Primordial Dwarfism

Five children with primordial dwarfism

Primordial has been defined as belonging to or being characteristic of the earliest stages of development of an organism. Therefore, Primordial Dwarfism is a class of disorders where growth delay occurs at the earliest stages of development. Unlike some of the other forms of dwarfism where newborn infants can have average lengths, children with Primordial Dwarfism are born smaller than average and have intrauterine growth retardation (IUGR).

 
Conditions Making Up the Class of Primordial Dwarfism

Unlike some of the other conditions described on this website, primordial dwarfism is not a specific diagnosis.

It is in fact a class of disorders to which at least 5 different conditions are currently grouped:

  • Russell-Silver syndrome
  • Seckel syndrome
  • Meier-Gorlin syndrome
  • Majewski osteodysplastic primordial dwarfism (MOPD) Types I/III
  • MOPD Type II

The Russell-Silver, Seckel and Meier-Gorlin syndromes are relatively well defined entities and we will not discuss them here.

We will limit our discussion to MOPD Type II. Most of the information below can be examined in more detail in Hall et. al (1).

 
How Common Is Primordial Dwarfism?

All of the conditions that make up primordial dwarfism are quite rare and very little is known concerning the incidences. For MOPD Type II, we estimate that there are no more than 100 patients in the United States and Canada giving a rough estimate of 1 in 3 million.

 
How MOPD Type II Is Inherited

MOPDII has an autosomal recessive pattern. This means that the genetic information from both parents was necessary for the child to have this condition. This means that the genetic information from both parents was necessary for the child to have primordial dwarfism.

 
Causes of MOPD Type II

Everyone has two copies of a gene called pericentrin (PCNT).  MOPDII results when there is a gene change (mutation) in each copy of an individual’s pericentrin gene, causing both copies to be nonfunctional (2).

 
Physical Characteristics of Primordial Dwarfism

Probably the most consistent physical characteristic of primordial dwarfism in children is severe intrauterine growth retardation (IUGR). Recognition of the deficiency can occur as early as 13-weeks gestation and it becomes progressively more severe over the length of the pregnancy.

At term, infants with primordial dwarfism typically weigh less than 3 lbs and are less than 16 inches in length. This is about the average size of a 28-week premature neonate. However, some children with genetically confirmed MOPDII have been born larger than this. Adult heights are typically less than 33" and the voice is high pitched.

Face & Skull
  • Microcephaly. Head size is proportionate to body size at birth. However, as children grow and develop, the head grows slower than the body and becomes disproportionately small.
  • Premature closure of the soft spots (fontanelles) and craniosynostosis
  • Prominent nose and eyes. The conspicuous nose may be obvious at birth or it may develop over the first year.
  • Small teeth with deficient enamel and increased spaces between them. Small roots in the secondary teeth. Secondary teeth can be missing or lost prematurely.
Trunk, Chest, & Spine:
  • Proportionately small trunk, chest, and spine
  • Scoliosis and thoracic kyphosis in later childhood
Arms & Legs:
  • Disproportionately short forearm in childhood, causing mesomelia
  • Dislocated radial head with decreased range of motion at the elbows
  • Dislocated hips and coxa vara at birth
  • Ligamentous laxity develops with age
Other Characteristics of Primordial Dwarfism:
  • Fine and relatively sparse hair
  • Pigmentary changes of the skin, such as acanthosis nigricans
What are the X-ray characteristics of primordial dwarfism?

In newborns with primordial dwarfism, the X-rays typically do not demonstrate major structural abnormalities, although the pelvis is narrow with small iliac wings and flattened acetabular angles. The long bones may be overtubulated. Eleven rib pairs are sometimes seen, rather than twelve. As children with primordial diagnosis age, the bones appear thin and delicate with progressive metaphyseal widening at the ends of the long bones.

Bone age studies usually show decreased bone age; that is, the skeletal maturation process is slowed in these children and can be delayed 2 - 5 years behind the actual age.

