MPPH Syndrome
What is MPPH Syndrome?
Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus (MPPH) syndrome is a rare genetic disorder primarily affecting brain development, with a constellation of neurological and physical features. The syndrome is characterized by the co-occurrence of the following physical characteristics, often developing within the first 2 years of life:
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Megalencephaly: Abnormally large brain and head size present at birth, with rapid growth in the first two years of life.
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Polymicrogyria: Abnormal development of the brain's cortex, particularly in the perisylvian region (involved in speech), resulting in excessive, small, and irregular gyri (folds).
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Polydactyly: Extra fingers or toes, typically postaxial (on the side of the pinky or little toe), present in about half of affected individuals.
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Hydrocephalus: Accumulation of cerebrospinal fluid in the brain, leading to ventriculomegaly (enlargement of the ventricles in the brain) and increased intracranial pressure in some cases.
These structural abnormalities in development lead to a diverse array of neurological signs and symptoms affecting the lives of those with the condition.
Synonyms
- Megalencephaly-capillary malformation syndrome
- Megalencephaly-polymicrogyria syndrome
Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus (MPPH) syndrome is a rare genetic disorder primarily affecting brain development, with a constellation of neurological and physical features. The syndrome is characterized by the co-occurrence of the following physical characteristics, often developing within the first 2 years of life:
-
Megalencephaly: Abnormally large brain and head size present at birth, with rapid growth in the first two years of life.
-
Polymicrogyria: Abnormal development of the brain's cortex, particularly in the perisylvian region (involved in speech), resulting in excessive, small, and irregular gyri (folds).
-
Polydactyly: Extra fingers or toes, typically postaxial (on the side of the pinky or little toe), present in about half of affected individuals.
-
Hydrocephalus: Accumulation of cerebrospinal fluid in the brain, leading to ventriculomegaly (enlargement of the ventricles in the brain) and increased intracranial pressure in some cases.
These structural abnormalities in development lead to a diverse array of neurological signs and symptoms affecting the lives of those with the condition.
MPPH syndrome is extremely rare, affecting less than 1 in 1,000,000 individuals with fewer than 100 cases reported in the medical literature to date.
| Name | Abbreviation |
|---|---|
| Megalencephaly-capillary malformation syndrome | |
| Megalencephaly-polymicrogyria syndrome |
MPPH is caused by dominant variants in genes involved in the P13K-AKT-mTOR cell growth signaling pathway. This pathway is responsible for cell growth and division and the creation of new proteins. Three genes are specifically associated with MPPH: AKT3, CCND2 and PIK3R2. Mutations in these genes are usually de novo (new in the patient and not inherited from a parent). However, if inherited this disorder is autosomal dominant, meaning one copy of an altered gene from either parent can cause MPPH in the offspring (see RareShare Guide on Genetic Inheritance). These genes reside on different chromosomes: AKT3 is located on chromosome 1 within the region 1q43-q44, CCND2 is found on chromosome 12 at 12p13.32, and PIK3R2 is situated on chromosome 19 at 19p13.11 (see RareShare guide on chromosomal nomenclature). Mutations in these genes lead to an abnormal increase in the number of nerve cells during brain development. The proteins encoded by these genes are expressed in greater quantities or not broken down, resulting in uncontrolled cell growth and increasing pressure on the brain.
MPPH is a congenital disorder marked by a combination of brain malformations and other physical anomalies. Key features include:
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Megalencephaly: Enlarged brain volume leading to macrocephaly (large head), prominent forehead, low nasal bridge, wide-spaced eyes.
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Polymicrogyria: Abnormal brain cortex development with too many small folds.
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Polydactyly: Extra fingers or toes.
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Hydrocephalus: Accumulation of cerebrospinal fluid in the brain.
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Developmental delay and intellectual disability: Difficulty coordinating mouth and tongue movements, drooling, difficulty swallowing, speech delay, autism spectrum features and repetitive behaviors in some cases.
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Seizures
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Hypotonia (low muscle tone)
Diagnosis of MPPH syndrome is typically based on a combination of clinical findings, characteristic neuroimaging results, and molecular genetic testing.
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Clinical: Megaencephaly and polymicrogyria are two core features, often accompanied with polydactyly, hypotonia, early-onset epilepsy and developmental delays.
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Imaging: MRI to evaluate brain structural abnormalities, including hydrocephalus.
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Genetic testing: Identification of pathogenic variants in the AKT3, CCND2 or PIK3R2 genes confirms the diagnosis.
There is no cure for MPPH syndrome. Management is supportive and symptomatic:
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Neurological care: Antiepileptic drugs for seizures, monitoring for hydrocephalus (may require surgical intervention), and regular developmental assessments.
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Therapies: Physical, occupational, and speech therapy to address developmental delays and oromotor dysfunction.
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Educational support: Special education and communication aids as needed.
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Monitoring: Regular MRI scans, especially in those with CCND2 mutations due to the risk of medulloblastoma tumors.
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Polydactyly, when present, can be managed through surgical removal of the extra digits particularly if hand or foot function is impaired.
