Macrocephaly-capillary malformation

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Macrocephaly-capillary malformation
Other namesMacrocephaly-cutis marmorata telangiectatica congenita syndrome, Megalencephaly-cutis marmorata telangiectatica congenita syndrome
A new born child with m-cm syndrome..png
A newborn child with M-CM syndrome. A port-wine stain is visible under the nose. On the right side of a cheek, capillary malformations are present.

Macrocephaly-capillary malformation (M-CM) is a multiple malformation syndrome causing abnormal body and head overgrowth and cutaneous, vascular, neurologic, and limb abnormalities. Though not every patient has all features, commonly found signs include macrocephaly, congenital macrosomia, extensive cutaneous capillary malformation (naevus flammeus or port-wine stain type birthmark over much of the body; a capillary malformation of the upper lip or philtrum is seen in many patients with this condition), body asymmetry (also called hemihyperplasia or hemihypertrophy), polydactyly or syndactyly of the hands and feet, lax joints, doughy skin, variable developmental delay and other neurologic problems such as seizures and low muscle tone.

Contents

Genetics

Mosaic mutations in PIK3CA have been found to be the genetic cause of M-CM. [1] Other overgrowth conditions with distinct phenotypes have also been found to be caused by mosaic mutations in PIK3CA. How different mutations in this gene result in a variety of defined clinical syndromes is still being clarified. [2] [3] [4] Mutations in PIK3CA have not been found in a non-mosaic state in any of these disorders, so it is unlikely that the conditions could be inherited.[ citation needed ]

Diagnosis

Diagnosis is usually based on clinical observation. Various sets of criteria have been suggested to identify the disorder in an individual patient, all of which include macrocephaly and a number of the following: somatic overgrowth, cutis marmorata, midline facial birthmark, polydactyly/syndactyly, asymmetry (hemihyperplasia or hemihypertrophy), hypotonia at birth, developmental delay, connective tissue defect and frontal bossing. [5] [6] Currently no consensus exists about which diagnostic criteria are definitive and so evaluation by a medical geneticist or other clinician with familiarity with the syndrome is usually needed to provide diagnostic certainty. It is not clear if there are some features which are mandatory to make the diagnosis, but macrocephaly appears essentially universal though may not be congenital. The distinctive vascular abnormalities of the skin often fade over time, making the diagnosis challenging in older children with this condition.[ citation needed ]

The brain can be affected in several ways in this syndrome. Some children are born with structural brain anomalies such as cortical dysplasia or polymicrogyria. While developmental delay is nearly universal in this syndrome it is variable in severity, with the majority having mild to moderate delays and a minority having severe cognitive impairment. Some patients are affected with a seizure disorder. White matter abnormalities on magnetic resonance imaging (MRI), suggesting a delay in white matter myelination, is commonly seen in early childhood. Some patients may have asymmetry of the brain, with one side being noticeably larger than the other.[ citation needed ]

One interesting phenomenon that seems very common in this syndrome is the tendency for disproportionate brain growth in the first few years of life, with crossing of percentiles on the head circumference growth charts. A consequence of this disproportionate brain growth appears to be a significantly increased risk of cerebellar tonsillar herniation (descent of the cerebellar tonsils through the foramen magnum of the skull, resembling a Chiari I malformation neuroradiologically) and ventriculomegaly/hydrocephalus. [7] Such cerebellar tonsil herniation may occur in up to 70% of children with M-CM.[ citation needed ]

The medical literature suggests that there is a risk of cardiac arrhythmias in early childhood. [8] [9] The cause for this is unknown. In addition, a variety of different congenital cardiac malformations have been reported in a small number of patients with this disorder. [10] [11]

Like other syndromes associated with disproportionate growth, there appears to be a slightly increased risk of certain types of childhood malignancies in M-CM (such as Wilms' tumor). However, the precise incidence of these malignancies is unclear.[ citation needed ]

Treatment

There is no cure for this condition. Treatment is supportive and varies depending on how symptoms present and their severity. Some degree of developmental delay is expected in almost all cases of M-CM, so evaluation for early intervention or special education programs is appropriate. Rare cases have been reported with no discernible delay in academic or school abilities.[ citation needed ]

Physical therapy and orthopedic bracing can help young children with gross motor development. Occupational therapy or speech therapy may also assist with developmental delays. Attention from an orthopedic surgeon may be required for leg length discrepancy due to hemihyperplasia.[ citation needed ]

Children with hemihyperplasia are thought to have an elevated risk for certain types of cancers. Recently published management guidelines recommend regular abdominal ultrasounds up to age eight to detect Wilms' tumor. AFP testing to detect liver cancer is not recommended as there have been no reported cases of hepatoblastoma in M-CM patients. [1]

Congenital abnormalities in the brain and progressive brain overgrowth can result in a variety of neurological problems that may require intervention. These include hydrocephalus, cerebellar tonsillar herniation (Chiari I), seizures and syringomyelia. These complications are not usually congenital, they develop over time often presenting complications in late infancy or early childhood, though they can become problems even later. Baseline brain and spinal cord MRI imaging with repeat scans at regular intervals is often prescribed to monitor the changes that result from progressive brain overgrowth.

