developmental delay

Gillespie Syndrome

Clinical Characteristics
Ocular Features: 

Bilateral aniridia, partial or complete, is the ocular characteristic of Gillespie syndrome.  The iris may be relatively intact but immobile leading to the description in some patients of "dilated and fixed pupils", or congenital mydriasis.  The pupillary margin may be scalloped with iris strands to the lens.  The pupillary sphincter is sometimes absent and the mesodermal surface missing.  The fovea sometimes appears hypoplastic and some patients have decreased visual acuity.  Strabismus and ptosis are often present.  There may also be retinal hypopigmentation.  Cataract, glaucoma, and corneal opacities are not present. 

Systemic Features: 

Most patients have some degree of developmental delay ranging from difficulties with fine motor tasks to frank mental retardation.  Many have a hand tremor, some degree of hypotonia, and learning difficulties.  MRI imaging often shows cerebellar and sometimes cerebral hypoplasia. 

Genetics

This is an autosomal dominant disorder usually due to a heterozygous mutation in the PAX6 gene (11p13).  However, some patients with typical features do not have a mutation in this gene suggesting that there is genetic heterogeneity.  Some patients without point mutations nevertheless have defects in adjacent DNA suggesting a positional effect.  The possibility of autosomal recessive inheritance in some families with parental consanguinity cannot be ruled out.  The PAX6 gene plays an important role in iris development as it is also mutant in simple aniridia (106210) and in Peters anomaly (604229).

Mutations in the ITPR1 gene have also been identified in Gillespie syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Spinocerebellar Ataxia 7

Clinical Characteristics
Ocular Features: 

Pigmentary changes in the retina are somewhat variable but often begin with a granular appearance in the macula and spread into the periphery.  The macula often becomes atrophic and dyschromatopsia is common.   Retinal thinning is evident, especially in the macula.  Decreased visual acuity and loss of color vision are early symptoms and the ERG shows abnormalities of both rod and cone function.  External ophthalmoplegia without ptosis is a frequent sign.  Most adults and some children eventually are blind. 

Systemic Features: 

Symptoms of developmental delay and failure to thrive may appear in the first year of life followed by loss of motor milestones.  Dysarthria and ataxia are nearly universal features while pyramidal and extrapyramidal signs are more variable.  This can be a rapidly progressive disease and children who develop symptoms by 14 months are often deceased before two years of age.  However, adults with mild disease can survive into the 5th and 6th decades.  Peripheral neuropathy with sensory loss and motor deficits are usually present to some degree but the range of clinical disease is wide.  Cognitive decline and some degree of dementia occur sometimes. 

Genetics

Spinocerebellar ataxia 7 is caused by expanded trinucleotide repeats (CAG) in the ATXN7 gene (3p21.1-p12) and inherited in an autosomal dominant pattern.  The number of repeats is variable and correlated with severity of disease.  Most patients with 36 or more repeats have significant disease. This disorder is sometimes classified as a progressive cone-rod dystrophy.  It is sometimes referred to as olivopontocerebellar atrophy type III or OPCA3.

This disorder exhibits genetic anticipation especially with paternal transmission as succeeding generations often have earlier onset with more severe and more rapidly progressive disease. This is explained by the fact that younger generations tend to have a larger number of repeats and sometimes the diagnosis is made in children before the disease appears in parents or grandparents.

Spinocerebellar ataxia 1 (164400) is a similar autosomal dominant disorder with many of the same clinical and genetic features.  It is caused by excess CAG repeats on the ATXN1 gene on chromosome 6. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is known for the disease.  Low vision aids and mobility training may be useful in early stages. 

References
Article Title: 

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: 

Hurler and Scheie Syndromes (MPS IH, IS, IH/S)

Clinical Characteristics
Ocular Features: 

Progressive corneal clouding is a major feature and appears early in life.  Intracellular accumulations of heparan and dermatan sulfate are responsible for the ground glass appearance.  However, congenital glaucoma also occurs in MPS I and must be considered as a concomitant cause of a diffusely cloudy cornea.

Abnormal storage of mucopolysaccharides has been found in all ocular tissues and in the retina leads to a pigmentary retinopathy.  The ERG may be abolished by 5 or 6 years of age.  Papilledema is often followed by optic atrophy.  Photophobia is a common symptom.  Shallow orbits give the eyes a prominent appearance.

Systemic Features: 

This group of lysosomal deficiency diseases is probably the most common.  MPS I is clinically heterogeneous encompassing three clinical entities: Hurler, Hurler-Scheie, and Scheie.  In terms of clinical severity, Hurler is the most severe and Scheie is the mildest.  Infants generally appear normal at birth and develop the typical coarse facial features in the first few months of life.  Physical growth often stops at about 2 years of age.  Skeletal changes of dysostosis multiplex are often seen and kyphoscoliosis is common as vertebrae become flattened.  The head is large with frontal bossing and a depressed nasal bridge.  Cranial sutures, especially the metopic and sagittal sutures, often close prematurely.  The lips are prominent and an open mouth with an enlarged tongue is characteristic.  The neck is often short.  Odontoid hypoplasia increases the risk of vertebral subluxation and cord compression.  Joints are often stiff and arthropathy eventually affects all joints.  Claw deformities of the hands and carpal tunnel syndrome are common.  Most patients are short in stature and barrel-chested.

Cardiac valves often are thickened and endocardial fibroelastosis is frequently seen.  The coronary arteries are often narrowed.  Respiratory obstructions are common and respiratory infections can be serious problems.  Hearing loss is common.

Most patients reach a maximum functional age of 2 to 4 years and then regress.  Language is limited.  Untreated, many patients die before 10 years of age.

Genetics

The Hurler/Scheie phenotypes are all the result of mutations in the IDUA gene (4p16.3).  They are inherited in an autosomal recessive pattern.  A deficiency in alpha-L-iduronidase causes three phenotypes: Hurler (607014; MPS IH), Hurler-Scheie (607015; MPS IH/S), and Scheie (607016; MPS IS) syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Various treatments have had some success.  Enzyme replacement using laronidase (Aldurazyme©) has been shown to reduce organomegaly and improve motor and respiratory functions.  It has been used alone and in combination with bone marrow transplantation but therapeutic effects are greater if given to younger patients.  It does not improve skeletal defects or corneal clouding.  MRI imaging has documented improvement in CNS signs.  Gene therapy has shown promise but remains experimental.  Regular lifelong monitoring is important using a multidisciplinary approach to identify potential problems.  Joint problems may be surgically correctable with special emphasis on the need for atlanto-occipital stabilization.  Corneal transplants may be helpful in the restoration of vision in selected patients.

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: 

Pelizeaus-Merzbacher Disease

Clinical Characteristics
Ocular Features: 

Nystagmus is the major ocular feature in this disease and may appear as early as the first weeks of life in severe cases.  However, more mildly affected individuals may never have nystagmus and, further, it can disappear later.  The ocular movements are usually pendular but may have horizontal and rotatory components as well.  The presence of nystagmus is diagnostically important as it is an uncommon finding in other leukodystrophies.

Systemic Features: 

The classic disease is infantile in onset with hypotonia, titubation, weakness, stridor, respiratory problems, and even seizures often noted in the first weeks of life.   Ataxia, spasticity and cognitive delay are soon apparent.  Infants affected early and severely may never achieve normal motor or mental milestones whereas those less severely affected may at some point ambulate and acquire some language skills.  However, acquired skills may be lost by adolescence.  Survival to the sixth decade of life is common but those with the most severe form of disease may not live beyond the second decade. 

This is an X-linked recessive disorder in which only males have the complete syndrome.  However, multiple carrier females have been studied and many have subtle evidence of disease mainly in gait and motor control.

Genetics

Pelizeaus-Merzbacher disease is the result of mutations in an X-linked gene PLP1 (Xq22).  It is inherited in an X-linked recessive pattern.  Duplication of the PLP1 gene is more common than point mutations.  The signs and symptoms are not diagnostic of PMD as mutations in other genes can cause a similar phenotype. 

Spastic paraplegia-2 (SPG2; 312920)is an allelic disorder in which nystagmus and optic atrophy are also found in some patients.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no effective treatment for this disease.  Airway protection and seizure control should be applied in specific situations.  Patients often need a feeding tube for adequate nutrition.

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 8 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 with autosomal recessive inheritance (NS2) (605275) patterns have been reported with biallelic mutations in LZTR1.

Pedigree: 
Autosomal dominant
Autosomal recessive
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: 

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants

Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schaffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C; Members of the Undiagnosed Diseases Network, Zenker M, Lee B, Biesecker LG. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. 2018 Oct;20(10):1175-1185.

PubMed ID: 
29469822

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

Lowe Oculocerebrorenal Syndrome

Clinical Characteristics
Ocular Features: 

Lens development is abnormal from the beginning secondary to abnormal migration of lens epithelium which has been described in fetuses by 20-24 weeks of gestation.  This leads to some degree of opacification in 100% of affected males.  The lens opacities may be polar or nuclear in location but complete opacification also occurs.   Leukocoria, miosis, microphthalmos and a shallow anterior chamber has been noted in neonates.  The cataractous lenses may be small and abnormally formed.  Glaucoma is present in more than half of affected males with onset by the age of 6 years and may be difficult to control.  Conjunctival and corneal keloids are found in about one-fourth of patients.

Adult female carriers characteristically have peripheral cortical opacities, appearing in a radial configuration.  These 'snowflake' opacities seldom cause visual symptoms.   It has been proposed that slit lamp examinations for such opacities can accurately determine the carrier status of females.

Systemic Features: 

Mental retardation, hypotonia, short stature, and developmental delays are common.  Seizures and behavior problems are seen in older children.  The renal defect secondary to defective phosphatidylinositol 4, 5-biphosphate 5- phosphatase results in a Fanconi-type aminoaciduria beginning late in the first year of life.  The phosphaturia leads to hypophosphatemia and eventually renal rickets.  Proteinuria, polyuria, as well as bicarbonate, sodium and potassium wasting with tubular acidosis are all part of the urinary profile.  Some patients have dental cysts and/or defective dentin.

Genetics

The mutation causing this X-linked disorder is in the OCRL gene located at Xq26.1.  New mutations have been found among nearly one-third of affected males.  

Another X-linked disorder with similar but less severe kidney disease, Dent disease 2 (300555), has been found to have mutations in the same gene.  However, none of the ocular features are present.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts need to be removed before sensory nystagmus and amblyopia develop.  Fluid and electrolyte balance must be maintained.  Growth hormone can be used in selected patients.  Supportive systemic care is necessary in most cases.  Lifelong kidney and ocular monitoring is recommended.

References
Article Title: 

Hallermann-Streiff Syndrome

Clinical Characteristics
Ocular Features: 

Nearly all patients (80+ %) have microphthalmia and bilateral congenital cataracts.  Microcornea is common.  The eyebrows may be hypoplastic and the eyelashes likewise are sparse.  The lid fissures often slant down and telecanthus has been noted.  The distance between the two eyes appears reduced.  Blue sclerae, nystagmus, strabismus, and glaucoma are present in 10 to 30% of patients.

Systemic Features: 

The facies are sometimes described as 'bird-like' with a beaked nose, brachycephaly, and micrognathia.  Microstomia with a shortened ramus and forward displacement of the termporomandibular joints is characteristic. Upper airway obstruction may occur with severe respiratory distress.  The forehead is relatively prominent, the palate is highly arched, and the teeth are often small and some may be missing with misalignment of others.  A few teeth may even be present at birth (natal teeth).  Children appear petite and are often short in stature.  Scalp hair is thin, especially in the frontal and occipital areas, and the skin is atrophic.  Developmental delays are common but most patients have normal or near-normal intelligence.

Genetics

Most cases are sporadic but some have mutations in the GJA1 gene (6q21-q23.2).  Both autosomal dominant and autosomal recessive inheritance have been postulated.  Reproductive fitness may be low but rare affected individuals have had affected offspring.  Males and females are equally affected.

This disorder is allelic to oculodentodigital dysplasia (257850, 164200).

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Airway obstruction may require intervention and its risks must be considered during administration of general anesthesia.  Lens opacification may be severe even early in life and requires prompt surgical intervention to prevent amblyopia.

References
Article Title: 

Smith-Magenis Syndrome

Clinical Characteristics
Ocular Features: 

Ocular abnormalities have been found in the majority of patients.  Microcornea, myopia, strabismus and iris dysplasia are the most common.  Rare patients have iris colobomas or correctopia.  The eyes appear deep-set and lid fissures are upward slanting.

Systemic Features: 

The facial features are considered to be distinctive, characterized by a broad, square face, prominent forehead, broad nasal bridge, and midface hypoplasia.  These and other features appear more pronounced with age as in the size of the jaw which is underdeveloped in infancy and eventually becomes prognathic.  Most patients have developmental delays, speech and motor deficits, cognitive impairments and behavioral abnormalities.  Hypotonia, hyporeflexia, failure to thrive, lethargy, and feeding difficulties are common in infants.  Older individuals have REM sleep disturbances with self-destructive behaviors, aggression, inattention, hyperactivity, and impulsivity.  Short stature, hypodontia, brachydactyly, hearing loss, laryngeal anomalies, and peripheral neuropathy are common. Seizures are uncommon.

The behavioral profile of this syndrome can resemble that of autism spectrum disorders although symptoms of compulsivity are more mild.

A related developmental disorder known as Potacki-Lupski syndrome (610883) involving the same locus on chromosome 17 has a similar behavioral profile.  Ocular and systemic malformations may be less severe though.

Genetics

Most patients (90%) with the Smith-Magenis syndrome have interstitial deletions in the short arm of chromosome 17 (17p11.2).  However, it is included here since a few have heterozygous molecular mutations in the RAI1 gene which is located in this region.  While there is considerable phenotypic overlap, individuals with chromosomal deletions have the more severe phenotype as might be expected.  For example, those with RAI1 mutations tend to be obese and are less likely to exhibit short stature, cardiac anomalies, hypotonia, hearing loss and motor delays than seen in patients with a deletion in chromosome 17.  However, the phenotype is highly variable among patients with deletions depending upon the nature and size of the deletion.

The retinoic acid induced 1 gene (RAI1) codes for a transcription factor whose activity is reduced by mutations within it.

Familial cases are rare and reproductive fitness is virtually zero.  If parental chromosomes are normal, the risk for recurrence in sibs is less than 1%.  Males and females are equally affected.

In Potocki-Lupski syndrome (610883) there is duplication of the 17p11.2 microdeletion as the reciprocal recombination product of the SMS deletion.   

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Medical monitoring, psychotropic medications and behavioral therapies are all useful.  Special education and vocational training may be helpful for those less severely affected.

References
Article Title: 

Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and

Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM,
Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C,
Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski
JR. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and
delineation of a dosage-sensitive critical interval that can convey an autism
phenotype. Am J Hum Genet. 2007 Apr;80(4):633-49.

PubMed ID: 
17357070

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