The prognosis for MPPH syndrome varies depending on the severity of neurological involvement and associated complications. Most children have lifelong developmental and intellectual disabilities. Some may achieve independent walking and basic speech, while others remain non-verbal and require significant support. Seizure control and management of hydrocephalus are important for quality of life. Life expectancy is not well-defined due to the rarity of the syndrome and variability in severity.
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Douzgou S, Rawson M, Baselga E, Danielpour M, Faivre L, Kashanian A, Keppler-Noreuil KM, Kuentz P, Mancini GMS, Maniere MC, Martinez-Glez V, Parker VE, Semple RK, Srivastava S, Vabres P, De Wit MY, Graham JM Jr, Clayton-Smith J, Mirzaa GM, Biesecker LG. (2022). “A standard of care for individuals with PIK3CA-related disorders: An international expert consensus statement.” Clin Genet.101(1):32-47. doi: 10.1111/cge.14027. Epub 2021 Jul 16. PMID: 34240408; PMCID: PMC8664971.
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Rare Chromosome Disorder Support Group: MPPH syndrome.
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Medline Plus Genetics: Megalenephaly-polymicrogyria-polydactyly-hydroephalus syndrome.
Last updated 8 Apr 2022, 11:38 AM
8 Apr 2022, 11:38 AM
Hi Hannah,
Thanks for writing back. It does so much good to hear from someone dealing with the same worries.
Your son sounds a little like mine at that age, it took him much longer to walk and talk. Until quite recently, he was still drooling whenever he spoke. He talks now, but he still says things that don't make any sense and repeats a lot of the same sentences. Speech therapy has made a big difference for him in the last couple of years.
I'll try to find the FB group, thanks for the tip.
8 Apr 2022, 05:08 AM
Hello Dejana,
Interesting to hear that your son is gifted in learning new languages. It gives us hope. Our son is 2.5 years old now but doesn't talk or read anything yet. Does your son talk yet? Physically, my son can sit on his own, cruise leaning on furniture, climb up and down sofa and bed, crawl and creep around the house, stand independently for 15-20 seconds.
There's so little interaction here in this forum. It would be easier to interact in MPPH Syndrome FaceBook group. Would love to see your son reading English and French! xx
7 Apr 2022, 08:36 AM
Hi all, I'm new to the community. My son is 5 years old now, and was diagnosed with MPPH 2 years ago. He was born with the characteristic large head circumference but it took a while to diagnose him with genetic testing. Like all your kids, he was very late in sitting up on his own, let alone walking and talking. He has suffered from seizures since 2019, which are getting more and more frequent. At the same time, he is really gifted in certain ways - he taught himself to read in French and English and is very good at learning new languages. Has anyone else noticed this with their kids?
We live in Switzerland and there are no known cases here, so we'd love to be a part of the community and talk to people who are going through the same thing.
Last updated 30 Dec 2020, 01:24 AM
30 Dec 2020, 01:24 AM
Hi, We have a son that is now 16 months old. He was diagnosed with MPPH syndrome some months back after we completed genome testing. We already knew before he was born that not everything was normal as we got indications of enlarged ventricles, large head and and extra digit during checkups.
He has global development delay, but is slowly making progress. By 16 months he is now able to sit un-assisted for short amount of time and he can army crawl to get toys that are right in front of him. It is good to see that step by step he is developing.
We are interested to get in touch with others that are on the journey with their child.
Last updated 26 Nov 2020, 05:16 AM
26 Nov 2020, 05:16 AM
Hi. I have a son who is near to 2 yo next month. He was diagnosed with MPPH syndrome 5 months back through genetic testing. He is still crawling, cannot walk ot stand by his own WITHOUT support. Complete non verbal only drooling. Globally delayed. We are seeing the early intervention program since 4 months and he's doing well. Would love to connect with parents personally whose children are now above 2 yo and how are they doing so far ?
Last updated 5 Feb 2017, 09:38 AM
5 Feb 2017, 09:38 AM
Hello, my name is Amandine and i live in Normandy in France. I've a little boy who has mpph syndrom. His name is Basile and he is 13 month. He doesn't sit alone and he doesn't speak. In my country, there is nothing about this syndrom It's a very very rare desease. I want to speak with people who have child like my son with this syndrom. I'm sorry for my english I don't speak very well. If you are ok I want to enter in your group on Facebook please. Thank you
30 May 2016, 11:08 AM
Hi - I'm sorry to hear about your son's diagnosis. My daughter is 18 mos and has MPPH. There is a Facebook group if you're interested in joining https://m.facebook.com/profile.php?id=459569770779913&tsid=0.9593255908694118&source=typeahead Good luck! Sarah
29 May 2016, 10:47 PM
Hello! I am new to this page, and our son is 11 months old and just diagnosed with MPPH. I was just curious to see if there were any updates as to how everyone's child is doing. None of our doctors can really tell us what to expect as far as his development, so I just wanted to see if anyone had any insight!