 
Diagnosing Primordial Dwarfism

The differential diagnosis for MOPD II is complex and is done clinically based upon history, physical characteristics, radiographic review and the exclusion of any other physical findings or laboratory abnormalities.

There is also research genetic testing available either through Texas
or Scotland that can help confirm what type of primordial dwarfism an individual has.

 
Medical Problems Associated With Primordial Dwarfism
Nutrition

Most infants with primordial dwarfism have feeding problems, but it is important that the treating physican lower their expectations of daily growth to at least half that of a typical child.

Small volumes and frequent feeding are typical. Sometimes naso-gastric feeding or g-tube feedings are used.

Brain

Some patients have structural or myelination abnormalities in the brain. Structural abnormalities have included: enlarged ventricles, abnormal gyral patterns and abnormal corpus callosum.

Development

Precocious puberty has been described in girls with breast development as early as 7 and menarche, or the beginning of periods, at 9 years. Boys do not seem to have precocious puberty.

 
Recommended Monitoring

Renal or kidney anomalies have been described and a renal ultrasound should be done as the diagnosis is being established.

Most of the patients develop farsightedness which requires glasses. Careful ophthalmologic evaluation is indicated at regular intervals.

A vast majority of individuals with MOPDII have had abnormalities in the cerebral vascular system, including moyamoya disease and aneurysms, which can predispose to stroke. Screenings with MRA/CTA of the brain should begin at diagnosis of MOPDII and continue every 12 to 18 months thereafter to permit early detection of these conditions. If diagnosed in the early stages, revascularization and aneurysm treatment can be performed safely and effectively. (3)

Insulin resistance is associated with MOPDII and can often progress to frank diabetes. Yearly screening labs should begin by 5 years of age and include: hemoglobin A1C, insulin levels, fasting blood sugars, liver functions and lipid profiles. The physician should maintain a high degree of suspicion and if any signs or symptoms develop, further testing is indicated. If changes are present, appropriate follow-up and management plans can be implemented. It does appear that these patients respond well to an oral antihyperglycemic medication like metformin. (4)

A yearly CBC should also be obtained as some children, especially post-pubertal girls, have developed anemia. Furthermore, it does appear that baseline platelet counts may be elevated. The clinical significance of this remains to be determined.

 
References
  1. Hall JG, Flora C, Scott CI Jr., Pauli RM, Tanaka KI. Majewski osteodysplastic primordial dwarfism type II (MOPDII): natural history and clinical findings. Am J Med Genet A. 2004 Sep 15;130A(1):55-72.
  2. Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dörfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, Voss E, Wilson L, Hennekam R, de Zegher F, Dörr HG, Reis A.  Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science. 2008 Feb 8; 319(5864):816-9.
  3. Bober MB, Khan N, Kaplan J, Lewis K, Feinstein JA, Scott CI Jr, Steinberg GK. Majewski osteodysplastic primordial dwarfism type II (MOPD II): expanding the vascular phenotype. Am J Med Genet A. 2010 Apr;152A(4):960-5.
  4. Huang-Doran I, Bicknell LS, Finucane FM, Rocha N, Porter KM, Tung YC, Szekeres F, Krook A, Nolan JJ, O'Driscoll M, Bober M, O'Rahilly S, Jackson AP, Semple RK; for the Majewski Osteodysplastic Primordial Dwarfism Study Group. Genetic Defects in Human Pericentrin Are Associated With Severe Insulin Resistance and Diabetes. 2011 Mar;60(3):925-35. Epub 2011 Jan 26.

Trusted Insights from Nemours' KidsHealth

Genetic Counseling

If you and your partner are newly pregnant, you may be amazed at the number and variety of prenatal tests available to you. Blood tests, urine tests, monthly medical exams, diet questionnaires, and family history tracking — each helps to assess the health of you and your baby, and to predict any potential health risks.

