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Hypotonia, infantile, with psychomotor retardation and characteristic facies 2(IHPRF2)

MedGen UID:
907651
Concept ID:
C4225203
Disease or Syndrome
Synonym: IHPRF2
 
Gene (location): UNC80 (2q34)
 
Monarch Initiative: MONDO:0014777
OMIM®: 616801

Disease characteristics

Excerpted from the GeneReview: UNC80 Deficiency
UNC80 deficiency is characterized by developmental delay, neonatal hypotonia, severe intellectual disability, dysmorphic facial features, strabismus, dyskinetic limb movements, and neurobehavioral manifestations. The majority of individuals do not learn to walk. All individuals lack expressive speech; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional common features include clubfeet, joint contractures, scoliosis, postnatal growth deficiency, increased risk of infections, sleeping difficulties, and constipation. Individuals have slow acquisition of developmental skills and do not have features suggestive of neurodegeneration. [from GeneReviews]
Authors:
Nuria C Bramswig  |  Maha S Zaki   view full author information

Additional descriptions

From OMIM
Infantile hypotonia with psychomotor retardation and characteristic facies-2 is a severe autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy. Affected individuals show severe global developmental delay with poor or absent speech and absent or limited ability to walk. Some patients may have seizures that can be controlled; brain structure is typically normal (summary by Shamseldin et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypotonia with psychomotor retardation and characteristic facies, see IHPRF1 (615419).  http://www.omim.org/entry/616801
From MedlinePlus Genetics
UNC80 deficiency is a severe disorder characterized by nervous system and developmental problems that are apparent from birth or early infancy. The disorder does not typically get worse over time; development of intellectual function and motor skills, such as rolling over and sitting, is slow and limited, but once skills are learned, they are usually retained.

People with UNC80 deficiency have profound intellectual disability. Muscle tone is generally weak (hypotonia), but affected individuals may have increased muscle tone (hypertonia) in the arms and legs. Most people with this disorder never learn to walk. Some affected individuals have feeding difficulties because hypotonia leads to problems controlling movements of the mouth. Speech is also generally absent, although in some cases individuals have limited communication using body language, gestures, and signs. Seizures, involuntary side-to-side movements of the eyes (nystagmus), eyes that do not point in the same direction (strabismus), and a high-pitched cry can also occur in this disorder.

People with UNC80 deficiency are of normal size at birth but grow slowly during infancy and childhood. Unusual facial features typically occur in this disorder, and vary among affected individuals. These features can include a wide, short skull (brachycephaly); a triangular face shape with a prominent forehead (frontal bossing); droopy eyelids (ptosis); folds of skin covering the inner corners of the eyes (epicanthal folds); outside corners of the eyes that point downward (downslanting palpebral fissures); a nose with a prominent bridge and a bulbous or upturned tip; a short, smooth space between the upper lip and nose (philtrum); a mouth that remains open; and low-set ears. Other physical differences that can occur in people with UNC80 deficiency include a short neck, abnormal curvature of the spine (scoliosis), permanently bent joints (contractures), and inward- and upward-turning feet (clubfeet).  https://medlineplus.gov/genetics/condition/unc80-deficiency

Clinical features

From HPO
Tapered finger
MedGen UID:
98098
Concept ID:
C0426886
Finding
The gradual reduction in girth of the finger from proximal to distal.
Cachexia
MedGen UID:
2773
Concept ID:
C0006625
Sign or Symptom
Severe weight loss, wasting of muscle, loss of appetite, and general debility related to a chronic disease.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Failure to thrive in infancy
MedGen UID:
358083
Concept ID:
C1867873
Finding
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
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.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Dyskinesia
MedGen UID:
8514
Concept ID:
C0013384
Disease or Syndrome
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
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.
Global brain atrophy
MedGen UID:
66840
Concept ID:
C0241816
Pathologic Function
Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Severe global developmental delay
MedGen UID:
332436
Concept ID:
C1837397
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
Poor speech
MedGen UID:
341172
Concept ID:
C1848207
Finding
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability, profound
MedGen UID:
892508
Concept ID:
C3161330
Mental or Behavioral Dysfunction
Profound mental retardation is defined as an intelligence quotient (IQ) below 20.
Profound global developmental delay
MedGen UID:
766364
Concept ID:
C3553450
Disease or Syndrome
A profound delay in the achievement of motor or mental milestones in the domains of development of a child.
Profound static encephalopathy
MedGen UID:
870497
Concept ID:
C4024944
Disease or Syndrome
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Brachycephaly
MedGen UID:
113165
Concept ID:
C0221356
Congenital Abnormality
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
Hip contracture
MedGen UID:
140815
Concept ID:
C0409354
Acquired Abnormality
Lack of full passive range of motion (restrictions in flexion, extension, or other movements) of the hip joint resulting from structural changes of non-bony tissues, such as muscles, tendons, ligaments, joint capsules and/or skin.
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).
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Plagiocephaly
MedGen UID:
1825944
Concept ID:
C2081594
Finding
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Appendicular hypotonia
MedGen UID:
868520
Concept ID:
C4022919
Finding
Muscular hypotonia of one or more limbs.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
Open mouth
MedGen UID:
116104
Concept ID:
C0240379
Finding
A facial appearance characterized by a permanently or nearly permanently opened mouth.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Prominent nose
MedGen UID:
98423
Concept ID:
C0426415
Finding
Distance between subnasale and pronasale more than two standard deviations above the mean, or alternatively, an apparently increased anterior protrusion of the nasal tip.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
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.
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Short philtrum
MedGen UID:
350006
Concept ID:
C1861324
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD below the mean. Alternatively, an apparently decreased distance between nasal base and midline upper lip vermilion border.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
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).
Esotropia
MedGen UID:
4550
Concept ID:
C0014877
Disease or Syndrome
A form of strabismus with one or both eyes turned inward ('crossed') to a relatively severe degree, usually defined as 10 diopters or more.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Recent clinical studies

