triangular facies

Hypotonia, Infantile, with Psychomotor Retardation And Characteristic Facies 2

Clinical Characteristics
Ocular Features: 

Anomalies of periocular structures are part of the characteristic facial morphology.  The lid fissures slant downward and epicanthal folds are with ptosis are generally present.  Strabismus and nystagmus are characteristic features.

Systemic Features: 

This is a severe congenital neurodevelopmental disorder with global delay, hypotonia, and characteristic facies.  It is usually present at birth and soon manifest as a profound intellectual delay.  Most patients do not develop speech or independent motor skills.  Feeding difficulties are evident early and often require gastric tube placement for nutrition.  Failure to thrive is common.   Most patients have seizures of a tonic-clonic or atonic type which may be controlled with medication. 

Microcephaly, brachycephaly, plagiocephaly, and brachycephaly have been described.  A high forehead with frontal bossing, facial hypotonia, triangular facies have been described.  The ears are low-set and posteriorly rotated.  The upper lip is often thin and the mouth is commonly open.  The neck appears short, the nose is bulbous while the nasal bridge is prominent and the nares may be anteverted.

Brain imaging is normal in some patients but there is evidence of generalized cerebral atrophy, with a thin corpus callosum and decreased myelination in others.  Variable features such as scoliosis, hip contractures, muscle wasting, and dyskinesias are sometimes seen.

Genetics

This disorder is caused by homozygous or compound heterozygous mutations in the UNC80 gene (2q34).  

For somewhat similar disorders see IHPRF1 (615419) and IHPRF3 (616900).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability

Stray-Pedersen A, Cobben JM, Prescott TE, Lee S, Cang C, Aranda K, Ahmed S, Alders M, Gerstner T, Aslaksen K, Tetreault M, Qin W, Hartley T, Jhangiani SN, Muzny DM, Tarailo-Graovac M, van Karnebeek CD; Care4Rare Canada Consortium; Baylor-Hopkins Center for Mendelian Genomics, Lupski JR, Ren D, Yoon G. Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability. Am J Hum Genet. 2016 Jan 7;98(1):202-9.

PubMed ID: 
26708751

UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN

Perez Y, Kadir R, Volodarsky M, Noyman I, Flusser H, Shorer Z, Gradstein L, Birnbaum RY, Birk OS. UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN. J Med Genet. 2016 Jun;53(6):397-402.

PubMed ID: 
26545877

Al Kaissi Syndrome

Clinical Characteristics
Ocular Features: 

Reported facial dysmorphism features include periocular anomalies of ptosis, hypertelorism, down-slanting lid fissures, and epicanthal folds.  

Systemic Features: 

The phenotype is somewhat variable.  Intrauterine and postnatal growth retardation with hypotonia are common.   Moderate to severe intellectual disability is usually present and speech may be severely delayed.  The forehead is narrow, the nasal tip is broad, the nasal bridge is depressed, and the ears are low-set and posteriorly rotated.   Small hands and sometimes joint laxity are commonly present.  Cervical spine abnormalities including clefting, improper fusion, and segmentation anomalies are common.

Brain MRI may be normal but a small corpus callosum was present in some patients.

Genetics

Homozygous mutations in the CDK10 gene (16q24.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Windpassinger C, Piard J, Bonnard C, Alfadhel M, Lim S, Bisteau X, Blouin S, Ali NB, Ng AYJ, Lu H, Tohari S, Talib SZA, van Hul N, Caldez MJ, Van Maldergem L, Yigit G, Kayserili H, Youssef SA, Coppola V, de Bruin A, Tessarollo L, Choi H, Rupp V, Roetzer K, Roschger P, Klaushofer K, Altmuller J, Roy S, Venkatesh B, Ganger R, Grill F, Ben Chehida F, Wollnik B, Altunoglu U, Al Kaissi A, Reversade B, Kaldis P. CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. Am J Hum Genet. 2017 Sep 7;101(3):391-403.

PubMed ID: 
28886341

SHORT Syndrome

Clinical Characteristics
Ocular Features: 

Deeply set eyes are frequently noted and perhaps are a result of the lipodystrophy.  Anterior segment abnormalities resembling Rieger anomalies are often associated with congenital glaucoma. 

Systemic Features: 

There is considerable clinical heterogeneity.  The facial gestalt, however, is said to be characteristic.  These are: triangular progeroid facies with a prominent forehead, absence of facial fat, midface hypoplasia, and hypoplastic nasal alae.  Insulin resistance seems to be a consistent feature as well and nephrocalcinosis is common.  Serum and urinary calcium may be elevated even in infancy.

Teeth are late to erupt and bone age is delayed with shortness of stature the final result in many cases.  Joints are often hyperextensible.  A neurosensory hear loss has been found in some individuals.  Notably, developmental milestones are usually timely although mild cognitive delays are rarely seen and speech may be delayed.  Inguinal hernias are part of the syndrome. 

Genetics

Heterozygous mutations in the PIK3R1 gene (5q31.1) are responsible for this syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Serum and urinary calcium should be monitored.  The risk of glaucoma is high and patients should be monitored and treated appropriately.  Blood sugar and insulin levels may require treatment.  Inguinal hernias may require surgical repair.

References
Article Title: 

Mutations in PIK3R1 cause SHORT syndrome

Dyment DA, Smith AC, Alcantara D, Schwartzentruber JA, Basel-Vanagaite L, Curry CJ, Temple IK, Reardon W, Mansour S, Haq MR, Gilbert R, Lehmann OJ, Vanstone MR, Beaulieu CL; FORGE Canada Consortium., Majewski J, Bulman DE, O'Driscoll M, Boycott KM, Innes AM. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013 Jul 11;93(1):158-66. 

PubMed ID: 
23810382
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