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Tuesday, 16 August 2011

Clinical Radiological Pathological Conference: August 2011. A female with sexual development problem

Clinical-Radiological-Pathological conference is the monthly acticity held by Department of Medciine, Faculty of Medicine, Chulalongkorn University.
There is presentation of a case and discussion by clinician (internal medicine staff), radiologist and a diagnostician (usually pathologist but can be any one aware of the final diagnosis such as microbiologist, geneticist, parasitologist or clinicians)
The CRPC case will be recorded and posted on our department website:

Before the date of CRPC, there is the active discussion board in another webboard:

This month, the CPC case is a 18-year-old woman who presented with primary amenorrhea, secondary sex characteristics underdevelopment, and a large lobulated heterogeneous enhancing mass with amorphous calcification in the pelvic cavity.

Who are interested in case discussion can follow the link and leave the comments.

Reference for the discussion: Books: Genetic Disorders of Human Sexual Development: Leonard Pinsky, Rober P Erickson and R Neil Schimke.
Gene reviews:

Sunday, 7 August 2011

Medical Genetics residency training in USA

Medical genetics residency training is relatively new medical specialty training in USA. As the growing body of genetic knowledge, the realization of application in practical medicine, this field has been developed but in a slow pace than previous expectation. Doctors who have been enrolled in the training will sit for the examination for board certification of clinical genetics. Only MD can be entered into this type of training. Currently, there are about 1000 american board certified medical geneticists in US and elsewhere in the world. This number is only about 1% of all doctors.

There are other three laboratory based subspecialty training: biochemical genetics, molecular genetics and cytogenetics which allow both MD and non MD doctorate graduate to enter this type of training. Another genetics sub specialty training are molecular genetics pathology and Neurogenetics that are run by American Board of Pathology and American board of neurology and psychiatry respectively. We will focus on training that are accredited by board of medical genetics.

Pathway of training

1.single specialty training with or without subspecialty training

2.combined specialty training (combined with internal medicine/ pediatrics or OB-GYN)

The first one is the most common pathway. There are about 50 programs owned for this type of training. These are the list of accredited programs from all states in USA.

or you can follow this link: for accredited programs search.
The eligible for enter each programs are set different by institution but the eligibility for sit in the exam for amedican board of medical genetics are set and evaluated by American Board of Medical Genetics as followings:

Training Requirements for Certification

Foreign Medical Graduates Credentials Check

Individuals seeking ABMG certification must fulfill all of the requirements for certification, as detailed in this document. Individuals who hold doctoral degrees earned outside of the US, Canada, or Puerto Rico or who underwent medical training outside of the US, Canada, or Puerto Rico, may need to meet additional requirements.

Doctoral degree requirements for each genetics specialty are as follows:

Clinical Genetics………………………...MD or DO

Clinical Cytogenetics……………………MD, DO, or PhD*

Clinical Biochemical Genetics…………. MD, DO, or PhD*

Clinical Molecular Genetics……………..MD, DO, or PhD*

*PhD must be in genetics, human genetics or a related field, as determined by the ABMG.

The Clinical Genetics specialty training requirements include:

24 months of satisfactorily completed full-time training in an ACGME-accredited residency program in a specialty (other than clinical genetics) that is recognized by the ABMS, (e.g., pediatrics, obstetrics and gynecology, internal medicine, etc.) and an additional 24-months of satisfactorily completed full-time training in an ACGME-accredited clinical genetics residency training program;


48 months of satisfactorily completed full-time training in an ACGME-accredited 4-year clinical genetics residency. (Note: In this instance the 48 months of training satisfy both the graduate medical training requirement and the medical genetics residency training requirement);


60 months of satisfactorily completed full-time training in an ACGME-accredited combined residency such as pediatrics/medical genetics, internal medicine/medical genetics, or obstetrics and gynecology/medical genetics. Upon successful completion of all the requirements of the combined residency, a trainee is qualified to apply for certification by either the American Board of Pediatrics (ABP), the American Board of Internal Medicine (ABIM), or the American Board of Obstetrics and Gynecology (ABOG) (depending on the other discipline) and the ABMG. Applicants must satisfactorily complete the specific credentialing requirements of each board to be eligible to sit for the examination of that board. Certification in one specialty is not contingent upon certification in the other specialty.

