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Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies(NEDDFSA)

MedGen UID:
1684792
Concept ID:
C5231448
Disease or Syndrome
Synonyms: NEDDFSA; NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND DISTAL SKELETAL ANOMALIES
 
Gene (location): ZMIZ1 (10q22.3)
 
Monarch Initiative: MONDO:0032855
OMIM®: 618659

Definition

Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a global neurodevelopmental disorder with highly variable features. Patients often show poor feeding, poor overall growth, and hypotonia from early infancy, followed by mildly delayed motor development, poor language acquisition, and behavioral abnormalities. Intellectual development varies from severe with absent speech to mild with the ability to attend special schools. Common features include dysmorphic facial features with notable eye anomalies, joint hypermobility, and mild skeletal anomalies of the hands and feet (summary by Carapito et al., 2019). [from OMIM]

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Vesicoureteral reflux
MedGen UID:
21852
Concept ID:
C0042580
Disease or Syndrome
Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).
Renal atrophy
MedGen UID:
574585
Concept ID:
C0341698
Acquired Abnormality
Atrophy of the kidney.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Hallux valgus
MedGen UID:
5416
Concept ID:
C0018536
Anatomical Abnormality
Lateral deviation of the great toe (i.e., in the direction of the little toe).
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Tapered finger
MedGen UID:
98098
Concept ID:
C0426886
Finding
The gradual reduction in girth of the finger from proximal to distal.
Short toe
MedGen UID:
322858
Concept ID:
C1836195
Finding
A toe that appears disproportionately short compared to the foot.
Short finger
MedGen UID:
334977
Concept ID:
C1844548
Anatomical Abnormality
Abnormally short finger associated with developmental hypoplasia.
Long fingers
MedGen UID:
346836
Concept ID:
C1858091
Finding
The middle finger is more than 2 SD above the mean for newborns 27 to 41 weeks EGA or above the 97th centile for children from birth to 16 years of age AND the five digits retain their normal length proportions relative to each other (i.e., it is not the case that the middle finger is the only lengthened digit), or, Fingers that appear disproportionately long compared to the palm of the hand.
Broad hallux
MedGen UID:
401165
Concept ID:
C1867131
Finding
Visible increase in width of the hallux without an increase in the dorso-ventral dimension.
2-3 toe syndactyly
MedGen UID:
1645640
Concept ID:
C4551570
Congenital Abnormality
Syndactyly with fusion of toes two and three.
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Prominent ear helix
MedGen UID:
892712
Concept ID:
C4024165
Finding
Abnormally prominent ear helix.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Periventricular nodular heterotopia
MedGen UID:
358387
Concept ID:
C1868720
Disease or Syndrome
Nodules of heterotopia along the ventricular walls. There can be a single nodule or a large number of nodules, they can exist on either or both sides of the brain at any point along the higher ventricle margins, they can be small or large, single or multiple.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Facial hypotonia
MedGen UID:
336889
Concept ID:
C1845251
Finding
Reduced muscle tone of a muscle that is innervated by the facial nerve (the seventh cranial nerve).
Cone-shaped epiphysis
MedGen UID:
351282
Concept ID:
C1865037
Finding
Cone-shaped epiphyses (also known as coned epiphyses) are epiphyses that invaginate into cupped metaphyses. That is, the epiphysis has a cone-shaped distal extension resulting from increased growth of the central portion of the epiphysis relative to its periphery.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Narrow mouth
MedGen UID:
44435
Concept ID:
C0026034
Congenital Abnormality
Distance between the commissures of the mouth more than 2 SD below the mean. Alternatively, an apparently decreased width of the oral aperture (subjective).
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Exaggerated cupid bow
MedGen UID:
376842
Concept ID:
C1850629
Finding
More pronounced paramedian peaks and median notch of the Cupid's bow.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Low hanging columella
MedGen UID:
344656
Concept ID:
C1856119
Finding
Columella extending inferior to the level of the nasal base, when viewed from the side.
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Amblyopia
MedGen UID:
8009
Concept ID:
C0002418
Disease or Syndrome
Reduced visual acuity that is uncorrectable by lenses in the absence of detectable anatomic defects in the eye or visual pathways.
Astigmatism
MedGen UID:
2473
Concept ID:
C0004106
Disease or Syndrome
Astigmatism (from the Greek 'a' meaning absence and 'stigma' meaning point) is a condition in which the parallel rays of light entering the eye through the refractive media are not focused on a single point. Both corneal and noncorneal factors contribute to refractive astigmatism. Corneal astigmatism is mainly the result of an aspheric anterior surface of the cornea, which can be measured readily by means of a keratometer; in a small fraction of cases (approximately 1 in 10) the effect is neutralized by the back surface. The curvature of the back surface of the cornea is not considered in most studies, because it is more difficult to measure; moreover, in the case of severe corneal astigmatism, there is evidence that both surfaces have the same configuration. Noncorneal factors are errors in the curvature of the 2 surfaces of the crystalline lens, irregularity in the refractive index of the lens, and an eccentric lens position. Since the cornea is the dominant component of the eye's refracting system, a highly astigmatic cornea is likely to result in a similarly astigmatic ocular refraction (summary by Clementi et al., 1998).
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Congenital ocular coloboma
MedGen UID:
1046
Concept ID:
C0009363
Congenital Abnormality
Coloboma is an eye abnormality that occurs before birth. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in one of several parts of the eye, including the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or the optic nerves, which carry information from the eyes to the brain.\n\nColobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision. Colobomas affecting the iris, which result in a "keyhole" appearance of the pupil, generally do not lead to vision loss. Colobomas involving the retina result in vision loss in specific parts of the visual field. Large retinal colobomas or those affecting the optic nerve can cause low vision, which means vision loss that cannot be completely corrected with glasses or contact lenses.\n\nSome people with coloboma also have a condition called microphthalmia. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with coloboma may also have other eye abnormalities, including clouding of the lens of the eye (cataract), increased pressure inside the eye (glaucoma) that can damage the optic nerve, vision problems such as nearsightedness (myopia), involuntary back-and-forth eye movements (nystagmus), or separation of the retina from the back of the eye (retinal detachment).\n\nColobomas involving the eyeball should be distinguished from gaps that occur in the eyelids. While these eyelid gaps are also called colobomas, they arise from abnormalities in different structures during early development.\n\nSome individuals have coloboma as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When coloboma occurs by itself, it is described as nonsyndromic or isolated.
Duane anomaly
MedGen UID:
4413
Concept ID:
C0013261
Disease or Syndrome
Duane syndrome is a strabismus condition clinically characterized by congenital non-progressive limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure. The lateral movement anomaly results from failure of the abducens nucleus and nerve (cranial nerve VI) to fully innervate the lateral rectus muscle; globe retraction occurs as a result of abnormal innervation of the lateral rectus muscle by the oculomotor nerve (cranial nerve III). At birth, affected infants have restricted ability to move the affected eye(s) outward (abduction) and/or inward (adduction), though the limitations may not be recognized in early infancy. In addition, the globe retracts into the orbit with attempted adduction, accompanied by narrowing of the palpebral fissure. Many individuals with Duane syndrome have strabismus in primary gaze but can use a compensatory head turn to align the eyes, and thus can preserve binocular vision and avoid diplopia. Individuals with Duane syndrome who lack binocular vision are at risk for amblyopia. The majority of affected individuals with Duane syndrome have isolated Duane syndrome (i.e., they do not have other detected congenital anomalies). Other individuals with Duane syndrome fall into well-defined syndromic diagnoses. However, many individuals with Duane syndrome have non-ocular findings that do not fit a known syndrome; these individuals are included as part of the discussion of nonsyndromic Duane syndrome.
Glaucoma
MedGen UID:
42224
Concept ID:
C0017601
Disease or Syndrome
Glaucoma refers loss of retinal ganglion cells in a characteristic pattern of optic neuropathy usually associated with increased intraocular pressure.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Recent clinical studies