Last updated 21 Apr 2015, 02:27 PM
20 Apr 2015, 03:10 PM
Thank you! We were initally diagnosed with just the PMG but the MRI findings came back saying MPPH is probable. Obviously we'll know more when he's here in a few weeks. Thank you for the info. I'm on the PMG FB pages so I'll be sure and look up the MPPH page.
20 Apr 2015, 07:16 AM
Hi, There is a fab page on facebook with lots of info and support. Its under MPPH Syndrome. Let me know if your having trouble accessing it xxxx
19 Apr 2015, 05:56 PM
Hi there! My son was just recently diagnosed with Mpph via fetal MRI. I just wanted to see how all of your children are progressing. How was the first year? I think we're moving forward with the c-section in 2 1/2 weeks. I'm pretty nervous and not sure what to expect.
Last updated 30 Jan 2011, 05:45 PM
30 Jan 2011, 05:45 PM
We seen a Dr. Dobyns in Chicago who was heading up a brain anomoly clinical study. The last I heard he moved to Texas to study children with autism. We did go to a genetic doctor while we were in the initial process of finding out a diagnosis. Looking back I am not sure we really gained much knowledge from the genetic testing. The MRI and the neurologist appointments are where we gained the most information. After our first diagnosis of lissencephaly we went for a second opionion, which was a waste of time and money, as that particular doctor had no clue what we were looking at. Dr. Dobyns was our third contact and we are still unsure if the diagnosis, signs and symptoms truely fit our son. We just encourage him every day to do his best and pray!!
29 Jan 2011, 09:30 PM
Mary, I enjoyed reading your story. I think I am on the other end of where you are though. Our baby is just now a year old. Since he was born he has kind of puzzled doctors as to what was wrong. We are still searching for a firm diagnosis as he does not meet the criteria for MPPH or MC-M 100%. So I am sorry to say I don't think I know any more than you already know. Can I ask who you saw in Chicago to get the diagnosis? My husband and I are wondering if we need to look for a geneticist who knows a little bit more about the syndromes they are considering.
27 Jan 2011, 07:41 PM
Hi My name is Mary and my son, Ethan is now 5 years old. We reside in Michigan and since he was about 11 months old we had noticed developmental delays. We received early intervention services for OT, Speech and PT. I can tell you that, at 5 years of age, he is already proving himself. He did not walk until he was two, did not really talk much at all until 3-4 years and he currently has to be reminded to use sentences. His speech is not always real clear. He still drools as he has low muscle tone through out his body. Cognitively he is right in line with what a child his age should know as far as letters, numbers, opposites, colors, etc. Initially we were told he had lissencephaly. With the information we obtained online we just didn't feel it fit him. We took him to Chicago last year where the MPPH diagnosis was made. He also has a Chiari Malformation Type 1. We just took him for an MRI and there is signs of a reduction in cranial sachral fluid, but nothing to be concerned about at this time. As many doctors have told us, the future cannot be predicted, even with children who have no anomolies. We were told that Ethan's large head size may be the reason he is doing so well. Not sure what that is all about. Early intervention was the greatest program - if you have one in your state do all you can to take advantage of those services. We also went through genetic testing and had blood work sent for a clinical study. We haven't heard anything back, but the doctor told us he believed this syndrome to be the result of a new genetic mutation. I would be interested to know if any of you have received an official reason.
Last updated 25 Jan 2011, 06:06 PM
25 Jan 2011, 06:06 PM
I am actually located in Utah. Where are you located at? My baby is 12 months as well. He just started sitting unassisted this week. However it is only for maybe a couple of minutes. He is no where close to crawling or walking as well. Our geneticist is looking at him having MPPH with MCM as well. However he does not have any capillary malformations. He also has not had hydrocephalus, just very large ventricles. My son currently sees a physical therapist twice a month, an occupational therapist, as well as a developmental specialist. He also see's a neurologist as well as orthopedic surgeon. I appreciate your link the the facebook group. I will try that and see if I can get some more help and answers as well.
23 Jan 2011, 12:11 AM
Hi my name is bec my son Koby is 12 months and we have been told he could hav MPPH / M-CM. Where bouts are u located? My son has epilepsy and now has a shunt inserted in December he cannot sit unassisted and no were near crawling or walking! I hav started him in physio to see if it helps and I had got no info from Docs to go to one so I went of my own back and she said why didn't I come earlier well no one told me too!! Cause it is such a rare condition I don't think Docs know how o treat it :-( I hav found a great support group through facebook any questions I hav they are happy to answer them. This is the link: http://www.facebook.com/group.php?gid=127511855574&ref=ts hope this helps
21 Jan 2011, 09:43 PM
I noticed this community had a few other members. Have any of you had any head way getting a firm diagnosis? Also how old are your kids? My baby turns one this month and I am trying to get a better of idea of possibly what the future holds for us. We were told there was a possibility our baby would not walk, just looking for any help or answers! Also have any of your docotors mentioned the combo of the MPPH syndrome with MCM syndrome?
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Hello everyone I hope everyone of you are safe and keeping in good health.... this post is created and dedicated for my baby Ananya Mohal, who is diagnosed with MPPH syndrome when she was 4 months...
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