The laboratory specialties (Clinical Biochemical, Clinical Cytogenetics and Clinical Molecular Genetics) training requirements include a minimum of 24 months of satisfactorily completed full-time training in an ABMG-accredited laboratory genetics training program.

For certification in each additional ABMG specialty (except Clinical Genetics): an additional 12 months of completed full-time training in an ABMG-accredited fellowship program in that specialty is required. For certification in Clinical Genetics as an additional ABMG specialty, the same requirements as those detailed above in IB apply.

Number of months of ABMG-approved medical genetics training to be completed by number of ABMG specialty certifications sought:

Number of ABMG

primary specialty certifications* Months of completed ABMG-approved medical genetics training

1 24 months

2 36 months

3 48 months

4 60 months

*Note: Certification in Clinical Genetics always requires 24 months of completed training in an ACGME-accredited clinical genetics residency.


Credentialing Requirements and Process

The credentialing process determines an applicant’s candidate status for the ABMG certifying examination. All documents required for the credentialing process must be submitted to the ABMG Administrative Office and postmarked by the deadline (see Deadlines, Section VI).

Full training options can be found at American Boards of Medical Genetics website

Thursday, 4 August 2011

genetics and skin colours: Human pigmentation: genetics and biology and cat coat colors

Skin colours are determined by genetics. Genetics of skin colours although quite complex. Racial skin colours are rather crude determination of human skin colours. This article will talk about skin colours in disease: albino and their underlying genetic mechanisms. The link of skin colours in human and albino might entertain the reader here.

There are large variations of cat coat colors which make cat breeders, cat lovers and scientists intrigue about the nature of these different shades, colors and patterns of their skin and fur for centuries. Until recently, that the comparative molecular genetics and newly developed techniques can uncover the genetic basis of these interesting characteristics of cats. These article series will talk about cat coat, color characters, and patterns and their genetic mechanisms and linking to human skin pigmentation understanding.

Skin and hairs or fur colors of mammalians including humans and cats are determined by many types of pigments. The most important one is called melanin. The cell produce melanin is called melanocytes. These cells are normally situated in the layer of skin cells or keratinocytes. Melanocytes will produce melanin by changing tyrosine, an amino acid, by the enzyme called tyrosinase through multiple steps.

There is constitutive production that is different among races and can be generally classified into three human races: Caucasian: white skin, Mongoloids: yellow skin and Negroids: dark skin. In cats, there is no such major groups. So we can see solid cats with color ranging from light brown, grey, to pure black. (Other characters and pattern will be discussed later) The production will be increased in some situations such as light, friction and injuries, or chemical agents and some disease states that can be generalized or localized such as freckles, melanoma, or malignant melanoma. Some genetic syndromes has increase incidence of these pigment disorders such as neurofibromatosis, McKune-Albright syndrome, Noonan syndrome and its spectrums.

In contrary, the rate of production can be reduced from various physical agents, chemical and disease conditions too. The disease with lowering production of melanin in human is called vitiligo that is usually localized but sometime can be generalized. A disease that has multiple small area of depigmentation causes only cosmetic problem. The disease as a fancie name: Hypomelanosis of Ito. The normal rate of production is primarily determined by racial difference in human and breed in cats and also the genetic mutation might switch off the production of melanin pigment at all which is so called albino. In the cat with complete no production of melanin pigments, the skin and fur are white, eyes will be in blue color. In human, all the hairs will be white and skin is also creamy white. Eyes are also blue like the cat eyes. This albino is called Oculocutaneous type 1a. Both cats and humans with this type of albino will have high incidence of skin cancers unravel the importance of melanin pigment for prevention of photodamage.

If the process is incomplete disruption, there will be some melanin produced leading to various level of dark color range from very light skin and hair to somewhat near normal pigment production. Clinical recognition of this mild form of albino is called Oculocutaneous type 1b. Normally, there will be no pigment production from birth like type 1 but lately produce some amount of melanin pigments that make light-brown or hazel color iris and dark eyelashes with some tanning of the skins. Oculocutaneous type I is autosomal dominant inherited. That means that the patients usually have one parent that also has the same condition. There is about 50% chance for transmission of the disease to the offspring and both male and female can be equally affected.

Recently, we found some families with typical type I albinism but with autosomal recessive like inherited pattern. There is no parent with the diseases but siblings. The parents are both carriers of the disease and normally, there will be some degree of consanguineous marriage. Genetic mutation underlying of this type of autosomal recessive albino is unknown.

