hirsutism

Sweeney-Cox Syndrome

Clinical Characteristics
Ocular Features: 

 Periorbital and facial anomalies were present in the two reported patients.  Pseudoproptosis (considered secondary to deficiency of the bony orbits) accentuated by midface hypoplasia, and upper lid colobomas have been observed.  The globes were described as "small" although there were no "concerns" regarding vision in the single male patient.  Electrodiagnostic tests were "normal."    

Systemic Features: 

Multiple anomalies and malformations were present in the two reported patients, an unrelated male and female.  Severe facial dysmorphism secondary to uneven skull bone formation and suture closures is present.  The metopic ridge is prominent, the orbital bones are deficient, the occiput is flattened, the anterior fontanel and coronal sutures are wide.  Midfacial hypoplasia is present.  The neck is broad and the shoulders are narrow.  The fingers are long and the distal phalanges may be fixed in flexion.  The ears are low-set, small, and cupped.  The palate is high and may be cleft.  Cutaneous syndactyly of the fingers has been observed.  Variable developmental delays/learning difficulties are present.

The male had an imperforate anus, undescended testes and a 60 dB hearing loss.  The female had a midline cleft palate with choanal atresia requiring a tracheostomy from birth and required fundoplication and gastrostomy for gastroesophageal reflux.

Genetics

Heterozygous missense mutations in the TWIST1 gene (7p21.1) were found in both reported individuals.  These appear to have arisen de novo.

Mutations in the same gene have also been found in the Saethre-Chotzen Syndrome (101400) in which some of the same skeletal features are found.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported for the general condition but individual malformations may require attention.  The lid colobomas were repaired in the female but corneal exposure remained and corneal scarring and phthisis developed in the right eye.  The left eye retained some vision ("able to see large objects").

References
Article Title: 

Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans

Kim S, Twigg SRF, Scanlon VA, Chandra A, Hansen TJ, Alsubait A, Fenwick AL, McGowan SJ, Lord H, Lester T, Sweeney E, Weber A, Cox H, Wilkie AOM, Golden A, Corsi AK. Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans. Hum Mol Genet. 2017 Jun 1;26(11):2118-2132.

PubMed ID: 
28369379

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Miller KA, Twigg SR, McGowan SJ, Phipps JM, Fenwick AL, Johnson D, Wall SA, Noons P, Rees KE, Tidey EA, Craft J, Taylor J, Taylor JC, Goos JA, Swagemakers SM, Mathijssen IM, van der Spek PJ, Lord H, Lester T, Abid N, Cilliers D, Hurst JA, Morton JE, Sweeney E, Weber A, Wilson LC, Wilkie AO. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017 Apr;54(4):260-268.

PubMed ID: 
27884935

Sweeney-Cox Syndrome

Clinical Characteristics
Ocular Features: 

Ophthalmologic examinations have not been reported.  However, periorbital and facial anomalies were present in the two reported patients.  Pseudoproptosis (considered secondary to deficiency of the bony orbits) accentuated by midface hypoplasia, and upper lid colobomas have been observed.  The globes were described as "small" although there were no "concerns" regarding vision in the single male patient.  Electrodiagnostic tests were "normal."    

Systemic Features: 

Multiple anomalies and malformations were present in the two reported patients, an unrelated male and female.  Severe facial dysmorphism secondary to uneven skull bone formation and suture closures is present.  The metopic ridge is prominent, the orbital bones are deficient, the occiput is flattened, the anterior fontanel and coronal sutures are wide.  Midfacial hypoplasia is present.  The neck is broad and the shoulders are narrow.  The fingers are long and the distal phalanges may be fixed in flexion.  The ears are low-set, small, and cupped.  The palate is high and may be cleft.  Cutaneous syndactyly of the fingers has been observed.  Variable developmental delays/learning difficulties are present.

The male had an imperforate anus, undescended testes and a 60 dB hearing loss.  The female had a midline cleft palate with choanal atresia requiring a tracheostomy from birth and required fundoplication and gastrostomy for gastroesophageal reflux.  

Genetics

Heterozygous missense mutations in the TWIST1 gene (7p21.1) were found in both reported individuals.  These appear to have arisen de novo.