Assessment of cardiac health with echocardiogram and EKG may be prescribed and arrhythmias or abnormalities may require surgical treatment.[ citation needed ]

Prognosis

Prognosis varies widely depending on severity of symptoms, degree of intellectual impairment, and associated complications. Because the syndrome is rare and so newly identified, there are no long term studies.[ citation needed ]

History

This disorder was recognized as a distinct syndrome in 1997 and named macrocephaly-cutis marmorata telangiectasia congenita or M-CMTC. [12] [13] A new name, macrocephaly-capillary malformation, abbreviated M-CM, was recommended in 2007. [14] This new name was chosen to more accurately describe the skin markings associated with this disorder. In January 2012, a paper proposed new names for the syndrome: megalencephaly-capillary malformation or megalencephaly-capillary malformation-polymicrogyria with an abbreviation of MCAP. [15]

Related Research Articles

<span class="mw-page-title-main">Megalencephaly</span> Medical condition

Megalencephaly is a growth development disorder in which the brain is abnormally large. It is characterized by a brain with an average weight that is 2.5 standard deviations above the mean of the general population. Approximately 1 out of 50 children (2%) are said to have the characteristics of megalencephaly in the general population.

<span class="mw-page-title-main">Macrocephaly</span> Abnormally large head size

Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to determine whether the syndrome is accompanied by particular disorders. Those with benign or familial macrocephaly are considered to have megalencephaly.

<span class="mw-page-title-main">Arthrogryposis</span> Medical condition

Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning 'curving of joints'.

<span class="mw-page-title-main">Noonan syndrome</span> Genetic condition involving facial, heart, blood and skeletal features

Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored eyes, low-set ears, a short neck, and a small lower jaw. Heart problems may include pulmonary valve stenosis. The breast bone may either protrude or be sunken, while the spine may be abnormally curved. Intelligence is often normal. Complications of NS can include leukemia.

<span class="mw-page-title-main">Fraser syndrome</span> Recessive genetic disorder involving eye and genital abnormalities

Fraser syndrome is an autosomal recessive congenital disorder, identified by several developmental anomalies. Fraser syndrome is named for the geneticist George R. Fraser, who first described the syndrome in 1962.

Adams–Oliver syndrome (AOS) is a rare congenital disorder characterized by defects of the scalp and cranium, transverse defects of the limbs, and mottling of the skin.

<span class="mw-page-title-main">Simpson–Golabi–Behmel syndrome</span> Congenital disorder

Simpson–Golabi–Behmel syndrome (SGBS), is a rare inherited congenital disorder that can cause craniofacial, skeletal, vascular, cardiac, and renal abnormalities. There is a high prevalence of cancer associated in those with sgbs which includes wilms tumors, neuroblastoma, tumors of the adrenal gland, liver, lungs and abdominal organs. The syndrome is inherited in an X-linked recessive manner. Females that possess one copy of the mutation are considered to be carriers of the syndrome but may still express varying degrees of the phenotype, suffering mild to severe malady. Males experience a higher likelihood of fetal death.

<span class="mw-page-title-main">Cutis marmorata telangiectatica congenita</span> Medical condition

Cutis marmorata telangiectatica congenita is a rare congenital vascular disorder that usually manifests in affecting the blood vessels of the skin. The condition was first recognised and described in 1922 by Cato van Lohuizen, a Dutch pediatrician whose name was later adopted in the other common name used to describe the condition – Van Lohuizen Syndrome. CMTC is also used synonymously with congenital generalized phlebectasia, nevus vascularis reticularis, congenital phlebectasia, livedo telangiectatica, congenital livedo reticularis and Van Lohuizen syndrome.

3C syndrome is a rare condition whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.

Weaver syndrome is a rare autosomal dominant genetic disorder associated with rapid growth beginning in the prenatal period and continuing through the toddler and youth years. It is characterized by advanced osseous maturation and distinctive craniofacial, skeletal and neurological abnormalities. It is similar to Sotos syndrome and is classified as an overgrowth syndrome.

<span class="mw-page-title-main">Lujan–Fryns syndrome</span> Medical condition

Lujan–Fryns syndrome (LFS) is an X-linked genetic disorder that causes mild to moderate intellectual disability and features described as Marfanoid habitus, referring to a group of physical characteristics similar to those found in Marfan syndrome. These features include a tall, thin stature and long, slender limbs. LFS is also associated with psychopathology and behavioral abnormalities, and it exhibits a number of malformations affecting the brain and heart. The disorder is inherited in an X-linked dominant manner, and is attributed to a missense mutation in the MED12 gene. There is currently no treatment or therapy for the underlying MED12 malfunction, and the exact cause of the disorder remains unclear.

