Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 1

A number sign (#) is used with this entry because megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-1 (MPPH1) is caused by heterozygous mutation in the PIK3R2 gene (603157) on chromosome 19p13.

Description

This disorder comprises megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome (MCAP; 602501) (summary by Gripp et al., 2009).

Genetic Heterogeneity of the Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome

See also MPPH2 (615937), caused by mutation in the AKT3 gene (611223) on chromosome 1q43-q44; and MPPH3 (615938), caused by mutation in the CCND2 gene (123833) on chromosome 12p13.

Clinical Features

Gohlich-Ratmann et al. (1998) reported 3 sporadic cases of in utero-onset megalencephaly. The children were born to healthy nonconsanguineous parents after uneventful pregnancies. Head circumferences were just above the 97th centile at birth in 2 patients, 2 cm above the 97th centile in 1 patient, and subsequently increased to 4.5 to 6.5 cm above the 97th centile at age 5 years. All patients completely lacked motor and speech development and showed very little intellectual progress. There was a distinctive facial aspect with frontal bossing, low nasal bridge, and large eyes, but no cutaneous abnormalities and no signs of other organ involvement. Magnetic resonance imaging showed bilateral megalencephaly with a broad corpus callosum, enlarged white matter, and focally thick gray matter, resulting in pachygyric appearance of the cortex. Formation of the frontoparietal operculum was incomplete, and the Sylvian fissures were wide. Gohlich-Ratmann et al. (1998) knew of no reports of similar cases. On review of the MRI figures in the paper by Gohlich-Ratmann et al. (1998), Mirzaa et al. (2004) concluded that the cortical dysplasia suggested polymicrogyria rather than typical pachygyria, a point with which the authors of the 1998 paper agreed. Mirzaa et al. (2004) thus suggested the designation megalencephaly-polymicrogyria-mega-corpus callosum (MEG-PMG-MegaCC) syndrome. Postaxial polydactyly was also seen in the patients reported by Mirzaa et al. (2004).

Tohyama et al. (2007) reported a Japanese girl with MPPH. She was noted to have enlarged ventricles on prenatal ultrasound at 30 weeks' gestational age. At birth, she had macrocephaly (+3.5 SD) and polydactyly of the lower limbs. She developed partially refractory seizures at age 3 months, and showed global developmental delay. Dysmorphic features included prominent forehead, hypertelorism, telecanthus, and depressed nasal bridge. Se also had visual impairment, but ophthalmic examination was normal. Brain MRI showed polymicrogyria, decreased white matter volume, and signal abnormalities in the occipital lobe.

Dagli et al. (2008) reported a female infant with a phenotype similar to that described by Gohlich-Ratmann et al. (1998). At birth, she had macrocephaly, hypotonia, frontal bossing, depressed nasal bridge, and normal brain MRI. Features noted later included open anterior fontanel, wide palpebral fissures, ptosis, and profound mental retardation with no psychomotor development. Brain MRI at age 15 months showed bilateral megalencephaly with generalized thickening of the cortex, severe enlargement of the corpus callosum, and a cavum septum pellucidum. There was abnormal sulcation, which may be seen with polymicrogyria. The ventricles were normal in size, and the Sylvian fissures were not wide. The patient died at home at 21 months of age from respiratory complications associated with a flu-like illness.

Hengst et al. (2010) reported a 3-year-old girl who was born with macrocephaly and showed hypotonia, reduced spontaneous movements, and severely delayed motor development. Brain MRI at age 8 months showed extensive polymicrogyria sparing the midline cortical structures and the visual cortex, a markedly enlarged corpus callosum, and megalencephaly of the hemispheres and cerebellum. There was increased diameter of the internal cerebral vein, the vein of Galen, and the straight sinus. By age 2 years, she had learned to control her head for a short time and to roll around, but could not sit or grasp. She had hypotonia, with salivation, mental retardation, and lack of speech. There was no facial dysmorphism and she did not have seizures. Hengst et al. (2010) suggested the term 'megalencephaly-mega corpus callosum-motor retardation syndrome (MMM)' as a more accurate designation.

Diagnosis

Mirzaa et al. (2012) reviewed the phenotypic features of 42 patients with a megalencephalic syndrome in an attempt to clarify and simplify the categorization and diagnosis of these disorders. Statistical analysis of particular features yielded 2 main groups: 21 patients with a vascular malformation consistent with MCAP and 19 with no vascular malformation consistent with MPPH; 2 patients were in an overlap group. Vascular malformations were significantly associated with syndactyly and somatic overgrowth at birth, and lack of vascular malformations was associated with polydactyly. The various features were assigned to 5 major classes of developmental abnormalities. Both MCAP and MPPH had (1) megalencephaly and variable somatic overgrowth (particularly in MCAP); (2) distal limb malformations, syndactyly being more associated with MCAP and polydactyly with MPPH; and (3) similar cortical brain malformations (mainly polymicrogyria). In addition, MCAP included (4) developmental vascular abnormalities and (5) occasional connective tissue dysplasia, such as hyperelasticity or thick skin. MPPH lacks vascular malformations, connective tissue dysplasia, and heterotopia. Based on these findings, Mirzaa et al. (2012) proposed diagnostic criteria for the MCAP and MPPH syndromes, and postulated that the 2 disorders represent different, although overlapping, syndromes that may be caused by different genes involved in the same biologic pathway.

Molecular Genetics

Riviere et al. (2012) performed exome sequencing in the oldest of 3 affected sibs with MPPH and identified a heterozygous mutation in the PIK3R2 gene (G373R; 603157.0001), which encodes the p85B regulatory subunit of class IA PI3K. Sanger sequencing confirmed the presence of the mutation in all 3 affected sibs and its absence in the saliva and blood of both parents and the unaffected sister, showing germline mosaicism in 1 parent. Sequencing of the PIK3R2 gene in 40 individuals with megalencephaly identified the same nucleotide change in 10 additional subjects with MPPH, and this mutation was shown to be de novo in all subjects for whom parental DNA was available. The mutation occurred at a CpG dinucleotide, which might explain its recurrence.

In a Japanese girl with MPPH originally reported by Tohyama et al. (2007), Nakamura et al. (2014) identified a de novo heterozygous missense mutation in the PIK3R2 gene (L401P; 603157.0002). Functional studies of the variant were not performed.