growth delay

Carey-Fineman-Ziter Syndrome

Clinical Characteristics
Ocular Features: 

Abnormal eye movements with prominent external ophthalmoplegia are hallmarks of this disease.  An oculomotor nerve palsy with limited abduction and some degree of facial palsy are usually present.  The Moebius sequence is present in many patients.  Epicanthal folds, downslanting lid fissures, and ptosis are frequently seen.

Systemic Features: 

Clinical signs are highly variable.  Unusual facies with features of the Pierre Robin complex are characteristic.  Micrognathia and retrognathia are often present with glossoptosis.  Hypotonia and failure to thrive are commonly seen.  Dysphagia and even absent swallowing likely contribute to this.  Respiratory insufficiency can be present from birth, often with laryngostenosis, and some patients develop pulmonary hypertension and restrictive lung disease as adults.  Progressive scoliosis may contribute to this.  Many patients have club feet with joint contractures.  Skull formation consisting of microcephaly, or macrocephaly, or plagiocephaly is commonly seen.  Cardiac septal defects are common.

Intellectual disability is present in some but not all individuals.  Neuronal heterotopias, enlarged ventricles, reduced white matter, a small brainstem, microcalcifications, and enlarged ventricles have been observed.

Genetics

Homozygous or compound heterozygosity of the MYMK gene (9q34) is responsible for this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.

References
Article Title: 

A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome

Di Gioia SA, Connors S, Matsunami N, Cannavino J, Rose MF, Gilette NM, Artoni P, de Macena Sobreira NL, Chan WM, Webb BD, Robson CD, Cheng L, Van Ryzin C, Ramirez-Martinez A, Mohassel P, Leppert M, Scholand MB, Grunseich C, Ferreira CR, Hartman T, Hayes IM, Morgan T, Markie DM, Fagiolini M, Swift A, Chines PS, Speck-Martins CE, Collins FS, Jabs EW, Bonnemann CG, Olson EN; Moebius Syndrome Research Consortium, Carey JC, Robertson SP, Manoli I, Engle EC. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun. 2017 Jul 6;8:16077. doi: 10.1038/ncomms16077.

PubMed ID: 
28681861

Möbius sequence, Robin complex, and hypotonia: severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome

Verloes A, Bitoun P, Heuskin A, Amrom D, van de Broeck H, Nikkel SM, Chudley AE, Prasad AN, Rusu C, Covic M, Toutain A, Moraine C, Parisi MA, Patton M, Martin JJ, Van Thienen MN. Mobius sequence, Robin complex, and hypotonia: severe expression of brainstem disruption spectrum versus Carey-Fineman-Ziter syndrome. Am J Med Genet A. 2004 Jun 15;127A(3):277-87.

PubMed ID: 
15150779

Mitochondrial DNA Depletion Syndrome 3

Clinical Characteristics
Ocular Features: 

Nystagmus, disconjugate eye movements, and "optic dysplasia" have been noted.

Systemic Features: 

Infants feed poorly which is frequently associated with vomiting, failure to thrive, and growth delay.  They are hypothermic, hypoglycemic, and often jaundiced with signs of liver failure noted between birth and 6 months of age and death by approximately 1 year of age.  Hepatosplenomegaly is present early with abnormal liver enzymes, cholestasis, steatosis, and hepatocellular loss followed by cirrhosis with portal hypertension.  Metabolic acidosis, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia are often present.  Mitochondrial DNA depletion in the liver approaches 84-90%.

All patients have encephalopathic signs with evidence of cerebral atrophy, microcephaly, hypotonia.  Hyperreflexia may be present and some infants have seizures.  Muscle tissue, however, has normal histology and respiratory chain activity.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the DGUOK gene (2p13).

The same gene is mutated in PEOB4 (617070).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment.  Liver transplantation in one infant was unsuccessful.  

References
Article Title: 

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

Microcephaly, Congenital Cataracts, and Psoriasiform Dermatitis

Clinical Characteristics
Ocular Features: 

Congenital cataracts are usually present.  No further description is available.  Some individuals have a chronic blepharitis.

Systemic Features: 

Small stature, microcephaly, and developmental delay are important features. The skin in early life, even in infancy, may have an psoriasiform dermatitis that waxes and wanes in some patients while others have only dry skin.  Chronic arthralgias are sometimes present leading to joint contractures especially in the lower extremities.  Skeletal maturation is delayed and there may be cognitive deficits.

Serum total cholesterol levels are generally low but triglycerides are in the normal range.  Serum levels of IgE and IgA may be elevated.  This condition results from defects in the cholesterol synthesis pathway.