Mutations in the same gene have also been found in the Saethre-Chotzen Syndrome (101400) in which some of the same skeletal features are found.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported for the general condition but individual malformations may require attention.  The lid colobomas were repaired in the female but corneal exposure remained and corneal scarring and phthisis developed in the right eye.  The left eye retained some vision ("able to see large objects").

References
Article Title: 

Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans

Kim S, Twigg SRF, Scanlon VA, Chandra A, Hansen TJ, Alsubait A, Fenwick AL, McGowan SJ, Lord H, Lester T, Sweeney E, Weber A, Cox H, Wilkie AOM, Golden A, Corsi AK. Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans. Hum Mol Genet. 2017 Jun 1;26(11):2118-2132.

PubMed ID: 
28369379

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Miller KA, Twigg SR, McGowan SJ, Phipps JM, Fenwick AL, Johnson D, Wall SA, Noons P, Rees KE, Tidey EA, Craft J, Taylor J, Taylor JC, Goos JA, Swagemakers SM, Mathijssen IM, van der Spek PJ, Lord H, Lester T, Abid N, Cilliers D, Hurst JA, Morton JE, Sweeney E, Weber A, Wilson LC, Wilkie AO. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017 Apr;54(4):260-268.

PubMed ID: 
27884935

Corpus Callosum Agenesis with Facial Anomalies and Cerebellar Ataxia

Clinical Characteristics
Ocular Features: 

The thick, bushy eyebrows and long eyelashes are part of the generalized hirsutism.  The eyelids appear puffy.  Strabismus of unknown type has been reported.

Systemic Features: 

Infants are hypertonic at birth but this seems to be less evident as they grow.  Slow physical growth and psychomotor delay are common.  The skull in newborns is small.  The ears are low-set, protruding, and posteriorly rotated.  The nostrils are anteverted and the lower lip protrudes.  There are severe cognitive defects which has been called mental retardation.  Speech is poor or may never develop.  Cerebellar ataxia and uncoordinated hand movements are features.  Brain imaging reveals cerebellar hypoplasia and some degree of corpus callosum agenesis including absence.

Genetics

Homozygous mutations in the FRMD4A gene (10p13) have been found to segregate with this disorder in a large consanguineous Bedouin kindred.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Filippi Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features have not been fully described.  The most consistent features are long eyelashes, thick (bushy) eyebrows, and 'visual disturbance'.  Most individuals have a facial dysmorphism which includes a broad nasal base suggestive of hypertelorism.  Optic atrophy and proptosis have been noted. 

Systemic Features: 

Intrauterine growth retardation is sometimes seen.  Microcephaly, short stature, syndactyly, intellectual disability (often labeled mental retardation), and a dysmorphic face are characteristic.  Some individuals have cryptorchidism, seizures, and ectodermal abnormalities including nail hypoplasia, hirsutism, and microdontia.  Mental and physical delays are common.  The syndactyly usually involves only soft tissue between toes 2, 3, and 4 and fingers 3 and 4 accompanied by clinodactyly of the 5th finger.  Polydactyly is sometimes present while radiologically the radial head may show evidence of hypoplasia. 

Genetics

Homozygosity or compound heterozygosity in the CKAP2L gene (2q13) segregates with this phenotype. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome

Hussain MS, Battaglia A, Szczepanski S, Kaygusuz E, Toliat MR, Sakakibara S, Altmuller J, Thiele H, Nurnberg G, Moosa S, Yigit G, Beleggia F, Tinschert S, Clayton-Smith J, Vasudevan P, Urquhart JE, Donnai D, Fryer A, Percin F, Brancati F, Dobbie A, Smigiel R, Gillessen-Kaesbach G, Wollnik B, Noegel AA, Newman WG, Nurnberg P. Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome. Am J Hum Genet. 2014 Nov 6;95(5):622-32.

PubMed ID: 
25439729

GM1 Gangliosidosis

Clinical Characteristics
Ocular Features: 

Based on clinical manifestations, three types have been described: type I or infantile form, type II or late-infantile/juvenile form, and type III or adult/chronic form but all are due to mutations in the same gene.  Only the infantile form has the typical cherry red spot in the macula but is present in only about 50% of infants.  The corneal clouding is due to intracellular accumulations of mucopolysaccharides in corneal epithelium and keratan sulfate in keratocytes.  Retinal ganglion cells also have accumulations of gangliosides.  Decreased acuity, nystagmus, strabismus and retinal hemorrhages have been described. 

