlinks.washington.edu/helix/): Helix is a directory of laboratories providing testing for genetic disorders. Information on both research and diagnostic laboratories is included and labs are listed by disease name.

Lawson Wilkins Pediatric Endocrine Society (http://lwpes.org) - news, job listings, etc.

March of Dimes (http://modimes.org): Information for professionals and families on birth defects.

CONCLUSIONS

The World-Wide Web is here to stay. It offers an expediency to finding the answers to complex diagnoses and problems which previously has not been possible. It behoves every physician to capitalize upon the aids which the WWW and computer technology provide. As is true for most things in life, some effort has to be put forth to develop the expertise to accomplish the goals. Hopefully, this introduction will help you, the reader, succeed.

REFERENCES

1. Online Mendelian Inheritance in Man, OMIM (TM). Center for Medical Genetics, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 1998. World Wide Web URL: http://www3.ncbi.nlm.nih.gov/Omim/

2. Webster’s New World Pocket Internet Directory and Dictionary Simon & Shuster, Inc., New York, New York, 1997.

3. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 312870 : 11/03/98: . World Wide Web URL: http://www3.ncbi.nlm.nih.gov/Omim/

4. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 173110 : 09/29/98 : . World Wide Web URL: http://www3.ncbi.nlm.nih.gov/Omim/

5. Wu, W.; Cogan, J.D.; Pfaffle, R.W.; Dasen, J.S.; Frisch, H.; O’Connell, S.M.; Flynn, S.E.; Brown, M.R.; Mullis, P.E.; Parks, J.S.; Phillips, J.A., III; Rosenfeld, M.G.:Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nature Genet. 18:147-149, 1998.

FIGURE LEGENDS

Fig. 1: OMIM page showing first of seven pages of information on Simpson Dysmorphia Syndrome. Note Database Links below Table of Contents that provide immediate access to other databases including MEDLINE.

Fig. 2: OMIM page showing results of search initiated using "gh AND thyroid" as a search string.

Fig. 3: NCBl/PubMed page showing results of search initiated using "gh AND thyroid AND gonadotropin AND familial" as a search term. Note that eight publications match all three items in the search string and that the first three of these contain essential information.

Revised 3/16/99

Published in Growth Genetics and Hormones (in press 1999)