Malan syndrome (MALNS) is a rare overgrowth syndrome caused by

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

mutations in the ''

NFIX Nuclear factor 1 X-type is a protein that in humans is encoded by the ''NFIX'' gene. NFI-X3, a splice variant of NFIX, regulates Glial fibrillary acidic protein and YKL-40 in astrocytes. Interactions Nfix has been shown to interact with SKI pr ...

'' gene. The syndrome is characterized by overgrowth, craniofacial dysmorphia,

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

, and behavioral issues. It was formerly diagnosed as

Sotos syndrome Sotos syndrome is a rare genetic disorder characterized by excessive physical growth during the first years of life. Excessive growth often starts in infancy and continues into the early teen years. The disorder may be accompanied by autism, mild ...

Signs and symptoms

Malan syndrome is defined by initial overgrowth and mild-to-severe

. Almost all individuals with Malan syndrome display above-average height, weight, and head circumference in early life, but only one-third of adults with Malan syndrome are >2 standard deviations above the mean. Most individuals display advanced

bone age Bone age is the degree of a person's skeletal development. In children, bone age serves as a measure of physiological maturity and aids in the diagnosis of growth abnormalities, endocrine disorders, and other medical conditions. As a person grows fr ...

Hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

and

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

s may be observed. All individuals display some degree of

global developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive development, cognitive and developmental biology, physical development. It can be diagnosed when a child is delayed in one or more milest ...

and

which typically ranges from moderate to severe, though mild cases have been observed.

Cognitive function Cognitive skills, also called cognitive functions, cognitive abilities or cognitive capacities, are brain-based skills which are needed in acquisition of knowledge, manipulation of information and reasoning. They have more to do with the mechanisms ...

, adaptive function, and language skills are impaired.

Anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

and noise hypersensitivity are frequently reported.

Autism spectrum The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

features are observed in 31% of individuals. The facial gestalt of Malan syndrome includes

dolichocephaly Dolichocephaly (derived from the Ancient Greek δολιχός 'long' and κεφαλή 'head') is a condition where the head is longer than would be expected, relative to its width. In humans, scaphocephaly is a form of dolichocephaly. Dolichocep ...

, a long or triangular face, prominent forehead, depressed nasal bridge, deep-set eyes, downslanting

palpebral fissure The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open eyelids. In simple terms, it is the opening between the eyelids. In adult humans, this measures about 10 mm vertically and 30 mm horizontally. Var ...

s, short nose with anteverted nares, long

philtrum The philtrum ( la, philtrum from Ancient Greek ''phíltron,'' lit. "love charm"), or medial cleft, is a vertical indentation in the middle area of the upper lip, common to therian mammals, extending in humans from the nasal septum to the tubercl ...

, everted lower lip, and prominent chin.

Marfanoid Marfanoid (or Marfanoid habitus) is a constellation of symptoms resembling those of Marfan syndrome, including long limbs, with an arm span that is at least 1.03 of the height of the individual, and a crowded oral maxilla, sometimes with a high a ...

features are extremely common, including

scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...

, hyper

kyphosis Kyphosis is an abnormally excessive convex curvature of the spine as it occurs in the thoracic and sacral regions. Abnormal inward concave ''lordotic'' curving of the cervical and lumbar regions of the spine is called lordosis. It can result fr ...

or hyper

lordosis Lordosis is historically defined as an ''abnormal'' inward curvature of the lumbar spine. However, the terms ''lordosis'' and ''lordotic'' are also used to refer to the normal inward curvature of the lumbar and cervical regions of the human spi ...

pectus excavatum Pectus excavatum is a structural deformity of the anterior thoracic wall in which the sternum and rib cage are shaped abnormally. This produces a caved-in or sunken appearance of the chest. It can either be present at birth or develop after pubert ...

or carinatum, slender habitus, and long hands. Ophthalmological features are common in Malan syndrome and can be used to distinguish it from

. Vision impairments may include

strabismus Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...

myopia Near-sightedness, also known as myopia and short-sightedness, is an eye disease where light focuses in front of, instead of on, the retina. As a result, distant objects appear blurry while close objects appear normal. Other symptoms may include ...

hypermetropia Far-sightedness, also known as long-sightedness, hypermetropia, or hyperopia, is a condition of the eye where distant objects are seen clearly but near objects appear blurred. This blurred effect is due to incoming light being focused behind, i ...

astigmatism Astigmatism is a type of refractive error due to rotational asymmetry in the eye's refractive power. This results in distorted or blurred vision at any distance. Other symptoms can include eyestrain, headaches, and trouble driving at nig ...

, and

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...

. Blue

sclera The sclera, also known as the white of the eye or, in older literature, as the tunica albuginea oculi, is the opaque, fibrous, protective, outer layer of the human eye containing mainly collagen and some crucial elastic fiber. In humans, and som ...

e are often observed.

Cause

Malan syndrome is caused by

mutations in the ''

'' gene. Both variants and deletions have been reported. In some cases, the deletion also affects ''

CACNA1A Cav2.1, also called the P/ Q voltage-dependent calcium channel, is a calcium channel found mainly in the brain. Specifically, it is found on the presynaptic terminals of neurons in the brain and cerebellum. Cav2.1 plays an important role in con ...

'', which is associated with

episodic ataxia Episodic ataxia (EA) is an autosomal dominant disorder characterized by sporadic bouts of ataxia (severe discoordination) with or without myokymia (continuous muscle movement). There are seven types recognized but the majority are due to two recog ...

type 2 or

familial hemiplegic migraine Familial hemiplegic migraine (FHM) is an autosomal dominant type of hemiplegic migraine that typically includes weakness of half the body which can last for hours, days, or weeks. It can be accompanied by other symptoms, such as ataxia, coma, ...

. Nearly all cases are caused by ''de novo'' mutations, though familial cases have been observed due to gonadal or parental

mosaicism Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized e ...

Management

Individuals with Malan syndrome should receive comprehensive evaluation of all major body systems at diagnosis. Height, weight, head circumference, BMI, and food intake should be evaluated regularly. Orthopedic and visual evaluations are recommended annually until puberty. Risk of pathologic bone fracture is increased in Malan syndrome; bone integrity can be assessed via

DXA Dual-energy X-ray absorptiometry (DXA, or DEXA) is a means of measuring bone mineral density (BMD) using spectral imaging. Two X-ray beams, with different energy levels, are aimed at the patient's bones. When soft tissue absorption is subtracted ...

. Neurological features such as epilepsy and vegetative symptoms should receive standard treatment. Neuropsychiatric and behavioral issues should be evaluated at diagnosis and managed as appropriate.

References

External links

{{Congenital abnormality syndromes Autosomal dominant disorders Rare genetic syndromes Syndromes with autism Syndromes with intellectual disability Syndromes with macrocephaly Syndromes with seizures

Signs and symptoms

Cause

Management

See also

References

External links