A Novel CCND2 Mutation in a Previously Reported Case of Megalencephaly and Perisylvian Polymicrogyria with Postaxial Polydactyly and Hydrocephalus

In 2007, we reported a toddler girl with megalencephaly, perisylvian polymicrogyria, hydrocephalus, postaxial polydactyly, developmental delay, hypotonia, and minor dysmorphisms.[1] We identified her as being affected by megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus syndrome (MPPH).

MPPH had been described 3 years before by Mirzaa et al in five nonconsanguineous patients as a new disorder of brain overgrowth, partially overlapping with megalencephaly capillary malformation (MCAP).[2] Differences between these two conditions mainly involved somatic features: cutaneous vascular anomalies, syndactyly, and focal or segmental body overgrowth were more frequently linked to MCAP,[3] while polymicrogyria seemed more often associated with MPPH.

In 2012, germline and postzygotic mutations in the PI3K–AKT pathway were identified in these two syndromes.[4] Mutations in genes PIK3R2 and AKT3 were more frequent in patients with MPPH, while mutations in the PIK3CA gene were recurrent in patients with MCAP.[3]

Subsequently, mutations in CCND2, another gene of the same biochemical pathway, have been identified in 13 patients with MPPH.[5] [6]

All reported CCND2 mutations prevent phosphorylation of residue p.Thr280, some by premature termination, but mostly by nonconservative variants at and around the phosphorylation site.[5] This results in the accumulation of unphosphorylated, ubiquitin-mediated degradation-resistant cyclin D2 in neural precursors, and is the same functional end point as observed for PI3K and AKT mutations.[5]

In our patient, we initially investigated PIK3R2 and AKT3 by Sanger sequencing, and both resulted normal. Subsequently, we performed Whole Exome Sequencing and CCND2 sequence analysis and we identified a de novo missense mutation, NM_001759.3:c.839C > T (NP_001750.1:p.Thr280Ile). This specific variant has never been described before, but it affects the same critical residue mutated in five reported patients[5] ([Table 1]).

Table 1 Molecular and phenotypic data of patients with MPPH and CCND2 mutations (modified from Mirzaa et al. 2014)

	Sex	Age[a]	cDNA change	Amino acid change	Inheritance	MC	HYD/VMEG	Shunt age	PMG	Perisylvian PMG	Postaxial polydactyly	ID
Mirzaa et al 2014[5]	F	6y	c.808A > T	p.Lys270[*]	de novo	+	HYD	6y	+	+	+	+
	F	18m	c.808A > T	p.Lys270[*]	de novo	+	VMEG	−	+	+	+	+
	F	3y	c.838A > G	p.Thr280Ala	de novo	+	VMEG	−	+	+	+	+
	M	7y	c.838A > G	p.Thr280Ala	de novo	+	VMEG	−	+	+	+	+
	F	8m	c.839C > A	p.Thr280Asn	de novo	+	VMEG	−	+	+	+	+
	F	13y	c.839C > A	p.Thr280Asn	de novo	+	VMEG	−	+	+	+	+
	M	5y	c.839C > A	p.Thr280Asn	Parents NA	+	VMEG	−	+	+	+	+
	F	28w ga	c.841C > T	p.Pro281Ser	de novo	MEG	VMEG	−	+	−[b]	+	NA
	F	20y	c.842C > G	p.Pro281Arg	de novo	+	HYD	1m	+	+	−	+
	F	2y	c.842C > G	p.Pro281Arg	Mother negative, Father NA	+	VMEG	−	+	+	+	+
	M	9y	c.842C > T	p.Pro281Leu	NA	+	VMEG	−	+	+	+	+
	F	11y	c.851T > G	p.Val284Gly	Mother negative, Father NA	+	VMEG	−	+	+	+	+
McDermott et al. 2018	M	4y	c.841C > G	p.Pro281Ala	NA	+	−	−	+	NA[c]	+	+
Our patient	F	10y	c.839C > T	p.Thr280Ile	de novo	+	HYD	5m	+	+	+	+
Total	10F 4M				9 de novo 5 NA	14/14	13/14	3/14	14/14	12/14	13/14	13/14

Abbreviations: cDNA, complementary deoxyribonucleic acid; ga, gestational age; HYD, hydrocephalus; ID, intellectual disability; MC, macrocephaly; MEG, megalencephaly; MPPH, megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus syndrome; NA, not available or not applicable; PMG, polymicrogyria; VMEG, ventriculomegaly.

^a Age last assessed.

^b Frontoparietal polymicrogyria.

^c Unavailable data on polymicrogyria site.

^* Describes a truncated protein.

Our patient is now 10 years old. She is affected by severe intellectual disability with absent speech and she is unable to walk unaided. From the age of 6 months, she has had structural focal epilepsy. Electroencephalogram showed diffuse abnormality of the background activity and multifocal interictal epileptiform discharges, from temporal and frontal regions. Recent observations reported drug-resistant epilepsy with seizures characterized by limbs hypertonia and upward rolling of the eyes. Seizures occurred several times a week and sometimes in clusters of two or three seizures per day with spontaneous recovery.

It was suggested that MPPH patients carrying CCND2 mutations had polydactyly more frequently than those with PI3K–AKT pathway mutations.[5] Our patient also has this feature, but the mechanism underlying this phenotypic difference has yet to be explained.

• References

• 1 Garavelli L, Guareschi E, Errico S. , et al. Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus (MPPH): report of a new case. Neuropediatrics 2007; 38 (04) 200-203
• 2 Mirzaa G, Dodge NN, Glass I. , et al. Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus: a rare brain malformation syndrome associated with mental retardation and seizures. Neuropediatrics 2004; 35 (06) 353-359
• 3 Mirzaa GM, Rivière JB, Dobyns WB. Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP. Am J Med Genet C Semin Med Genet 2013; 163C [phone]
• 4 Rivière JB, Mirzaa GM, O'Roak BJ. , et al; Finding of Rare Disease Genes (FORGE) Canada Consortium. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 2012; 44 (08) 934-940
• 5 Mirzaa G, Parry DA, Fry AE. , et al; FORGE Canada Consortium. De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nat Genet 2014; 46 (05) 510-515
• 6 McDermott JH, Hickson N, Banerjee I. , et al. Hypoglycaemia represents a clinically significant manifestation of PIK3CA- and CCND2-associated segmental overgrowth. Clin Genet 2018; 93 (03) 687-692