short neck

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

Hyperphosphatasia with Mental Retardation Syndrome 6

Clinical Characteristics
Ocular Features: 

Congenital cataracts may be present.  The eyes appear deeply-set and strabismus has been seen in severely affected cases.   

Systemic Features: 

Two families have been reported.  The range of severity in symptoms is wide.  Birth may occur prematurely especially in the presence of polyhydramnios.  Postnatal development can be complicated by seizures, chronic lung disease, developmental regression, and renal disease.  Poor growth secondary to feeding difficulties have been reported.  Death can occur in early childhood.

Dysmorphic features include a short neck, bitemporal narrowing, depressed nasal bridge, and proximal limb shortening.  Osteopenia, flexion contractures, and hip dysplasia may be present.  Dilatation of the renal collecting system with increased echogenicity have been reported.  Creatine kinase and serum alkaline phosphatase may be increased and muscle histology shows small, atrophic fibers with increased fibrosis and considerable variations in fiber size.

Genetics

Homozygous mutations in the PIGY gene (4q22.1) resulting in deficiencies of glycosylphosphatidylinositol synthesis have been associated with this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Ilkovski B, Pagnamenta AT, O'Grady GL, Kinoshita T, Howard MF, Lek M, Thomas B, Turner A, Christodoulou J, Sillence D, Knight SJ, Popitsch N, Keays DA, Anzilotti C, Goriely A, Waddell LB, Brilot F, North KN, Kanzawa N, Macarthur DG, Taylor JC, Kini U, Murakami Y, Clarke NF. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum Mol Genet. 2015 Nov 1;24(21):6146-59.

PubMed ID: 
26293662

Pseudohypoparathyroidism, Type 1A

Clinical Characteristics
Ocular Features: 

Cataracts and nystagmus are sometimes present.  Optic neuritis and papilledema have been reported and can result in optic atrophy.  The combination of cataracts and swelling of the optic nerves in children requires evaluation for hypocalcemia.

Systemic Features: 

The title refers to a group of conditions that have organ resistance to parathyroid hormone.  The phenotype is variable since there usually is a usually some degree of end-organ resistance to other hormones such as gonadotropins and TSH as in the PHP1A disorder described here.  The grouped clinical features are often referred to as Albright hereditary oseodystrophy or AHO.

Short stature with a short neck, a round face, chubby cheeks, and a depressed nasal bridge are usually present.  There may be cognitive deficits and some patients are considered to be mentally retarded.  The fourth and fifth metacarpals and sometimes metatarsals are characteristically short.   The teeth are late to erupt and can have an enamel deficit.  End organ resistance to other hormones may lead to signs of hypothyroidism and hypogonadism.  Calcification of subcutaneous tissues can result in palpable hard nodules and calcium deposition in basal ganglia and choroidal plexus may be demonstrable.  Some patients experience hypocalcemic tetany and seizures.  Hypocalcemia and hyperphosphatemia are often present along with elevated serum parathyroid hormone levels.

Genetics

This transmission pattern is likely modified by the effects of imprinting which also can modify the phenotype.  Mutltigenerational family patterns have an excess of maternal transmission.  The full phenotype is more likely expressed among maternally transmitted cases whereas partial or incomplete expression is more often seen among individuals who received the paternal allele. 

Heterozygous muttions in the GNAS1 gene (20q13.32) plays a role in this disease.  Signal transduction failure likely plays a major role in the failure of organs to respond to the appropriate hormone.

Several subtypes of pseudohypoparathyroidism have been reported but some do not have ocular signs.  However, type 1C (612462) patients can have cataracts and nystagmus with an almost identical phenotype to that of IA and may be the same condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment focuses on normalization of calcium and phosphate serum levels.  A deficiency of vitamin D should also be corrected and has been reported to correct at least some of the lens opacities.  Cataract removal can be considered.

References
Article Title: 

Neu-Laxova Syndrome 1

Clinical Characteristics
Ocular Features: 

The globes are prominent, an appearance that is exaggerated sometimes by absence of the eyelids or ectropion.  The lashes may be absent in other patients.  Cloudy corneas and cataracts have been described.

Systemic Features: 

This is a lethal dysplasia-malformation syndrome in which some infants are stillborn while others do not live beyond a few days.  The placenta is often small and the umbilical cord is short.  Decreased fetal movements and polyhydramnios are often noted.  Microcephaly can be striking at birth but there is overall intrauterine growth retardation.  The skin is ichthyotic and dysplastic containing excess fatty tissue beneath the epidermis.  Digits are often small and may be fused (syndactyly).  There is generalized edema with ‘puffiness’ of the hands and feet.  The lungs are frequently underdeveloped and cardiac defects such as septal openings, patent ductus arteriosus and transposition of great vessels are common.  Males often have cryptorchidism while females have a bifid uterus and renal dysgenesis has been reported.

The face is dysmorphic with prominent globes (in spite of microphthalmia), the ears are large and malformed, the forehead is sloping, the nose is flattened and the jaw is small.  Some infants have a cleft lip and palate while the mouth is round and gaping.  The neck is usually short.

Severe brain malformations such as lissencephaly, cerebellar hypoplasia, and dysgenesis/agenesis of the corpus callosum are frequently present.

Genetics

This is an autosomal recessive disorder secondary to mutations in the PHGDH gene (1p12).

This condition has some clinical overlap with Neu-Laxova syndrome 2 (616038) but the latter is less severe and is caused by a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjold M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M. Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet. 2014 Sep 4;95(3):285-93.

PubMed ID: 
25152457

Meckel Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype is highly variable.  The globe is often malformed or may be clinically absent.  Cryptophthalmos, clinical anophthalmia, and microphthalmos with sclerocornea and microcornea have been reported.  Posterior staphylomas, retinal dysplasia, partial aniridia, cataracts, and hypoplasia or absence of the optic nerve are sometimes seen.  Some patients have incompletely formed eyes with shallow anterior chambers, angle anomalies, and a persistent tunica vasculosa with lens opacification.  Histopathology may reveal thinning of the nerve fiber layer and a paucity of retinal ganglion cells.  The retina has been described as dysplastic with foci of rosette-like structures and abundant glial cells.

Systemic Features: 

Meckel or Meckel-Gruber syndrome is a clinically and genetically heterogeneous group of disorders with severe multisystem manifestations.  The triad of cystic renal disease, polydactyly (and sometimes syndactyly), and a skull malformation (usually an encephalocele) is considered characteristic of MKS.  However, these signs are variable and only about 60% of patients have all three features.  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones.  Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. 

Many clinical abnormalities resemble those present in the Smith-Lemli-Opitz syndrome (270400) and in Joubert syndrome (213300).

Genetics

Most conditions in this group are inherited in an autosomal recessive pattern.  Mutations in 9 genes have been identified as responsible for some variant of MKS in which there is a considerable range of clinical expression.  There is significant clinical overlap with Joubert syndrome and it is not surprising that at least 5 of these mutations have been identified in both conditions.  Further nosological confusion is generated by those who consider patients with the severe, lethal phenotype to have Meckel syndrome while those with milder disease are labeled Joubert syndrome, regardless of genotype.

Rare heterozygotes have been reported with isolated features such as polydactyly.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this syndrome.  The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system.

References
Article Title: 

Clinical and genetic heterogeneity in Meckel syndrome

Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997 Nov;101(1):88-92.

PubMed ID: 
9385376

Iridogoniodysgenesis and Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Megalocornea, congenital glaucoma, a concave iris with stromal atrophy and corectopia, and deep anterior chambers are typical ocular features.  High myopia has been reported and retinal detachments have been observed.  Glaucoma control can be difficult to achieve and there is a significant risk of cataracts and phthisis bulbi following surgery.  Posterior embryotoxon has not been observed.

Systemic Features: 

Facial features seem to be consistent.  The forehead is wide, the nose appears broad with a large nasal tip and broad nares although the bridge appears narrow.  The philtrum is long and wide.  The ears may appear large and the neck is short.  The thorax is abnormally wide and the nipples are widely spaced and umbilicated.  The long bones are slender with thin cortices and wide metaphyses.  There is generalized osteopenia.  Vertebral bodies are cuboid-shaped with narrow vertebral canals and enlarged apophyses

Genetics

Two non-consanguineous families each with 3 sibs have been reported suggesting autosomal recessive inheritance.  Nothing is known about the mutation or its locus.

