Significant overlap and possible identity of macrocephaly capillary malformation and megalencephaly polymicrogyria‐polydactyly hydrocephalus syndromes

Abstract

We report on three patients with macrocephaly and polymicrogyria, and additional anomalies seen in megalencephaly polymicrogyria-polydactyly hydrocephalus (MPPH) and macrocephaly capillary malformation (MCM) syndromes. Based on their characteristic brain malformations they were originally diagnosed with MPPH. In one patient the phenotype evolved during early infancy, and ultimately resulted in a diagnosis of MCM. A second was prenatally diagnosed with MPPH, but postnatally visualized capillary malformations led to a diagnosis of MCM. In a third, the original MPPH diagnosis was reconsidered after a critical review revealed additional subtle findings suggestive of MCM. Characteristic brain malformations are thought to distinguish between MPPH with perisylvian polymicrogyria, and MCM with megalencephaly with Chiari 1 malformation. However, polymicrogyria was reported in a significant number of patients with MCM. Conversely, upon review of imaging studies of patients with MPPH, we noted progressive crowding of the posterior fossa and acquired tonsillar herniation, a process deemed characteristic for MCM. Thus, neither polymicrogyria nor acquired tonsillar herniation are distinguishing features, and occur in both disorders. In addition to brain abnormalities, shared findings include cognitive impairment, coarse facial features and postaxial polydactyly. Facial nevus flammeus and cutis marmorata are most noticeable in infancy, and ligamentous laxity and redundant soft tissue are somewhat subjective findings. While asymmetric overgrowth is considered typical for MCM, it is not universally present. These variable and subtle findings can be identified in patients with MPPH. We propose that MPPH and MCM may not represent distinct entities and that the term MPPH-CM syndrome be used to describe this spectrum.

High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: Brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities

“…Chiari 1 is a multifactorial condition generally attributed to a small posterior fossa, with reduced posterior fossa size due to either occipital bone hypoplasia (or dysplasia) or cranial settling associated with hypermobility of occipito-atlantal and atlanto-axial joints in many hereditary disorders of connective tissue [Stovner et al, 1993; Badie et al, 1995; Gripp et al, 1997; Nishikawa et al, 1997; Milhorat et al, 1999; Mesiwala et al, 2001; Milhorat et al, 2007; Noudel et al, 2009]. But these mechanisms are not sufficient to explain all cases of Chiari 1 malformation, as we now present data suggesting that in Costello syndrome, similar to macrocephaly-capillary malformation [Conway et al, 2007; Gripp et al, 2009], Chiari 1 malformation is associated with increased or relatively increased postnatal brain growth, leading to relatively enlarged cerebellum within a normal posterior fossa. It may be appropriate to reexamine the assumption that a Chiari 1 malformation is a congenital anomaly, and to view it as an abnormality resulting from an growth imbalance allowing for CBTH to occur and to progress over time, either pre- or postnatally.…”

Four-year follow-up of megalencephaly, polymicrogyria, postaxial polydactyly and hydrocephalus (MPPH) syndrome

“…Two related infants with an ‘MPPH-like’ phenotype were found to have a common unbalanced translocation resulting in a submicroscopic chromosome 5q35 deletion, but this finding has not been replicated in other patients with MPPH 10. Additionally, a case of MPPH/M-CM with overlapping features was found to have a paternally derived loss of 4q28.3, likely a benign variant 9 10. Most recently, exome sequencing in families affected by MPPH or the closely related syndrome MCAP has identified a potential common biological pathway.…”

“…This constellation of findings was again described in several subsequent small or single case reports 3–8. The defining characteristics of this syndrome have been debated due to overlap with other syndromes of macrocephaly, most notably MEG-PMG-MegaCC and M-CM or MCAP 9. Mirzaa et al recently published a comprehensive review of MCAP and MPPH in an effort to delineate the unique characteristics of these rare, newly identified and overlapping syndromes.…”

“…Megalencephaly is often severe and in most cases has required surgical intervention to relieve presumed hydrocephalus. Interestingly, of the children with MPPH that have had hydrocephalus and subsequent surgical intervention, mild to moderate ventricular enlargement and progressive megalencephaly persisted postoperatively 2 9. Tore et al 8 report a child with the core features of MPPH without frank hydrocephalus and with normal psychomotor development at 1 year of age despite findings of diffuse polymicrogyria and a seizure disorder.…”

Macrocephaly–capillary malformation syndrome: Three new cases

“…However, addition of facial gestalt in the diagnostic criteria can lead to proper evaluation of the suspected cases. Macrocephaly is also found in some other conditions like linear sebaceous nevus syndrome, KTWS, PTEN hamartoma tumor syndrome (PHTS), hemihypertrophy-hemimegalencephaly-polydactyly, and hemimegalencephaly-cerebral asymmetry-cortical dysplasia [10][11][12]. Gripp in 2009 identified significant overlap and possible identity of M-CM and Megalencephaly Polymicrogyria-Polydactyly Hydrocephalus (MPPH) syndromes.…”