Microcephaly

From bonepath

Microcephaly refers to the condition of having a cranial circumference more than 2 (Kaindl et al. 2010) or 3 (Woods 2004; Waldron 2009) standard deviations below an age- and sex-specific mean circumference. This is an important distinction because cranial sizes up to 2 standard deviations below the population mean generally do not lead to mental impairment, whereas cranial circumference at least 3 standard deviations below the mean almost always result in mental retardation. The characteristic phenotype of a very small brain case but usually ‘normal’ sized facial skeleton results from the brain’s failure to grow. This aberrant neurological development can occur prior to birth (“primary microcephaly”), or can be normal prenatally and aberrant only postnatally (“secondary microcephaly; Woods 2004, Woods et al. 2005).

Aberrant neural growth and development, and so microcephaly, can result from a number of conditions, many of which are congenital but not syndromic. Autosomal Recessive Primary Microcephaly (“MCPH”), for example, is a recessive condition caused by having two copies of mutant alleles at any loci of the “microcephalin” gene family (MCPH1-7; Woods 2004, Kaindl et al. 2010), though it is likely that other unidentified loci can also be involved. According to Woods and colleagues (2005: 722) “all data to date suggest that MCPH is a primary disorder of neurogenic mitosis,” (i.e. of neural cell proliferation) and thereby brain growth. The clinical definition (or manifestation) of the of the condition is a head circumference at 4 standard deviations below average (neonatally and onward), and mental retardation. An autosomal recessive disease, this condition has a general prevalence of 1 to 150 of 100,000 live births (Woods et al. 2005), and has a much higher frequency in areas where consanguineous marriage (i.e. to closely related individuals) is common (Woods et al. 2005, Darvish et al. 2010).

Microcephaly can also be syndromic. Laron Syndrome (LS) is another autosomal-recessive cause of primary mirocephaly. Unlike MCPH, LS affects not only the brain but results in total somatic dwarfism, and is caused by a defective Growth Hormone receptor (GHR) gene (Zhou et al. 1997, Laron 2004). For additional symptoms of the condition, see the recent review by Laron (2004). Microcephaly often accompanies primordial (congenital) dwarfism in conditions such as Seckel Syndrome (due to a defective ATR gene; O’Driscoll et al. 2004), Meier-Gorlin syndrome (Bicknell et al. 2011) and Majewski osteodysplastic primordial dwarfism type II (MOPD II; Hall et al. 2004). Non-congenital etiologies include of microcephaly maternal alcohol consumption during pregnancy (e.g. fetal alcohol syndrome), maternal syphilis and poor prenatal care.

[edit] Examples from Ford Collection

• 96-11-107
• 96-11-125
• 96-11-126
• 96-11-128
• 96-11-129
• 96-11-131
• 96-11-132
• 96-11-136
• 96-11-159
• 96-11-160
• 96-11-161
• 96-11-162

[edit] References

Bicknell LS, Bongers EM, Leitch A, Brown S, et al. 2011. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet 43:356-9

Hall JG, Flora C, Scott CI, Pauli RM, Tanaka KI. 2004. Majewski osteodysplastic primordial dwarfism type II (MOPD II): natural history and clinical findings. Am J Med Genet A 130A:55-72

Kaindl AM, Passemard S, Kumar P, Kraemer N, et al. 2010. Many roads lead to primary autosomal recessive microcephaly. Prog Neurobiol 90:363-83

Laron Z. 2004. Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. Journal of Clinical Endocrinology & Metabolism 89:1031

O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA. 2003. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497-501

Waldron T. 2009. Paleopathology. New York: Cambridge University Press.

Woods CG. 2004. Human microcephaly. Curr Opin Neurobiol 14:112-7

Woods CG, Bond J, Enard W. 2005. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. The American Journal of Human Genetics 76:717-28

Zhou Y, Xu BC, Maheshwari HG, He L, et al. 1997. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A 94:13215-20