Unlike your parents, you may also have the option of genetic testing. These tests identify the likelihood of passing certain genetic diseases or disorders (those caused by a defect in the genes — the tiny, DNA-containing units of heredity that determine the characteristics and functioning of the entire body) to your children.

Some of the more familiar genetic disorders are:

If your history suggests that genetic testing would be helpful, you may be referred to a genetic counselor. Or, you might decide to seek out genetic counseling yourself.

But what do genetic counselors do, and how can they help your family?

What Is Genetic Counseling?

Genetic counseling is the process of:

  • evaluating family history and medical records
  • ordering genetic tests
  • evaluating the results of this investigation
  • helping parents understand and reach decisions about what to do next

Genetic tests are done by analyzing small samples of blood or body tissues. They determine whether you, your partner, or your baby carry genes for certain inherited disorders.

Genes are made up of DNA molecules, which are the simplest building blocks of heredity. They're grouped together in specific patterns within a person's chromosomes, forming the unique "blueprint" for every physical and biological characteristic of that person.

Humans have 46 chromosomes, arranged in pairs in every living cell of our bodies. When the egg and sperm join at conception, half of each chromosomal pair is inherited from each parent. This newly formed combination of chromosomes then copies itself again and again during fetal growth and development, passing identical genetic information to each new cell in the growing fetus.

Current science suggests that human chromosomes carry from 25,000 to 35,000 genes. An error in just one gene (and in some instances, even the alteration of a single piece of DNA) can sometimes be the cause for a serious medical condition.

Some diseases, such as Huntington's disease (a degenerative nerve disease) and Marfan syndrome (a connective tissue disorder), can be inherited from just one parent. Most disorders, including cystic fibrosis, sickle cell anemia, and Tay-Sachs disease, cannot occur unless both the mother and father pass along the gene.

Other genetic conditions, such as Down syndrome, are usually not inherited. In general, they result from an error (mutation) in the cell division process during conception or fetal development. Still others, such as achondroplasia (the most common form of dwarfism), may either be inherited or the result of a genetic mutation.

Genetic tests don't yield easy-to-understand results. They can reveal the presence, absence, or malformation of genes or chromosomes. Deciphering what these complex tests mean is where a genetic counselor comes in.

About Genetic Counselors

Genetic counselors are professionals who have completed a master's program in medical genetics and counseling skills. They then pass a certification exam administered by the American Board of Genetic Counseling.

Genetic counselors can help identify and interpret the risks of an inherited disorder, explain inheritance patterns, suggest testing, and lay out possible scenarios. (They refer you to a doctor or a laboratory for the actual tests.) They will explain the meaning of the medical science involved, provide support, and address any emotional issues raised by the results of the genetic testing.

Who Should See One?

Most couples planning a pregnancy or who are expecting don't need genetic counseling. About 3% of babies are born with birth defects each year, according to the Centers for Disease Control and Prevention (CDC) — and of the malformations that do occur, the most common are also among the most treatable. Cleft palate and clubfoot, two of the more common birth defects, can be surgically repaired, as can many heart malformations.

The best time to seek genetic counseling is before becoming pregnant, when a counselor can help assess your risk factors. But even after you become pregnant, a meeting with a genetic counselor can still be helpful. For example, sometimes babies have been diagnosed with spina bifida before birth. Recent research suggests that delivering a baby with spina bifida via cesarean section (avoiding the trauma of travel through the birth canal) can minimize damage to the spine — and perhaps reduce the likelihood that the child will need a wheelchair.

Experts recommend that all pregnant women, regardless of age or circumstance, be offered genetic counseling and testing to screen for Down syndrome.

