epicanthal folds

Potter Disease, Type I

Clinical Characteristics
Ocular Features: 

As part of the facial morphology said to be characteristic of Potter disease, there is usually hypertelorism, telecanthus and epicanthal folds.  Cataracts and angiomas of the optic disc area have also been described.

Systemic Features: 

Polycystic kidney disease and hepatic system anomalies are major features of Potter disease.   Pulmonary hypoplasia with neonatal respiratory distress, however, is often the most immediate cause of death in most infants.  Antenatal oligohydramnios and low birth weight are commonly present.  As many as 33% of fetuses die in utero, often the result of bilateral renal agenesis.  Infants that survive can have chronic lung disease and renal dysfunction.  Congenital heart malformations are common, including septal defects, tetralogy of Fallot and patent ductus arteriosis.  Vertebrae may have a ‘butterfly’ shape but other skeletal findings include hemivertebrae and sacral agenesis.  The neck has been described as short and the skull is brachycephalic.

The facial appearance, known as Potter facies, is said to be characteristic and may be helpful in distinguishing this type of polycystic kidney disease.  In addition to the ocular findings, the nares are often anteverted, and the external ears are large and often posteriorly rotated.

Genetics

The uniqueness of this syndrome remains to be established.  There are several polycystic kidney disorders which have a monogenic basis. These often have overlapping renal features with the condition described here but lack the facial features said to be characteristic of Potter type I disease.  Autosomal recessive inheritance has been suggested on the basis of several reported families with affected sibs from consanguineous parents but so far no gene locus or mutation has been identified.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the condition but symptoms of respiratory distress and renal failure may need to be addressed acutely.  Long-term therapy for pulmonary disease and renal dysfunction can be considered for older individuals.  Many infants die in the neonatal period.

References
Article Title: 

Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p

Hallermann C, M?ocher G, Kohlschmidt N, Wellek B, Schumacher R, Bahlmann F, Shahidi-Asl P, Theile U, Rudnik-Schoneborn S, M?ontefering H, Zerres K. Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p. Am J Med Genet. 2000 Jan 17;90(2):115-9. Review.

PubMed ID: 
10607948

Peroxisome Biogenesis Disorder 1A (Zellweger)

Clinical Characteristics
Ocular Features: 

Ocular signs resemble those of other peroxisomal disorders with cataracts and retinopathy.  The lethal consequences of ZWS have hampered delineation of the full spectrum of ocular manifestations but many infants have these features plus optic atrophy and horizontal nystagmus.  Most infants do not follow light.  Pupillary responses may be normal in early stages but disappear later. Hypertelorism has been described but metrics are often normal.

Systemic Features: 

Many infants have hepatomegaly at birth and may develop splenomegaly as well.  Jaundice often occurs with intrahepatic biliary dysgenesis.   Severe hypotonia is present at birth but improves in those patients who survive for several years.  Psychomotor retardation can be profound and seizures may occur but sensory examinations are normal.  Most infants have a peculiar craniofacial dysmorphology with frontal bossing, large fontanels, and wide set eyes.  Pipecolic acid levels are low in serum and absent in the CSF.  Most infants do not survive beyond 6 months of age.

 

Genetics

This is a peroxisome biogenesis disorder with a complex biochemical profile resulting from a large number of mutations in at least 13 PEX genes.  It is inherited in an autosomal recessive pattern.

What was formerly called Zellweger Syndrome is now more properly called Zellweger Spectrum Disorder, or sometimes a peroxisomal biogenesis disorder in the Zellweger spectrum of disorders.  The spectrum also includes neonatal adrenoleukodystrophy (601539) and Infantile Refsum disease (601539). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Carpenter Syndrome

Clinical Characteristics
Ocular Features: 

A variety of ocular anomalies have been reported in Carpenter syndrome with none being constant or characteristic.  The inner canthi are often spaced widely apart and many have epicanthal folds and a flat nasal bridge.  Other reported abnormalities are nystagmus, foveal hypoplasia, corneal malformations including microcornea, corneal opacity, and mild optic atrophy and features of pseudopapilledema.

Systemic Features: 

Premature synostosis involves numerous cranial sutures with the sagittal suture commonly involved causing acrocephaly (tower skull).  Asymmetry of the skull and a 'cloverleaf' deformity are often present.  The polydactyly is preaxial and some degree of syndactyly is common especially in the toes.  The digits are often short and may be missing phalanges.  Some patients are short in stature.  Structural brain defects may be widespread including atrophy of the cortex and cerebellar vermis.  Septal defects in the heart are found in about one-third of patients.  The ears can be low-set and preauricular pits may be seen.  Some but not all patients have obesity and a degree of mental retardation.

Genetics

This is an autosomal recessive syndrome caused by a mutation in the RAB23 gene (6p12.1-q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment of the ocular defects is necessary in most cases. Craniectomy may be required in cases with severe synostosis.

References
Article Title: 

Carpenter syndrome

Hidestrand P, Vasconez H, Cottrill C. Carpenter syndrome. J Craniofac Surg. 2009 Jan;20(1):254-6.

PubMed ID: 
19165041

RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity

Jenkins D, Seelow D, Jehee FS, Perlyn CA, Alonso LG, Bueno DF, Donnai D, Josifova D, Mathijssen IM, Morton JE, Orstavik KH, Sweeney E, Wall SA, Marsh JL, Nurnberg P, Passos-Bueno MR, Wilkie AO. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet. 2007 Jun;80(6):1162-70. Erratum in: Am J Hum Genet. 2007 Nov;81(5):1114. Josifiova, Dragana [corrected to Josifova, Dragana].

PubMed ID: 
17503333

Neuhauser Syndrome

Clinical Characteristics
Ocular Features: 

This rare disorder is characterized by profound mental retardation and megalocornea together with nonspecific facial features including epicanthal folds, broad nasal root, frontal bossing and antimongoloid lid slanting.

Systemic Features: 

Hypotonia and marked psychomotor retardation are the most prominent systemic features.   Short stature, hypercholesterolemia, seizures and hypothyroidism have also been reported.

Genetics

No specific mutation has been found.  Most cases occur sporadically.  The mode of inheritance is presumed to be autosomal recessive on the basis of parental consanquinity found in occasional parents with multiple affected offspring.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.
 

References
Article Title: 

Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhäuser Syndrome and Central Corneal Thickness

Davidson AE, Cheong SS, Hysi PG, Venturini C, Plagnol V, Ruddle JB, Ali H, Carnt N, Gardner JC, Hassan H, Gade E, Kearns L, Jelsig AM, Restori M, Webb TR, Laws D, Cosgrove M, Hertz JM, Russell-Eggitt I, Pilz DT, Hammond CJ, Tuft SJ, Hardcastle AJ. Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhauser Syndrome and Central Corneal Thickness. PLoS One. 2014 Aug 5.

PubMed ID: 
25093588

PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum

Synofzik M, Gonzalez MA, Lourenco CM, Coutelier M, Haack TB, Rebelo A, Hannequin D, Strom TM, Prokisch H, Kernstock C, Durr A, Schols L, Lima-Martinez MM, Farooq A, Schule R, Stevanin G, Marques W Jr, Zuchner S. PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2013 Dec 19. [Epub ahead of print].

PubMed ID: 
24355708

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