Primordial Dwarfism Causes & Symptoms

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About Microcephalic Osteodysplastic Primordial Dwarfism Type II


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 have intrauterine growth retardation (IUGR) and are born smaller than average. We will limit our discussion to one specific kind of primordial dwarfism here: microcephalic primordial dwarfism type II (MOPDII). Most of the information below can be examined in more detail in Bober and Jackson (1).

Little is known concerning the incidence. We estimate that there are around 100 individuals in the United States and Canada, giving a rough estimate of 1 in 3 million.

MOPDII has an autosomal recessive inheritance pattern. This means that the genetic information from both parents is necessary for the child to have MOPDII, and there would be a 25% recurrence chance in future pregnancies.

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 not work as they usually do (2).

Probably the most consistent physical characteristic of MOPDII is severe intrauterine growth retardation (IUGR) before birth, and very slow growth after birth. This can be recognized as early as 13 weeks’ gestation, and it becomes more apparent over the length of the pregnancy.

At term, infants with MOPDII typically weigh less than 3 pounds and are less than 16 inches long. This is about the average size of a 28-week premature neonate. However, some children with MOPDII have been born larger than this. Average height for an adult with MOPDII is around 33" (3).

Face and Skull

  • Microcephaly. Head size is basically proportionate to the small body size at birth. However, as children grow and develop, the head grows slower than the body and becomes disproportionately small.  As an adult the head will still be the size of a typical infant’s head.
  • Premature closure of the soft spots (fontanelles) and craniosynostosis can sometimes occur
  • Prominent nose and eyes. This may be obvious at birth or it may become more distinctive over the first year of life.
  • Teeth are small with deficient enamel and increased spaces between them. The secondary teeth are usually misshapen, with small, short, or missing roots.  This leads them to be “wiggly”, and often lost prematurely.
  • High-pitched voice

Trunk, Chest and Spine

  • proportionately small trunk, chest and spine
  • scoliosis and thoracic kyphosis in later childhood

Arms and Legs

  • disproportionately short forearms, called mesomelia
  • dislocated radial head with decreased range of motion at the elbows
  • hip differences like coxa vara, and can develop slipped capital femoral epiphyses in early childhood
  • ligamentous laxity develops with age

Other Characteristics

  • fine and relatively sparse hair
  • pigmentary (color) changes of the skin can sometimes develop, such as darker or lighter patches, or something called acanthosis nigricans which can relate with insulin resistance

X-Ray Characteristics

In newborns with MOPDII, the X-rays typically do not show major structural problems, although the pelvis is narrow with small iliac wings and flattened acetabular angles. As children with MOPDII get older, the bones can appear thin and delicate with progressive metaphyseal widening at the ends of the long bones. This is in addition to the hip and spine issues that can sometimes develop, as noted above.

Bone age studies usually show decreased bone age. That is, the skeletal maturation process is slowed in these children and can be read as delayed 2–5 years behind the chronologic age.

There is genetic testing clinically available to confirm this diagnosis. MOPDII is associated with changes in a gene called pericentrin (PCNT).

 

Nutrition

Many infants with MOPDII have been described as having feeding problems. However, it is important that the care provider lower their expectations of daily growth to 2 grams/day in the newborn period as well as throughout childhood (4). With the proper perspective, most children with MOPDII are noted to eat appropriately for their size and growing ability.

Small volumes and frequent feeding are typical. Sometimes nasogastric feeding or g-tube feedings are used, but unclear how often that is actually needed.


Development

Even though the head size is small, cognitive development is close to typical for individuals who have not had any associated strokes.


Vasculature

A majority of individuals with MOPDII will develop moyamoya, brain aneurysms, or both.  Moyamoya is diagnosed at a younger age than aneurysms, as early as the neonatal period.  Aneurysm risk continues throughout the lifespan. (5) If diagnosed in the early stages, revascularization and aneurysm treatment can be performed safely and effectively (6).

Renal, coronary, and external carotid arteries can also develop stenosis. Hypertension has been noted in about half of the individuals with MOPDII who have been measured (5).


Cardiac

Some individuals have structural heart defects at birth, and/or coronary artery disease as young adults (5)


Genitourinary

Some individuals have structural differences at birth.  Chronic kidney disease has also been noted in about a third of adults with MOPDII. (5)


Endocrine

Insulin resistance is associated with MOPDII and can progress to frank diabetes (7), often in the teens.


Hematologic

Asymptomatic anemia and thrombocytosis are often seen. (5)

Congenital renal and kidney anomalies have been described, so a renal ultrasound and an echocardiogram should be performed when the diagnosis is made (1)

Given dental differences, routine dental care should begin once teeth erupt (1).

Serial screening of hips is recommended in early childhood, as is monitoring for scoliosis as the child approaches puberty (1).

Moyamoya disease and aneurysms can predispose to stroke. Screening with MRA/CTA of the brain should begin at diagnosis of MOPDII and continue every 12 to 18 months thereafter for early detection (5).

Yearly screening labs for insulin resistance should begin by 5 years of age and include studies of glucose homeostasis, liver function, and lipid profiles.  Once diagnosed, many individuals with MOPDII respond well to an oral diabetes medication like metformin. (7)  Once identified, hypercholesterolemia is often treated with statins. (5)

Blood pressure should be monitored by a specialist such as a nephrologist or cardiologist, once school-aged (5).

References
  1. Bober MB, Jackson AP. Microcephalic Osteodysplastic Primordial Dwarfism, Type II: a Clinical Review. Curr Osteoporos Rep. 2017 Apr;15(2):61-69.
  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; 319(5864):816-9.
  3. Bober MB, Niiler T, Duker AL, Murray JE, Ketterer T, Harley ME, Alvi S, Flora C, Rustad C, Bongers EM, Bicknell LS, Wise C, Jackson AP. Growth in individuals with Majewski osteodysplastic primordial dwarfism type II caused by pericentrin mutations. Am J Med Genet A. 2012 Nov;158A(11):2719-25.
  4. Duker AL, Niiler T, Bober MB. Expected weight gain for children with microcephalic osteodysplastic primordial dwarfism type II. Am J Med Genet A. 2017 Nov;173(11):3067-3069.
  5. Duker AL, Kinderman D, Jordan C, Niiler T, Baker-Smith CM, Thompson L, Parry DA, Carroll RS, Bober MB. Microcephalic osteodysplastic primordial dwarfism type II is associated with global vascular disease. Orphanet J Rare Dis. 2021 May 20;16(1):231.
  6. Teo M, Johnson JN, Bell-Stephens TE, Marks MP, Do HM, Dodd RL, Bober MB, Steinberg GK. Surgical outcomes of Majewski osteodysplastic primordial dwarfism Type II with intracranial vascular anomalies. J Neurosurg Pediatr. 2016 Dec;25(6):717-723.
  7. 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. Diabetes.2011 Mar;60(3):925-35.

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