There is some interesting feature of the pigment producing that leads to cat fanciers interest. It is called temperature sensitive albino. Some mutations in the tyrosinase genes make them sensitive to temperature change. It stops producing melanin when the temperature is high. So the terminal parts of their body that is colder will be darker than the body that is the characteristics of Siamese pointed cat breed, mink Tonkinese and Sepia Burmese breed. It is more interesting that we also found many families with show the features like this temperature sensitive albino cat breeds. Some areas that are less warn: facial and pubic hairs develop slightly pigmentation and arms and leg hairs which is cold will be normally pigmented.

Albino Chimpanzi and his normal friend

Temperature sensitive albino cat (Siamese cat - pointed breed)
Source: A Tyrosinase Gene Missense Mutation in Temperature-sensitive Type I Oculocutaneous Albinism
The same document with more demonstrative picture can be found at

Sunday, 31 July 2011

Gene patents: pros and cons (again)

There is a recent hot debate again about gene patents after the New York federal Judge Robert Sweet ruled that human gnee isolation is unpatentable. (2010) Seven patents involving genes and genetic diagnostic methods by Myriad Genetics were invalidated. A decade before, the United State Patent and Trademark office argued that gene sequences can be patented and it open the era of BRCA gene for breast cancer genes research and diagnostics in Europe and USA. The decision is under appealed and the European community is still unchanging but who know the future impact of this rule by the US legal system that always have a strong impact in world market.

In US patent law, the subject matter may be patentable if it belongs to one of four classes: a process, a machine, manufacture or composition of matter. It has to be new and non-obvious. In Europe, an isolated gene  from human body or produced by other technical process can be patented even if the structure of that element is identical to that of the natural element. In USA, in 1980, the Supreme court held that a human made, living, genetically modified bacterium, capable of breaking down components of crude oil was patentable. The products had to have markedly different characteristics from a product of nature. According to Judge sweet, the identification of the BRCA genes is unquestionably a valuable scientific achievement for which Myriad deserves recognition,  but that is not the same as concluding that it is something for which they are entitled for a patent. The techniques of purification and isolation of DNA are well-known to those skilled in the art and as a consequence, such claims on isolated DNA constitute unpatentable subject matter.

We will consider about the health care access, scientific research and moral issue of gene patents.
From the patent-pro stand points, patent exclusivity is needed to incentivize invention and innovation. Big pharmaceutical companies have benefited from this principle and claim that drug development and research cost them a lot. It is actually insufficient evident to conclude that patent system is the only effective system to encourage such invention and innovation.

Gene patents can limit the access to the particular gene based therapy, biologic drug and diagnostic modalities. Such restriction can increase patient burden and costs. Ethical and moral against human gene patents go further to human dignity. We are not the same as birds, flies, plants and bacteriu. It seems weird that someone can own the body of knowledge about somepart of the human, in this case, gene sequence and isolation for their own benefits. Although there is some objections of this moral argument, it is still debatable about what can be patented and what should not be patented based on different legal sets, big pharma or scientist, health care providers or people.

Genetics and miscarriage (2)

Genetics and miscarriage. Miscarriage or spontaneous abortion is the problem in nearly about 10% of known pregnancies. The etiologies are normally obscured. Recurrent problems are the nightmares for every families. To uncover the genetics causes of miscarriage might help in family planning and make a good decision among choices of reproduction. This paper is technical, please see the final conclusion about genetic and miscarriage that can get from this paper below.

High-throughput analysis of chromosome abnormality in spontaneous miscarriage using an MLPA subtelomere assay with an ancillary FISH test for polyploidy†

Damien L. Bruno1, Trent Burgess1, Hua Ren1, Sara Nouri1, Mark D. Pertile1, David I. Francis1, Fiona Norris1, Bronwyn K. Kenney1, Jan Schouten2, K.H. Andy Choo1, Howard R. Slater1,*Article first published online: 14 NOV 2006