<span class="mw-page-title-main">Parkes Weber syndrome</span> Medical condition

Parkes Weber syndrome (PWS) is a congenital disorder of the vascular system. It is an extremely rare condition, and its exact prevalence is unknown. It is named after British dermatologist Frederick Parkes Weber, who first described the syndrome in 1907.

<span class="mw-page-title-main">Perlman syndrome</span> Medical condition

Perlman syndrome (PS) is a rare overgrowth disorder present at birth. It is characterized by polyhydramnios and fetal overgrowth, including macrocephaly, neonatal macrosomia, visceromegaly, dysmorphic facial features, and an increased risk for Wilms' tumor at an early age. The prognosis for Perlman syndrome is poor and it is associated with a high neonatal mortality.

Malpuech facial clefting syndrome, also called Malpuech syndrome or Gypsy type facial clefting syndrome, is a rare congenital syndrome. It is characterized by facial clefting, a caudal appendage, growth deficiency, intellectual and developmental disability, and abnormalities of the renal system (kidneys) and the male genitalia. Abnormalities of the heart, and other skeletal malformations may also be present. The syndrome was initially described by Georges Malpuech and associates in 1983. It is thought to be genetically related to Juberg-Hayward syndrome. Malpuech syndrome has also been considered as part of a spectrum of congenital genetic disorders associated with similar facial, urogenital and skeletal anomalies. Termed "3MC syndrome", this proposed spectrum includes Malpuech, Michels and Mingarelli-Carnevale (OSA) syndromes. Mutations in the COLLEC11 and MASP1 genes are believed to be a cause of these syndromes. The incidence of Malpuech syndrome is unknown. The pattern of inheritance is autosomal recessive, which means a defective (mutated) gene associated with the syndrome is located on an autosome, and the syndrome occurs when two copies of this defective gene are inherited.

<span class="mw-page-title-main">CLOVES syndrome</span> Medical condition

CLOVES syndrome is a rare overgrowth syndrome with complex vascular anomalies. CLOVES syndrome affects people with various symptoms, ranging from mild fatty soft-tissue tumors to vascular malformations encompassing the spine or internal organs.

ZTTK syndrome is a rare disease caused in humans by a genetic mutation of the SON gene. Common symptoms include developmental delay and sometimes moderate to several intellectual disability.

<span class="mw-page-title-main">COACH syndrome</span> Medical condition

COACH syndrome, also known as Joubert syndrome with hepatic defect, is a rare autosomal recessive genetic disease. The name is an acronym of the defining signs: cerebellar vermis aplasia, oligophrenia, congenital ataxia, coloboma and hepatic fibrosis. The condition is associated with moderate intellectual disability. It falls under the category of a Joubart Syndrome-related disorder (JSRD).

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term for rare syndromes characterized by malformations and tissue overgrowth caused by somatic mutations in PIK3CA gene. In PROS diseases individuals malformations are seen in several different tissues such as skin, vasculature, bones, fat and brain tissue depending on the specific disease.

Diffuse capillary malformation with overgrowth (DCMO) is a subset of capillary malformations (CM) associated with hypertrophy, i.e. increased size of body structures. CM can be considered an umbrella term for various vascular anomalies caused by increased diameter or number of capillary blood vessels. It is commonly referred to as "port-wine stain", and is thought to affect approximately 0.5% of the population. Typically capillaries in the papillary dermis are involved, and this gives rise to pink or violaceous colored lesions. The majority of DCMO lesions are diffuse, reticulated pale-colored stains.

<span class="mw-page-title-main">Chudley–Mccullough syndrome</span> Medical condition

Chudley–Mccullough syndrome is a rare genetic disorder which is characterized by bilateral congenital hearing loss associated with brain malformations. It is a type of syndromic deafness.

