Macrocephaly is a condition in which

circumference In geometry, the circumference () is the perimeter of a circle or ellipse. The circumference is the arc length of the circle, as if it were opened up and straightened out to a line segment. More generally, the perimeter is the curve length arou ...

of the

human head In human anatomy, the head is at the top of the human body. It supports the face and is maintained by the human skull, skull, which itself encloses the human brain, brain. Structure The human head consists of a fleshy outer portion, which s ...

is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further

medical test A medical test is a medical procedure performed to detect, diagnose, or monitor diseases, disease processes, susceptibility, or to determine a course of treatment. Medical tests such as, physical and visual exams, diagnostic imaging, genetic ...

s to determine whether the

syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...

is accompanied by particular disorders. Those with

benign Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...

or familial macrocephaly are considered to have megalencephaly.

Causes

Many people with abnormally large heads or large skulls are healthy, but macrocephaly may be pathological. Pathologic macrocephaly may be due to megalencephaly (enlarged brain),

hydrocephalus Hydrocephalus is a condition in which cerebrospinal fluid (CSF) builds up within the brain, which can cause pressure to increase in the skull. Symptoms may vary according to age. Headaches and double vision are common. Elderly adults with n ...

(abnormally increased

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

), cranial hyperostosis (bone overgrowth), and other conditions. Pathologic macrocephaly is called "syndromic", when it is associated with any other noteworthy condition, and "nonsyndromic" otherwise. Pathologic macrocephaly may be caused by

congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...

anatomic abnormalities, genetic conditions, or by environmental events. Many genetic conditions are associated with macrocephaly, including familial macrocephaly related to the holgate gene,

autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...

, ''PTEN'' mutations such as Cowden disease, neurofibromatosis type 1, and

tuberous sclerosis Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combinatio ...

; overgrowth syndromes such as Sotos syndrome (cerebral gigantism), Weaver syndrome, Simpson–Golabi–Behmel syndrome (bulldog syndrome), and macrocephaly-capillary malformation (M-CMTC) syndrome; neurocardiofacial-cutaneous syndromes such as Noonan syndrome, Costello syndrome, Gorlin syndrome, (also known as basal cell nevus syndrome) and cardiofaciocutaneous syndrome;

Fragile X syndrome Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...

; leukodystrophies (brain

white matter White matter refers to areas of the central nervous system that are mainly made up of myelinated axons, also called Nerve tract, tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distr ...

degeneration) such as

Alexander disease Alexander disease is a very rare autosomal dominant leukodystrophy, which are neurological conditions caused by anomalies in the myelin which protects nerve fibers in the brain. The most common type is the infantile form that usually begins durin ...

, Canavan disease, and megalencephalic leukoencephalopathy with subcortical cysts; and glutaric aciduria type 1 and D-2-hydroxyglutaric aciduria. At one end of the genetic spectrum, duplications of chromosomes have been found to be related to autism and macrocephaly; at the other end, deletions of chromosomes have been found to be related to

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

and microcephaly. Environmental events associated with macrocephaly include infection, neonatal

intraventricular hemorrhage Intraventricular hemorrhage (IVH), also known as intraventricular bleeding, is a bleeding into the brain's ventricular system, where the cerebrospinal fluid is produced and circulates through towards the subarachnoid space. It can result from p ...

(bleeding within the infant brain), subdural hematoma (bleeding beneath the outer lining of the brain), subdural effusion (collection of fluid beneath the outer lining of the brain), and arachnoid cysts (cysts on the brain surface). In research, cranial height or brain imaging may be used to determine intracranial volume more accurately. Below is a list of conditions featuring macrocephaly from NCBI's MedGen: *

Achondroplasia Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. It is the most common cause of dwarfism and affects about 1 in 27,500 people. In those with the condition, the Rhizomeli ...

* Acrocallosal syndrome * Adams-Oliver syndrome * Adenosine kinase deficiency * Antley-Bixler syndrome * Autosomal dominant Kenny-Caffey syndrome * Autosomal recessive osteopetrosis * Axenfeld-Rieger anomaly * B4GALT1- congenital disorder of glycosylation * Bardet-Biedl syndrome * Brittle cornea syndrome * Camptomelic dysplasia * Cardio-facio-cutaneous syndrome * Cobblestone lissencephaly without muscular or ocular involvement * Coffin-Siris syndrome * Cohen-Gibson syndrome * Cole-Carpenter syndrome * Congenital disorder of glycosylation, type Iw, autosomal dominant * Corpus callosum, agenesis of * Costello syndrome * Cowden syndrome * Craniodiaphyseal dysplasia, autosomal dominant *

Cranioectodermal dysplasia Sensenbrenner syndrome (OMIM #218330) is a rare (less than 20 cases reported by 2010) multisystem disease first described by Judith A. Sensenbrenner in 1975. It is inherited in an autosomal recessive fashion, and a number of genes appear to be resp ...

