Microcephaly

Microcephaly

Head circumference more than 2 standard deviations below the mean for sex and gestational age. Terms that are sometimes used synonymously: microcrania, microcephalus. Not a single entity, many conditions may be associated with microcephaly. It may also result from maternal cocaine abuse. It is important to differentiate microcephaly from a small skull resulting from craniosynostosis in which surgical treatment may provide opportunity for improved cerebral development.

Etiology

Effects of maternal cocaine use on the fetal nervous system include: microcephaly 1).

May be present in Dandy Walker malformationAgenesis of the corpus callosumHydranencephaly.

Overshunting (controversial): Microcephaly accounted for ≈ 6% of skull deformities after shunting (about half of these had sagittal synostosis). Some of these changes were reversible (except when complete synostosis was present) if intracranial hypertension recurred.

Diagnosis

Occipitofrontal circumference:

Deviations below the curves or head growth in the premature infant in the neonatal period of less than 0.5 cm/wk (excluding the first few weeks of life) may indicate microcephaly.

Associations

Holoprosencephaly with:

Cyclopia

Ethmocephaly

Cebocephaly

with median cleft lip

with median philtrum-premaxilla anlage

Shaheen et al., previously suggested that a single founder splicing variant in human CTU2 causes a multiple congenital anomalies syndrome consisting of dysmorphic facies, renal agenesis, ambiguous genitalia, microcephalypolydactyly, and lissencephaly (DREAM-PL).

They described five new patients with DREAM-PL phenotype and whose molecular analysis expands the allelic heterogeneity of the syndrome to five different alleles; four of which predict protein truncation. Functional characterization using patient-derived cells for each of these alleles, as well as the original founder allele; revealed a specific impairment of wobble uridine thiolation in all known thiol-containing tRNAs.

This data establish a recognizable CTU2-linked autosomal recessive syndrome in humans characterized by defective thiolation of the wobble uridine. The potential deleterious consequences for the translational efficiency and fidelity during development as a mechanism for pathogenicity represent an attractive target of future investigations 2).


Majewski osteodysplastic primordial dwarfism Type II (MOPD II) is a rare genetic disorder. Features of it include extremely small stature, severe microcephaly, and normal or near-normal intelligence. Previous studies have found that more than 50% of patients with MOPD II have intracranial vascular anomalies, but few successful surgical revascularization or aneurysm-clipping cases have been reported because of the diminutive arteries and narrow surgical corridors in these patients.

Teo et al., report on a large series of patients with MOPD II who underwent surgery for an intracranial vascular anomaly.

In conjunction with an approved prospective registry of patients with MOPD II, a prospectively collected institutional surgical database of children with MOPD II and intracranial vascular anomalies who underwent surgery was analyzed retrospectively to establish long-term outcomes.

Ten patients with MOPD II underwent surgery between 2005 and 2012; 5 patients had moyamoya disease (MMD), 2 had intracranial aneurysms, and 3 had both MMD and aneurysms. Patients presented with transient ischemic attack (TIA) (n = 2), ischemic stroke (n = 2), intraparenchymal hemorrhage from MMD (n = 1), and aneurysmal subarachnoid hemorrhage (n = 1), and 4 were diagnosed on screening. The mean age of the 8 patients with MMD, all of whom underwent extracranial-intracranial revascularization (14 indirect, 1 direct) was 9 years (range 1-17 years). The mean age of the 5 patients with aneurysms was 15.5 years (range 9-18 years). Two patients experienced postoperative complications (1 transient weakness after clipping, 1 femoral thrombosis that required surgical repair). During a mean follow-up of 5.9 years (range 3-10 years), 3 patients died (1 of subarachnoid hemorrhage, 1 of myocardial infarct, and 1 of respiratory failure), and 1 patient had continued TIAs. All of the surviving patients recovered to their neurological baseline.

Patients with MMD presented at a younger age than those in whom aneurysms were more prevalent. Microneurosurgery with either intracranial bypass or aneurysm clipping is extremely challenging but feasible at expert centers in patients with MOPD II, and good long-term outcomes are possible 3).

References

1)

Volpe JJ. Effect of Cocaine Use on the Fetus. N Engl J Med. 1992; 327:399–407
2)

Shaheen R, Mark P, Prevost CT, AlKindi A, Alhag A, Estwani F, Al-Sheddi T, Alobeid E, Alenazi MM, Ewida N, Ibrahim N, Hashem M, Abdulwahab F, Bryant EM, Spinelli E, Millichap J, Barnett SS, Kearney HM, Accogli A, Scala M, Capra V, Nigro V, Fu D, Alkuraya FS. Biallelic Variants in CTU2 Cause DREAM-PL Syndrome and Impair Thiolation of tRNA Wobble U34. Hum Mutat. 2019 Jul 13. doi: 10.1002/humu.23870. [Epub ahead of print] PubMed PMID: 31301155.
3)

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. PubMed PMID: 27611897.

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