short stature

Microphthalmia, Syndromic 7

Clinical Characteristics
Ocular Features: 

Microphthalmia and rarely clinical anophthalmia are the ocular hallmarks of this disorder.  Corneal leukomas and some degree of sclerocornea are usually present as well.  Orbital cysts have been observed.  Other less consistent findings include iridocorneal adhesions, glaucoma, microcornea, cataracts, aniridia, persistence of the anterior hyaloid artery and other vitreous opacities, and patchy hypopigmentation of the RPE.

Systemic Features: 

The skin on the nose, cheeks and neck has linear red rashes and scar-like lesions.  Biopsy of these has revealed smooth muscle hemartomata rather than simple dermal aplasia.  There may be some healing of the skin defects.  The corpus callosum is sometimes absent.  Diaphragmatic hernias are often present.  Cardiac abnormalities include hypertrophic cardiomyopathy, arrhythmias, and septal defects.   Preauricular pits and hearing loss have been found in some patients.  Patients may be short in stature and some have nail dysplasia.  GU and GI anomalies may be present.

Genetics

This is an X-linked dominant disorder with lethality in the hemizygous male.  Many patients (79%) have interstitial deletions of the Xp22.2 region of the X chromosome.  Sequence analysis of this region has revealed heterozygous point mutations in the HCCS gene (Xp22.2) in numerous other patients.  In several additional cases deleterious mutations have been found in the X-linked COX7B gene.  However, familial occurrence is uncommon.  X chromosome inactivation may be skewed with the abnormal X being inactive in virtually all cases. Several 46 XX males with this syndrome have been described.

Goltz syndrome (305600), also called focal dermal hypoplasia, may have similar skin and ocular findings but the limb anomalies are not found in the disorder described here.  Goltz syndrome (305600) is the result of mutations in PORCN at another locus on the X chromosome and is thus unrelated.

Other X-linked dominant disorders with lethality in hemizygous males and abnormalities in skin and the eye are Incontinentia pigmenti (308300) and Aicardi syndrome (304050).  The skin lesions and ocular anomalies are dissimilar to those in MLS and they often have far more severe CNS abnormalities.   Further, the mutation causing Aicardi is in the NEMO (IKBKG) gene at another location on the X chromosome.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Treatment is organ-specific with repair of septal defects and diaphragmatic hernias.  Progressive orbital prosthetics should be considered in patients with blind, microphthalmic and clinically anophthalmic eyes.

References
Article Title: 

Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern

Ogata T, Wakui K, Muroya K, Ohashi H, Matsuo N, Brown DM, Ishii T, Fukushima Y. Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern. Hum Genet. 1998 Jul;103(1):51-6. Review.

PubMed ID: 
9737776

Stickler Syndrome, Type IV

Clinical Characteristics
Ocular Features: 

Evidence of vitreoretinal degeneration is common and the risk of retinal detachment is high.  High myopia is common.  Cataracts are not a feature in contrast to types I and II Stickler syndrome.

It is likely that the ocular phenotype will be expanded with the report of additional families.

Systemic Features: 

Sensorineural hearing loss and short stature are often present. The latter is not usually a feature in other types of Stickler syndrome.  However, midface hypoplasia and micrognathia may be present in all types as well as in Marshall syndrome.  Midline clefting usually does not occur.

Genetics

A reported pedigree suggests autosomal recessive inheritance based on parental consanguinity and the lack of parent-to-child transmission.  Affected individuals have homozygous deletion mutations leading to loss of function in COL9A2 (1p33-p32) while parents are heterozygous.  A family with mutations in COL9A1 (6q12-q14), usually causing multiple epiphyseal dysplasia, has been reported to have autosomal recessive Stickler syndrome as well.  Homozygous individuals had typical ocular and auditory findings of autosomal dominant Stickler syndrome but with evidence of epiphyseal dysplasia.

Type I Stickler syndrome (108300, 609508) is an autosomal dominant disorder with somewhat similar ocular manifestations resulting from mutations in COL2A1.

Type II Stickler syndrome (604841) with a somewhat similar ocular phenotype is also an autosomal dominant disorder but caused by mutations in COL11A1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The myopia and hearing loss can be corrected.  Lifelong vigilance and prompt treatment are required for the vitreoretinal disease.

References
Article Title: 

MELAS Syndrome

Clinical Characteristics
Ocular Features: 

This progressive mitochondrial disorder primarily affects muscles and the CNS, including the visual system.  The pattern of ocular deficits is not consistent and those that are present are not specific, requiring the clinician to take the entire neurological picture into consideration.  Hemianopsia, cortical blindness and ophthalmoplegia may be present.  The ERG can show reduced b-wave amplitudes and VEPs may be absent.  The optic nerve head has been described as normal without the atrophy often seen with other mitochondrial disorders.  A pigmentary retinopathy may be present.

Systemic Features: 

The clinical picture is highly variable.  Most commonly patients have myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.  The onset of symptoms is usually in the first two decades of life, most commonly consisting of headaches of sudden onset accompanied by vomiting and seizures.  The headaches may simulate migraines.  Weakness, lethargy, and apathy may be present early.  However, infants and young children may present with failure to thrive, developmental delay, and learning disabilities.  Neurosensory deafness is often seen and peripheral neuropathy is usually evident.  MRIs may show cerebellar hypoplasia and infarctions in the cerebral hemispheres.  Some patients have calcifications in the basal ganglia.  Patients may develop lactic acidosis.  Muscle biopsies often show ragged, red fibers.  The heart is commonly involved with both structural and rhythm defects.  Depending upon the degree and location of brain damage, patients may have hemiparesis, lethargy, ataxia, myoclonic jerks, cognitive decline, and dementia.  Morbidity and mortality are high.

Genetics

MELAS syndrome is a group of disorders caused by mutations in mitochondrial genes (at least 9 have been identified) that alter transfer RNA molecules resulting in disruption of intramitochondrial synthesis of proteins involved in oxidative phosphorylation pathways.  It is both clinically and genetically heterogeneous.  One can expect that any familial occurrence would result from maternal transmission but the occurrence of heteroplasmy results in considerable variability in the severity of clinical disease.

Treatment
Treatment Options: 

There is no effective treatment that prevents development of disease or that slows its progress.

References
Article Title: 

Cataracts, Ataxia, Short Stature, and Mental Retardation

Clinical Characteristics
Ocular Features: 

Cataracts are present in both sexes but the opacification is more extensive in males and only partial in females.  The cataracts are congenital in males but apparently develop later in females who complain of blurred vision from early childhood or during teenage years.  The lenses in females have punctate and pulverulent opacities as well as posterior subcapsular sclerosis.  Vision has been estimated as hand motion from early childhood in boys and about 20/40 in females in the first two decades of life.

Systemic Features: 

Males have mild to moderate mental retardation, muscle hypotonia and weakness with postural tremor.  Their standing position is broad-based and they are unable to sit or stand otherwise without some support.  They are usually unable to walk unassisted.  Speech is dysarthric and its development is delayed.  Females are neurologically normal.

Genetics

A locus containing the disease allele at Xpter-q13.1 cosegregates with the cataract phenotype in both sexes.  The gene mutation has not been identified.  This can be called an X-linked recessive disorder with partial expression in heterozygous females.

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

Cataract surgery may be indicated in young females and may be beneficial in infant boys.

References
Article Title: 

Cockayne Syndrome, Type B

Clinical Characteristics
Ocular Features: 

The eyes are deep-set.  Congenital cataracts are present in 30% of infants.  The aggressive course of this form of CS has precluded full delineation of the ocular features but infants have been described with microphthalmos, microcornea and iris hypoplasia. 

Systemic Features: 

Evidence of somatic and neurologic delays is present at birth or shortly thereafter with microcephaly and short stature.  Infants never develop normal milestones and may not grow in size beyond that of a 6 month-old child.  Communication skills are minimal.  They have a progeroid appearance, age rapidly, and most do not live beyond 5 years of age.   Feeding problems are common with considerable risk of aspiration, a common cause of respiratory infections and early death.  Severe flexion contractures develop early and may interfere with motor function.  Tremors and weakness contribute as well.  The skin is sensitive to UV radiation in some but not all patients.  However, the frequency of skin cancer is not increased.  Endogenous temperature regulation may be a problem. 

At least some cases with what has been called cerebro-oculo-facio-skeletal syndrome have been genotypically documented to have type B CS, the severe form of Cockayne syndrome.

Genetics

This is an autosomal recessive disorder resulting from mutations in ERCC6 (10q11) rendering the excision-repair cross-complementing protein ineffective in correcting defects during DNA replication.  Mutations in this gene account for about 75% of CS patients.  However, using date of onset and clinical severity, type A CS (216400) disease is far more common even though the ERCC8 mutations are found in only 25% of individuals.  Type A CS (216400) also has a somewhat later onset and is less severe in early stages.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation is type III is unknown.

Some patients have combined  phenotypical features of cerebrooculofacioskeletal syndrome (214150) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Feeding tubes may be necessary to maintain nutrition.  Protection from the sun is important.  Physical therapy can be used to minimize contractures.  Cataract surgery might be considered in selected cases as well as assistive devices for hearing problems but the limited lifespan should be considered. 

References
Article Title: 

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, Gibson L, Goodship JA, Jackson AP, Keng WT, King MD, McCann E, Motojima T, Murray JE, Omata T, Pilz D, Pope K, Sugita K, White SM, Wilson IJ. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2015 Jul 23. doi: 10.1038/gim.2015.110. [Epub ahead of print].

PubMed ID: 
26204423

Cockayne syndrome and xeroderma pigmentosum

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579

Cockayne Syndrome, Type A

Clinical Characteristics
Ocular Features: 

A progressive pigmentary retinopathy of a salt-and-pepper type and optic atrophy are commonly seen.  Retinal vessels are often narrowed and older patients can have typical bone spicule formation.  Night blindness, strabismus, and nystagmus may be present as well.  Enophthalmos, hyperopia, poor pupillary responses, and cataracts have been observed.  The lens opacities may in the nucleus or in the posterior subcapsular area and are often present in early childhood.  The ERG is often flat but may show some scotopic and photopic responses which are more marked in older individuals.  Vision loss is progressive but is better than expected in some patients based on the retina and optic nerve appearance.  The cornea may have evidence of exposure keratitis as many patients sleep with their eyes incompletely closed.  Recurrent corneal erosions have been reported in some patients.

The complete ocular phenotype and its natural history have been difficult to document due to the aggressive nature of this disease.

Ocular histopathology in a single patient (type unknown) revealed widespread pigment dispersion, degeneration of all retinal layers as well as thinning of the choriocapillaris and gliosis of the optic nerve.  Excessive lipofuscin deposition in the RPE was seen.

Systemic Features: 

Slow somatic growth and neural development are usually noted in the first few years of life.  Young children may acquire some independence and motor skills but progressive neurologic deterioration is relentless with loss of milestones and eventual development of mental retardation or dementia.  Patients often appear small and cachectic, with a 'progeroid' appearance.  The hair is thin and dry, and the skin is UV-sensitive but the risk of skin cancer is not increased.  Sensorineural hearing loss and dental caries are common.  Skeletal features include microcephaly, kyphosis, flexion contractures of the joints, large hands and feet, and disproportionately long arms and legs.  Perivascular calcium deposits are often seen, particularly in various brain structures while the brain is small with diffuse atrophy and patchy demyelination of white matter.  Peripheral neuropathy is characterized by slow conduction velocities.  Poor thermal regulation is often a feature. 

Type A is considered the classic form of CS.  Neurological deterioration and atherosclerotic disease usually lead to death early in the 2nd decade of life but some patients have lived into their 20s.  

Genetics

There is a great deal of clinical heterogeneity in Cockayne syndrome.  Type A results from homozygous or heterozygous mutations in ERCC8 (5q12).  CS type B (133540), is caused by mutations in ERCC6, and has an earlier onset with more rapidly progressive disease.  Both mutations impact excision-repair cross-complementing proteins important for DNA repair during replication.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation in type III is unknown. 

Some patients have combined phenotypical features of Cockayne syndrome (CS) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in nucleotide excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

There may be considerable overlap in clinical features and rate of disease progression among all types.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for Cockayne syndrome.  Supportive care for specific health problems, such as physical therapy for joint contractures, is important. 

Justification of cataract extraction should be made on a case by case basis.  Lagophthalmos requires that corneal lubrication be meticulously maintained.

References
Article Title: 

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, Gibson L, Goodship JA, Jackson AP, Keng WT, King MD, McCann E, Motojima T, Murray JE, Omata T, Pilz D, Pope K, Sugita K, White SM, Wilson IJ. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2015 Jul 23. doi: 10.1038/gim.2015.110. [Epub ahead of print].

PubMed ID: 
26204423

Ocular findings in Cockayne syndrome

Traboulsi EI, De Becker I, Maumenee IH. Ocular findings in Cockayne syndrome. Am J Ophthalmol. 1992 Nov 15;114(5):579-83.

PubMed ID: 
1443019

Cockayne syndrome and xeroderma pigmentosum

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579

Fucosidosis

Clinical Characteristics
Ocular Features: 

Retinal and conjunctival vessels may appear tortuous, dilated, and irregular in diameter, characteristics sometimes seen in Fabry disease.  Diffuse opacities may be seen in the superficial cornea but do not have the whorl-like pattern seen in Fabry disease.  The majority of ocular cells contain cytoplasmic, membrane-bound aggregates of fibrillogranular and multilaminated material.  The orbits may be shallow as a result of bony dysplasia of the cranial bones. 