* Craniometaphyseal dysplasia *

Craniosynostosis Craniosynostosis is a condition in which one or more of the fibrous sutures in a young infant's skull prematurely fuses by turning into bone (ossification), thereby changing the growth pattern of the skull. Because the skull cannot expand perpe ...

* D-2-hydroxyglutaric aciduria * Deficiency of alpha-mannosidase * Desmosterolosis * Donnai-Barrow syndrome * Early-onset parkinsonism-intellectual disability syndrome * Ehlers-Danlos syndrome, spondylodysplastic type *

Epidermolysis bullosa simplex Epidermolysis bullosa simplex (EBS) is a disorder resulting from mutations in the genes encoding keratin 5 or keratin 14.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . It is one of the major f ...

* Giant axonal neuropathy * Glutaric aciduria, type 1 * Gorlin syndrome * Greenberg dysplasia *

Greig cephalopolysyndactyly syndrome Greig cephalopolysyndactyly syndrome is a disorder that affects development of the limbs, head, and face. The features of this syndrome are highly variable, ranging from very mild to severe. People with this condition typically have one or more ...

Hamartoma A hamartoma is a mostly benign, local malformation of cells that resembles a neoplasm of local tissue but is usually due to an overgrowth of multiple aberrant cells, with a basis in a systemic genetic condition, rather than a growth descended fr ...

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

Holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...

* Hurler syndrome Peterson 283

Hydrocephalus Hydrocephalus is a condition in which cerebrospinal fluid (CSF) builds up within the brain, which can cause pressure to increase in the skull. Symptoms may vary according to age. Headaches and double vision are common. Elderly adults with n ...

, nonsyndromic, autosomal recessive *

Hypochondroplasia Hypochondroplasia (HCH) is a developmental disorder caused by an autosomal dominant genetic defect in the fibroblast growth factor receptor 3 gene ('' FGFR3'') that results in a disproportionately short stature, micromeliaupdate 2013 and a head t ...

* Hypophosphatemic rickets and

hyperparathyroidism Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands ( primary hyperparathyroidism) or as response to external stimuli ( secondary hyperparathyroi ...

Hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...

, congenital, nongoitrous * Ito hypomelanosis *

Joubert syndrome Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the Human brain, brain that controls balance and coordination. Joubert syndrome is one of the many genetic syndromes associated with syndromic ...

* Keipert syndrome * Legius syndrome * LEOPARD syndrome * Lethal congenital contracture syndrome * MASA syndrome Stoddart 79

* Megalencephaly, autosomal dominant * Megalocornea-intellectual disability syndrome * MGAT2- congenital disorder of glycosylation * MOMO syndrome * Mucopolysaccharidosis type 6 * Mucopolysaccharidosis type 7 * Mucopolysaccharidosis, MPS-II * Mucopolysaccharidosis, MPS-III-D * Muenke syndrome * Multiple acyl-CoA dehydrogenase deficiency * Multiple congenital anomalies-hypotonia-seizures syndrome * Multiple epiphyseal dysplasia, Al-Gazali type * Myhre syndrome * Neurofibromatosis, type 1 * Neurofibromatosis-Noonan syndrome * Niemann-Pick disease, type A * Noonan syndrome * Opsismodysplasia * Optic atrophy * Osteopathia striata with cranial sclerosis * Pallister-Killian syndrome * Parietal foramina * Parietal foramina with cleidocranial dysplasia * Pelger-Huët anomaly * Peroxisome biogenesis disorder 1A (Zellweger) * Peroxisome biogenesis disorder 4B * Phelan-McDermid syndrome *

Plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is enco ...

deficiency, type I * Primrose syndrome *

Proteus syndrome Proteus syndrome is a rare genetic disorder that can cause tissue overgrowth involving all three Germ layer, embryonic lineages. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development.Freedberg, et al. (2003). ...

* Ritscher-Schinzel syndrome *

Robinow syndrome Robinow syndrome is an extremely rare genetic disorder characterized by short-limbed dwarfism, abnormalities in the head, face, and external sex organ, genitalia, and vertebrae, vertebral segmentation. The disorder was first described in 1969 by h ...

* Sandhoff disease * Schneckenbecken dysplasia *

Sclerosteosis Sclerosteosis is an autosomal recessive disorder characterized by bone overgrowth. It was first described in 1958 but given the current name in 1967. Excessive bone formation is most prominent in the skull, mandible and tubular bones. It can cause ...