Diagnosis

Bouasse M, Impheng H, Servant Z, Lory P, Monteil A
Sci Rep 2019 Aug 13;9(1):11791. doi: 10.1038/s41598-019-48071-x. PMID: 31409833Free PMC Article
Kuptanon C, Srichomthong C, Ittiwut C, Wechapinan T, Sri-Udomkajorn S, Iamopas O, Phokaew C, Suphapeetiporn K, Shotelersuk V
Gene 2019 May 15;696:21-27. Epub 2019 Feb 14 doi: 10.1016/j.gene.2019.01.049. PMID: 30771478
Obeid T, Hamzeh AR, Saif F, Nair P, Mohamed M, Al-Ali MT, Bastaki F
Metab Brain Dis 2018 Jun;33(3):869-873. Epub 2018 Feb 11 doi: 10.1007/s11011-018-0200-z. PMID: 29430593

Therapy

Winczewska-Wiktor A, Hirschfeld AS, Badura-Stronka M, Wojsyk-Banaszak I, Sobkowiak P, Bartkowska-Śniatkowska A, Babak V, Steinborn B
Int J Environ Res Public Health 2022 Jan 11;19(2) doi: 10.3390/ijerph19020775. PMID: 35055596Free PMC Article

Prognosis

Kelesoglu FM, Kaya M, Sayili ET
Am J Med Genet A 2023 Jul;191(7):1959-1962. Epub 2023 Apr 17 doi: 10.1002/ajmg.a.63213. PMID: 37067163
Winczewska-Wiktor A, Hirschfeld AS, Badura-Stronka M, Wojsyk-Banaszak I, Sobkowiak P, Bartkowska-Śniatkowska A, Babak V, Steinborn B
Int J Environ Res Public Health 2022 Jan 11;19(2) doi: 10.3390/ijerph19020775. PMID: 35055596Free PMC Article
Bramswig NC, Bertoli-Avella AM, Albrecht B, Al Aqeel AI, Alhashem A, Al-Sannaa N, Bah M, Bröhl K, Depienne C, Dorison N, Doummar D, Ehmke N, Elbendary HM, Gorokhova S, Héron D, Horn D, James K, Keren B, Kuechler A, Ismail S, Issa MY, Marey I, Mayer M, McEvoy-Venneri J, Megarbane A, Mignot C, Mohamed S, Nava C, Philip N, Ravix C, Rolfs A, Sadek AA, Segebrecht L, Stanley V, Trautman C, Valence S, Villard L, Wieland T, Engels H, Strom TM, Zaki MS, Gleeson JG, Lüdecke HJ, Bauer P, Wieczorek D
Hum Genet 2018 Sep;137(9):753-768. Epub 2018 Aug 23 doi: 10.1007/s00439-018-1929-5. PMID: 30167850Free PMC Article

Clinical prediction guides

Kelesoglu FM, Kaya M, Sayili ET
Am J Med Genet A 2023 Jul;191(7):1959-1962. Epub 2023 Apr 17 doi: 10.1002/ajmg.a.63213. PMID: 37067163
Winczewska-Wiktor A, Hirschfeld AS, Badura-Stronka M, Wojsyk-Banaszak I, Sobkowiak P, Bartkowska-Śniatkowska A, Babak V, Steinborn B
Int J Environ Res Public Health 2022 Jan 11;19(2) doi: 10.3390/ijerph19020775. PMID: 35055596Free PMC Article
Bramswig NC, Bertoli-Avella AM, Albrecht B, Al Aqeel AI, Alhashem A, Al-Sannaa N, Bah M, Bröhl K, Depienne C, Dorison N, Doummar D, Ehmke N, Elbendary HM, Gorokhova S, Héron D, Horn D, James K, Keren B, Kuechler A, Ismail S, Issa MY, Marey I, Mayer M, McEvoy-Venneri J, Megarbane A, Mignot C, Mohamed S, Nava C, Philip N, Ravix C, Rolfs A, Sadek AA, Segebrecht L, Stanley V, Trautman C, Valence S, Villard L, Wieland T, Engels H, Strom TM, Zaki MS, Gleeson JG, Lüdecke HJ, Bauer P, Wieczorek D
Hum Genet 2018 Sep;137(9):753-768. Epub 2018 Aug 23 doi: 10.1007/s00439-018-1929-5. PMID: 30167850Free PMC Article