Systemic Features: 

The coarse facial features have been described as "Hurler-like".  Two major types have been described: type 1 with onset in the first 6 months of life and rapid psychomotor and general neurologic deterioration, and the later onset, less severe type 2 in which angiokeratomas resembling Fabry disease occur.  Infants with type 1 may not survive beyond one year of age.  The Hurler-like face is less pronounced and the neurologic deterioration is less rapid in type 2 with survival often into the third decade or later.  The intracellular accumulation of glycolipids and glycoproteins leads to cell death accounting for the progression of CNS disease.   Abnormal bone growth (dysostosis multiplex) can lead to short stature.  Elevated sweat NaCl, hypohidrosis, and poor temperature control can be a feature of both types but this is more pronounced in type 1.  The DNA mutation is the same in both types and there may be overlap in some of the clinical features.  Furthermore, both types have been reported in the same family.

Low levels of alpha-L-fucosidase can be detected in plasma, urine, and leukocytes.  Glycolipids and glycoproteins have also been shown to accumulate in the cells of the skin, liver, spleen, pancreas and kidneys. 

Genetics

Fucosidosis is a rare, progressive, autosomal recessive, lysosomal storage disease in which fucose accumulates in tissue as a result of defective alpha-L-fucosidase.  The responsible mutations are found in the FUCA1 gene (1p34). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the primary disease.  A multidisciplinary supportive program can be beneficial for some patients.  Respiratory therapy especially is important to reduce the threat of infections.

References
Article Title: 

Fucosidosis revisited: a review of 77 patients

Willems PJ, Gatti R, Darby JK, Romeo G, Durand P, Dumon JE, O'Brien JS. Fucosidosis revisited: a review of 77 patients. Am J Med Genet. 1991 Jan;38(1):111-31. Review.

PubMed ID: 
2012122

Neuraminidase Deficiency

Clinical Characteristics
Ocular Features: 

A cherry red spot is may be seen in late childhood or early adolescence.  It occurs in nearly 100% of patients with type I while only 75% of type II patients have this feature possibly because their early death from the more severe systemic disease prevents full ascertainment.  Visual acuity is reduced, sometimes severely.  Some but not all individuals have corneal and lens opacities.  A subtle corneal haze has also been seen.  Nystagmus has been reported. 

Systemic Features: 

This is a neurodegenerative disorder with progressive deterioration of muscle and central nervous system functions.  Myoclonus, mental deterioration, hepatosplenomegaly, muscle weakness and atrophy are common.  The defect in neuraminidase activity leads to abnormal amounts of sialyl-oligosaccharides in the urine.  Spinal deformities such as kyphosis are common.  Deep tendon reflexes are exaggerated.  Ataxia and hearing loss may be present.  Coarse facies, a barrel chest, and short stature are characteristic.  Hepatic cells contain numerous vacuoles and numerous inclusions.

Sialidosis types I and II are both caused by mutations in the neuroaminidase gene.  Type I is associated with milder disease than type II which has an earlier age of onset and may present in infancy or even begin in utero.  Early death within two years of age is common in the congenital or infantile forms.  There is, however, significant variability in age of onset and the course of disease among types. 

Genetics

The sialidoses are autosomal recessive lysosomal storage disorders resulting from mutations in the NEU1 gene (6p21.3) which lead to an intracellular accumulation of glycoproteins containing sialic acid residues.  Both types I and II are caused by mutations in the same gene. 

Treatment
Treatment Options: 

Treatment is focused on symptom management. 

References
Article Title: 

RAB18 Deficiency

Clinical Characteristics
Ocular Features: 

Microphthalmia with microcornea, lens opacities, small and unresponsive pupils, and optic atrophy are the outstanding ocular features of this syndrome.  The eyes appear deeply set.  Some but not all have ERG evidence of rod and cone dysfunction.  The VEP is usually abnormal.  Short palpebral fissures have been described. 

Systemic Features: 

Patients with the micro syndrome have many somatic and neurologic abnormalities.  Infants usually have feeding problems that is sometimes accompanied by gastroesophageal reflux.  Some degree of psychomotor retardation and developmental delays is common.  Both spasticity and hypotonia have been described.  Some patients have seizures.  Facial hypertrichosis, anteverted ears, and a broad nasal bridge are often noted.   There may be absence of the corpus callosum while diffuse cortical and subcortical atrophy, microgyria, and pachygyria may be evident on MRI imaging.  Hypogenitalism may be a feature in both sexes.  Males may also have cryptorchidism and a micropenis while females can have hypoplasia of the labia minora and clitoris and a small introitus.  Microcephaly is inconsistently present. 

Genetics

This is a clinically and genetically heterogeneous disorder caused by homozygous mutations in at least 4 genes: RAB3GAP1 (WARBM1), RAB3GAP2 (WARBM2), RAB18 (WARBM3), and TBC1D20 (WARBM4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.  Vision remains subnormal even after cataracts are removed.  Nutrition may be improved with placement of a gastrostomy tube.

References
Article Title: 

New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish

Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, M?oller L,Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010 Oct;18(10):1100-6.

PubMed ID: 
20512159

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: 

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