Chromosome analysis of spontaneous miscarriages is clinically important but is hampered by frequent tissue culture failure and relatively low-resolution analysis. We have investigated replacement of conventional karyotype analysis with a quantitative subtelomere assay performed on uncultured tissue samples, which is based on Multiplex Ligation-Dependent Probe Amplification. This assay is suitable for this purpose as approximately 98% of all observed karyotype abnormalities in spontaneous miscarriages involve copy-number change to one or more subtelomere regions. A pilot study has compared karyotyping and subtelomere analysis on 78 samples. Extensive tissue necrosis accounted for failure of both karyotyping and subtelomere testing in four (5.1%) samples. Excluding these, there were no (0/74) subtelomere test failures compared to 9.5% (7/74) karyotype failures. Twenty-two (30%) whole chromosome aneuploidies and five (6.8%) structural abnormalities were detected using the subtelomere assay. With the exception of three cases of triploidy, all karyotype abnormalities were detected by the subtelomere assay. Following on from this study, a further 100 samples were tested using the subtelomere assay in conjunction with a simple ancillary FISH test using uncultured cells to exclude polyploidy in the event of a normal subtelomere assay result. Except for three necrotic samples, tests results were obtained for all cases revealing 18 abnormalities including one case of triploidy. Taking into consideration the high success rate for the combined MLPA and FISH test results, and the very significant additional advantages of cost-effective, high-throughput batching, and automated, objective analysis, this approach greatly facilitates routine investigation of chromosome abnormalities in spontaneous miscarriage

What does it mean from this paper?

We already knows that genetic play a substantive role in cases of miscarriages. To identify the underlying etiologies of specific family will be necessary for genetic counselling and planning for next pregnancy. This paper show that at the moment, the genetic test is revolutionalized to a very rapid and comprehensive style that can detect the genetic abnormalities and give the results to the patients and families with a satisfied proportion. Conventional methods using long and tedious process of cytogenetics method will be replaced by these techniques. Contact your local medical geneticists and genetic counselers for more information, Do not trust Direct to consumer genetic tests without genetic counselers service!

Friday, 29 July 2011

History of Medical genetics II

The 17th-century English Physician Kenelm Digby noted the presence of the double thumb in a n Algerian Muslim family, a trait that reportedly occured in five generations and was confined to females, although Digby personally observed only mother and daughter.

The earliest definitive example, however, was that published by Pierre Louis de Maupertius (whose more theoretical contributions are noted later). In 1753, he described a German family (the proband was a Berlin surgeon named Ruhe) in whom extra digits were inherited through four generations. Maupertius specifically nored that traits was trasmitted equally by father and mother.

He also estimate that if polydactyly had a frequency of 1 in 20000 in the general population, the likelihood of its appearing by chance in three subsequent generations is 1 in 8 trillion. However, his estimate should not be taken as precise, because his ascertainment of polydactyly undoubtedly depended on the occurence of multiple cases- although, whatever allownace one makes for this, there is still a convincing departure from chance!

History of Medical Genetics I

Before Mendel time (1)

The study of inherited disorders represents the core of medical genetics. It is quite clear, however, that specific observations on inherited disorders and more general thoughts about human inheritance have been at the fore-front of concepts of heredity at the very beginning, and do not represent just an afterthoughts o nlate arrival.

The period of before Mendel is the entire period up to the end of the 19th century, during the latter part of which Mendel's work already existed but remained unknown, and have left a discussion of Mendel's own contribution at the end.

Early family reports of some disorders now recoginzed as following Mendelian Inheritance Patterns

Autosomal dominant
Double Thumb                                  Digby 1645
Polydactyly                                       Maupertius 1753
Progressive blindness                        Martin 1809

Autosomal recessive
Albinism                                           Wafer 1699
Congenital deafness                          WIlde 1853
Congenital cataract                           Adams 1814

Color blindness                                Dalton 1798
Hemophilia                                       Otto 1803
Dechenned Muscular Dystrophy       Meryon 1852

Source: A Short History of Medical Genetics: Peter Harper

Genetics training: combined internal medicine/medical genetics

Internal Medicine / Medical Genetics Policies
The American Board of Internal Medicine and the American Board of Medical Genetics offer dual Certification in internal medicine and medical genetics. A combined residency includes a total of five years of coherent training integral to residencies in the two disciplines. The participating residencies must be within a single institution and its affiliated hospitals.

Both Boards encourage residents to extend their training for an additional sixth year in investigative, administrative or academic pursuits in order to prepare graduates of combined training in medial genetics and internal medicine programs for careers in research, teaching or departmental administration.

To meet the eligibility requirements for the Certification processes in internal medicine and medical genetics, the resident must satisfactorily complete 60 months of combined training leading to satisfactory performance in the six competencies that is verified by the director and associate director or the co-directors of these combined training programs.

Please follow the link: