pectus carinatum

Hypotonia, Infantile, with Psychomotor Retardation And Characteristic Facies 1

Clinical Characteristics
Ocular Features: 

Nystagmus, strabismus and sometimes optic atrophy have been noted.  Poor fixation may be present.   

Systemic Features: 

This progressive disorder can be evident at birth based on the facial dysmorphism.  The face is triangular, the forehead is prominent, the nose is small, the ears appear large and low-set.  The mouth appears wide with a thin upper lip.  Early development may be near normal for the first 6 months but thereafter psychomotor regression and slow physical growth are evident.  Patients have microcephaly and seldom achieve normal milestones.  Spasticity in the extremities and truncal hypotonia with distal muscle atrophy are evident.  The face appears triangular, the forehead is prominent, the nose is small, and the ears appear large and low-set.  Pectus carinatum and pes varus may be present.   Males often have cryptorchidism.

Brain imaging has revealed cerebellar atrophy and "while matter abnormalities".  Sural nerve biopsies show evidence of infantile neuroaxonal dystrophy.

Some individuals are less severely affected, retain the ability to speak, and are able to walk at least into the second decade of life.

Genetics

Based on transmission patterns this condition is inherited as an autosomal recessive disorder caused by mutations in in the NALCN gene (13q32.3-q33.1.

For somewhat similar disorders caused by mutations in other genes see IHPRF2 (616801) and IHPRF3 (616900).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Morquio Syndrome (MPS IVB)

Clinical Characteristics
Ocular Features: 

Corneal clouding may not be seen until 10 years of age and is sometimes associated with photophobia.  The stroma has fine dust-like particles most dense centrally.  Penetrating keratoplasty is rarely indicated. There is little retinal degeneration unlike that often seen in other mucopolysaccharidoses but the corneal clouding often precludes detailed examination.

Systemic Features: 

This form of mucopolysaccharidosis is characterized by the urinary excretion of keratin sulfate.  Age of onset is highly variable but most children are diagnosed by 6 years of age.  It is a milder disease than the somewhat similar but genetically distinct Morquio type A (253000)  disorder.  Intelligence is normal and there is no central nervous system involvement.  Hip joints are dysplastic and frequently painful.  Vertebral malformations lead to kyphoscoliosis and short trunk dwarfism.  Odontoid hypoplasia can cause cervical instability and increases the risk of myelopathy with secondary bowel and bladder dysfunction.  Coxa valgum, and narrow phalanges are common.  Many individuals have a characteristic gait secondary to genu valgum.  Patients with MPS IVB initially do not have the coarse facies seen in some other forms of MPS.  Further accumulation of cellular keratin sulfate may lead to some coarsening of facial features, increased corneal clouding, and hepatomegaly.  Some form of hearing loss is common.

Genetics

This is an autosomal recessive lysosomal storage disease caused by a mutation in the GLB1 gene (3p21.33) encoding beta-galactosidase.  It is allelic to GM1 gangliosidosis (230500).  Type A Morquio syndrome (253000) is a separate disorder secondary to a mutation in a different gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A variety of treatments are under investigation including enzyme replacement, gene therapy, and bone marrow transplantation.  Supportive and palliative measures for respiratory difficulties and skeletal deformities can be used.  Atlantoaxial subluxation is a constant risk and some physicians recommend prophylactic vertebral fusion.  Intubation for general anesthesia carries special risks.

References
Article Title: 

Mucopolysaccharidoses and the eye

Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006 Jan-Feb;51(1):1-17. Review.

PubMed ID: 
16414358

Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B

Paschke E, Milos I, Kreimer-Erlacher H, Hoefler G, Beck M, Hoeltzenbein M, Kleijer W, Levade T, Michelakakis H, Radeva B. Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B. Hum Genet. 2001 Aug;109(2):159-66.

PubMed ID: 
11511921

Morquio Syndrome (MPS IVA)

Clinical Characteristics
Ocular Features: 

Corneal clouding in the form of fine deposits in the stroma is the major ocular manifestation but it may not be noted for several years after birth.  Penetrating keratoplasty is rarely needed.  Glaucoma occurs rarely.

Systemic Features: 

There is wide variation in the clinical disease in this disorder and some have grouped cases into severe, intermediate and mild categories.   Onset is about 2 years of age and three-quarters of patients are diagnosed by the age of 6 years.  Intelligence is usually normal and the central nervous system is spared similar to MPS IVB. However, the skeletal dysplasia can lead to neurologic complications.  In particular, odontoid hypoplasia raises the risk of atlantoaxial dislocation and spinal cord damage. The maxillary teeth are often abnormal with wide spacing and a flared appearance.  Truncal dwarfism is characteristic but the facies are often more fine-featured than in other mucopolysaccharidoses.  Lifespan is shortened in most patients.

Genetics

This is an autosomal recessive disorder resulting from mutations in the GALNS gene (16q24.3) encoding galactosamine-6-sulfate sulfatase.  Keratan sulfate and chondroitin-5-sulfate accumulates in lysosomes.  Urinary keratin sulfate excretion is increased.

A clinically similar disease, Morquio syndrome B (253010), is caused by a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this disease.  Some have recommended cervical spine fusion to stabilize the atlantoaxial joint. Orthopedic surgery may be indicated for joint and spine deformities.  Special precautions should be taken during intubation for general anesthesia.

Enzyme replacement therapies and hematopoietic stem cell transplantation techniques now being developed hold promise for more specific treatment for the underlying enzyme deficiencies in mucopolysaccharidoses.

References
Article Title: 

Mucopolysaccharidoses and the eye

Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006 Jan-Feb;51(1):1-17. Review.

PubMed ID: 
16414358
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