References

  1. 1 2 Rivière, JB.; Mirzaa, GM.; O'Roak, BJ.; Beddaoui, M.; Alcantara, D.; Conway, RL.; St-Onge, J.; Schwartzentruber, JA.; et al. (2012). "De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes". Nat Genet. 44 (8): 934–40. doi:10.1038/ng.2331. PMC   3408813 . PMID   22729224.
  2. ↑ Kurek, KC.; Luks, VL.; Ayturk, UM.; Alomari, AI.; Fishman, SJ.; Spencer, SA.; Mulliken, JB.; Bowen, ME.; et al. (Jun 2012). "Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome". American Journal of Human Genetics. 90 (6): 1108–15. doi:10.1016/j.ajhg.2012.05.006. PMC   3370283 . PMID   22658544.
  3. ↑ Lee, JH.; Huynh, M.; Silhavy, JL.; Kim, S.; Dixon-Salazar, T.; Heiberg, A.; Scott, E.; Bafna, V.; et al. (2012). "De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly". Nat Genet. 44 (8): 941–5. doi:10.1038/ng.2329. PMC   4417942 . PMID   22729223.
  4. ↑ Lindhurst, MJ.; Parker, VE.; Payne, F.; Sapp, JC.; Rudge, S.; Harris, J.; Witkowski, AM.; Zhang, Q.; et al. (2012). "Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA". Nat Genet. 44 (8): 928–33. doi:10.1038/ng.2332. PMC   3461408 . PMID   22729222.
  5. ↑ Franceschini P, Licata D, Di Cara G, Guala A, Franceschini D, Genitori L (2000). "Macrocephaly-Cutis marmorata telangiectatica congenita without cutis marmorata?". American Journal of Medical Genetics. 90 (4): 265–9. doi:10.1002/(SICI)1096-8628(20000214)90:4<265::AID-AJMG1>3.0.CO;2-S. PMID   10710221.
  6. ↑ Robertson SP, Gattas M, Rogers M, Adès LC (2000). "Macrocephaly--cutis marmorata telangiectatica congenita: report of five patients and a review of the literature". Clin Dysmorphol. 9 (1): 1–9. doi:10.1097/00019605-200009010-00001. PMID   10649789.
  7. ↑ Conway RL, Pressman BD, Dobyns WB, Danielpour M, Lee J, Sanchez-Lara PA, et al. (2007). "Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients". American Journal of Medical Genetics. 143A (24): 2981–3008. doi:10.1002/ajmg.a.32040. PMC   6816457 . PMID   18000912.
  8. ↑ Yano S, Watanabe Y (2001). "Association of arrhythmia and sudden death in macrocephaly-cutis marmorata telangiectatica congenita syndrome". American Journal of Medical Genetics. 102 (2): 149–52. doi: 10.1002/ajmg.1428 . PMID   11477607.
  9. ↑ Kuint, J.; Globus, O.; Ben Simon, GJ.; Greenberger, S. (2012). "Macrocephaly-capillary malformation presenting with fetal arrhythmia". Pediatr Dermatol. 29 (3): 384–6. doi:10.1111/j.1525-1470.2011.01677.x. PMID   22329570. S2CID   205678794.
  10. ↑ Erener Ercan, T.; Oztunc, F.; Celkan, T.; Bor, M.; Kizilkilic, O.; Vural, M.; Perk, Y.; Islak, C.; Tuysuz, B. (Mar 2012). "Macrocephaly-Capillary Malformation Syndrome in a Newborn With Tetralogy of Fallot and Sagittal Sinus Thrombosis". J Child Neurol. 28 (1): 115–9. doi:10.1177/0883073812439346. PMID   22451530. S2CID   206549770.
  11. ↑ Dueñas-Arias, JE.; Arámbula-Meraz, E.; Frías-Castro, LO.; Ramos-Payán, R.; Quibrera-Matienzo, JA.; Luque-Ortega, F.; Aguilar-Medina, EM. (Sep 2009). "Tetralogy of Fallot associated with macrocephaly-capillary malformation syndrome: a case report and review of the literature". Journal of Medical Case Reports. 3 (1): 9215. doi:10.4076/1752-1947-3-9215. PMC   2827170 . PMID   20210980.
  12. ↑ Clayton-Smith J, Kerr B, Brunner H, Tranebjaerg L, Magee A, Hennekam RC, et al. (1997). "Macrocephaly with cutis marmorata, haemangioma and syndactyly--a distinctive overgrowth syndrome". Clin Dysmorphol. 6 (4): 291–302. doi:10.1097/00019605-199710000-00001. PMID   9354837.
  13. ↑ Moore CA, Toriello HV, Abuelo DN, Bull MJ, Curry CJ, Hall BD, et al. (1997). "Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities". American Journal of Medical Genetics. 70 (1): 67–73. doi:10.1002/(SICI)1096-8628(19970502)70:1<67::AID-AJMG13>3.0.CO;2-V. PMID   9129744.
  14. ↑ Toriello HV, Mulliken JB (2007). "Accurately renaming macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) as macrocephaly-capillary malformation (M-CM)". American Journal of Medical Genetics. 143A (24): 3009. doi:10.1002/ajmg.a.31971. PMID   17963258. S2CID   6067902.
  15. ↑ Mirzaa, GM.; Conway, RL.; Gripp, KW.; Lerman-Sagie, T.; Siegel, DH.; deVries, LS.; Lev, D.; Kramer, N.; et al. (Feb 2012). "Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis". American Journal of Medical Genetics. 158A (2): 269–91. doi: 10.1002/ajmg.a.34402 . PMID   22228622. S2CID   25253301.
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