Etiology

Goldenberg A, Riccardi F, Tessier A, Pfundt R, Busa T, Cacciagli P, Capri Y, Coutton C, Delahaye-Duriez A, Frebourg T, Gatinois V, Guerrot AM, Genevieve D, Lecoquierre F, Jacquette A, Khau Van Kien P, Leheup B, Marlin S, Verloes A, Michaud V, Nadeau G, Mignot C, Parent P, Rossi M, Toutain A, Schaefer E, Thauvin-Robinet C, Van Maldergem L, Thevenon J, Satre V, Perrin L, Vincent-Delorme C, Sorlin A, Missirian C, Villard L, Mancini J, Saugier-Veber P, Philip N
Am J Med Genet A 2016 Nov;170(11):2847-2859. Epub 2016 Sep 8 doi: 10.1002/ajmg.a.37878. PMID: 27605097

Diagnosis

Goldenberg A, Riccardi F, Tessier A, Pfundt R, Busa T, Cacciagli P, Capri Y, Coutton C, Delahaye-Duriez A, Frebourg T, Gatinois V, Guerrot AM, Genevieve D, Lecoquierre F, Jacquette A, Khau Van Kien P, Leheup B, Marlin S, Verloes A, Michaud V, Nadeau G, Mignot C, Parent P, Rossi M, Toutain A, Schaefer E, Thauvin-Robinet C, Van Maldergem L, Thevenon J, Satre V, Perrin L, Vincent-Delorme C, Sorlin A, Missirian C, Villard L, Mancini J, Saugier-Veber P, Philip N
Am J Med Genet A 2016 Nov;170(11):2847-2859. Epub 2016 Sep 8 doi: 10.1002/ajmg.a.37878. PMID: 27605097
Luco SM, Pohl D, Sell E, Wagner JD, Dyment DA, Daoud H
BMC Med Genet 2016 Feb 27;17:15. doi: 10.1186/s12881-016-0276-4. PMID: 26922654Free PMC Article

Prognosis

Goldenberg A, Riccardi F, Tessier A, Pfundt R, Busa T, Cacciagli P, Capri Y, Coutton C, Delahaye-Duriez A, Frebourg T, Gatinois V, Guerrot AM, Genevieve D, Lecoquierre F, Jacquette A, Khau Van Kien P, Leheup B, Marlin S, Verloes A, Michaud V, Nadeau G, Mignot C, Parent P, Rossi M, Toutain A, Schaefer E, Thauvin-Robinet C, Van Maldergem L, Thevenon J, Satre V, Perrin L, Vincent-Delorme C, Sorlin A, Missirian C, Villard L, Mancini J, Saugier-Veber P, Philip N
Am J Med Genet A 2016 Nov;170(11):2847-2859. Epub 2016 Sep 8 doi: 10.1002/ajmg.a.37878. PMID: 27605097

Clinical prediction guides

Kjaer I, Hansen N, Becktor KB, Birkebaek N, Balslev T
Cleft Palate Craniofac J 2001 Nov;38(6):645-51. doi: 10.1597/1545-1569_2001_038_0645_cmdasm_2.0.co_2. PMID: 11681999

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