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 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. It also means that parents of children with MOPDII have a 25% chance with each pregnancy of having another child with MOPDII.

 
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

Probably the most consistent physical characteristic in these 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 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:
  • Fine and relatively sparse hair
  • Pigmentary changes of the skin, such as acanthosis nigricans
What are the X-ray characteristics?

In the newborn, 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 the children 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.

 
Making the Diagnosis

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.

 
Associated Medical Problems
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.

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