* Severe X-linked myotubular myopathy * Sialuria * Simpson-Golabi-Behmel syndrome * Snijders Blok-Campeau syndrome * Sotos syndrome * Sturge-Weber syndrome * Sulfite oxidase deficiency due to

molybdenum cofactor deficiency Molybdenum cofactor deficiency is a rare human disease in which the absence of molybdopterin – and consequently its molybdenum complex, commonly called molybdenum cofactor – leads to accumulation of toxic levels of sulphite and neurological d ...

* Symphalangism with multiple anomalies of hands and feet * Syndromic X-linked intellectual disability * Thanatophoric dysplasia type 1 * Vanishing white matter disease * Weaver syndrome * X-linked dominant chondrodysplasia, Chassaing-Lacombe type * X-linked hydrocephalus syndrome * X-linked intellectual disability with marfanoid habitus * Zimmermann-Laband syndrome * ZTTK syndrome

Diagnosis

Macrocephaly is customarily diagnosed if head circumference is greater than two

standard deviation In statistics, the standard deviation is a measure of the amount of variation of the values of a variable about its Expected value, mean. A low standard Deviation (statistics), deviation indicates that the values tend to be close to the mean ( ...

s (SDs) above the mean. Relative macrocephaly occurs if the measure is less than two SDs above the mean, but is disproportionately above that when ethnicity and stature are considered. Diagnosis can be determined in utero or can be determined within 18–24 months after birth in some cases where head circumference tends to stabilize in

infant In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to juveniles of ...

s. Diagnosis in infants includes measuring the circumference of the child's head and comparing how significant it falls above the 97.5 percentile of children similar to their demographic. If falling above the 97.5th percentile then the patient will be checked to determine whether there is any

intracranial pressure Intracranial pressure (ICP) is the pressure exerted by fluids such as cerebrospinal fluid (CSF) inside the skull and on the brain tissue. ICP is measured in millimeters of mercury ( mmHg) and at rest, is normally 7–15 mmHg for a supine adu ...

present and whether or not immediate surgery is needed. If immediate surgery is not needed then further testing will be done to determine whether the patient has either macrocephaly or benign macrocephaly. Diagnosis for macrocephaly involves the comparison of the infant's head circumference to that of other infants of the same age and

ethnicity An ethnicity or ethnic group is a group of people with shared attributes, which they Collective consciousness, collectively believe to have, and long-term endogamy. Ethnicities share attributes like language, culture, common sets of ancestry, ...

. If a patient is suspected of having macrocephaly molecular testing will be used to confirm diagnosis. Symptoms vary on the cause of macrocephaly on the child and if the child has any other accompanying syndromes which will be determined through molecular testing.

Benign or familial macrocephaly

Benign macrocephaly can occur without reason or be inherited by one or both parents (in which it is considered benign familial macrocephaly and is considered a megalencephaly form of macrocephaly). Diagnosis for familial macrocephaly is determined by measuring the head circumference of both parents and comparing it to the child's. Benign and familial macrocephaly is not associated with

neurological disorder Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...

s. While benign and familial macrocephaly do not result in neurological disorders, neurodevelopment will still need to be assessed. Although neurological disorders do not occur, temporary symptoms of benign and familial macrocephaly include: developmental delay,

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

, and mild hypotonia.

Neurodevelopment The development of the nervous system in humans, or neural development, or neurodevelopment involves the studies of embryology, developmental biology, and neuroscience. These describe the cellular and molecular mechanisms by which the complex ...

is assessed for all cases and suspected cases of macrocephaly to determine whether and what treatments may be needed, and whether any other syndrome/s may be present or likely to develop.

Other forms

Other forms of macrocephaly include: * Macrocephaly at birth: congenital macrocephaly already present at birth. * Postnatal macrocephaly: macrocephaly developed postnatally (after birth). * Progressive macrocephaly: macrocephaly developed progressively over time. * Relative macrocephaly: mild macrocephaly measured under 2 SD from mean, but larger in appearance due to other factors (ex. short stature).

Treatment

Treatment varies depending on whether or not it occurs with other medical conditions in the child and where the

is present. If benign and found between the brain and skull then no surgery is needed. If excess fluid is found between the ventricle spaces in the brain then surgery will be needed.

Associated syndromes

Below is a list of

s associated with macrocephaly that are noted in ''Signs and Symptoms of Genetic Conditions: A Handbook''. Lujan

Include multiple major and or minor anomalies

* Acrocallosal syndrome *

Apert syndrome Apert syndrome is a form of acrocephalosyndactyly, a congenital disorder characterized by malformations of the skull, face, hands and feet. It is classified as a branchial arch syndrome, affecting the first Pharyngeal arch, branchial (or pharyn ...

