Microcephaly Syndromes
Section snippets
Diagnosis
The OFC should be determined by placing a measuring tape around the cranial vault to include the widest part of the forehead and the most prominent part of the occipital area to arrive at the largest possible measurement. If abnormal, a second measurement should be performed to confirm the result. Accurate head circumference measurements at birth can be of crucial importance in contributing to determining the timing and etiology of the brain insult but unfortunately are not always done or
Incidence
It is not possible to quote a reliable figure from the literature because a variety of estimates have been published, reflecting differences in both definitions and methodology. The general incidence using the definition of −3 SD is about 1 per 10,000.2 The incidence from the Collaborative Perinatal Project was estimated to be 1:1,360. There are other estimates both above and below that figure, depending on characteristics (eg, consanguinity) of the population studied.1
Classification
Microcephaly can be isolated, with no other obvious abnormalities, or it may be associated with other anomalies, which is termed syndromic. When present at birth, it has been termed “primary” microcephaly as opposed to “secondary” microcephaly, which develops later.6 Some authors believe that the term primary microcephaly should be used to imply genetic influences, whereas secondary microcephaly would designate factors that are environmental in nature.1 Here again is a potentially confusing
Pathogenesis
Pathogenesis is very heterogeneous, which can present a challenge for the clinician attempting to determine whether environmental or genetic factors are causative (Table 1). These factors may act prenatally, perinatally, or postnatally to inhibit brain growth.
Environmental causes include hypoxic-ischemic encephalopathy; vascular or viral induced disruption7, 8, 9; intrauterine infection (eg, with rubella, cytomegalovirus, or toxoplasmosis); teratogens such as alcohol, hydantoin, and radiation;
Isolated Microcephaly
“Microcephaly vera” or true microcephaly has been defined14 as being uncomplicated by other anomalies, present at birth, with normal pregnancy, delivery, and postnatal periods, compatible with normal early gross motor development, and nonprogessive. The brain has normal architecture but is small. The phenotype includes a receding forehead (Fig 1), a normal-size face, and ears that appear somewhat large in proportion to the cranium. Stature can be somewhat short. This condition has long been
How To Search for Syndromes
This article includes descriptions of a representative sample of the syndromes that are associated with small head size, which we have chosen because they have distinctive, recognizable phenotypes. We will not review the common trisomies22, 18, 13 here because their phenotypes are familiar to most clinicians, and their definitive diagnoses are made easily on routine chromosome analysis. For other conditions, the reader is referred to textbooks that include large listings26 and databases
Smith-Lemli-Opitz Syndrome (OMIM #270400)
Affected infants are identified by typical dysmorphism and/or characteristic congenital anomalies. There is ptosis of the eyelids, broad nasal tip with anteverted nostrils, and micrognathia (Fig 3). Approximately 50% have congenital heart disease (eg, atrial septal defect, ventricular septal defect, endocardial cushion defect, and hypoplastic left heart), and 70% have genital abnormalities (eg, hypospadias and cryptorchidism). Most have syndactyly of the 2nd and 3rd toes; many have postaxial
Clinical Evaluation of Patients With Microcephaly
The first step is to obtain the prenatal and birth histories, which include the maternal medical and medication information, evidence of possible infection, and questions about substance abuse. The birth history should include Apgar scores and head measurements, and the neonatal history and developmental milestones should be noted. The family history should include questions about similarly affected individuals or other possible manifestations of the condition. A complete physical and
After the Birth of an Affected Child
Accurate genetic counseling depends on arriving at a correct etiologic diagnosis in the proband. To give some examples of genetic counseling for the syndromes described previously, in the case of Wolf-Hirschhorn syndrome, Williams syndrome, or other chromosome deletions, parental karyotypes must be obtained before recurrence risk figures can be given to rule out the possibility that one of the parents carries a balanced translocation. If either parent is a translocation carrier, prenatal
Conclusion
There are a variety of causes of microcephaly, which can present an initial challenge for the clinician. However, if one takes a complete history and family history, performs a thorough physical examination focusing on dysmorphism in both the patient and the parents, obtains appropriate laboratory tests and imaging studies, and searches the available textbooks and databases, a diagnosis can frequently be made. This can be helpful not only for managing the patient but also for providing genetic
References (47)
- et al.
Familial variation of head size and adjustment for parental head circumference
J Pediatr
(1980) Human microcephaly
Curr Opin Neurobiol
(2004)- et al.
Fetal brain disruption sequence
J Pediatr
(1990) - et al.
Abnormally small head size and intellect in children
J Pediatr
(1968) - et al.
Identification of microcephalin, a protein implicated in determining the size of the human brain
Am J Hum Genet
(2002) - et al.
Protein-truncating mutations in ASPM cause variable reduction in brain size
Am J Hum Genet
(2003) - et al.
Autosomal recessive primary microcephaly (MCPH): A review of clinical, molecular and evolutionary findings
Am J Hum Genet
(2005) A small step for the cell, a giant leap for mankind: A hypothesis of neocortical expansion during evolution
Trends Neurosci
(1995)- et al.
Autosomal dominant microcephaly
J Pediatr
(1979) - et al.
Renpenning syndrome maps to Xp11
Am J Hum Genet
(1998)