It's especially important to consider genetic counseling if any of the following risk factors apply to you:

  • a standard prenatal screening test (such as the alpha fetoprotein test) yields an abnormal result
  • an amniocentesis yields an unexpected result (such as a chromosomal defect in the unborn baby)
  • either parent or a close relative has an inherited disease or birth defect
  • either parent already has children with birth defects or genetic disorders
  • the mother-to-be has had two or more miscarriages or babies that died in infancy
  • the mother-to-be will be 35 or older when the baby is born. Chances of having a child with Down syndrome increase with the mother's age: a woman has a 1 in 350 chance of conceiving a child with Down syndrome at age 35, a 1 in 110 chance at age 40, and a 1 in 30 chance at age 45.
  • you are concerned about genetic defects that occur frequently in certain ethnic or racial groups. For example, couples of African descent are most at risk for having a child with sickle cell anemia; couples of central or eastern European Jewish (Ashekenazi), Cajun, or Irish descent may be carriers of Tay-Sachs disease; and couples of Italian, Greek, or Middle Eastern descent may carry the gene for thalassemia, a red blood cell disorder.

Meeting With a Genetic Counselor

Before you meet with a genetic counselor in person, you'll be asked to gather information about your family history. The counselor will want to know of any relatives with genetic disorders, multiple miscarriages, and early or unexplained deaths. The counselor will also want to look over your medical records, including any ultrasounds, prenatal test results, past pregnancies, and medications you may have taken before or during pregnancy.

If more tests are necessary, the counselor will help you set up those appointments and track the paperwork. When the results come in, the counselor will call you with the news and often will encourage you to come in for a discussion.

The counselor will study your records before meeting with you, so you can make the best use of your time together. During the session, you'll go over any gaps or potential problem areas in your family or medical history. The counselor can help you understand the inheritance patterns of any potential disorders and help assess your chances of having a child with those disorders.

The counselor will distinguish between risks that every pregnancy faces and risks that you personally face. Even if you discover you have a particular problem gene, science can't always predict the severity of the related disease. For instance, a child with cystic fibrosis can have debilitating lung problems or, less commonly, milder respiratory symptoms.

After Counseling

Genetic counselors can help you understand your options and adjust to any uncertainties you face, but you and your family will have to decide what to do next.

If you've learned prior to conception that you and/or your partner are at high risk for having a child with a severe or fatal defect, your options might include:

  • pre-implantation diagnosis — when eggs that have been fertilized in vitro (in a laboratory, outside of the womb) are tested for defects at the 8-cell (blastocyst) stage, and only nonaffected blastocysts are implanted in the uterus to establish a pregnancy
  • using donor sperm or donor eggs
  • adoption
  • taking the risk and having a child
  • establishing pregnancy and have specific prenatal testing

If you've received a diagnosis of a severe or fatal defect after conception, your options might include:

  • preparing yourself for the challenges you'll face when you have your baby
  • fetal surgery to repair the defect before birth (surgery can only be used to treat some defects, such as spina bifida or congenital diaphragmatic hernia, a hole in the diaphragm that can cause severely underdeveloped lungs. Most defects cannot be surgically repaired.)
  • ending the pregnancy

For some families, knowing that they'll have an infant with a severe or fatal genetic condition seems too much to bear. Other families are able to adapt to the news — and to the birth — remarkably well.

Genetic counselors can share the experiences they've had with other families in your situation. But they will not suggest a particular course of action. A good genetic counselor understands that what is right for one family may not be right for another.

Genetic counselors can, however, refer you to specialists for further help. For instance, many babies with Down syndrome are born with heart defects. Your counselor might encourage you to meet with a cardiologist to discuss heart surgery, and a neonatologist to discuss the care of a post-operative newborn. Genetic counselors can also refer you to social workers, support groups, or mental health professionals to help you adjust to and prepare for your complex new reality.

Finding a Genetic Counselor

Working with a genetic counselor can be reassuring and informative, especially if you or your partner have known risk factors. Talk to your doctor if you feel you would benefit from genetic counseling. Many doctors have a list of local genetic counselors with whom they work. You can also contact the National Society of Genetic Counselors for more information.

Reviewed by: Louis E. Bartoshesky, MD, MPH
Date reviewed: June 2010
Originally reviewed by: Linda Nicholson, MS, MC