Systemic Features: 

Infants with type I disease are usually hypotonic from birth but develop spasticity, psychomotor retardation, and hyperreflexia within 6 months.  Early death from cardiopulmonary disease or infection is common.  Hepatomegaly, coarse facial features, brachydactyly, and cardiomyopathy with valvular dysfunction are common.  Dermal melanocytosis has also been described in infants in a pattern some have called Mongolian spots.  Skeletal dysplasia is a feature and often leads to vertebral deformities and scoliosis.  The ears are often large and low-set, the nasal bridge is depressed, the tongue is enlarged and frontal bossing is often striking.  Hirsutism, coarse skin, short digits, and inguinal hernias are common.

The juvenile form, type II, has a later onset with psychomotor deterioration, seizures and skeletal changes apparent between 7 and 36 months and death in childhood.  Visceral involvement and cherry-red spots are usually not present. 

Type III, or adult form, is manifest later in the first decade or even sometime by the 4th decade.  Symptoms and signs are more localized.  Neurological signs are evident as dystonia or speech and gait difficulties.  Dementia, parkinsonian signs, and extrapyramidal disease are late features.  No hepatosplenomegaly, facial dysmorphism, or cherry red spots are present in most individuals. Lifespan may be normal in this type. 

Genetics

This is an autosomal recessive lysosomal storage disease secondary to a mutations in GLB1 (3p21.33).  It is allelic to Morquio B disease (MPS IVB) (253010).  The mutations in the beta-galactosidase-1 gene result in intracellular accumulation of GM1 ganglioside, keratan sulfate, and oligosaccharides.  The production of the enzyme varies among different mutations likely accounting for the clinical heterogeneity. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment that effectively alters the disease course. 

References
Article Title: 

Sanfilippo Syndrome (MPS IIIA, B, C, D)

Clinical Characteristics
Ocular Features: 

This form of mucopolysaccharidosis causes little or no corneal clouding.  Abnormal retinal pigmentation can be seen.

Systemic Features: 

Sanfilippo syndrome differs from other forms of mucopolysaccharidoses in the severity of the neurologic degeneration compared to the amount of somatic disease.  Infants usually appear healthy but developmental delay becomes evident by 2 or 3 years of age and physical growth slows.  Deterioration in mental development is progressive and seizures occur in some.  Gait and speech are impaired and by age 10 years patients have severe disabilities.  Behavioral problems including hyperactivity and aggression are often severe.

There is some hepatosplenomegaly, mild coarseness of the facial features, claw hands and mild bony changes such as biconvexity of the vertebral bodies and thick calvaria.  Hirsutism and synophrys are common.  The hair is unusually coarse.  Joints are frequently stiff and more severely affected individuals may have hearing loss.  Diarrhea is frequently a problem and most patients have some airway obstruction and are susceptible to recurrent respiratory infections.  Some patients have cardiovascular problems.

Genetics

MPS III is a lysosomal storage disease and may be caused by mutations in 1 of 4 genes that result in defective enzymes unable to break down mucopolysaccharides (glycosaminoglycans).  MPS IIIA (252900)results from a defect in the heparan sulfate sulfatase gene SGSH (17q25.3), type IIIB (252920)from a defect in the N-acetyl-alpha-D-glucosaminidase gene NAGLU (17q21), type IIIC (252930) from a defect in the acetyl-CoA:alpha-glucosaminide acetyltransferase gene HGSNAT (8p11.1), and type IIID (252940) from a defect in the N-acetylglucosamine-6-sulfatase gene GNS (12q14).  Heparan sulfate is excreted in all types.  Because of their clinical similarities these are discussed as a group in this database.  All are inherited in autosomal recessive patterns.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the underlying disease.  Therapy is primarily supportive.  A multidisciplinary approach with neurologists, ophthalmologists, audiologists, cardiologists, gastroenterologists, and orthopedists is most likely to result in treatments that can improve quality of life.

References
Article Title: 
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