The ocular features may resemble Rieger or Axenfeld anomaly but these are inherited in autosomal dominant patterns and the skeletal features are dissimilar.       

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Vigorous treatment of glaucoma is indicated but successful control, even with surgery, is difficult to achieve.

References
Article Title: 

Noonan Syndrome

Clinical Characteristics
Ocular Features: 

Noonan syndrome has prominent anomalies of the periocular structures including downward-slanting lid fissures, hypertelorism, epicanthal folds, high upper eyelid crease, and some limitation of ocular mobility most commonly of the levator.  Ptosis and strabismus are present in nearly half of patients. Amblyopia has been found in one-third of patients and almost 10% have nystagmus.  Corneal nerves are prominent and a substantial number of individuals have optic nerve abnormalities including drusen, hypoplasia, colobomas and myelinated nerves.  Evidence of an anterior stromal dystrophy, cataracts, or panuveitis is seen in a minority of patients.  About 95% of patients have some ocular abnormalities.

Systemic Features: 

Patients are short in stature.  Birth weight and length may be normal but lymphedema is often present in newborns.  The neck is usually webbed (pterygium colli) and the ears low-set.  The sternum may be deformed.  Cardiac anomalies such as coarctation of the aorta, pulmonary valve stenosis, hypertrophic cardiomyopathy, and septal defects are present in more than half of patients.  Dysplasia of the pulmonic valve has been reported as well.  Thrombocytopenia and abnormal platelet function with abnormalities of coagulation factors are found in about 50% of cases resulting in easy bruising and prolonged bleeding.  Cryptorchidism is common in males.  Some patients have intellectual disabilities with speech and language problems.  Most have normal intelligence.   

Parents of affected children often have subtle signs of Noonan Syndrome.

Genetics

This is an autosomal dominant disorder that can result from mutations in at least 7 genes.  Nearly half are caused by mutations in the PTPN11 gene (12q24.1) (163950).  Mutations in the SOS1 gene (2p22-p21) cause NS4 (610733) and account for 10-20% of cases, those in the RAF1 gene (3p25) causing NS5 (611553) for about the same proportion, and mutations in the KRAS gene (12p12.1) (NS3; 609942) cause about 1%.  Mutations in BRAF (7q34) causing NS7 (613706), NRAS (1p13.2) responsible for NS6 (613224), and MEK1 genes have also been implicated and it is likely that more mutations will be found.  The phenotype is similar in all individuals but with some variation in the frequency and severity of specific features.  New mutations are common. 

Several families suggestive of autosomal recessive inheritance (NS2) (605275) have been reported but no homozygous genotype has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for most of the developmental problems but some patients benefit from special education. Cardiac surgery may be required in some cases to correct the developmental defects.  Bleeding problems can be treated with supplementation of the defective coagulation factor.  Growth hormone therapy can increase the growth velocity.

References
Article Title: 

Update on turner and noonan syndromes

Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on turner and noonan syndromes. Endocrinol Metab Clin North Am. 2012 Dec;41(4):713-34. Epub 2012 Sep 28.

PubMed ID: 
23099266

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

Keratoconus Posticus Circumscriptus

Clinical Characteristics
Ocular Features: 

The posterior corneal surface has area(s) of excavation (indentation) associated with overlying opacification.  The lens-corneal separation is reduced and iridocorneal adhesions are often present.  The clinical picture has been described as ‘posterior conical cornea’ or posterior keratoconus.

Systemic Features: 

The neck is short and has webbing.  The facies appear ‘coarse’, the posterior hairline is low, the nose is prominent, digits are short, and the vertebral anomalies may lead to scoliosis.  Individuals are short of stature and brachydactyly is often present.  Developmental delays and mental retardation are usually features.  Other variable anomalies have been reported.

Genetics

Autosomal recessive inheritance seems most likely in view of the family patterns.  Based on the few families reported, it is uncertain if this is a single entity with variable expression or a combination of disorders.  No gene or locus has been associated with this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond surgical repair of the cleft lip and palate or scoliosis is available.  Peripheral iridotomies have been done in the presence of shallow anterior chambers.

References
Article Title: 
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