* Bannayan–Riley–Ruvalcaba syndrome * Cardiofaciocutaneous syndrome * Chromosome 14 - maternal disomy * Chromosome 22qter deletion *

Cleidocranial dysostosis Cleidocranial dysostosis (CCD), also called cleidocranial dysplasia, is a congenital disorder, birth defect that mostly affects the bones and teeth. The collarbones are typically either poorly developed or absent, which allows the shoulders to be ...

* Costello syndrome * Encephalocraniocutaneous lipomatosis *

FG syndrome FG syndrome (FGS) is a rare genetic syndrome caused by one or more recessive genes located on the X chromosome and causing physical anomalies and developmental delays. FG syndrome was named after the first letters of the surnames of the first pat ...

* Hallermann–Streiff syndrome * Hydrolethalus syndrome * Hypomelanosis syndrome * Hypomelanosis of Ito * Kelvin Peter anomaly plus syndrome * Lujan–Fryns syndrome * Macrocephaly-CM (MCAP) * Marshall–Smith syndrome * Neuhauser megalocornea/MR syndrome * Neurofibromatosis type I * Nevoid basal-cell carcinoma syndrome * Noonan syndrome * Ocular-ectodermal syndrome * Osteopathia striata - cranial sclerosis *

Perlman syndrome Perlman syndrome (PS), also known as nephroblastomatosis-fetal ascites-macrosomia-Wilms tumor syndrome, is a rare overgrowth syndrome caused by Dominance (genetics), autosomal recessive mutations in the ''DIS3L2'' gene. PS is characterized by mac ...

* Simpson–Golabi–Behmel syndrome * Sotos syndrome *

Sturge–Weber syndrome Sturge–Weber syndrome, sometimes referred to as encephalotrigeminal angiomatosis, is a rare congenital neurocutaneous disorder (also known as phakomatoses). It is often associated with port-wine stains of the face, glaucoma, seizures, intellect ...

* Weaver syndrome * Wiedemann–Rautenstrauch syndrome * 3C syndrome Boomerang splenial infarct

Secondary to a metabolic disorder

* Glutaric aciduria type II * GM1 gangliosidosis *

Hunter syndrome Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a rare genetic disorder, inherited lysosomal storage disease in which large sugar molecules called glycosaminoglycans (or GAGs or mucopolysaccharides) build up in body tissues. Hunte ...

* Hurler syndrome * MPS VII * Sanfilippo syndrome *

Zellweger syndrome Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called Zellweger spectrum disorders which are leukodystrophy, l ...

Associated with a skeletal dysplasia

* Campomelic dysplasia * Craniodiaphyseal dysplasia * Craniometaphyseal dysplasia * Hypochondrogenesis *

* Kenny-Caffey syndrome *

Kniest dysplasia Kniest dysplasia is a rare form of dwarfism caused by a mutation in the '' COL2A1'' gene on chromosome 12. The ''COL2A1'' gene is responsible for producing type II collagen. The mutation of the ''COL2A1'' gene leads to abnormal skeletal growth an ...

* Lenz–Majewski syndrome * Osteogenesis imperfecta III * Osteopetrosis, autosomal recessive form * Schneckenbecken dysplasia *

* Short rib syndrome, beemer-langer type * Short rib-polydactyly 2 (majewski type) * Spondyloepiphyseal dysplasia congenita * Thanatophoric dysplasia Tay-sachsUMich

With no obvious physical findings

* Canavan disease * Cobalamin deficiency (combined methylmalonic aciduria and homocystinuria) *

Dandy–Walker malformation Dandy–Walker malformation (DWM), also known as Dandy–Walker syndrome (DWS), is a rare congenital brain malformation in which the part joining the two hemispheres of the cerebellum (the cerebellar vermis) does not fully form, and the fourth ...

* Glutaric aciduria type 1 *

L-2-hydroxyglutaric aciduria 2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. It is either autosomal recessive or autosomal dominant. Presentation The signs/symptoms of this ...

* Megalencephalic leukoencephalopathy with subcortical cysts * Osteogenesis imperfecta IV * Osteopathia striata-cranial sclerosis * Periventricular heterotopia * Sandhoff disease *

Tay–Sachs disease Tay–Sachs disease is an Genetic disorder, inherited fatal lysosomal storage disease that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent arou ...

References

External links

GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)

GeneReviews/NCBI/NIH/UW entry on 9q22.3 Microdeletion
{{Authority control Congenital disorders of musculoskeletal system