Genetics

Compound heterozygosity or homozygosity of mutations in the SC4MOL gene (4q32.3) (also known as MSMO1) is responsible for this condition.  Parents with a single mutation may have mildly elevated plasma methylsterol levels.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cholesterol supplementation and the use of statins has been reported to improve symptoms.  The usual treatments for psoriasis may provide some temporary relief.  Physical therapy may prevent joint contractures.  Antibiotic drops or ointment may be helpful in the treatment of blepharitis.

References
Article Title: 

The role of sterol-C4-methyl oxidase

He M, Smith LD, Chang R, Li X, Vockley J. The role of sterol-C4-methyl oxidase
in epidermal biology
. Biochim Biophys Acta. 2014 Mar;1841(3):331-5. Review.

PubMed ID: 
24144731

Sickle Cell Anemia

Clinical Characteristics
Ocular Features: 

The majority of serious ocular manifestations in sickle cell anemia are secondary to red blood cell sickling under conditions of relative hypoxia or dehydration resulting in thrombosis of retinal vessels with secondary ischemia.  Thrombosis of the central retinal artery and vein may also occur.  Other vessels of the orbit tissue and orbital walls when involved can result in acute proptosis with restrictions to globe motion and severe vascular congestion.

The conjunctival vessels are often comma-shaped and sludging or boxcaring of vascular flow is evident in a majority (70-90%) of patients.  Anterior uveitis of a granulomatous nature and frank anterior segment ischemia may occur.  Hyphemas are sometimes seen and an associated elevated intraocular pressure is a major risk.

The retina and its responses to small vessel occlusive disease constitute a major threat to vision and the risk is higher in patients with SC disease.  In early disease only arteriolar occlusions are seen but the localized ischemia stimulates the formation of arteriovenous anastomoses.  The involvement of larger areas of ischemia results in frank neovascularization, often in a formation known as retinal sea fans.  Intravitreal bleeding results in vitreal fibrosis with retinal traction that may result in a detachment.

Retinal imaging reveals general thinning.  SD-OCT imaging shows this to be especially visible in the macula and is present early in the disease.  The temporal retina likewise has significant thinning and microperimetry may demonstrate decreased function in these areas.

Systemic Features: 

The term sickle cell anemia as generally used refers to the disease caused by homozygous mutations in the HBB gene in which both beta chains contain a change in the 6th position from glutamic acid to valine yielding hemoglobin S.  These cells are susceptible to distortion into a sickle shape under certain conditions such as relative dehydration or anoxia and, as a result, form microthrombi with downstream ischemia.

The term sickle cell disease is commonly used to refer to sickling disorders in which only one beta chain contains the S change and the other chain has another variant such as Hb C (Hb SC disease), beta thalassemia (Hb S beta thalassemia) or some other more rare change in the beta chain.  Symptoms of the variant diseases generally have a later onset and cause a less severe disease.

Hb SS disease accounts for 60-70% of sickle cell disease and often leads to symptoms in the first month of life.  The diagnosis is usually made through newborn screening programs and should be followed by confirmatory testing using genotyping within 6 weeks.

The major early symptom is intermittent pain which can be incapacitating.  This can occur in virtually any organ and results from vascular occlusion, especially in small vessels such as arterioles and capillaries with downstream microinfarctions and hemolysis.  These vasoocclusive episodes can eventually lead to organ failure, especially in adults in which the major causes of death by midlife are pulmonary hypertension, cerebrovascular events, and acute chest syndrome.  Children are more likely to die of infections and organ sequestration.  In particular, the spleen is damaged as early as 3 months of age leaving infants vulnerable to recurrent septicemia and meningitis.  Severe bone pain with osteomyelitis can be debilitating.  Priapism, anemia, and ischemic strokes can occur at any age but are especially worrisome in young children.

Sickle cell disease can damage any part of the body and global evaluations are recommended when the diagnosis is under consideration. 

Genetics

Sickle cell disease and sickle cell anemia are autosomal recessive disorders resulting from homozygous or compound heterozygous mutations in the genes that code for hemoglobin molecules.  Usually at least one beta chain contains the amino acid substitution of valine for glutamic acid at the 6 position.  The HBB gene is located at 11p15.4.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

In general, patients with SS and S-variant disease should avoid strenuous exercise, low oxygen environments, extreme cold, and dehydration. Avoidance of contact with others who may have infectious disease is always recommended.  Hydroxyurea therapy may lessen or prevent chronic pain but it has little value in the treatment of acute painful crises.  Specific organ treatment should be applied as indicated for acute episodes.  All patients with sickle disease need to be under lifelong surveillance.

Epsilon aminocaproic acid is especially useful in the management of hyphemas and reduces the risk of recurrence.  The usual treatment for subretinal neovascularization and retinal detachment may be applied.  Anterior segment disease must be appropriately treated.

More recent approaches that show some promise include stem-cell transplantation.

References
Article Title: 

Epileptic Encephalopathy, Early Infantile 28

Clinical Characteristics
Ocular Features: 

Infants with this lethal neuropathy often have minimal or absent eye contact from birth.  Responses to visual stimuli are often but not always absent.  Optic atrophy may be present and the ERG is abnormal in some individuals. The retinas may have "abnormal" pigmentation while scotopic and photopic flash ERG responses are reduced as are visual evoked potentials indicating delayed visual maturation with severe macular and optic nerve dysfunction. 

Systemic Features: 

Seizures begin within weeks after birth and are resistant to pharmacological treatment.  There is no spontaneous motility and little or no psychomotor development.  Normal developmental milestones are usually not achieved.  Spasticity and hyperreflexia are often present but some newborn infants are hypotonic.  MRI imaging reveals cortical atrophy with hippocampal hypoplasia and a hypoplastic corpus callosum. Progressive microcephaly has been described.

Infants generally do not live beyond two years of age and may die within weeks or a few months. Pulmonary dysfunction can be a significant cause of morbidity. 

Genetics

The transmission pattern is consistent with autosomal recessive inheritance.  Homozygous and compound heterozygous mutations in the WWOX gene (16q23) have been found in several families.

Among the limited number of patients reported, at least two with compound heterozygous mutations had normal brain imaging, appropriate visual responses, and some ability to interact with their environment.  Profound psychomotor delays, however, remained.  Hypotonia replaced spasticity as a neurological feature in some infants.

The same gene is mutated in autosomal recessive spinocerebellar ataxia 12 (614322), a less severe condition in which gaze-evoked nystagmus occurs.

Other forms of epileptic encephalopathy have been reported (see 617105, 617106, and 617113) including Early Onset Epileptic Encephalopathy 48 (617276).  For an autosomal dominant form of epileptic encephalopathy in this database, see Epileptic Encephalopathy, Early Onset 47 (617166).

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for this condition.

References
Article Title: 

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

Mignot C, Lambert L, Pasquier L, Bienvenu T, Delahaye-Duriez A, Keren B, Lefranc J, Saunier A, Allou L, Roth V, Valduga M, Moustaine A, Auvin S, Barrey C, Chantot-Bastaraud S, Lebrun N, Moutard ML, Nougues MC, Vermersch AI, Heron B, Pipiras E, Heron D, Olivier-Faivre L, Gueant JL, Jonveaux P, Philippe C. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J Med Genet. 2015 Jan;52(1):61-70..

PubMed ID: 
25411445

Baraitser-Winter Syndrome 1

Clinical Characteristics
Ocular Features: 

Ptosis (both unilateral and bilateral), hypertelorism, prominent epicanthal folds, and colobomata are common.  The iris stroma may be dysplastic and correctopia has been observed.  Visual acuity has not been measured.

Systemic Features: 

Postnatal growth retardation leads to short stature.  Microcephaly and morphological aberrations in the brain such as lissencephaly, agenesis of the corpus callosum and pachygyria are present.  Seizures and developmental delays are common.  Hearing loss is sensorineural in type.

The ears are low-set and the posterior hair line may be low as well.  The nasal bridge appears broad and the nose appears short. Male genitalia are often underdeveloped.  Bicuspid aortic valves, patent ductus arteriosus, and aortic stenosis have been reported.

Genetics

Heterozygous mutations in the ACTB gene (7p22.1) are responsible for this apparent autosomal dominant syndrome.  However, all patients have been sporadic.

This condition is clinically similar to Baraitser-Winter syndrome 2 (614583) which is a unique entity caused by a mutation in ACTG1

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No specific treatment is available.

References
Article Title: 

New ocular finding in Baraitser-Winter syndrome

Rall N, Leon A, Gomez R, Daroca J, Lacassie Y. New ocular finding in Baraitser-Winter syndrome. Eur J Med Genet. 2017 Oct 9. pii: S1769-7212(17)30156-8. doi: 10.1016/j.ejmg.2017.10.006. [Epub ahead of print].

PubMed ID: 
29024830

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenco CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Riviere JB, Dobyns WB, Pilz DT. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet. 2014 Jul 23.

PubMed ID: 
25052316

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4.

PubMed ID: 
22366783
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